CN104003979B - Benzimidazolyl-2 radicals-piperazine compounds, its pharmaceutical composition and its production and use - Google Patents

Benzimidazolyl-2 radicals-piperazine compounds, its pharmaceutical composition and its production and use Download PDF

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CN104003979B
CN104003979B CN201310056066.8A CN201310056066A CN104003979B CN 104003979 B CN104003979 B CN 104003979B CN 201310056066 A CN201310056066 A CN 201310056066A CN 104003979 B CN104003979 B CN 104003979B
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compound
hydrogen
base
piperazine
prepare
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CN104003979A (en
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樊兴
秦继红
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Shanghai Huilun Pharmaceutical Co ltd
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SHANGHAI HUILUN TECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

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Abstract

The present invention relates to a class benzimidazolyl-2 radicals-piperazine derivative, its preparation method and in application pharmaceutically.Concrete, the present invention relates to the new benzimidazolyl-2 radicals-piperazine derivative shown in a kind of logical formula (I), its preparation method and the pharmaceutical composition containing this derivant and its as therapeutic agent especially as the purposes of poly-(ADP-ribose) polymerase (PARP) inhibitor.Wherein: in logical formula (I): R is hydrogen or halogen；G is carbonyl or methylene；M is 1 ~ 2；N is 1 ~ 3；Q is hydrogen or C1-C4Alkyl；When X is methylene, Y is NR1Or when Y is methylene, X is NR1；R1For hydrogen, C1-C6Alkyl, benzyl, COR2And SO2R2；R2For following groups that is unsubstituted or that replaced by 1-3 substituent group: C1-C6Alkyl, C3-C8Cycloalkyl, phenyl, benzyl, naphthyl, C5-C10Aromatic heterocycle base, described C5-C10Heterocycle in aromatic heterocycle base includes 1-3 the hetero atom in N, O and S, and described substituent group is selected from following atom or group: C1-C6Alkyl, C1-C6Alkoxyl, halogen, amino, nitro, sulfydryl, hydroxyl, cyano group and trifluoromethyl.

Description

Benzimidazolyl-2 radicals-piperazine compounds, its pharmaceutical composition and preparation method thereof and Purposes
Technical field
The present invention relates to benzimidazolyl-2 radicals-piperazine derivative, its preparation method and the medicine group containing this derivant Compound and it is as therapeutic agent with as the purposes of poly-(ADP-ribose) polymerase (PARP) inhibitor.
Background technology
Chemotherapeutics and ionizing radiation treatment are two kinds of common methods for the treatment of cancer.Both Therapeutic Method all can induce DNA strand and/or double-strand break and then produce cytotoxic effect, target tumor due to chromosome damage thus dead. An important results as response DNA damage signal is that cell cycle regulating site signal is activated, and its object is to protection Cell does not carries out mitosis in the case of DNA damage thus avoids cell injury.In most of the cases, tumor cell exists While showing cell cycle regulating site signal defect, there is the highest appreciation rate.It can therefore be concluded that in tumor cell There is specific DNA repair mechanism, can quickly respond and repair the chromosome damage relevant to breeding regulation, so that it is certainly Body survives cytotoxic effect the maintenance survival of some medicines.
In clinical practice, valid density or the treatment radiant intensity of chemotherapeutics can resist these DNA repair mechanisms, Ensure the fragmentation effect to target tumor.But, tumor cell can be to treatment by strengthening its DNA damage repair mechanism Generation tolerance effect, is allowed to survive from fatal DNA damage.In order to overcome the toleration of generation, it usually needs increase The dosage of medicine or raising radiant intensity, the adverse effect that the normal structure near focus will be produced by this way, from And make in therapeutic process with serious untoward reaction, and then increase Operative risk.Meanwhile, ever-increasing toleration will Reduce therapeutic effect, it can therefore be concluded that by the regulation to DNA damage signal repair mechanism, it is possible to special with tumor cell The mode of property realizes the Cytotoxic raising to DNA damage medicament.
The PARPs(Poly(ADP-ribose being characterized with poly-adenosine diphosphate-ribosylating activity) Polymerases), the superfamily of 18 kinds of cell ribozyme nucleus matter enzymes is constituted.This poly-adenosine diphosphate-ribosyl is turned into With regulating catalysis activity and the protein-protein interaction of destination protein, and bioprocess basic to many adjust Control, repairs including DNA, and cell death, Genome stability is the most associated.
PARP-1 activity accounts for the 80% of total cell PARP activity, and it and the PARP-2 the most close with it become jointly PARP family possesses the member of DNA plerosis lesion capability.As induction apparatus and the signal protein of DNA damage, PARP-1 is permissible Quickly detect and be bonded directly to DNA damage site, the multiple protein needed for induced aggregation DNA repairs afterwards, and then make DNA damage Wound is repaired.When the PARP-1 in cell lacks, PARP-2 can substitute PARP-1 and realize the reparation of DNA damage.Research Showing, compared with normal cell, the expression in solid tumor of the PARPs albumen generally strengthens.Additionally, repair dependency basis for DNA Because lacking the tumor (such as breast tumor and ovarian cancer) of (such as BRCA-1 or BRCA-2), show PARP-1 inhibitor is extreme Sensitivity, this show PARP inhibitor as single dose in this potential use being known as in terms of three negative breast cancer for the treatment of.Meanwhile, Owing to DNA damage repair mechanism is tumor cell reply chemotherapeutics and the ionizing radiation treatment resistance to main machine the affected of generation System, therefore PARP-1 is considered as the Effective target site exploring new cancer treatment method.
The PARP inhibitor of early development design is using the nicotiamide of the NAD as PARP catalytic substrate as template, opens Send out its analog.These inhibitor as the competitive inhibitor of NAD, and the catalytic site of NAD competition PARP, and then stop poly- The synthesis of (ADP-ribose) chain.PARP under not having poly-(ADP-ribosylation) to modify cannot disintegrate down from DNA damage site, Other protein participating in repairing will be caused to cannot be introduced into injury site, and then repair process can not be performed.Therefore, at cell toxicant Under the effect of property medicine or radiation, the tumor cell that the existence of PARP inhibitor makes DNA impaired is the most dead.
Additionally, the NAD being consumed as PARP catalytic substrate, it is requisite during cell synthesizes ATP, because of This.Under high PARP activity level, intracellular NAD level can be remarkably decreased, and then affects the ATP level of intracellular.Due to born of the same parents Interior ATP content is not enough, and cell cannot realize the programmed cell death process that ATP relies on, and can only turn to this special apoptosis downright bad Process.During necrosis, substantial amounts of inflammatory factor can be released, thus other organs and tissue are produced toxicity and makees With.Therefore, PARP inhibitor can be used for treating the multiple disease relevant with this mechanism, including neurodegenerative diseases (such as senile dementia, Huntington chorea, parkinson disease), diabetes, the complication in ischemia or Ischemia-Reperfusion Injury, Such as myocardial infarction and acute renal failure, blood circulation diseases, such as septic shock, and diseases associated with inflammation, such as chronic rheumatism etc..
Summary of the invention
An object of the present invention is to provide a kind of new benzimidazolyl-2 radicals-piperazine compounds and derivant thereof, with And their tautomer, enantiomer, diastereomer, raceme and pharmaceutically useful salt, and metabolite and metabolite Precursor or prodrug.
The two of the purpose of the present invention are to provide the medicine using described benzimidazolyl-2 radicals-piperazine compounds as active component Compositions.
The three of the purpose of the present invention are to provide the preparation method of above-mentioned benzimidazolyl-2 radicals-piperazine compounds.
The four of the purpose of the present invention are the application providing above-mentioned benzimidazolyl-2 radicals-piperazine compounds in medicine.
As the benzimidazolyl-2 radicals-piperazine compounds of first aspect present invention, it is the compound shown in logical formula (I):
Wherein: in logical formula (I):
R is hydrogen or halogen；
G is carbonyl or methylene；
M is 1 ~ 2；
N is 1 ~ 3；
Q is hydrogen or C1-C4Alkyl；
When X is methylene, Y is NR1Or when Y is methylene, X is NR1；
R1For hydrogen, C1-C6Alkyl, benzyl, COR2And SO2R2；
R2For following groups that is unsubstituted or that replaced by 1-3 substituent group: C1-C6Alkyl, C3-C8Cycloalkyl, phenyl, benzyl Base, naphthyl, C5-C10Aromatic heterocycle base, described C5-C10Heterocycle in aromatic heterocycle base includes 1-3 selected from N, O and S In hetero atom, described substituent group be selected from following atom or group: C1-C6Alkyl, C1-C6Alkoxyl, halogen, amino, nitre Base, sulfydryl, hydroxyl, cyano group and trifluoromethyl.
It is further preferred that the compound that the structure of present invention offer is as shown in logical formula (I), wherein:
R is hydrogen or fluorine；
G is carbonyl or methylene；
M is 1 ~ 2；
N is 1 ~ 3；
Q is hydrogen or C1-C4Alkyl；
When X is methylene, Y is NR1Or when Y is methylene, X is NR1；
R1For hydrogen, C1-C6Alkyl, benzyl, COR2And SO2R2；
R2For following groups that is unsubstituted or that replaced by 1-3 substituent group: C1-C6Alkyl, C3-C8Cycloalkyl, phenyl, benzyl Base, naphthyl, pyrimidine radicals, pyridine radicals, pyridazinyl, pyrazinyl, indyl, quinolyl, benzopyranyl, benzothienyl, benzo Furyl, benzimidazolyl, benzotriazole base, described substituent group is selected from following atom or group: C1-C6Alkyl, C1-C6Alkane Epoxide, halogen, amino, nitro, sulfydryl, hydroxyl, cyano group and trifluoromethyl.
It is further preferred that the compound that the structure of present invention offer is as shown in logical formula (I), wherein:
R is hydrogen；
G is carbonyl or methylene；
M is 1 ~ 2；
N is 1 ~ 3；
Q is hydrogen or C1-C4Alkyl；
When X is methylene, Y is NR1Or when Y is methylene, X is NR1；
R1For hydrogen, C1-C6Alkyl, benzyl, COR2And SO2R2；
R2For following groups that is unsubstituted or that replaced by 1-3 substituent group: C1-C6Alkyl, C3-C8Cycloalkyl, phenyl, benzyl Substituent group described in base, pyridine radicals is selected from following atom or group: C1-C6Alkyl, C1-C6Alkoxyl, halogen, amino, nitro, Sulfydryl, hydroxyl, cyano group and trifluoromethyl.
Most preferably, the present invention leads to the compound shown in formula (I) is one of following compound (1)～(51) compound:
Described logical formula (I) compound be in enantiomer, diastereomer, conformer any one or Arbitrarily both or the mixture of three.
Described logical formula (I) compound is pharmaceutically acceptable derivant.
Logical formula (I) compound of the present invention can exist as a pharmaceutically acceptable salt form.
Pharmaceutically acceptable salt of the present invention is the logical hydrochlorate of formula (I) compound, sulfate, phosphate, acetic acid Salt, trifluoroacetate, mesylate, fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, Succinate or malate.
In a preferred embodiment of the invention, the benzimidazolyl-2 radicals-piperazine compounds of described logical formula (I) is 2- (piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide compounds and its officinal salt.
As the preparation method of the compound shown in the formula (1) of second aspect present invention, its reaction equation is as follows:
Wherein, R, m, n, G, Q, X and Y are as defined above；Specifically comprise the following steps that
Step 1): substituted 2,3-diamidogen yl benzoic acid methyl ester and carbonyl dimidazoles ring-closure reaction, obtains substituted 2-oxygen Generation-2,3-dihydro-1 hydrogen-benzimidazole-4-methyl formate (II)；
Step 2): substituted 2-oxo-2,3-dihydro-1 hydrogen-benzimidazole-4-methyl formate (II) that step 1) obtains Carry out chlorination reaction with phosphorus oxychloride, obtain chloro-1 hydrogen of substituted 2--benzimidazole-4-methyl formate (III)；
Step 3): in the presence of a base, by step 2) chloro-1 hydrogen of substituted 2--benzimidazole-4-methyl formate of obtaining (III) carry out nucleophilic substitution with piperazine, obtain substituted 2-(piperazine-1-base)-1 hydrogen-benzimidazole-4-methyl formate (IV)；
Step 4): substituted 2-(piperazine-1-base)-1 hydrogen-benzimidazole-4-methyl formate (IV) that step 3) is obtained In methanolic ammonia solution, there is the aminolysis reaction of ester group, obtain substituted 2-(piperazine-1-base)-1 hydrogen-benzimidazole-4-formyl Amine (V)；
Step 5): substituted 2-(piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide (V) that step 4) is obtained with Acid occur coupling reaction or with aldehyde generation reductive amination process, generate logical compound shown in formula (I).
As the pharmaceutical composition of third aspect present invention, comprise the logical formula (I) of the therapeutically effective amount constituting active component Compound and one or more medicinal carrier substances and/or diluent.Or comprise the therapeutically effective amount of composition active component Logical formula (I) compound and pharmaceutically acceptable carrier, excipient or diluent.
As the pharmaceutical composition of third aspect present invention, comprise the logical formula (I) of the therapeutically effective amount constituting active component The pharmaceutically acceptable derivant of compound and one or more medicinal carrier substances and/or diluent.Or comprise composition to live The pharmaceutically acceptable derivant of the logical formula (I) compound of the therapeutically effective amount of property composition and pharmaceutically acceptable carrier, tax Shape agent or diluent.
As the pharmaceutical composition of third aspect present invention, comprise the logical formula (I) of the therapeutically effective amount constituting active component The pharmaceutically acceptable salt of compound and one or more medicinal carrier substances and/or diluent.Or comprise composition activity The pharmaceutically acceptable salt of the logical formula (I) compound of the therapeutically effective amount of composition and pharmaceutically acceptable carrier, excipient Or diluent.
Described pharmaceutical composition make tablet, capsule, aqueous suspension, Oil suspensions, dispersible powder, Granule, lozenge, Emulsion, syrup, ointment, ointment, suppository or injection.
In described pharmaceutical composition, described logical formula (I) compound exists in a free form.
As the application of fourth aspect present invention, it is wherein that described logical formula (I) compound is treated because of PARP activity in preparation Application in the disease medicament suppressed and improve.
As the application of fourth aspect present invention, it it is wherein the pharmaceutically acceptable derivant of described logical formula (I) compound Application in the disease medicament that preparation treatment improves because of the suppression of PARP activity.
As the application of fourth aspect present invention, it is wherein that the pharmaceutically useful salt of described logical formula (I) compound is controlled in preparation Treat the application in the disease medicament improved because of the suppression of PARP activity.
As the application of fourth aspect present invention, it is wherein that described pharmaceutical composition is treated because PARP activity suppresses in preparation And the application in the disease medicament improved.
The described disease improved because of the suppression of PARP activity is angiopathy, septic shock, ischemic injuries, Nervous toxicity Property, hemorrhagic shock, inflammatory diseases or multiple sclerosis.
As the application of fourth aspect present invention, it is wherein that described logical formula (I) compound is being prepared for oncotherapy Application in ancillary drug.
As the application of fourth aspect present invention, it it is wherein the pharmaceutically acceptable derivant of described logical formula (I) compound In preparation application in the ancillary drug of oncotherapy.
As the application of fourth aspect present invention, it is wherein that the pharmaceutically useful salt of described logical formula (I) compound is used in preparation Application in the ancillary drug of oncotherapy.
As the application of fourth aspect present invention, it is wherein that described pharmaceutical composition is preparing the auxiliary for oncotherapy Application in medicine.
As the application of fourth aspect present invention, it is wherein that described logical formula (I) compound is put for tumor strengthening in preparation Application in the medicine treated.
As the application of fourth aspect present invention, it it is wherein the pharmaceutically acceptable derivant of described logical formula (I) compound In preparation application in the medicine of tumor strengthening radiotherapy.
As the application of fourth aspect present invention, it is wherein that the pharmaceutically useful salt of described logical formula (I) compound is used in preparation Application in the medicine of tumor strengthening radiotherapy.
As the application of fourth aspect present invention, it is wherein that described pharmaceutical composition strengthens radiotherapy in preparation for tumor Application in medicine.
As the application of fourth aspect present invention, it is wherein that described logical formula (I) compound is being prepared for chemotherapy of tumors Application in medicine.
As the application of fourth aspect present invention, it it is wherein the pharmaceutically acceptable derivant of described logical formula (I) compound In preparation application in the medicine of chemotherapy of tumors.
As the application of fourth aspect present invention, it is wherein that the pharmaceutically useful salt of described logical formula (I) compound is used in preparation Application in the medicine of chemotherapy of tumors.
As the application of fourth aspect present invention, it is wherein that described pharmaceutical composition is preparing the medicine for chemotherapy of tumors In application.
As the application of fourth aspect present invention, it is wherein that described logical formula (I) compound lacks homologous recombination in preparation (HR) application in the medicine of the individuation treatment of cancer that dependent DNA double chain interruption (DSB) is repaired.
As the application of fourth aspect present invention, it it is wherein the pharmaceutically acceptable derivant of described logical formula (I) compound In preparation lacks the medicine of the individuation treatment of cancer that homologous recombination (HR) dependent DNA double chain interruption (DSB) is repaired Application.
As the application of fourth aspect present invention, it is wherein that the pharmaceutically useful salt of described logical formula (I) compound lacks in preparation Application in the medicine of the individuation treatment of cancer that weary homologous recombination (HR) dependent DNA double chain interruption (DSB) is repaired.
As the application of fourth aspect present invention, it is wherein that described pharmaceutical composition depends in preparation shortage homologous recombination (HR) Application in the medicine of the individuation treatment of cancer that the DNA double chain interruption (DSB) of bad property is repaired.
As preferably, described cancer be containing one or more by the ability of the DSB of HR DNA plerosis relative to normally Cell and the cancer of cancerous cell that lowers or lose.
As preferably, described cancer is the cancer with BRCA-1 or BRCA-2 defect, mutant phenotype.
As preferably, described cancer is breast carcinoma, ovarian cancer, cancer of pancreas or carcinoma of prostate.
In order to check compound that the present invention provides for the exposure level of PARP enzyme, use the test of biochemistry level enzymatic activity Determine the various compounds of the present invention activity to PARP enzyme.
PARP is a kind of posttranscriptional modification enzyme, and DNA damage can activate this enzyme, and PARP catalytic process in vivo is mainly The poly(ADP-ribose that a kind of NAD relies on) process, its substrate mainly nucleoprotein of some including PARP, Histone is one of which, and the present invention is by measuring PARP under NAD effect to being coated in Histone poly in 96 orifice plates (ADP-ribose) degree, measures PARP activity, correspondingly measures PARP activity after PARP inhibitor effect, thus evaluates such The compound suppression degree to PARP activity.
Detailed description of the invention
Unless stated to the contrary, following have following implication with term in the specification and in the claims.
In the present invention, term " C1-C6Alkyl " refer to there is straight or branched part and contain the saturated of 1 to 6 carbon atom Monovalent hydrocarbon.The example of this type of group includes but not limited to methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group and tertiary fourth Base.
Term " C3-C8Cycloalkyl " refer to the saturated ring structure with 3 to 8 carboatomic ring atoms altogether.The reality of this type of group Example includes but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl.
Term " C5-C10Heteroaryl " refer in its ring, contain 5 to 10 carbon atoms and contain 1 to 4 independently of one another Heteroatomic aromatic heterocyclic group selected from O, S and N.Condition is without two adjacent O atom or two on the ring of described group Individual adjacent S atom.This heterocyclic group includes fused benzo ring system.C5-C10The example of heteroaryl include but not limited to pyridine radicals, Imidazole radicals, pyrimidine radicals, triazolyl, pyrazinyl, tetrazole radical, furyl, thienyl, isoxazolyl, thienyl, oxazolyl, different thiophene Oxazolyl, pyrrole radicals, quinolyl, isoquinolyl, indyl, benzimidazolyl, benzofuranyl, phthalazinyl, isoindolyl, Purine radicals, benzothienyl, benzothiazolyl.Described C5-C10Heteroaryl can be that C-connects in the conceived case or N connects Connect.
Term " halogen " and " halo " refer to F, Cl, Br, I.
" pharmaceutically acceptable salt " represents biological effectiveness and those salt of character retaining parent compound.This kind of salt Including:
(1) become salt with acid, obtained, mineral acid bag by the free alkali of parent compound and mineral acid or the reaction of organic acid Include hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, Metaphosphoric acid, sulphuric acid, sulfurous acid and perchloric acid etc.；Organic acid includes acetic acid, propanoic acid, propylene Acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxy benzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, adjacent benzene Dioctyl phthalate, methanesulfonic acid, ethyl sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, tartaric acid, citric acid, breast Acid, mandelic acid, succinic acid or malonic acid etc..
(2) acid proton being present in parent compound is replaced by metal ion or gives birth to organic base ligand compound The salt become, metal ion such as alkali metal ion, alkaline-earth metal ions or aluminium ion, organic bases such as ethanolamine, diethanolamine, Triethanolamine, trometamol, N-METHYL-ALPHA-L-GLUCOSAMINE etc..
" pharmaceutical composition " refers to one or more or its pharmaceutically acceptable salt in the compound in the present invention, molten Agent compound, hydrate or prodrug and other chemical composition, the most pharmaceutically acceptable carrier, mixing.The mesh of pharmaceutical composition Be to promote to be administered to the process of animal.
" pharmaceutical carrier " refers to organism does not cause obvious zest and does not disturb the biology of given compound Non-active ingredient in the pharmaceutical composition of activity and character, such as but not limited to: calcium carbonate, calcium phosphate, various sugar (such as breast Sugar, mannitol etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylate copolymer or methacrylic polymeric Thing, gel, water, Polyethylene Glycol, propylene glycol, ethylene glycol, Oleum Ricini or castor oil hydrogenated or many ethoxy aluminium Oleum Ricini, Semen Sesami Oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen etc..
In aforesaid pharmaceutical composition, in addition to including pharmaceutically acceptable carrier, it is also possible to be included in medicine (agent) and learn Upper conventional adjuvant, such as: antibacterial agent, antifungal, antimicrobial, preservative, toner, solubilizing agent, thickening agent, table Face activating agent, chelating agent, protein, aminoacid, fat, saccharide, vitamin, mineral, trace element, sweeting agent, pigment, perfume (or spice) Essence or their combination etc..
The invention discloses the application as poly-(ADP-ribose) AG14361 of a kind of compound and this compound, this Skilled person can use for reference present disclosure, is suitably modified technological parameter and realizes.Special needs to be pointed out is, all similar Replacing and change apparent to those skilled in the art, they are considered as being included in the present invention.The present invention's Method and application are described by preferred embodiment, and related personnel substantially can be without departing from present invention, spirit With in scope, method described herein and application are modified or suitably change and combine, realize and apply skill of the present invention Art.
Below in conjunction with embodiment, the present invention it is expanded on further:
Preparation embodiment
Embodiment 1
Compound (1): 3-(4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-carbonyl) pyrrolidine-1- T-butyl carbonate, reaction equation is as follows:
Step 1: compound a: 2-oxo-2,3-dihydro-1 hydrogen-benzimidazole-4-methyl formate
At an anhydrous tetrahydrofuran solution (20mL) dissolved with 2,3-diamidogen yl benzoic acid methyl ester (0.8g, 4.8mmol) Middle addition carbonyl dimidazoles (1.56g, 9.6mmol), is warming up to backflow, cools down, removal of solvent under reduced pressure after reacting 8 hours, remaining Thing separates (petroleum ether: ethyl acetate=5:1) through rapid column chromatography and obtains faint yellow solid compound a (0.3g, yield 33%).MS (ESI)m/z:[M+H]+=193。
Step 2: chloro-1 hydrogen of compound b:2--benzimidazole-4-methyl formate
Compound a (1.1g, 5.7mmol) is added phosphorus oxychloride (8mL), is warming up to backflow, cool down after reacting 8 hours, Removal of solvent under reduced pressure, residue separates (petroleum ether: ethyl acetate=5:1) through rapid column chromatography and obtains compound as white solid b (1.5g, yield 100%).MS(ESI)m/z:[M+H]+=211。
Step 3: compound c:2-(piperazine-1-base)-1 hydrogen-benzimidazole-4-methyl formate
Will be dissolved with compound b(59mg, 0.28mmol) dimethylformamide (5mL) in add piperazine (110mg, 1.12mmol), being warming up to 100 DEG C, cool down, removal of solvent under reduced pressure after reacting 8 hours, residue separates (two through rapid column chromatography Chloromethanes: methanol=10:1) obtain compound as white solid c(100mg, yield 100%).MS(ESI)m/z:[M+H]+=261。
Step 4: compound d:2-(piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide
Will be dissolved with compound c(100mg, 0.28mmol) tetrahydrofuran solution (5mL) in add ammonia (5mL), heat up To 70 DEG C, tube sealing reaction cooled down after 8 hours, removal of solvent under reduced pressure, residue through rapid column chromatography separate (dichloromethane: methanol= 10:1) obtain compound as white solid d(20mg, yield 28%).MS(ESI)m/z:[M+H]+=246。
Step 5: compound (1): 3-(4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-carbonyl) pyrroles Alkane-1-t-butyl carbonate
Will be dissolved with compound d(105mg, 0.43mmol) dimethyl formamide solution (5mL) in add 1-tertiary butyloxycarbonyl Base pyrrolidine-3-formic acid (19mg, 0.22mmol), 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluoro phosphorus Acid esters (245mg, 0.64mmol) and triethylamine (87mg, 0.86mmol), stir 8 hours under room temperature, removal of solvent under reduced pressure, remaining Thing separates (dichloromethane: methanol=10:1) through rapid column chromatography and obtains compound as white solid (1) (27mg, yield 15%).MS (ESI)m/z:[M+H]+=443.1H NMR(300MHz,DMSO-d6):δ11.93(br,1H),9.12(br,1H),7.63(d, 1H,J=7.8Hz),7.52(s,1H),7.34(d,1H,J=7.8Hz),7.00(t,1H,J=7.8Hz),3.71-3.68(m,3H), 3.63-3.57(m,10H),2.00(br,2H),1.40(s,9H)。
Embodiment 2
Compound (2): (S)-2-(4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-carbonyl) pyrroles Alkane-1-t-butyl carbonate
Embodiment 1 is used to prepare the method that compound (1) is similar, i.e. by compound d and (S)-1-tertbutyloxycarbonyl pyrrole Cough up the condensation of alkane-2-formic acid and prepare compound (2) (21mg, yield 11%).MS(ESI)m/z:[M+H]+=443.1H NMR (300MHz,DMSO-d6):δ11.99(br,1H),9.10(br,1H),7.61(d,1H,J=7.5Hz),7.51(br,1H), 7.33(d,1H,J=7.5Hz),6.98(t,1H,J=7.5Hz),4.70-4.63(m,1H),3.70-3.56(m,10H),2.19- 2.11(m,2H),1.79-1.73(m,2H),1.36(s,9H)。
Embodiment 3
Compound (3): (R)-2-(4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-carbonyl) pyrroles Alkane-1-t-butyl carbonate
Embodiment 1 is used to prepare the method that compound (1) is similar, by compound d and (R)-1-tertbutyloxycarbonyl pyrroles The condensation of alkane-2-formic acid prepares compound (3) (18mg, yield 10%).MS(ESI)m/z:[M+H]+=443.1H NMR(300MHz, DMSO-d6):δ11.84(br,1H),9.10(br,1H),7.61(d,1H,J=7.5Hz),7.51(br,1H),7.32(d,1H,J =7.5Hz),6.99(t,1H,J=7.5Hz),4.69-4.65(m,1H),3.70-3.55(m,10H),2.21-2.09(m,2H), 1.79-1.74(m,2H),1.29(s,9H)。
Embodiment 4
Compound (4): 2-(4-(pyrrolidine-3-carbonyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide
The compound (1) (30mg, 0.07mmol) embodiment 1 prepared adds saturated methanol hydrochloride solution (5mL), room temperature Stirring 8 hours, removal of solvent under reduced pressure, residue separates (dichloromethane: methanol=5:1) through rapid column chromatography and obtains white solid Compound (4) (16mg, yield 57%).MS(ESI)m/z:[M+H]+=343.1H NMR(300MHz,DMSO-d6):δ9.41(br, 1H),9.18(br,1H),8.49-8.44(m,1H),7.70-7.68(m,3H),7.55-7.51(m,1H),7.27-7.25(m, 1H),3.73-3.68(m,8H),3.17-3.14(m,2H),3.05-3.01(m,3H),2.24-2.20(m,2H)。
Embodiment 5
Compound (5): (S)-2-(4-(pyrrolidine-2-carbonyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide
Using embodiment 4 to prepare the method that compound (4) is similar, the compound (2) prepared by embodiment 2 is anti-with hydrochloric acid Deprotection is answered to prepare compound (5) (24mg, yield 72%).MS(ESI)m/z:[M+H]+=343.1H NMR(300MHz, DMSO-d6):δ10.38(br,1H),8.50(br,1H),8.38(s,H),.73-7.71(m,2H),7.58-7.56(m,1H), 7.32-7.27(m,1H),4.68(br,1H),3.88-3.78(m,8H),3.23-3.17(m,2H),2.42-2.35(m,2H), 1.87(br,2H)。
Embodiment 6
Compound (6): (R)-2-(4-(pyrrolidine-2-carbonyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide
The method that compound (4) is similar is prepared in employing, prepares compound by compound (3) and hydrochloric acid reaction deprotection (6) (15mg, yield 63%).MS(ESI)m/z:[M+H]+=343.1H NMR(300MHz,DMSO-d6):δ10.23(br,1H), 8.50(br,1H),8.41(br,1H),7.72-7.69(m,2H),7.56-7.54(m,1H),7.30-7.27(m,1H),4.66 (br,1H),3.84-3.77(m,8H),3.16(br,2H),1.84(br,4H)。
Embodiment 7
Compound (7): 3-(4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl)-1,4-homopiperazine-1-carbonyl) pyrrole Coughing up alkane-1-t-butyl carbonate, concrete reaction equation is as follows:
Step 1: compound e:2-(1,4-homopiperazine-1-base)-1 hydrogen-benzimidazole-4-methyl formate
Embodiment 1 is used to prepare the similar method of compound c, by compound b and homopiperazine generation nucleophilic substitution Prepare compound e(780mg, yield 87%).MS(ESI)m/z:[M+H]+=275.
Step 2: compound f:2-(1,4-homopiperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide
Embodiment 1 is used to prepare the similar method of compound d, by the ammonolysis reaction system of compound e Yu ammonia generation ester Obtain compound f(275mg, yield 37%).MS(ESI)m/z:[M+H]+=260.
Step 3: compound (7): 3-(4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl)-1,4-homopiperazine-1-carbonyl Base) pyrrolidine-1-t-butyl carbonate
Embodiment 1 is used to prepare the method that compound (1) is similar, by compound f and 1-tertbutyloxycarbonyl pyrrolidine-3- Formic acid condensation prepares compound (7) (18mg, yield 10%).MS(ESI)m/z:[M+H]+=457.1HNMR(300MHz,DMSO- d6):δ11.88-11.75(m,1H),9.16-9.12(m,1H),7.56(d,1H,J=8.4Hz),7.44(s,1H),7.27(d, 1H,J=8.4Hz),6.92(t,1H,J=8.4Hz),3.84-3.55(m,7H),3.22-3.11(m,6H),1.91-1.78(m, 4H),1.35(s,9H)。
Embodiment 8
Compound (8): (S)-2-(4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl)-1,4-homopiperazine-1-carbonyl Base) pyrrolidine-1-t-butyl carbonate
Embodiment 1 is used to prepare the method that compound (1) is similar, by compound f and (S)-1-tertbutyloxycarbonyl pyrroles The condensation of alkane-2-formic acid prepares compound (8) (22mg, yield 22%).MS(ESI)m/z:[M+H]+=457.1H NMR(300MHz, DMSO-d6):δ11.62(br,1H),9.18-9.15(m,1H),7.60-7.56(m,1H),7.49-7.44(m,1H),7.31- 7.27(m,1H),6.99-6.90(m,1H),4.60-4.52(m,1H),3.87-3.52(m,10H),2.31-1.99(m,2H), 1.90-1.69(m,4H),1.20(s,9H)。
Embodiment 9
Compound (9): (R)-2-(4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl)-1,4-homopiperazine-1-carbonyl Base) pyrrolidine-1-t-butyl carbonate
Embodiment 1 is used to prepare the method that compound (1) is similar, by compound f and (R)-1-tertbutyloxycarbonyl pyrroles The condensation of alkane-2-formic acid prepares compound (9) (25mg, yield 24%).MS(ESI)m/z:[M+H]+=457.1H NMR(300MHz, DMSO-d6):δ11.79-11.68(m,1H),9.13(br,1H),7.56-7.53(m,1H),7.46-7.42(m,1H),7.29- 7.22(m,1H),6.94-6.89(m,1H),4.57-4.48(m,1H),3.90-3.45(m,10H),2.16-2.02(m,2H), 1.83-1.63(m,4H),1.18(s,9H)。
Embodiment 10
Compound (10): 2-(4-(pyrrolidine-3-carbonyl)-1,4-homopiperazine-1-base)-1 hydrogen-benzimidazole-4-formyl Amine
Embodiment 4 is used to prepare the method that compound (4) is similar, by compound (7) and hydrochloric acid reaction deprotection system Obtain compound (10) (38mg, yield 76%).MS(ESI)m/z:[M+H]+=357.1H NMR(300MHz,DMSO-d6):δ9.65 (br,1H),9.53(br,1H),7.74-7.65(m,2H),7.54-7.47(m,1H),7.27-7.19(m,1H),3.94-3.85 (m,8H),3.29-3.24(m,2H),3.13-3.02(m,4H),2.15(br,1H),1.96-1.85(m,3H)。
Embodiment 11
Compound (11): (S)-2-(4-(pyrrolidine-2-carbonyl)-1,4-homopiperazine-1-base)-1 hydrogen-benzimidazole-4- Methanamide
Embodiment 4 is used to prepare the method that compound (4) is similar, by compound (8) and hydrochloric acid reaction deprotection system Obtain compound (11) (23mg, yield 65%).MS(ESI)m/z:[M+H]+=357.1H NMR(300MHz,DMSO-d6):δ 10.05(br,1H),8.54(br,1H),7.67-7.62(m,2H),7.53-7.47(m,1H),7.26-7.19(m,1H), 4.55-4.47(m,1H),3.99-3.88(m,6H),3.71-3.65(m,2H),3.17-3.03(m,3H),1.93-1.69(m, 6H)。
Embodiment 12
Compound (12): (R)-2-(4-(pyrrolidine-2-carbonyl)-1,4-homopiperazine-1-base)-1 hydrogen-benzimidazole-4- Methanamide
The method that compound (4) is similar is prepared in employing, prepares compound by compound (9) and hydrochloric acid reaction deprotection (12) (17mg, yield 48%).MS(ESI)m/z:[M+H]+=357.1H NMR(300MHz,DMSO-d6):δ10.19(br, 1H),8.39(br,1H),7.67-7.64(m,2H),7.54-7.52(m,1H),7.26-7.17(m,1H),4.56-4.50(m, 1H),3.93-3.67(m,8H),3.19-3.09(m,3H),1.93-1.66(m,6H)。
Embodiment 13
Compound (13): (S)-2-(4-(1-benzyl-pyrrole alkane-2-carbonyl)-1,4-homopiperazine-1-base)-1 hydrogen-benzo miaow Azoles-4-Methanamide
Cylite (27mg, 0.15mmol) and potassium carbonate (21mg, 0.15mmol) are added dissolved with embodiment 11 preparation In the dimethyl formamide solution (5mL) being dried of compound (11) (50mg, 0.14mmol), reduce pressure after being stirred at room temperature 8 hours Removing solvent, residue separates (dichloromethane: methanol=10:1) through rapid column chromatography and obtains compound as white solid (13) (28mg, yield 45%).MS(ESI)m/z:[M+H]+=447.1H NMR(300MHz,DMSO-d6):δ12.01-11.83(m, 1H),9.18-9.13(m,1H),7.58-7.46(m,2H),7.26-7.10(m,6H),6.95-6.86(m,1H),3.80-3.57 (m,9H),3.15(s,2H),2.27-2.09(m,2H),1.73-1.60(m,6H)。
Embodiment 14
Compound (14): (S)-2-(4-(1-acetyl-pyrrolidine-2-carbonyl)-1,4-homopiperazine-1-base)-1 hydrogen-benzo Imidazoles-4-Methanamide
Chloroacetic chloride (11mg, 0.14mmol) is added the diformazan being dried dissolved with compound (11) (50mg, 0.14mmol) In base formamide solution (5mL), 8 hour after removal of solvent under reduced pressure being stirred at room temperature, residue separates (dichloromethane through rapid column chromatography Alkane: methanol=10:1) obtain compound as white solid (14) (22mg, yield 40%).MS(ESI)m/z:[M+H]+=399.1H NMR(300MHz,DMSO-d6):δ9.15(br,1H),7.58-7.55(m,1H),7.46(br,1H),7.29-7.24(m,1H), 6.96-6.90(m,1H),4.70-4.64(m,1H),3.91-3.58(m,10H),2.07-2.03(m,2H),1.93(s,3H), 1.82-1.76(m,4H)。
Embodiment 15
Compound (15): (S)-2-(4-(1-p-toluenesulfonyl pyrrolidine-2-carbonyl)-1,4-homopiperazine-1-base)-1 Hydrogen-h-benzimidazole-4-carboxamide
Use embodiment 14 to prepare the method that compound (14) is similar, occurred with paratoluensulfonyl chloride by compound (11) Acylation reaction prepares compound (15) (32mg, yield 45%).MS(ESI)m/z:[M+H]+=511.1H NMR(300MHz, DMSO-d6):δ11.63(br,1H),9.16(br,1H),7.67-7.61(m,3H),7.55-7.47(m,1H),7.40-7.37 (m,1H),7.31-7.26(m,2H),6.95-6.89(m,1H),4.65-4.58(m,1H),3.83-3.48(m,10H),2.38 (s,3H),2.10-1.75(m,6H)。
Embodiment 16
Compound (16): (S)-2-(4-(1-benzoyl pyrrole compound alkane-2-carbonyl)-1,4-homopiperazine-1-base)-1 hydrogen-benzene And imidazoles-4-Methanamide
Use embodiment 1 to prepare the method that compound (1) is similar, prepare chemical combination by compound (11) with benzoic acid condensation Thing (16) (27mg, yield 42%).MS(ESI)m/z:[M+H]+=461.1H NMR(300MHz,DMSO-d6):δ11.72(br, 1H),9.17(br,1H),7.59-7.56(m,1H),7.48-7.43(m,4H),7.30-7.18(m,2H),7.08-7.02(m, 1H),6.96-6.90(m,1H),4.91-4.66(m,1H),3.98-3.55(m,8H),3.10-2.96(m,2H),2.25-1.68 (m,6H)。
Embodiment 17
Compound (17): (S)-2-(4-(1-ring valeryl pyrrolidine-2-carbonyl)-1,4-homopiperazine-1-base)-1 hydrogen-benzene And imidazoles-4-Methanamide
Use embodiment 1 to prepare the method that compound (1) is similar, prepared with the condensation of cyclopenta formic acid by compound (11) Compound (17) (29mg, yield 46%).MS(ESI)m/z:[M+H]+=453.1H NMR(300MHz,DMSO-d6):δ11.74- 11.62(m,1H),9.15(br,1H),7.58-7.53(m,1H),7.46(br,1H),7.29-7.22(m,1H),6.96-6.90 (m,1H),4.57-4.64(m,1H),3.85-3.51(m,10H),2.97-2.92(m,1H),2.07-1.50(m,14H)。
Embodiment 18
Compound (18): (S)-2-(4-(1-nicotinoyl pyrrolidine-2-carbonyl)-1,4-homopiperazine-1-base)-1 hydrogen-benzo Imidazoles-4-Methanamide
The method that compound (1) is similar is prepared in employing, prepares compound (18) by compound (11) with nicotinic acid condensation (35mg, yield 43%).MS(ESI)m/z:[M+H]+=462.1H NMR(300MHz,DMSO-d6):δ9.18(br,1H), 8.70-8.17(m,2H),7.93-7.70(m,1H),7.59-7.48(m,3H),7.31-7.27(m,1H),6.97-6.92(m, 1H),4.90-4.77(m,1H),3.95-3.55(m,10H),2.21-1.58(m,6H)。
Embodiment 19
Compound (19): (R)-2-(4-(1-(2-phenyl acetyl) pyrrolidine-2-carbonyl)-1,4-homopiperazine-1-base)- 1 hydrogen-h-benzimidazole-4-carboxamide
Use embodiment 1 to prepare the method that compound (1) is similar, prepare chemical combination by compound (12) with phenylacetic acid condensation Thing (19) (40mg, yield 39%).MS(ESI)m/z:[M+H]+=475.1H NMR(300MHz,DMSO-d6):δ11.71(s, 1H),9.15(s,1H),7.58-7.55(m,1H),7.45(br,1H),7.28-7.22(m,5H),7.10-6.79(m,2H), 4.83-4.70(m,1H),4.11-3.52(m,12H),2.02-1.54(m,6H)。
Embodiment 20
Compound (20): (R)-2-(4-(1-valeryl pyrrolidine-2-carbonyl)-1,4-homopiperazine-1-base)-1 hydrogen-benzene And imidazoles-4-Methanamide
Use embodiment 1 to prepare the method that compound (1) is similar, prepare chemical combination by compound (12) with pivalic acid condensation Thing (20) (38mg, yield 40%).MS(ESI)m/z:[M+H]+=441.1H NMR(300MHz,DMSO-d6):δ11.72(s, 1H),9.16(s,1H),7.58-7.55(m,1H),7.45(m,1H),7.27-7.26(m,1H),6.95-6.89(m,1H), 4.71(br,1H),4.11-3.53(m,10H),1.98-1.73(m,6H),1.13(s,9H)。
Embodiment 21
Compound (21): (R)-2-(4-(1-ethyl pyrrolidine-2-carbonyl)-1,4-homopiperazine-1-base)-1 hydrogen-benzo miaow Azoles-4-Methanamide
The method that compound (1) is similar is prepared in employing, is contracted with (R)-1-ethyl pyrrolidine-2-formic acid by compound (12) Close and prepare compound (21) (49mg, yield 58%).MS(ESI)m/z:[M+H]+=385.1H NMR(300MHz,DMSO-d6):δ 11.99(br,1H),9.26-9.08(m,1H),7.57-7.49(m,2H),7.34-7.24(m,1H),6.94-6.91(m,1H), 4.56-4.50(m,1H),4.15-3.83(m,4H),3.64-3.48(m,4H),2.85-2.64(m,4H),1.96-1.64(m, 6H),0.73-0.66(m,3H)。
Embodiment 22
Compound (22): (S)-2-(4-(pyrrolidin-2-yl methyl)-1,4-homopiperazine-1-base)-1 hydrogen-benzimidazole- 4-Methanamide, concrete reaction equation is as follows:
Step 1: compound g:(S)-2-(methylol) pyrrolidine-1-t-butyl carbonate
Lithium aluminium hydride reduction (38mg, 1mmol) is added dissolved with (S)-2-methyl carbonate pyrrolidine-1-t-butyl carbonate In the dry tetrahydrofuran solution (10mL) of (229mg, 1mmol), it is stirred overnight under room temperature, adds water (0.5mL) cancellation reaction, Removal of solvent under reduced pressure, residue separates (petroleum ether: ethyl acetate=5:1) through rapid column chromatography and obtains weak yellow liquid compound g (187mg, yield 93%).MS(ESI)m/z:[M+H]+=202.
Step 2: compound h:(S)-2-carbonyl pyrrolidine-1-t-butyl carbonate
1,1,1-triacetyl oxygen-1,1-dihydro-1,2-benzenesulfonyl-3-(1H)-one (424mg, 1mmol) is added dissolved with change Compound g(100mg, 0.5mmol) dry methylene chloride solution (10mL) in, be stirred overnight under room temperature, add unsaturated carbonate hydrogen Sodium water solution (0.5mL) cancellation react, removal of solvent under reduced pressure, residue through rapid column chromatography separate (petroleum ether: ethyl acetate= 5:1) obtain weak yellow liquid compound h(87mg, yield 87%).MS(ESI)m/z:[M+H]+=200.
Step 3: compound i:(S)-2-((4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals base)-1,4-homopiperazine-1 Base) methyl) pyrrolidine-1-t-butyl carbonate
By compound h(480mg, 2.4mmol) add dissolved with compound f(350mg, 1.3mmol) methanol solution (10mL) in, continuously add sodium cyanoborohydride (255mg, 3.9mmol), be stirred overnight under room temperature, add saturated sodium bicarbonate Aqueous solution (0.5mL) cancellation react, removal of solvent under reduced pressure, residue through rapid column chromatography separate (petroleum ether: ethyl acetate=5: 1) weak yellow liquid compound i(400mg, yield 70% are obtained).MS(ESI)m/z:[M+H]+=443.
Step 4: compound (22): (S)-2-(4-(pyrrolidin-2-yl methyl)-1,4-homopiperazine-1-base)-1 hydrogen-benzo Imidazoles-4-Methanamide
Use embodiment 4 to prepare the method that compound (4) is similar, prepared with hydrochloric acid reaction deprotection by compound i Compound (22) (240mg, yield 62%).MS(ESI)m/z:[M+H]+=343.1H NMR(300MHz,DMSO-d6):δ11.86 (br,1H),9.21(br,1H),7.57-7.53(m,1H),7.45(br,1H),7.28-7.25(m,1H),6.93-6.88(m, 1H),3.75-3.68(m,5H),3.14-2.70(m,8H),1.92-1.84(m,6H)。
Embodiment 23
Compound (23): (S)-2-(4-((1-(4-fluoro benzoyl) pyrrolidin-2-yl) methyl)-1,4-homopiperazine-1- Base)-1 hydrogen-h-benzimidazole-4-carboxamide
Use embodiment 1 to prepare the method that compound (1) is similar, the compound (22) prepared by embodiment 22 with to fluorine Benzoic acid condensation prepares compound (23) (17mg, yield 21%).MS(ESI)m/z:[M+H]+=465.1HNMR(300MHz, DMSO-d6):δ11.57(br,1H),9.19(br,1H),7.58-7.47(m,4H),7.28-7.21(m,3H),6.95-6.90 (m,1H),3.75-3.58(m,7H),2.75-2.59(m,6H),2.01-1.75(m,6H)。
Embodiment 24
Compound (24): (S)-2-(4-((1-(4-methoxy-benzyl) pyrrolidin-2-yl) methyl)-1,4-homopiperazine-1- Base)-1 hydrogen-h-benzimidazole-4-carboxamide
Use embodiment 13 to prepare the method that compound (13) is similar, occurred with to methoxybenzyl bromine by compound (22) Nucleophilic substitution prepares compound (24) (24mg, yield 30%).MS(ESI)m/z:[M+H]+=463.1HNMR(300MHz, DMSO-d6):δ11.78(br,1H),9.21(br,1H),7.55-7.47(m,2H),7.34-7.22(m,3H),6.90-6.79 (m,3H),4.45-4.36(m,1H),4.06-3.99(m,1H),3.42-2.65(m,16H),2.10-1.87(m,6H)。
Embodiment 25
Compound (25): (S)-2-(4-((1-acetyl-pyrrolidine-2-base) methyl)-1,4-homopiperazine-1-base)-1 hydrogen- H-benzimidazole-4-carboxamide
Use embodiment 1 to prepare the method that compound (1) is similar, prepare compound by compound (22) with acetic acid condensation (25) (18mg, yield 21%).MS(ESI)m/z:[M+H]+=385.1H NMR(300MHz,DMSO-d6):δ11.48(br, 1H),9.18(br,1H),7.55(d,1H,J=7.5Hz),7.41(br,1H),7.24(d,1H,J=7.5Hz),6.90(t,1H,J =7.5Hz),3.92-3.64(m,5H),2.89-2.60(m,8H),1.95-1.76(m,6H),1.87(s,3H)。
Embodiment 26
Compound (26): (S)-2-(4-((1-different nicotinoyl pyrrolidin-2-yl) methyl)-1,4-homopiperazine-1-base)-1 Hydrogen-h-benzimidazole-4-carboxamide
Use embodiment 1 to prepare the method that compound (1) is similar, prepare compound by compound (22) with nicotinic acid condensation (26) (25mg, yield 25%).MS(ESI)m/z:[M+H]+=448.1H NMR(300MHz,DMSO-d6):δ11.65(br, 1H),9.92(br,1H),8.61(br,2H),7.55(d,1H,J=7.5Hz),7.43-7.37(m,3H),7.26(d,1H,J= 7.5Hz),6.90(t,1H,J=7.5Hz),3.87-3.65(m,7H),2.97-2.71(m,6H),2.30-2.17(m,1H), 1.92-1.78(m,5H)。
Embodiment 27
Compound (27): (R)-2-(4-(piperidines-3-carbonyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide, tool Vivo reaction type is as follows:
Step 1: compound j:(R)-3-(4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals base) piperazine-1-carbonyl) piperazine Pyridine-1-t-butyl carbonate
Embodiment 1 is used to prepare the method that compound (1) is similar, by compound d and (R)-3-piperidines tertiary fourth of-1-carbonic acid Ester condensation prepares compound j(120mg, yield 93%).MS(ESI)m/z:[M+H]+=457.
Step 2: compound (27): (R)-2-(4-(piperidines-3-carbonyl) piperazine-1-base)-1 hydrogen-benzimidazole-4-formyl Amine
Use embodiment 4 to prepare the method that compound (4) is similar, prepared with hydrochloric acid reaction deprotection by compound j Compound (27) (24mg, yield 36%).MS(ESI)m/z:[M+H]+=357.1H NMR(300MHz,DMSO-d6):δ12.08 (br,1H),9.11-8.97(m,1H),7.62-7.54(m,2H),7.41-7.33(m,1H),7.08-6.97(m,1H),3.66- 3.60(m,10H),3.22-3.14(m,3H),3.01-2.88(m,1H),1.97-1.55(m,4H)。
Embodiment 28
Compound (28): (S)-2-(4-(piperidines-3-carbonyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide, tool Vivo reaction type is as follows:
Step 1: compound k:(S)-3-(4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals base) piperazine-1-carbonyl) piperazine Pyridine-1-t-butyl carbonate
Embodiment 1 is used to prepare the method that compound (1) is similar, by compound d and (S)-3-piperidines tertiary fourth of-1-carbonic acid Ester condensation prepares compound k(155mg, yield 100%).MS(ESI)m/z:[M+H]+=457.
Step 2: compound (28): (S)-2-(4-(piperidines-3-carbonyl) piperazine-1-base)-1 hydrogen-benzimidazole-4-formyl Amine
Use embodiment 4 to prepare the method that compound (4) is similar, prepared with hydrochloric acid reaction deprotection by compound k Compound (28) (22mg, yield 22%).MS(ESI)m/z:[M+H]+=357.1H NMR(300MHz,DMSO-d6):δ12.04 (br,1H),9.11(br,1H),7.60(d,1H,J=7.5Hz),7.53(br,1H),7.33(d,1H,J=7.5Hz),6.98(t, 1H,J=7.5Hz),3.64-3.38(m,12H),2.97-2.84(m,2H),1.88-1.54(m,4H)。
Embodiment 29
Compound (29): (R)-2-(4-(pyrrolidin-2-yl methyl) piperazine-1-base)-1 hydrogen-benzimidazole-4-formyl Amine, concrete reaction equation is as follows:
Step 1: compound l:(R)-2-(methylol) pyrrolidine-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound g, by compound (R)-2-methyl carbonate pyrrolidine-1-carbon Tert-butyl acrylate and lithium aluminium hydride reduction prepare compound l(167mg, yield 82%).MS(ESI)m/z:[M+H]+=202.
Step 2: compound m:(R)-2-carbonyl pyrrolidine-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound h, occur oxidation to prepare compound m by compound l (151mg, yield 42%).MS(ESI)m/z:[M+H]+=200.
Step 3: compound n:(R)-2-((4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-base) first Base) pyrrolidine-1-t-butyl carbonate
The method that compound i is similar is prepared in employing, occurs reduction amination to prepare compound n by compound m and compound d (67mg, yield 54%).MS(ESI)m/z:[M+H]+=429.
Step 4: compound (29): (R)-2-(4-(pyrrolidin-2-yl methyl) piperazine-1-base)-1 hydrogen-benzimidazole-4- Methanamide
Use embodiment 4 to prepare the method that compound (4) is similar, prepared with hydrochloric acid reaction deprotection by compound n Compound (29) (30mg, yield 58%).MS(ESI)m/z:[M+H]+=329.1H NMR(300MHz,DMSO-d6):δ9.11 (br,1H),7.58(d,1H,J=7.5Hz),7.47(br,1H),7.30(d,1H,J=7.5Hz),6.96(t,1H,J=7.5Hz), 3.45(br,4H),3.01-2.87(m,3H),2.60(br,4H),2.40-2.32(m,2H),1.90-1.74(m,5H)。
Embodiment 30
Compound (30): (R)-2-(4-((1-(4-nitrobenzyl) pyrrolidin-2-yl) methyl)-1,4-homopiperazine-1- Base)-1 hydrogen-h-benzimidazole-4-carboxamide, concrete reaction equation is as follows:
Step 1: compound o:(R)-2-((4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl)-1,4-homopiperazine- 1-yl) methyl) pyrrolidine-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound i, by compound m and compound f, reduction amination system occurs Obtain compound o(260mg, yield 46%).MS(ESI)m/z:[M+H]+=443.
Step 2: compound p:(R)-2-(4-(pyrrolidin-2-yl methyl)-1,4-homopiperazine-1-base)-1 hydrogen-benzo miaow Azoles-4-Methanamide
Use embodiment 4 to prepare the method that compound (4) is similar, prepared with hydrochloric acid reaction deprotection by compound o Compound p(136mg, yield 68%).MS(ESI)m/z:[M+H]+=343.
Step 3: compound (30): (R)-2-(4-((1-(4-nitrobenzyl) pyrrolidin-2-yl) methyl)-1,4-height piperazine Piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide
Embodiment 13 is used to prepare the method that compound (13) is similar, by compound p and to nitrobenzyl bromine generation nucleophilic Substitution reaction prepares compound (30) (15mg, yield 25%).MS(ESI)m/z:[M+H]+=478.1H NMR(300MHz, DMSO-d6):δ11.49(br,1H),9.15(br,1H),8.09-8.06(m,2H),7.53-7.42(m,4H),7.22-7.19 (m,1H),6.90-6.84(m,1H),3.75-3.63(m,6H),2.92-2.70(m,9H),1.97-1.86(m,6H)。
Embodiment 31
Compound (31): (R)-2-(4-((1-ethyl pyrrolidine-2-base) methyl)-1,4-homopiperazine-1-base)-1 hydrogen-benzene And imidazoles-4-Methanamide
Embodiment 13 is used to prepare the method that compound (13) is similar, by compound p and bromoethane generation nucleophilic displacement of fluorine Reaction prepares compound (31) (18mg, yield 21%).MS(ESI)m/z:[M+H]+=371.1H NMR(300MHz,DMSO- d6):δ11.76(br,1H),9.20(br,1H),7.55(d,1H,J=7.8Hz),7.45(br,1H),7.26(d,1H,J= 7.8Hz),6.90(t,1H,J=7.8Hz),3.74-3.67(m,4H),2.96-2.58(m,11H),2.05-1.86(m,6H), 1.03(t,3H,J=7.2Hz)。
Embodiment 32
Compound (32): (S)-2-(4-(pyrrolidin-2-yl methyl) piperazine-1-base)-1 hydrogen-benzimidazole-4-formyl Amine, concrete reaction equation is as follows:
Step 1: compound q:(S)-2-((4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-base) first Base) pyrrolidine-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound i, by compound d and compound h, reduction amination system occurs Obtain compound q(100mg, yield 84%).MS(ESI)m/z:[M+H]+=429.
Step 2: compound (32): (S)-2-(4-(pyrrolidin-2-yl methyl) piperazine-1-base)-1 hydrogen-benzimidazole-4- Methanamide
Use embodiment 4 to prepare the method that compound (4) is similar, prepared with hydrochloric acid reaction deprotection by compound q Compound (32) (44mg, yield 56%).MS(ESI)m/z:[M+H]+=329.1H NMR(300MHz,DMSO-d6):δ9.11 (br,1H),7.58(d,1H,J=7.5Hz),7.46(br,1H),7.30(d,1H,J=7.5Hz),6.96(t,1H,J=7.5Hz), 3.52-3.45(m,2H),3.15-2.89(m,3H),2.65-2.52(m,6H),2.42-2.36(m,2H),1.95-1.74(m, 4H),1.47-1.37(m,1H)。
Embodiment 33
Compound (33): 2-(4-(pyrrolidin-3-yl methyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide, tool Vivo reaction type is as follows:
Step 1: compound r:3-((4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-base) methyl) pyrrole Cough up alkane-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound i, by compound d and compound 3-carbonyl pyrrolidine- 1-t-butyl carbonate generation reduction amination prepares compound r(180mg, yield 100%).MS(ESI)m/z:[M+H]+=429.
Step 2: compound (33): 2-(4-(pyrrolidin-3-yl methyl) piperazine-1-base)-1 hydrogen-benzimidazole-4-formyl Amine
Use embodiment 4 to prepare the method that compound (4) is similar, prepared with hydrochloric acid reaction deprotection by compound r Compound (33) (34mg, yield 25%).MS(ESI)m/z:[M+H]+=329.1H NMR(300MHz,DMSO-d6):δ9.12 (br,1H),7.58(d,1H,J=7.5Hz),7.46(br,1H),7.30(d,1H,J=7.5Hz),6.95(t,1H,J=7.5Hz), 3.17-2.75(m,6H),2.48-2.30(m,8H),2.00-1.83(m,2H),1.58-1.47(m,2H)。
Embodiment 34
Compound (34): (R)-2-(4-(piperidines-3-ylmethyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide, Concrete reaction equation is as follows:
Step 1: compound s:(R)-3-(methylol) piperidines-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound g, by compound (R)-3-methyl carbonate piperidines-1-carbonic acid The tert-butyl ester and lithium aluminium hydride reduction prepare compound s(187mg, yield 72%).MS(ESI)m/z:[M+H]+=216.
Step 2: compound t:(R)-3-formyl piperidine-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound h, occur oxidation to prepare compound t by compound s (120mg, yield 47%).MS(ESI)m/z:[M+H]+=214.
Step 3: compound u:(S)-3-((4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-base) first Base) piperidines-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound i, by compound d and compound t, reduction amination system occurs Obtain compound u(115mg, yield 90%).MS(ESI)m/z:[M+H]+=443.
Step 4: compound (34): (R)-2-(4-(piperidines-3-ylmethyl) piperazine-1-base)-1 hydrogen-benzimidazole-4-first Amide
Use embodiment 4 to prepare the method that compound (4) is similar, prepared with hydrochloric acid reaction deprotection by compound u Compound (34) (80mg, yield 90%).MS(ESI)m/z:[M+H]+=343.1H NMR(300MHz,DMSO-d6):δ9.11 (br,1H),7.57(d,1H,J=7.5Hz),7.46(br,1H),7.30(d,1H,J=7.5Hz),6.95(t,1H,J=7.5Hz), 3.19-3.05(m,4H),2.70-2.60(m,4H),2.42-1.96(m,8H),1.73-1.54(m,4H)。
Embodiment 35
Compound (35): (S)-2-(4-(piperidines-3-ylmethyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide, Concrete reaction equation is as follows:
Step 1: compound v:(S)-3-(methylol) piperidines-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound g, by compound (S)-3-methyl carbonate piperidines-1-carbonic acid The tert-butyl ester and lithium aluminium hydride reduction prepare compound v(167mg, yield 78%).MS(ESI)m/z:[M+H]+=216.
Step 2: compound w:(S)-3-formyl piperidine-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound h, occur oxidation to prepare compound w by compound v (118mg, yield 38%).MS(ESI)m/z:[M+H]+=214.
Step 3: compound x:(R)-3-((4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-base) first Base) piperidines-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound i, by compound d and compound w, reduction amination system occurs Obtain compound x(105mg, yield 82%).MS(ESI)m/z:[M+H]+=443.
Step 4: compound (35): (S)-2-(4-(piperidines-3-ylmethyl) piperazine-1-base)-1 hydrogen-benzimidazole-4-first Amide
Use embodiment 4 to prepare the method that compound (4) is similar, prepared with hydrochloric acid reaction deprotection by compound x Compound (35) (49mg, yield 63%).MS(ESI)m/z:[M+H]+=343.1H NMR(300MHz,DMSO-d6):δ9.11 (br,1H),7.58(d,1H,J=7.5Hz),7.46(br,1H),7.30(d,1H,J=7.5Hz),6.96(t,1H,J=7.5Hz), 3.15-3.03(m,4H),2.75-2.58(m,6H),2.41-2.11(m,6H),1.91-1.51(m,4H)。
Embodiment 36
Compound (36): 2-(4-(2-methylpyrrolidin-2-carbonyl) piperazine-1-base)-1 hydrogen-benzimidazole-4-formyl Amine, concrete reaction equation is as follows:
Step 1: compound y:2-(4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-carbonyl)-2-first Base pyrrolidine-1-t-butyl carbonate
Embodiment 1 is used to prepare the method that compound (1) is similar, by compound d and 1-tertbutyloxycarbonyl 2-methyl pyrrole Cough up the condensation of alkane-2-formic acid and prepare compound y(110mg, yield 100%).MS(ESI)m/z:[M+H]+=457.
Step 2: compound (36): 2-(4-(2-methylpyrrolidin-2-carbonyl) piperazine-1-base)-1 hydrogen-benzimidazole-4- Methanamide
Use embodiment 4 to prepare the method that compound (4) is similar, prepared with hydrochloric acid reaction deprotection by compound y Compound (36) (37mg, yield 44%).MS(ESI)m/z:[M+H]+=357.1H NMR(300MHz,DMSO-d6):δ10.02 (br,1H),8.89(br,1H),8.47(br,1H),7.73(d,1H,J=7.5Hz),7.70(br,1H),7.52(d,1H,J= 7.5Hz),7.26(t,1H,J=7.5Hz),3.83(br,4H),3.74(br,4H),3.19-3.09(m,2H),2.25(br, 2H),2.04-1.97(m,2H),1.65(s,3H)。
Embodiment 37
Compound (37): 2-(4-((2-methylpyrrolidin-2-yl) methyl) piperazine-1-base)-1 hydrogen-benzimidazole-4-first Amide, concrete reaction equation is as follows:
Step 1: compound z:2-(methylol)-2-methylpyrrolidin-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound g, by compound 2-methyl-2-methyl carbonate pyrrolidine- 1-t-butyl carbonate and lithium aluminium hydride reduction prepare compound z(192mg, yield 86%).MS(ESI)m/z:[M+H]+=216.
Step 2: compound a ': 2-formoxyl-2-methylpyrrolidin-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound h, occur oxidation to prepare compound a by compound z ' (113mg, yield 44%).MS(ESI)m/z:[M+H]+=214.
Step 3: compound b ': 2-((4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-base) methyl)- 2-methylpyrrolidin-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound i, by compound d and compound a ' there is reduction amination system Obtain compound b ' (85mg, yield 94%).MS(ESI)m/z:[M+H]+=443.
Step 4: compound (37): 2-(4-((2-methylpyrrolidin-2-yl) methyl) piperazine-1-base)-1 hydrogen-benzo miaow Azoles-4-Methanamide
The method that compound (4) is similar is prepared in employing, prepares compound by compound b ' with hydrochloric acid reaction deprotection (37) (40mg, yield 62%).MS(ESI)m/z:[M+H]+=343.1H NMR(300MHz,DMSO-d6):δ12.15(br, 1H),9.38(br,1H),7.56-7.23(m,4H),3.61(br,4H),3.24-3.14(m,2H),2.73-2.62(m,6H), 1.96(br,2H),1.77-1.71(m,2H),1.32(s,3H)。
Embodiment 38
Compound (38): (S)-2-(4-(2-methylpyrrolidin-2-carbonyl) piperazine-1-base)-1 hydrogen-benzimidazole-4-first Amide, concrete reaction equation is as follows:
Step 1: compound c ': (S)-2-(4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-carbonyl)- 2-methylpyrrolidin-1-t-butyl carbonate
Embodiment 1 is used to prepare the method that compound (1) is similar, by compound d and (S)-1-tertbutyloxycarbonyl 2-first The condensation of base pyrrolidine-2-formic acid prepares compound c ' (100mg, yield 76%).MS(ESI)m/z:[M+H]+=457.
Step 2: compound (38): (S)-2-(4-(2-methylpyrrolidin-2-carbonyl) piperazine-1-base)-1 hydrogen-benzo miaow Azoles-4-Methanamide
The method that compound (4) is similar is prepared in employing, prepares compound by compound c ' with hydrochloric acid reaction deprotection (38) (54mg, yield 69%).MS(ESI)m/z:[M+H]+=357.1H NMR(300MHz,DMSO-d6):δ12.17(br, 1H),9.09(br,1H),7.62-7.55(m,2H),7.34(d,1H,J=7.8Hz),6.99(t,1H,J=7.8Hz),3.71 (br,4H),3.62(br,4H),3.15-3.05(m,2H),2.25-2.20(m,2H),2.02-1.89(m,2H),1.60(s, 3H)。
Embodiment 39
Compound (39): 2-(4-(piperidines-4-carbonyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide
Step 1: compound d ': 4-(4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals base) piperazine-1-carbonyl) piperidines- 1-t-butyl carbonate
Embodiment 1 is used to prepare the method that compound (1) is similar, by compound d and 1-t-butoxycarbonylpiperidin-4-first Acid condensation prepares compound d ' (125mg, yield 96%).MS(ESI)m/z:[M+H]+=457.
Step 2: compound (39): 2-(4-(piperidines-4-carbonyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide
The method that compound (4) is similar is prepared in employing, prepares compound by compound d ' with hydrochloric acid reaction deprotection (39) (64mg, yield 67%).MS(ESI)m/z:[M+H]+=357.1H NMR(300MHz,DMSO-d6):δ12.23(br, 1H),9.11(br,1H),7.59(d,1H,J=7.5Hz),7.53(br,1H),7.33(d,1H,J=7.5Hz),6.98(t,1H,J =7.5Hz),3.68-3.59(m,9H),3.26-3.21(m,2H),3.00-2.92(m,3H),1.80-1.77(m,4H)。
Embodiment 40
Compound (40): 2-(4-(piperidines-2-carbonyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide, the most instead Answer formula as follows:
Step 1: compound e ': 2-(4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals base) piperazine-1-carbonyl) piperidines- 1-t-butyl carbonate
Embodiment 1 is used to prepare the method that compound (1) is similar, by compound d and 1-t-butoxycarbonylpiperidin-2-first Acid condensation prepares compound e ' (126mg, yield 96%).MS(ESI)m/z:[M+H]+=457.
Step 2: compound (40): 2-(4-(piperidines-2-carbonyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide
The method that compound (4) is similar is prepared in employing, prepares compound by compound e ' with hydrochloric acid reaction deprotection (40) (63mg, yield 67%).MS(ESI)m/z:[M+H]+=357.1H NMR(300MHz,DMSO-d6):δ11.94(br, 1H),9.10(br,1H),7.60(d,1H,J=7.8Hz),7.53(br,1H),7.33(d,1H,J=7.8Hz),6.96(t,1H,J =7.8Hz),3.96-3.93(m,1H),3.69-3.60(m,8H),3.09-3.04(m,1H),2.71-2.61(m,2H),1.79- 1.39(m,6H)。
Embodiment 41
Compound (41): (S)-2-(4-((2-methylpyrrolidin-2-yl) methyl) piperazine-1-base)-1 hydrogen-benzimidazole- 4-Methanamide, concrete reaction equation is as follows:
Step 1: compound f ': (S)-2-(methylol)-2-methylpyrrolidin-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound g, by compound (S)-2-methyl-2-methyl carbonate pyrroles Alkane-1-t-butyl carbonate and lithium aluminium hydride reduction prepare compound f ' (187mg, yield 82%).MS(ESI)m/z:[M+H]+= 216。
Step 2: compound g ': (S)-2-formoxyl-2-methylpyrrolidin-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound h, occur oxidation to prepare compound g ' by compound f ' (123mg, yield 47%).MS(ESI)m/z:[M+H]+=214.
Step 3: compound h ': (S)-2-((4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-base) first Base)-2-methylpyrrolidin-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound i, by compound d and compound g ', reduction amination system occurs Obtain compound h ' (46mg, yield 36%).MS(ESI)m/z:[M+H]+=443.
Step 4: compound (41): (S)-2-(4-((2-methylpyrrolidin-2-yl) methyl) piperazine-1-base)-1 hydrogen-benzene And imidazoles-4-Methanamide
Use embodiment 4 to prepare the method that compound (4) is similar, prepared with hydrochloric acid reaction deprotection by compound g ' Compound (41) (18mg, yield 53%).MS(ESI)m/z:[M+H]+=343.1H NMR(300MHz,DMSO-d6):δ11.98 (br,1H),9.22(br,1H),7.61-7.58(m,1H),7.50-7.44(m,1H),7.33-7.27(m,1H),7.11-6.98 (m,1H),3.59(br,8H),2.72-2.62(m,5H),1.99-1.92(m,2H),1.77-1.70(m,2H),1.32(s, 3H)。
Embodiment 42
Compound (42): 2-(4-(azetidine-3-carbonyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide, Concrete reaction equation is as follows:
Step 1: compound i ': 3-(4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals base) piperazine-1-carbonyl) azacyclo- Butane-1-t-butyl carbonate
Embodiment 1 is used to prepare the method that compound (1) is similar, by compound d and 1-tertbutyloxycarbonyl azetidin The condensation of alkane-3-base formic acid prepares compound i ' (134mg, yield 100%).MS(ESI)m/z:[M+H]+=429.
Step 2: compound (42): 2-(4-(azetidine-3-carbonyl) piperazine-1-base)-1 hydrogen-benzimidazole-4-first Amide
Use embodiment 4 to prepare the method that compound (4) is similar, prepared with hydrochloric acid reaction deprotection by compound i ' Compound (42) (53mg, yield 53%).MS(ESI)m/z:[M+H]+=329.1H NMR(300MHz,DMSO-d6):δ9.76 (br,1H),9.30(br,1H),8.40(br,1H),7.73-7.71(m,2H),7.56(d,1H,J=7.5Hz),7.28(t,1H, J=7.5Hz),4.09-4.06(m,8H),3.79(br,5H)。
Embodiment 43
Compound (43): 2-(4-(piperidin-2-yl methyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide, specifically Reaction equation is as follows:
Step 1: compound j ': 2-(methylol) piperidines-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound g, by the compound 2-methyl carbonate piperidines tertiary fourth of-1-carbonic acid Ester and lithium aluminium hydride reduction prepare compound j ' (161mg, yield 73%).MS(ESI)m/z:[M+H]+=216.
Step 2: compound k ': 2-formyl piperidine-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound h, occur oxidation to prepare compound k ' by compound j ' (110mg, yield 40%).MS(ESI)m/z:[M+H]+=214.
Step 3: compound l ': 2-((4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-base) methyl) Piperidines-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound i, by compound d and compound k ', reduction amination system occurs Obtain compound 1 ' (70mg, yield 78%).MS(ESI)m/z:[M+H]+=443.
Step 4:2-(4-(piperidin-2-yl methyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide
Use embodiment 4 to prepare the method that compound (4) is similar, prepared with hydrochloric acid reaction deprotection by compound l ' Compound (43) (42mg, yield 77%).MS(ESI)m/z:[M+H]+=343.1H NMR(300MHz,DMSO-d6):δ11.96 (br,1H),9.13(br,1H),7.58(d,1H,J=7.5Hz),7.48(br,1H),7.31(d,1H,J=7.5Hz),6.96(t, 1H,J=7.5Hz),3.63-3.57(m,5H),3.21-3.16(m,6H),2.74-2.57(m,3H),1.75-1.71(m,4H), 1.57-1.38(m,2H)。
Embodiment 44
Compound (44): 2-(4-(piperidin-4-ylmethyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide, specifically Reaction equation is as follows:
Step 1: compound m ': 4-(methylol) piperidines-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound g, by the compound 4-methyl carbonate piperidines tertiary fourth of-1-carbonic acid Ester and lithium aluminium hydride reduction prepare compound m ' (181mg, yield 79%).MS(ESI)m/z:[M+H]+=216.
Step 2: compound n ': 4-formyl piperidine-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound h, occur oxidation to prepare compound n ' by compound m ' (102mg, yield 41%).MS(ESI)m/z:[M+H]+=214.
Step 3: compound o ': 4-((4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-base) methyl) Piperidines-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound i, by compound d and compound n ', reduction amination system occurs Obtain compound o ' (54mg, yield 61%).MS(ESI)m/z:[M+H]+=443.
Step 4: compound (44): 2-(4-(piperidin-4-ylmethyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide
Use embodiment 4 to prepare the method that compound (4) is similar, prepared with hydrochloric acid reaction deprotection by compound o ' Compound (44) (20mg, yield 49%).MS(ESI)m/z:[M+H]+=343.1H NMR(300MHz,DMSO-d6):δ11.79 (br,1H),9.13(br,1H),7.63-7.59(m,1H),7.50(br,1H),7.37-7.34(m,1H),7.08-6.97(m, 1H),3.66(br,8H),3.25-3.20(m,4H),2.88-2.76(m,2H),1.97-1.91(m,3H),1.48-1.36(m, 2H)。
Embodiment 45
Compound (45): the fluoro-2-of (R)-5-(4-(pyrrolidin-2-yl methyl) piperazine-1-base)-1 hydrogen-benzimidazole-4- Methanamide, concrete reaction equation is as follows:
Step 1: the fluoro-3-nitrobenzene methyl of compound p ': 2,6-bis-
Under ice bath, sulphuric acid (37mL) is slowly added to nitric acid (20mL), adds 2,6-difluoro-benzoic acid methyl ester (25.7g, 149mmol), reaction is gradually increased to room temperature, continues stirring 1 hour, pours in frozen water by above-mentioned reaction system, filter white solid Body compound p ' (20.7g, yield 64%).MS(ESI)m/z:[M+H]+=218.
Step 2: compound q ': 2-amido-6-fluoro-3-nitrobenzene methyl
Ammonia (13mL) is added dissolved with in ethanol (300mL) solution of compound p ' (32.55g, 150mmol), room temperature It is stirred overnight, filters to obtain yellow solid compound q ' (18.31g, yield 57%).MS(ESI)m/z:[M+H]+=215.
Step 3: compound r ': 2,3-bis-amido-6-fluorophenyl carbamate
10% palladium carbon (0.7g) is added dissolved with in methanol (50mL) solution of compound q ' (7g, 32.7mmol), under room temperature Hydrogenating 7 hours, filter, residue separates (petroleum ether: ethyl acetate=5:1) through rapid column chromatography and obtains yellow solid compound R ' (2.16g, yield 36%).MS(ESI)m/z:[M+H]+=185.
Step 4: compound s ': 5-fluoro-2-oxo-2,3-dihydro-1 hydrogen-benzimidazole-4-methyl formate
Embodiment 1 is used to prepare the method that compound a is similar, by compound r ' and carbonyl dimidazoles (CDI) cyclization system Obtain compound s ' (726mg, yield 39%).MS(ESI)m/z:[M+H]+=211.
Step 5: fluoro-1 hydrogen of the chloro-5-of compound t ': 2--benzimidazole-4-methyl formate
Embodiment 1 is used to prepare the similar method of compound b, by compound s ' and phosphorus oxychloride generation chlorination system Obtain compound t ' (688mg, yield 96%).MS(ESI)m/z:[M+H]+=229.
Step 6: the fluoro-2-of compound u ': 5-(piperazine-1-base)-1 hydrogen-benzimidazole-4-methyl formate
Embodiment 1 is used to prepare the similar method of compound c, by compound t ' and piperazine generation nucleophilic substitution system Obtain compound u ' (550mg, yield 78%).MS(ESI)m/z:[M+H]+=279.
Step 7: the fluoro-2-of compound v ': 5-(piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide
Embodiment 1 is used to prepare the similar method of compound d, by the ammonolysis reaction system of compound u ' Yu ammonia generation ester Obtain compound v ' (35mg, yield 38%).MS(ESI)m/z:[M+H]+=264.
Step 8: compound w ': (R)-2-((4-(fluoro-1 hydrogen of 4-carbamoyl-5--benzimidazolyl-2 radicals-yl) piperazine-1- Base) methyl) piperidines-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound i, by compound m and compound v ', reduction amination system occurs Obtain compound w ' (85mg, yield 83%).MS(ESI)m/z:[M+H]+=447.
Step 9: compound (45): the fluoro-2-of (R)-5-(4-(pyrrolidin-2-yl methyl) piperazine-1-base)-1 hydrogen-benzo miaow Azoles-4-Methanamide
Use embodiment 4 to prepare the method that compound (4) is similar, prepared with hydrochloric acid reaction deprotection by compound w ' Compound (45) (35mg, yield 53%).MS(ESI)m/z:[M+H]+=347.1H NMR(300MHz,DMSO-d6):δ12.19 (br,1H),8.86(br,1H),7.56-7.40(m,2H),7.22(br,1H),3.59(br,6H),3.17-3.08(m,4H), 2.71(br,4H),2.03-1.85(m,4H)。
Embodiment 46
Compound (46): 2-(4-(azetidine-3-ylmethyl) piperazine-1-base)-1 hydrogen-benzimidazole-4-formyl Amine, concrete reaction equation is as follows:
Step 1: compound x ': 3-(methylol) azetidine-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound g, by compound 3-methyl carbonate azetidine-1-carbon Tert-butyl acrylate and lithium aluminium hydride reduction prepare compound x ' (158mg, yield 71%).MS(ESI)m/z:[M+H]+=188.
Step 2: compound y ': 3-formoxyl azetidine-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound h, occur oxidation to prepare compound y ' by compound x ' (92mg, yield 43%).MS(ESI)m/z:[M+H]+=186.
Step 3: compound z ': 3-((4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-base) methyl) Azetidine-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound i, by compound d and compound y ', reduction amination system occurs Obtain compound z ' (45mg, yield 52%).MS(ESI)m/z:[M+H]+=415.
Step 4: compound (46): 2-(4-(azetidine-3-ylmethyl) piperazine-1-base)-1 hydrogen-benzimidazole-4- Methanamide
Use embodiment 4 to prepare the method that compound (4) is similar, prepared with hydrochloric acid reaction deprotection by compound z ' Compound (46) (23mg, yield 67%).MS(ESI)m/z:[M+H]+=315.1H NMR(300MHz,DMSO-d6):δ12.06 (br,1H),9.51(br,1H),9.28(br,1H),8.46(br,1H),7.74-7.71(m,2H),7.55(d,1H,J= 7.5Hz),7.28(t,1H,J=7.5Hz),4.03-3.86(m,8H),3.42(br,4H),3.28-3.21(m,3H)。
Embodiment 47
Compound (47): (R)-2-(4-((2-methylpyrrolidin-2-yl) methyl) piperazine-1-base)-1 hydrogen-benzimidazole- 4-Methanamide, concrete reaction equation is as follows:
Step 1: compound a ": (R)-2-(methylol)-2-methylpyrrolidin-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound g, by compound (R)-2-methyl-2-methyl carbonate pyrroles Alkane-1-t-butyl carbonate and lithium aluminium hydride reduction prepare compound a " (191mg, yield 81%).MS(ESI)m/z:[M+H]+= 216。
Step 2: compound b ": (R)-2-formoxyl-2-methylpyrrolidin-1-t-butyl carbonate
Use embodiment 22 to prepare the similar method of compound h, pass through compound a " occur oxidation to prepare compound b " (120mg, yield 45%).MS(ESI)m/z:[M+H]+=214.
Step 3: compound c ": (R)-2-((4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-base) first Base)-2-methylpyrrolidin-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound i, by compound d and compound b " there is reduction amination system Obtain compound c " (25mg, yield 35%).MS(ESI)m/z:[M+H]+=443.
Step 4:(S)-2-(4-((2-methylpyrrolidin-2-yl) methyl) piperazine-1-base)-1 hydrogen-benzimidazole-4-first Amide
Embodiment 4 is used to prepare the method that compound (4) is similar, by compound c " prepare with hydrochloric acid reaction deprotection Compound (47) (13mg, yield 64%).MS(ESI)m/z:[M+H]+=343.1H NMR(300MHz,DMSO-d6):δ12.08 (br,1H),9.36(br,1H),7.66-7.48(m,2H),7.29(s,1H),7.17-6.97(m,1H),3.62-3.53(m, 6H),3.26-3.15(m,3H),2.84-2.62(m,5H),1.96-1.71(m,3H),1.32(s,3H)。
Embodiment 48
Compound (48): (R)-2-(4-(piperidin-2-yl methyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide, Concrete reaction equation is as follows:
Step 1: compound d ": (R)-2-(methylol) piperidines-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound g, by compound (R)-2-methyl carbonate piperidines-1-carbonic acid The tert-butyl ester and lithium aluminium hydride reduction prepare compound d " (191mg, yield 82%).MS(ESI)m/z:[M+H]+=216.
Step 2:(R)-2-formyl piperidine-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound h, by compound d " occur oxidation to prepare compound e " (105mg, yield 42%).MS(ESI)m/z:[M+H]+=214.
Step 3: compound f ": (R)-2-((4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-base) first Base) piperidines-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound i, by compound d and compound e " there is reduction amination system Obtain compound f " (50mg, yield 70%).MS(ESI)m/z:[M+H]+=443.
Step 4: compound (48): (R)-2-(4-(piperidin-2-yl methyl) piperazine-1-base)-1 hydrogen-benzimidazole-4-first Amide
Embodiment 4 is used to prepare the method that compound (4) is similar, by compound f " prepare with hydrochloric acid reaction deprotection Compound (48) (26mg, yield 85%).MS(ESI)m/z:[M+H]+=343.1H NMR(300MHz,DMSO-d6):δ12.01 (br,1H),9.13(br,1H),7.58(d,1H,J=7.5Hz),7.49(br,1H),7.30(d,1H,J=7.5Hz),6.96(t, 1H,J=7.5Hz),3.60-3.55(m,5H),3.18-3.14(m,6H),2.72-2.57(m,3H),1.70-1.41(m,6H)。
Embodiment 49
Compound (49): (S)-2-(4-(piperidin-2-yl methyl) piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide, Concrete reaction equation is as follows:
Step 1: compound g ": (S)-2-(methylol) piperidines-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound g, by compound (S)-2-methyl carbonate piperidines-1-carbonic acid The tert-butyl ester and lithium aluminium hydride reduction prepare compound g " (187mg, yield 81%).MS(ESI)m/z:[M+H]+=216.
Step 2: compound h ": (S)-2-formyl piperidine-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound h, by compound g " occur oxidation to prepare compound h " (112mg, yield 45%).MS(ESI)m/z:[M+H]+=214.
Step 3: compound i ' ': (S)-2-((4-(4-carbamoyl-1 hydrogen-benzimidazolyl-2 radicals-yl) piperazine-1-base) Methyl) piperidines-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound i, by compound d and compound h " there is reduction amination system Obtain compound i " (55mg, yield 77%).MS(ESI)m/z:[M+H]+=443.
Step 4: compound (49): (S)-2-(4-(piperidin-2-yl methyl) piperazine-1-base)-1 hydrogen-benzimidazole-4-first Amide
Embodiment 4 is used to prepare the method that compound (4) is similar, by compound i " prepare with hydrochloric acid reaction deprotection Compound (49) (22mg, yield 54%).MS(ESI)m/z:[M+H]+=343.1H NMR(300MHz,DMSO-d6):δ11.95 (br,1H),9.12(br,1H),7.59(d,1H,J=7.5Hz),7.49(br,1H),7.30(d,1H,J=7.5Hz),6.96(t, 1H,J=7.5Hz),3.63-3.55(m,5H),3.22-3.17(m,6H),2.73-2.60(m,3H),1.76-1.71(m,4H), 1.61-1.52(m,2H)。
Embodiment 50
Compound (50): the fluoro-2-of (R)-6-(4-((2-methylpyrrolidin-2-yl) methyl) piperazine-1-base)-1 hydrogen-benzo Imidazoles-4-Methanamide, concrete reaction equation is as follows:
Step 1: compound j ": 5-fluoro-3-nitro-2-(2,2,2-trifluoroacetamide) benzoic acid
Under ice bath, the fluoro-benzoic acid of 2-trifluoroacetamide-5-(2.5g, 10mmol) is added fuming nitric aicd slowly (14mL), in, reaction is poured in frozen water after continuing stirring under ice bath 1 hour, is filtrated to get compound as white solid j " (1.9g, Yield 65%).MS(ESI)m/z:[M-H]-=295.
Step 2: compound k ": 2-amido-5-fluoro-3-nitrobenzoic acid
10% sodium hydrate aqueous solution (20mL) is added dissolved with compound j " ethanol solution of (1.18g, 4mmol) (20mL), in, reaction is warming up to 80 DEG C and stirs 3 hours.Decompression removes ethanol, residue salt acid for adjusting pH to 4, filters, obtains yellow Color solid chemical compound k " (0.72g, yield 90%) MS (ESI) m/z:[M-H]-=199.
Step 3: compound l ": 2-amido-5-fluoro-3-nitrobenzene methyl
Under ice bath, thionyl chloride (2.38g) is slowly added dropwise into dissolved with compound k " methanol solution of (0.8g, 4mmol) (20mL) in, being heated to backflow, cool down, removal of solvent under reduced pressure after reacting 8 hours, residue separates (oil through rapid column chromatography Ether: ethyl acetate=5:1) obtain yellow solid compound l " (0.5g, yield 58%).MS(ESI)m/z:[M+H]+=215.
Step 4: compound m ": 2,3-bis-amido-5-fluorophenyl carbamate
Embodiment 45 is used to prepare the similar method of compound r ', by compound l " occur catalytic hydrogenation to prepare compound M " (812mg, yield 46%).MS(ESI)m/z:[M+H]+=185.
Step 5: compound n ": 6-fluoro-2-oxo-2,3-dihydro-1 hydrogen-benzimidazole-4-methyl formate
Embodiment 1 is used to prepare the method that compound a is similar, by compound m " and carbonyl dimidazoles (CDI) cyclization system Obtain compound n " (711mg, yield 37%).MS(ESI)m/z:[M+H]+=211.
Step 6: compound o ": fluoro-1 hydrogen of the chloro-6-of 2--benzimidazole-4-methyl formate
Embodiment 1 is used to prepare the similar method of compound b, by compound n " and phosphorus oxychloride generation chlorination system Obtain compound o " (681mg, yield 94%).MS(ESI)m/z:[M+H]+=229.
Step 7: compound p ": the fluoro-2-of 6-(piperazine-1-base)-1 hydrogen-benzimidazole-4-methyl formate
Embodiment 1 is used to prepare the similar method of compound c, by compound o " and piperazine generation nucleophilic substitution system Obtain compound p " (430mg, yield 65%).MS(ESI)m/z:[M+H]+=279.
Step 8: compound q ": the fluoro-2-of 6-(piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide
Embodiment 1 is used to prepare the similar method of compound d, by compound p " and the ammonolysis reaction system of ammonia generation ester Obtain compound q " (25mg, yield 34%).MS(ESI)m/z:[M+H]+=264.
Step 9:(R)-2-((4-(fluoro-1 hydrogen of 4-carbamoyl-6--benzimidazolyl-2 radicals-yl) piperazine-1-base) methyl)- 2-methylpyrrolidin-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound i, by compound q " and compound b " there is reduction amination Prepare compound r " (28mg, yield 31%).MS(ESI)m/z:[M+H]+=461.
Step 10:(R) the fluoro-2-of-6-(4-((2-methylpyrrolidin-2-yl) methyl) piperazine-1-base)-1 hydrogen-benzo miaow Azoles-4-Methanamide
Embodiment 4 is used to prepare the method that compound (4) is similar, by compound r " prepare with hydrochloric acid reaction deprotection Compound (50) (14mg, yield 65%).MS(ESI)m/z:[M+H]+=361.1H NMR(300MHz,DMSO-d6):δ12.36 (br,1H),9.32(br,1H),7.67-7.53(m,1H),7.36-7.14(m,2H),3.61(br,8H),2.80-2.68(m, 5H),1.92-1.20(m,7H)。
Embodiment 51
Compound (51): the fluoro-2-of (R)-6-(4-(piperidin-2-yl methyl) piperazine-1-base)-1 hydrogen-benzimidazole-4-first Amide, concrete reaction equation is as follows:
Step 1: compound s ": (R)-2-((4-(fluoro-1 hydrogen of 4-carbamoyl-6--benzimidazolyl-2 radicals-yl) piperazine-1- Base) methyl) piperidines-1-t-butyl carbonate
Embodiment 22 is used to prepare the similar method of compound i, by compound e " and compound q " there is reduction amination Prepare compound s " (61mg, yield 78%).MS(ESI)m/z:[M+H]+=461.
Step 2: compound (51): the fluoro-2-of (R)-6-(4-(piperidin-2-yl methyl) piperazine-1-base)-1 hydrogen-benzo miaow Azoles-4-Methanamide
Embodiment 4 is used to prepare the method that compound (4) is similar, by compound s " prepare with hydrochloric acid reaction deprotection Compound (51) (31mg, yield 67%).MS(ESI)m/z:[M+H]+=361.1H NMR(300MHz,DMSO-d6):δ12.28 (br,1H),9.08(br,1H),7.66(br,1H),7.30-7.25(m,1H),7.15-7.12(m,1H),3.63-3.37(m, 9H),2.82-2.62(m,5H),1.75-1.63(m,4H),1.45-1.34(m,2H)。
Biological assessment
Experimental principle:
After the translation that the poly ADP of nucleoprotein is ribosylating when being to occur at DNA damage response.PARP, full name is poly-adenosine Diphosphonic acid ribose polymerase, in the presence of having NAD, is catalyzed on the nucleoprotein that poly (ADP-ribose) is connected to close on, thus draws Send out the DNA repair mechanism via base excision repair path.The HTUniversal that Trevigen company produces Chemiluminescent PARP Assay Kit can measure this by biotin labeled ADP-ribose and histone In conjunction with level.
Reagent and consumptive material
1.HT Universal Chemiluminescent PARP Assay Kit with Histone-coated Strip Wells, U.S. Trevigen, article No.: 4676-096-K.
2. read plate instrument, U.S. Perkin Elmer, EnVision Multilabel Plate Reader.
Solution and buffer
1. washing liquid: containing the PBS solution of 0.1%Triton X-100.
2.20X PARP buffer: 20X PARP buffer dilution 20 times is i.e. obtained 1X buffer with deionized water, should Buffer is used to dilution restructuring PARP enzyme, PARP Cocktail and tested compound.
3.10X PARP Cocktail: preparation 1X PARP Cocktail:10X PARP in accordance with the following methods Cocktail2.5 μ l/well, 10X activated dna 2.5 μ l/well, 1X PARP buffer 20 μ l/well.
4.PARP Enzyme the most before use, carefully dilutes recombinase with 1X PARP buffer, the enzymatic solution diluted To use as early as possible, unspent to discard.
5.Strep-HRP the most before use, obtains 1X solution by 1X Strep diluted Strep-HRP500 times.
6. chemical luminous substrate is the most before use, obtains peppery by PeroxyGlowA and the B solution mix homogeneously of same volume The substrate of root peroxidase.
Experimental technique
Compound is prepared
1. with DMSO, each for 10mM test compound mother solution is diluted to 10uM, 1uM.
The most only before experiment starts, the gradient concentration solution 1X PARP of each compound being dissolved in DMSO delays Rush liquid and dilute 20 times, obtain the compound solution of 5X, i.e. can be utilized for detection, positive control (POSITIVE) and negative control (NEGATIVE) hole is 1X PARP buffer (DMSO content 5%).
Operating procedure
1. every hole adds 50 μ l1X PARP buffer moistening histones, incubated at room orifice plate 30 minutes, then by hole 1X PARP buffer sucking-off, and on napkin, residual liquid is patted dry only.
2., according to compound arrangement figure, the 5X compound solution diluted is added in corresponding hole, every hole 10 μ l is positive Comparison (POSITIVE) and negative control (NEGATIVE) hole are 1X PARP buffer (DMSO content 5%)
3. with 1X PARP buffer, PARP enzyme is diluted to every 15 μ l solution and contains 0.5Unit, then except negative right Adding 15 μ l enzymatic solution according to other holes beyond hole, negative control hole only adds 1X PARP buffer, incubated at room orifice plate 10 points Clock.
4. continuously add the 1X PARP Cocktail of 25 μ l in each hole.
5.27 ° of C hatch orifice plate 60 minutes.
6., after hatching end, by the reactant liquor sucking-off in hole, and on napkin, residual liquid is patted dry only.Then with containing The PBS solution of 0.1%Triton X-100 rinses orifice plate 4 times, and the most every hole is with 200 μ l, and is patted dry by residual liquid on napkin Only.
7., it follows that add the 1X Strep-HRP solution diluted in every hole, then hatch orifice plate 60 points at 27 ° of C Clock.
8., after hatching end, by the reactant liquor sucking-off in hole, and on napkin, residual liquid is patted dry only.Then with containing The PBS solution of 0.1%Triton X-100 rinses orifice plate 4 times, and the most every hole is with 200 μ l, and is patted dry by residual liquid on napkin Only.
9. after washing the bundle that hardens, by PeroxyGlow A and the B solution mix homogeneously of same volume, every hole adds 100 μ l, vertical I.e. put into reading plate instrument record chemiluminescence signal.
Data process
Reading in every hole needs to be converted into suppression ratio.The suppression ratio of compound can use following equation to calculate Go out:
Note: Positive control wells reading is positive hole reading, meaning is enzyme 100% activity；Negative control hole reading is Negative hole reading, meaning is enzyme 0%；Activity X is the reading of each each concentration of sample.
Table 1 compound inhibitory activity to PARP-1 enzyme
Compound number The suppression ratio (%) of 500nM concentration The suppression ratio (%) of 100nM concentration IC50 value
(1) 78 41 --
(2) 65 22 --
(3) 79 45 --
(4) -- -- 41nM
(5) -- -- 45nM
(6) -- -- 37nM
(7) 59 40 --
(8) 54 40 --
(9) 62 43 --
(10) 82 62 --
(11) 92 69 --
(12) -- -- 95nM
(13) 47 15 --
(14) 57 27 --
(15) 31 16 --
(16) 74 37 --
(17) 37 7 --
(18) 49 14 --
(19) 50 12 --
(20) 51 12 --
(21) 33 4 --
(22) 75 54 --
(23) 54 31 --
(24) 49 26 --
(25) 74 46 --
(26) 63 33 --
(27) -- -- 48nM
(28) -- -- 60nM
(29) -- -- 21nM
(30) 51 32 --
(31) 62 40 --
(32) -- -- 19nM
(33) -- -- 24nM
(34) -- -- 76nM
(35) -- -- 26nM
(36) -- -- 56nM
(37) -- -- 24nM
(38) -- -- 37nM
(39) -- -- 39nM
(40) -- -- 38nM
(41) -- -- 33nM
(42) -- -- 43nM
(43) -- -- 36nM
(44) -- -- 84nM
(45) -- -- 100nM
(46) -- -- 36nM
(47) -- -- 49nM
(48) -- -- 29nM
(49) -- -- 56nM
(50) -- -- 17nM
(51) -- -- 15nM
The activity data listed in table 1 fully shows, the compound of the present invention is all the inhibitor of PARP-1, wherein implements In example, compound (4), (5), (6), (10), (11), (12), (22), (27), (28), (29), (32), (33), (34), (35), (36), (37), (38), (39), (40), (41), (42), (43), (44), (45), (46), (47), (48), (49), (50), the IC50 value of (51) no more than 100nM, compound (1), (2), (3), (7), (8), (9), (14), (16), (19), (20), (23), (25), (26), (30), the IC50 value of (31) is not more than 500nM.

Claims (27)

1. lead to the compound shown in formula (I) or its pharmaceutically acceptable salt:
Wherein: in logical formula (I):
R is hydrogen or halogen；
G is carbonyl or methylene；
M is 1～2；
N is 1～3；
Q is hydrogen or C1-C4Alkyl；
When X is methylene, Y is NR1Or when Y is methylene, X is NR1；
R1For hydrogen, C1-C6Alkyl, benzyl, COR2And SO2R2；
R2For following groups that is unsubstituted or that replaced by 1-3 substituent group: C1-C6Alkyl, C3-C8Cycloalkyl, phenyl, benzyl, Pyridine radicals, described substituent group is selected from following atom or group: C1-C6Alkyl, C1-C6Alkoxyl, halogen, amino, nitro, mercapto Base, hydroxyl, cyano group and trifluoromethyl.
2. logical formula (I) compound as claimed in claim 1 or its pharmaceutically acceptable salt, it is characterised in that wherein:
R is hydrogen or fluorine；
G is carbonyl or methylene；
M is 1～2；
N is 1～3；
Q is hydrogen or C1-C4Alkyl；
When X is methylene, Y is NR1Or when Y is methylene, X is NR1；
R1For hydrogen, C1-C6Alkyl, benzyl, COR2And SO2R2；
R2For following groups that is unsubstituted or that replaced by 1-3 substituent group: C1-C6Alkyl, C3-C8Cycloalkyl, phenyl, benzyl, Pyridine radicals, described substituent group is selected from following atom or group: C1-C6Alkyl, C1-C6Alkoxyl, halogen, amino, nitro, mercapto Base, hydroxyl, cyano group and trifluoromethyl.
3. logical formula (I) compound as claimed in claim 1 or its pharmaceutically acceptable salt, it is characterised in that wherein:
R is hydrogen；
G is carbonyl or methylene；
M is 1～2；
N is 1～3；
Q is hydrogen or C1-C4Alkyl；
When X is methylene, Y is NR1Or when Y is methylene, X is NR1；
R1For hydrogen, C1-C6Alkyl, benzyl, COR2And SO2R2；
R2For following groups that is unsubstituted or that replaced by 1-3 substituent group: C1-C6Alkyl, C3-C8Cycloalkyl, phenyl, benzyl, Substituent group described in pyridine radicals is selected from following atom or group: C1-C6Alkyl, C1-C6Alkoxyl, halogen, amino, nitro, mercapto Base, hydroxyl, cyano group and trifluoromethyl.
4. logical formula (I) compound as claimed in claim 1 or its pharmaceutically acceptable salt, it is characterised in that described formula (I) compound is one of following compound (1)～(51) compound:
5. logical formula (I) compound as claimed in claim 1 or its pharmaceutically acceptable salt, it is characterised in that described pharmacy Upper acceptable salt be the logical hydrochlorate of formula (I) compound, sulfate, phosphate, acetate, trifluoroacetate, mesylate, Fluoroform sulphonate, tosilate, tartrate, maleate, fumarate, succinate or malate.
6. the method for the preparation logical formula (I) compound described in claim 1, its reaction equation is as follows:
Wherein, the definition of R, n, G, Q, X and Y is as claimed in claim 1, m=1；Specifically comprise the following steps that
Step 1): substituted 2,3-diamidogen yl benzoic acid methyl ester and carbonyl dimidazoles ring-closure reaction, obtain substituted 2-oxo-2, 3-dihydro-1 hydrogen-benzimidazole-4-methyl formate (II)；
Step 2): step 1) substituted 2-oxo-2,3-dihydro-1 hydrogen-benzimidazole-4-methyl formate (II) and three of obtaining Chlorethoxyfos carries out chlorination reaction, obtains chloro-1 hydrogen of substituted 2--benzimidazole-4-methyl formate (III)；
Step 3): in the presence of a base, by step 2) chloro-1 hydrogen of substituted 2--benzimidazole-4-methyl formate (III) of obtaining with Piperazine carries out nucleophilic substitution, obtains substituted 2-(piperazine-1-base)-1 hydrogen-benzimidazole-4-methyl formate (IV)；
Step 4): by step 3) substituted 2-(piperazine-1-base)-1 hydrogen-benzimidazole-4-methyl formate (IV) of obtaining is at ammonia Methanol solution occurs the aminolysis reaction of ester group, obtains substituted 2-(piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide (Ⅴ)；
Step 5): by step 4) substituted 2-(piperazine-1-base)-1 hydrogen-h-benzimidazole-4-carboxamide (V) of obtaining sends out with acid Raw coupling reaction or with aldehyde generation reductive amination process, generate logical compound shown in formula (I).
7. pharmaceutical composition, comprise logical formula (I) compound shown in the claim 1 of the therapeutically effective amount constituting active component or its Pharmaceutically acceptable salt and one or more medicinal carrier substances and/or diluent.
8. pharmaceutical composition as claimed in claim 7, its described pharmaceutical composition makes tablet, capsule, aqueous suspendible Agent, Oil suspensions, dispersible powder, granule, lozenge, Emulsion, syrup, ointment, ointment, suppository or injection Agent.
9. pharmaceutical composition, comprise logical formula (I) compound shown in the claim 1 of the therapeutically effective amount constituting active component or its Pharmaceutically acceptable salt and pharmaceutically acceptable carrier, excipient or diluent.
10. pharmaceutical composition as claimed in claim 9, its described pharmaceutical composition makes tablet, capsule, aqueous suspendible Agent, Oil suspensions, dispersible powder, granule, lozenge, Emulsion, syrup, ointment, ointment, suppository or injection Agent.
Logical formula (I) compound described in 11. Claims 1-4 any one claim or its pharmaceutically acceptable salt are in preparation Treat the application in the disease medicament improved because of the suppression of PARP activity.
12. apply as claimed in claim 11, and the described disease improved because of the suppression of PARP activity is angiopathy, septic Shock, ischemic injuries, neurotoxicity, hemorrhagic shock, inflammatory diseases or multiple sclerosis.
Pharmaceutical composition described in 13. claim 7 or 8 is in the disease medicament that preparation treatment improves because of the suppression of PARP activity Application.
14. apply as claimed in claim 13, and the described disease improved because of the suppression of PARP activity is angiopathy, septic Shock, ischemic injuries, neurotoxicity, hemorrhagic shock, inflammatory diseases or multiple sclerosis.
Pharmaceutical composition described in 15. claim 9 or 10 is in the disease medicament that preparation treatment improves because of the suppression of PARP activity Application.
16. apply as claimed in claim 15, and the described disease improved because of the suppression of PARP activity is angiopathy, septic Shock, ischemic injuries, neurotoxicity, hemorrhagic shock, inflammatory diseases or multiple sclerosis.
Logical formula (I) compound described in 17. Claims 1-4 any one claim or its pharmaceutically acceptable salt are in preparation Application in the ancillary drug of oncotherapy.
Logical formula (I) compound described in 18. Claims 1-4 any one claim or its pharmaceutically acceptable salt are in preparation Application in the medicine of tumor strengthening radiotherapy.
Logical formula (I) compound described in 19. Claims 1-4 any one claim or its pharmaceutically acceptable salt are in preparation Application in the medicine of cancer chemotherapy.
Logical formula (I) compound described in 20. Claims 1-4 any one claim or its pharmaceutically acceptable salt are in preparation Lack the application in the medicine of the individuation treatment of cancer that homologous recombination (HR) dependent DNA double chain interruption (DSB) is repaired.
21. apply as claimed in claim 20, and wherein said cancer is by the DSB of HR DNA plerosis containing one or more The ability cancer of cancerous cell that lowers relative to normal cell or lose.
22. apply as claimed in claim 20, and wherein said cancer is to have BRCA-1 or BRCA-2 defect, mutant phenotype Cancer.
23. apply as claimed in claim 20, and wherein said cancer is breast carcinoma, ovarian cancer, cancer of pancreas or carcinoma of prostate.
The application in preparation is used for the medicine of cancer chemotherapy of the pharmaceutical composition described in 24. claim 7 or 8 or 9 or 10.
25. apply as claimed in claim 24, and wherein said cancer is by the DSB of HR DNA plerosis containing one or more The ability cancer of cancerous cell that lowers relative to normal cell or lose.
26. apply as claimed in claim 24, and wherein said cancer is to have BRCA-1 or BRCA-2 defect, mutant phenotype Cancer.
27. apply as claimed in claim 24, and wherein said cancer is breast carcinoma, ovarian cancer, cancer of pancreas or carcinoma of prostate.
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