CN101641360B - Piperazine derivatives, preparation process and pharmaceutical use thereof - Google Patents

Piperazine derivatives, preparation process and pharmaceutical use thereof Download PDF

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CN101641360B
CN101641360B CN200880009683XA CN200880009683A CN101641360B CN 101641360 B CN101641360 B CN 101641360B CN 200880009683X A CN200880009683X A CN 200880009683XA CN 200880009683 A CN200880009683 A CN 200880009683A CN 101641360 B CN101641360 B CN 101641360B
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trifluoromethyl
piperazine
imidazo
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amino
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邓炳初
杨方龙
王阳
沈光远
陈天鹏
梁金栋
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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Abstract

The present invention discloses piperazine derivatives of formula (I), methods for their preparation, pharmaceutical compositions containing the same and their use as a therapeutic agent, especially as a dipeptidyl peptidase IV inhibitor. The definition of substituents in formula (I) are the same as the description.

Description

Piperazine derivative, its preparation method and in pharmaceutically application
Technical field
The present invention relates to piperazine derivative, its preparation method new shown in a kind of general formula (I) and contain this verivate pharmaceutical composition, with and as therapeutical agent particularly as the purposes of inhibitors of dipeptidyl IV.
Background technology
Mellitus are metabolic troubles of a kind of multi-pathogenesis, and characteristics are chronic hyperglycemias, follow because of insulin secretion and/or effect the defective sugar, fat and the protein metabolism disorder that cause.Mellitus are a kind of very ancient disease, are that glucose concn raises in the blood that causes owing to Regular Insulin in the human body definitely or relatively lacks, and then sugar discharges from urine in a large number, and many drinks, diuresis occur, eat more, become thin, symptom such as dizzy, weak.
Nonvolatil or uncontrolled hyperglycemia causes the increase of incidence and mortality.The usually sugar stable state is unusual relevant with the hemodynamics disease with lipid, lipoprotein, the metabolic change of Apo or other metabolism directly or indirectly.The type ii diabetes patient suffers from macrovesicle and capillary blood vessel syndromes, significantly increases as diseases such as coronary heart disease, apoplexy, Peripheral blood vessel disease, hypertension, ephrosis, neuropathy and retinopathy are dangerous.Therefore, diseases such as sugared stable state, lipid metabolism, hypertension being treated control, is extremely important for treating mellitus clinically.
Two types mellitus as a rule, are arranged.The type 1 diabetes people, i.e. the Regular Insulin of insulin-dependent diabetes mellitus (IDDM) patient self generation seldom or does not almost have.Regular Insulin is a kind of hormone that is used for regulating glucose utilization in the body.The type ii diabetes people; Be that Regular Insulin non-insulin dependent diabetes (NIDDM) patient is identical or higher with the interior insulin level of ND's blood plasma; Yet; This type of patient but produces resistibility to Regular Insulin, and these Regular Insulin are for the histocyte of main insulin sensitivity, plays hormesis like the glucose and the lipid metabolism of muscle, liver, 25 fatty tissues etc.Even plasma insulin level improves, also can't overcome the patient for the significant resistibility of Regular Insulin.
Insulin resistance also mainly because the minimizing of insulin receptor quantity produces, also has insulin receptor defect, and up to the present this mechanism also fails to understand.The resistibility of insulin replies property causes Regular Insulin in muscle tissue, glucose uptake, oxidation, storage to be activated, and can't effectively suppress the generation and the secretion of fatty tissue lipolysis and liver glucose.
Dipeptidyl peptidase-IV (DPPIV) is a kind of Tryase; It can contain the terminal pepx of cracking N-in the peptide chain of a proline residue at inferior end; Although DPPIV is not also confirmed mammiferous physiological action completely; But it is at neural enzymes metabolism, the T-cell-stimulating, and cancer metastasis goes in endothelium and the HIV virus entering lymphoidocyte process all to play important effect (WO98/19998).
Recently; There are some researches show that DPPIV can stop the secretion of Glucagon-like peptide (GLP)-1; Especially, it can cracking GLP-1 in terminal group-third pepx of N-, make its GLP-1 (7-36) NH2 be degraded to GLP-1 (9-36) NH2 (Endocrinology of non-activity from activity form; 1999,140:5356～5363).Because under the physiological conditions, in the circulation blood transformation period of complete GLP-1 very short, thereby the non-activity metabolite behind the DPPIV degraded GLP-1 can shorten the physiological response to GLP-1 with GLP-1 receptors bind antagonistic activity GLP-1.And the DPPIV suppressor factor can protect endogenous even ectogenic GLP-1 not by the DPPIV deactivation fully; Improve the physiologically active (5～10 times) of GLP-1 greatly; Because GLP-1 is an important stimulator and the directly distribution of affecting glucose to the pancreas secretion of insulin, the DPPIV suppressor factor plays good effect (US6110949) to the treatment of non insulin dependent diabetes (NIDDM).
Some DPP-IV suppressor factor are disclosed (US5462928, US5543396, WO9515309, WO2003004498, WO2003082817, WO2004032836, WO2004085661) at present, and wherein the MK-0431 of Merck company is the structure of going on the market.
The purpose of this invention is to provide and a kind ofly have that to suppress DPPIV active and can be used for the compound of mellitus or similar treatment of diseases or the property alleviated medicine.
Summary of the invention
In order to overcome the weak point of prior art; The object of the present invention is to provide the piperazine compounds shown in a kind of general formula (I); And their tautomer, enantiomorph, diastereomer, raceme and pharmacy acceptable salt, and meta-bolites and metabolic precursor thereof or prodrug.
Wherein:
Ar is a phenyl, and this phenyl is unsubstituted or further by 1～5 R 7Replace;
R 1Be selected from Wasserstoffatoms, alkyl, trifluoromethyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl; Wherein alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl are further replaced by one or more halogen, cyanic acid, aryl, hydroxyl or amino substituting groups of being selected from, and are preferably trifluoromethyl;
R 2Be selected from Wasserstoffatoms, halogen, cyanic acid, amino, alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl ,-NR 3R 4,-NR 3C (O) R 4Or-NC (O) NR 3R 4, wherein naphthenic base, Heterocyclylalkyl, aryl, heteroaryl further by one or more be selected from halogen, amino, cyanic acid, nitro, hydroxyl, alkyl, naphthenic base, alkoxyl group, heteroaryl, tri haloalkyl ,-NR 3R 4,-NR 3C (O) R 4,-C (O) NR 3R 4,-NC (O) NR 3R 4,-COR 5Or-SO 2R 6Substituting group replace;
R 3And R 4Be selected from independently of one another Wasserstoffatoms, alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl or-SO 2R 6, wherein alkyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl further by one or more be selected from halogen, hydroxyl, amino, alkoxyl group, alkyl, aryl, Heterocyclylalkyl ,-SO 2R 6,-NR 3R 4, carboxylic acid or carboxylicesters substituting group replace;
Perhaps, R 3And R 4Form 4～8 yuan of heterocyclic radicals together; Wherein 4～8 yuan of heterocycles contain one or more N, O, S atom, and on 4～8 yuan of heterocycles further by one or more be selected from halogen, alkyl, aryl, heteroaryl, hydroxyl, carbonyl, cyanic acid, alkoxyl group, hydroxyalkyl, Heterocyclylalkyl or-NR 3R 4Substituting group replace;
R 5Be selected from Wasserstoffatoms or alkyl;
R 6Be selected from alkyl or aryl, wherein aryl is further replaced by one or more alkyl.
R 7Be selected from halogen, cyanic acid, hydroxyl, alkyl or alkoxyl group, wherein alkyl or alkoxyl group are unsubstituted or are further replaced by one or more halogens.
Typical compound of the present invention includes, but are not limited to:
Figure GPA00000755172000031
Figure GPA00000755172000041
Figure GPA00000755172000051
Figure GPA00000755172000061
Figure GPA00000755172000071
Figure GPA00000755172000081
Figure GPA00000755172000091
Figure GPA00000755172000101
Figure GPA00000755172000111
Figure GPA00000755172000121
Or their pharmacy acceptable salts.
Wherein, described salt is above-claimed cpd and the salt that is selected from following acid formation: phosphoric acid salt, oxysuccinic acid, lactic acid, toxilic acid, hydrochloric acid, methylsulfonic acid, sulfuric acid, phosphoric acid, Hydrocerol A, tartrate, acetate or trifluoroacetic acid.
The present invention relates to general formula compound (IA) or general formula compound (IB) on the other hand, and they are the midbody of synthetic general formula compound (I):
Figure GPA00000755172000122
Wherein:
X is selected from halogen;
R 1Be selected from Wasserstoffatoms, alkyl, trifluoromethyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl; Wherein alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl are further replaced by one or more halogen, cyanic acid, aryl, hydroxyl or amino substituting groups of being selected from, and are preferably trifluoromethyl;
R 2Be selected from Wasserstoffatoms, halogen, cyanic acid, amino, alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl ,-NR 3R 4,-NR 3C (O) R 4Or-NC (O) NR 3R 4, wherein naphthenic base, Heterocyclylalkyl, aryl, heteroaryl further by one or more be selected from halogen, amino, cyanic acid, nitro, hydroxyl, alkyl, naphthenic base, alkoxyl group, heteroaryl, tri haloalkyl ,-NR 3R 4,-NR 3C (O) R 4,-C (O) NR 3R 4,-NC (O) NR 3R 4,-COR 5Or-SO 2R 6Substituting group replace;
R 3And R 4Be selected from independently of one another Wasserstoffatoms, alkyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl or-SO 2R 6, wherein alkyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl further by one or more be selected from halogen, hydroxyl, amino, alkoxyl group, alkyl, aryl, Heterocyclylalkyl ,-SO 2R 6,-NR 3R 4, carboxylic acid or carboxylicesters substituting group replace;
Perhaps, R 3And R 4Form 4～8 yuan of heterocyclic radicals together; Wherein 4～8 yuan of heterocycles contain one or more N, O, S atom, and on 4～8 yuan of heterocycles further by one or more be selected from halogen, alkyl, aryl, heteroaryl, hydroxyl, carbonyl, cyanic acid, alkoxyl group, hydroxyalkyl, Heterocyclylalkyl or-NR 3R 4Substituting group replace;
R 5Be selected from Wasserstoffatoms or alkyl.
R 6Be selected from alkyl or aryl, wherein aryl is further replaced by one or more alkyl.
One aspect of the present invention relates to the preparation method of general formula compound (IA) and general formula compound (IB), may further comprise the steps:
The preparation method of a kind of general formula compound (IA), this method may further comprise the steps:
Figure GPA00000755172000131
With raw material R 2Substituted pyrazine 2-methylamine and acid anhydrides react, and the amide product of generation adds Vanadium Pentoxide in FLAKES with after POCl3 at room temperature mixes stirring, generates imidazo [1,5-a] pyrazine ring, and under Pd/C catalysis, hydro-reduction generates general formula compound (IA) then.
The preparation method of general formula compound (IB), this method may further comprise the steps:
Figure GPA00000755172000132
Raw material pyrazine 2-methylamine and acid anhydrides are reacted, and the amide product of generation adds Vanadium Pentoxide in FLAKES with after POCl3 at room temperature mixes stirring; Generate imidazo [1,5-a] pyrazine ring, then under Pd/C catalysis; Generate the imidazo [1 that tert-butoxycarbonyl is protected with the tert-Butyl dicarbonate reaction behind the hydrogen reducing; 5-a] the piperazine product, under N-halo succinimide condition, react then, obtain general formula compound (IB).
The preparation method of a kind of general formula compound (IA), this method may further comprise the steps:
Figure GPA00000755172000133
General formula compound (IB) under the catalysis of palladium class reagent, is reacted under microwave with boric acid or boric acid ester, carry out Suzuki coupling (J.Am.Chem.Soc., 2007,129,3358-3366; Chem.Soc.Rev., 2001,30,145-157), or under catalytic condition, carry out Buchwald coupling (J.Am.Chem.Soc., 2002,124,7421-7428 with substitutional amine-group; J.Am.Chem.Soc., 2001,123,7727-7429), obtain the protection base of product desamidizate under acidic conditions, obtain general formula compound (IA).
Be the preparation method of general formula (I) compound in one aspect of the invention, this method may further comprise the steps:
Figure GPA00000755172000134
General formula compound (IA) carries out condensation with 3-tert-butoxycarbonyl amino-4-aryl-butyric acid (WO03004498) under the condition of two (2-oxo-3-oxazolidinyl) the inferior phosphonyl chlorides of condensation reagent; The product that obtains is desamidizate protection base under acidic conditions, obtains general formula compound (I).
Figure GPA00000755172000135
React under the condition of two (2-oxo-3-oxazolidinyl) the inferior phosphonyl chlorides of condensation reagent with 3-tert-butoxycarbonyl amino-4-aryl-butyric acid behind general formula compound (IB) the deprotection base; The condensation product that obtains is under the catalysis of palladium class reagent; React under microwave with boric acid or boric acid ester, carry out Suzuki coupling (J.Am.Chem.Soc., 2007; 129,3358-3366; Chem.Soc.Rev., 2001,30,145-157), obtain general formula compound (I); Condensation product also can with substitutional amine-group under catalytic condition, carry out Buchwald coupling (J.Am.Chem.Soc., 2002,124,7421-7428; J.Am.Chem.Soc., 2001,123,7727-7429), obtain general formula compound (I); Condensation product also can be in oil bath; As catalyzer, with the alcohol reaction, the substituted carboxylic acid ester cpds that obtains further is hydrolyzed into carboxylic acid under carbon monoxide atmosphere with cobalt octacarbonyl and ethyl chloroacetate; With the acid amides that the volatile salt reaction generates, further dehydration generates R 2General formula compound (I) for cyanic acid.
One side of the present invention is that react in methyl alcohol, methylene dichloride or the ethyl acetate solution of acid the purified back of general formula compound (I), obtains its sour adduct salt.Wherein said acid is phosphoric acid salt, oxysuccinic acid, lactic acid, toxilic acid, hydrochloric acid, methylsulfonic acid, sulfuric acid, phosphoric acid, Hydrocerol A, tartrate, acetate or trifluoroacetic acid.
One side of the present invention is a kind of medicinal compsns, and it contains treatment effective dose general formula (I) compound or its pharmacy acceptable salt, reaches pharmaceutically acceptable carrier or vehicle.
One side of the present invention is to suppress the method for DPP IV catalytic activity, comprising any one described compound in described DPP IV and the general formula (I) or salt are contacted.
Another aspect of the present invention is the purposes that any one said compound, salt or pharmaceutical composition are used for treating diseases such as type ii diabetes, hyperglycemia, obesity or insulin resistant disease in the general formula (I).
One side of the present invention is to contain treatment effective dose general formula (I) compound or its pharmacy acceptable salt, and the purposes of pharmaceutical composition in the medicine of preparation treatment type ii diabetes, hyperglycemia, obesity or insulin resistant disease of acceptable carrier or vehicle pharmaceutically.
Detailed description of the invention
Only if the phase counter-statement is arranged, the following term that is used in specification sheets and claims has following implication.
" alkyl " refers to saturated aliphatic hydrocarbon group, comprises the straight chain and the branched group of 1 to 20 carbon atom.The alkyl that preferably contains 1 to 10 carbon atom, for example methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl, amyl group etc.The low alkyl group that more preferably contains 1 to 4 carbon atom, for example methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-or the tertiary butyl etc.Alkyl can be substituted or unsubstituted, and when being substituted, substituting group is preferably one or more, be independently selected from halogen, amino, cyanic acid, hydroxyl, alkyl, naphthenic base, Heterocyclylalkyl, aryl, alkoxyl group, heteroaryl, tri haloalkyl ,-SO 2R 6,-NR 3R 4,-NR 3C (O) R 4,-C (O) NR 3R 4Or-NC (O) NR 3R 4
" naphthenic base " refers to 3 to 8 yuan of full carbon monocycles, complete 5 yuan/6 yuan or 6 yuan/6 yuan fused rings of carbon or encircles fused rings (" condensing " ring system mean that each ring in the system share a pair of carbon atom that adjoins with other rings in the system) group more; Wherein one or more rings can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.The instance of naphthenic base has cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenes, hexanaphthene, cyclohexadiene, diamantane, suberane, cycloheptatriene etc.Naphthenic base can be replacement or unsubstituted; When being substituted; Substituting group is preferably one or more, be independently selected from halogen, amino, cyanic acid, hydroxyl, alkyl, naphthenic base, Heterocyclylalkyl, aryl, alkoxyl group, heteroaryl, tri haloalkyl, carboxylic acid, carboxylicesters ,-COR 5,-SO 2R 6,-NR 3R 4,-NR 3C (O) R 4,-C (O) NR 3R 4Or-NC (O) NR 3R 4
" aryl " refers to have the group of at least one aromatic ring structure, promptly has the aromatic ring of conjugated πDian Zi system, comprises isocyclic aryl, heteroaryl and dibenzyl.Alkynyl can be substituted or unsubstituted; When being substituted; Substituting group is preferably one or more, be independently selected from halogen, amino, cyanic acid, hydroxyl, alkyl, naphthenic base, Heterocyclylalkyl, aryl, alkoxyl group, heteroaryl, tri haloalkyl, carboxylic acid, carboxylicesters ,-COR 5,-SO 2R 6,-NR 3R 4,-NR 3C (O) R 4,-C (O) NR 3R 4Or-NC (O) NR 3R 4
" heteroaryl " refers to have 1 to 3 heteroatoms as annular atoms, and remaining annular atoms is the aryl of carbon, and heteroatoms comprises oxygen, sulphur and nitrogen.Said ring can be 5 yuan or 6 yuan of rings.The heterocyclic aryl examples of groups comprises furyl, thienyl, pyridyl, pyrroles, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl etc.Heteroaryl can be substituted or unsubstituted; When being substituted; Substituting group is preferably one or more, be independently selected from halogen, amino, cyanic acid, hydroxyl, alkyl, naphthenic base, Heterocyclylalkyl, aryl, alkoxyl group, heteroaryl, tri haloalkyl, carboxylic acid, carboxylicesters ,-COR 5,-SO 2R 6,-NR 3R 4,-NR 3C (O) R 4,-C (O) NR 3R 4Or-NC (O) NR 3R 4
" Heterocyclylalkyl " refers to monocycle or condensed ring group, in ring, has 5 to 9 annular atomses, and one of them or two annular atomses are selected from the heteroatoms of nitrogen, oxygen or S (O) n (wherein n is an integer 0 to 2), and all the other annular atomses are carbon.These rings can also have one or more pairs of keys.But, these rings do not have the πDian Zi system of total conjugated.Unsubstituted Heterocyclylalkyl include but not limited to pyrrolidyl, piperidino-(1-position only), Piperazino, morpholinyl, thio-morpholinyl, high piperazine its etc., Heterocyclylalkyl can be substituted or unsubstituted.Alkynyl can be substituted or unsubstituted; When being substituted; Substituting group is preferably one or more, be independently selected from halogen, amino, cyanic acid, hydroxyl, alkyl, naphthenic base, Heterocyclylalkyl, aryl, alkoxyl group, heteroaryl, tri haloalkyl, carboxylic acid, carboxylicesters ,-COR 5,-SO 2R 6,-NR 3R 4,-NR 3C (O) R 4,-C (O) NR 3R 4Or-NC (O) NR 3R 4
" hydroxyl " refers to-the OH group.
" alkoxyl group " refer to-O-(alkyl) and-O-(unsubstituted naphthenic base).Representative example includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.
" halogen " refers to fluorine, chlorine, bromine or iodine, preferred fluorine or chlorine.
" trifluoromethyl " refers to-CF 3
" amino " refers to-NH 2
" cyanic acid " refers to-CN.
" nitro " refers to-NO 2
" carboxylic acid " refers to (alkyl) C (=O) OH.
" carboxylicesters " refers to (alkyl) C (=O) O (alkyl).
" pharmaceutical composition " represent on one or more compounds described herein or its physiology/mixture of pharmacy acceptable salt or prodrug and other chemical compositions, and other components are physiology/pharmaceutically acceptable carrier and vehicle for example.The purpose of pharmaceutical composition is to promote the administration of compound to organism.
The compound method of The compounds of this invention
In order to accomplish the object of the invention, the present invention adopts following technical scheme:
The preparation method of general formula compound of the present invention (IA) may further comprise the steps:
Figure GPA00000755172000161
With raw material R 2Substituted pyrazine 2-methylamine and acid anhydrides react, and the amide product of generation adds Vanadium Pentoxide in FLAKES with after POCl3 at room temperature mixes stirring, generates imidazo [1,5-a] pyrazine ring, and under Pd/C catalysis, hydro-reduction generates general formula compound (IA) then.
The preparation method of general formula compound of the present invention (IB) may further comprise the steps:
Figure GPA00000755172000162
Raw material pyrazine 2-methylamine and acid anhydrides are reacted, and the amide product of generation adds Vanadium Pentoxide in FLAKES with after POCl3 at room temperature mixes stirring; Generate imidazo [1,5-a] pyrazine ring, then under Pd/C catalysis; Generate the imidazo [1 that tert-butoxycarbonyl is protected with the tert-Butyl dicarbonate reaction behind the hydrogen reducing; 5-a] the piperazine product, under N-halo succinimide condition, react then, obtain general formula compound (IB).
The preparation method of general formula compound of the present invention (IA) may further comprise the steps:
Figure GPA00000755172000163
General formula compound (IB) under the catalysis of palladium class reagent, is reacted under microwave with boric acid or boric acid ester, carry out Suzuki coupling (J.Am.Chem.Soc., 2007,129,3358-3366; Chem.Soc.Rev., 2001,30,145-157), or under catalytic condition, carry out Buchwald coupling (J.Am.Chem.Soc., 2002,124,7421-7428 with substitutional amine-group; J.Am.Chem.Soc., 2001,123,7727-7429), obtain the protection base of product desamidizate under acidic conditions, obtain general formula compound (IA).
The preparation method of general formula of the present invention (I) compound may further comprise the steps:
Figure GPA00000755172000164
General formula compound (IA) carries out condensation with 3-tert-butoxycarbonyl amino-4-aryl-butyric acid (WO03004498) under the condition of two (2-oxo-3-oxazolidinyl) the inferior phosphonyl chlorides of condensation reagent; The product that obtains is desamidizate protection base under acidic conditions, obtains general formula compound (I).
The preparation method of general formula of the present invention (I) compound may further comprise the steps:
Figure GPA00000755172000171
React under the condition of two (2-oxo-3-oxazolidinyl) the inferior phosphonyl chlorides of condensation reagent with 3-tert-butoxycarbonyl amino-4-aryl-butyric acid behind general formula compound (IB) the deprotection base; The condensation product that obtains is under the catalysis of palladium class reagent; Further under microwave, react, carry out Suzuki coupling (J.Am.Chem.Soc., 2007 with boric acid or boric acid ester; 129,3358-3366; Chem.Soc.Rev., 2001,30,145-157), obtain general formula compound (I); Condensation product also can with substitutional amine-group under catalytic condition, carry out Buchwald coupling (J.Am.Chem.Soc., 2002,124,7421-7428; J.Am.Chem.Soc., 2001,123,7727-7429), obtain general formula compound (I); Condensation product also can be in oil bath; As catalyzer, with the alcohol reaction, the substituted carboxylic acid ester cpds that obtains further is hydrolyzed into carboxylic acid under carbon monoxide atmosphere with cobalt octacarbonyl and ethyl chloroacetate; With the acid amides that the volatile salt reaction generates, further dehydration generates R 2General formula compound (I) for cyanic acid.
Figure GPA00000755172000172
With raw material imidazo [1; 5-a] the nitrated substituted imidazo of nitro [1,5-a] the pyrazine ring that obtains of pyrazine ring, then under Pd/C catalysis; Hydrogen reducing generates amino substituted imidazo [1; 5-a] the piperazine product, then with 3-t-butoxycarbonyl amino-4-aryl-butyric acid under the condition of two (2-oxo-3-oxazolidinyl) the inferior phosphonyl chlorides of condensation reagent, stirred overnight at room temperature obtains R 2General formula compound (I) for amino.
React in methyl alcohol, methylene dichloride or the ethyl acetate solution of acid the purified back of general formula compound (I), obtains its sour adduct salt.
Embodiment
The structure of compound is confirmed through nucleus magnetic resonance (NMR) or mass spectrum (MS).NMR displacement (δ) provides with 1,000,000/(ppm) unit.The mensuration of NMR is with Bruker AVANCE-400 nuclear magnetic resonance spectrometer, and measuring solvent is deuterated methanol (CD 3OD), deuterochloroform (CDCl 3), being designated as trimethyl silane (TMS) in the hexadeuterated dimethyl sulfoxide (DMSO-d6), chemical shift is with 10 -6(ppm) provide as unit;
The mensuration of MS is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Therm, model: FinniganLCQ advantage MAX;
IC 50The mensuration of value is with NovoStar ELIASA (German BMG company);
Thin layer silica gel uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate;
Column chromatography generally uses Huanghai Sea silica gel 200～300 order silica gel in Yantai to be carrier;
DMSO-d6: hexadeuterated dimethyl sulfoxide;
CD 3OD: deuterated methanol;
CDCl 3: deuterochloroform;
Suzuki coupling reference: J.Am.Chem.Soc., 2007,129,3358-3366; Chem.Soc.Rev., 2001,30,145-157;
Buchwald coupling reference: J.Am.Chem.Soc., 2002,124,7421-7428; J.Am.Chem.Soc., 2001,123,7727-7429.
Preparation embodiment:
Embodiment 1
(R)-3-amino-1-(3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000181
The first step
2,2-dimethyl--5-[2-(2,4,5-three fluoro-phenyl)-ethanoyl]-[1,3] diox-4,6-diketone
With 2, the 2-dimethyl--[1,3] diox-4, (5.69g 39.5mmol) is dissolved in the 400mL methylene dichloride under the stirring 6-diketone; In ice bath cooling down, adding 2,4, (7.15g is 37.6mmol) with to Dimethylamino pyridine (7.35g for the 5-trifluoro benzene acetic acid; 60.2mmol), (8.28g, dichloromethane solution 43.2mmol) stir after 36 hours under the room temperature slowly to drip 250mL 1-(3-dimethylamino-propyl group)-3-ethyl-carbodiimide hydrochloride; With 5% sodium bisulfate (250mL * 7) and saturated nacl aqueous solution washing reaction liquid, anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure filtrating; Obtain title product 2,2-dimethyl--5-[2-(2,4,5-three fluoro-phenyl)-ethanoyl]-[1; 3] dioxs-4,6-diketone 1a (11.4g, white solid), yield: 96%.
MS?m/z(ESI)：315.5[M-1]。
Second step
3-oxo-4-(2,4,5-three fluoro-phenyl)-ethyl n-butyrate
With 2,2-dimethyl--5-[2-(2,4,5-three fluoro-phenyl)-ethanoyl]-[1,3] diox-4, (15.72g 49.6mmol) is dissolved in the 280mL ethanol 70 ℃ of following stirred overnight of oil bath under the stirring to 6-diketone 1a.Cooling, concentrating under reduced pressure is removed solvent in the reaction solution, uses the silica gel column chromatography purifying, obtains title product 3-oxo-4-(2,4,5-three fluoro-phenyl)-ethyl n-butyrate 1b (12g, yellow liquid), yield: 88%.
MS?m/z(ESI)：259[M-1]。
The 3rd step
3-amino-4-(2,4,5-three fluoro-phenyl)-but-2-ene acetoacetic ester
(24.6g 94.5mmol) is dissolved in the 240mL methyl alcohol, adds ammonium acetate (36.4g with 3-oxo-4-(2,4,5-three fluoro-phenyl)-ethyl n-butyrate 1b; 473mmol), reflux is after 3 hours, and TLC follows the tracks of and reacts to the raw material disappearance, and solvent evaporated adds 100mL water; With ETHYLE ACETATE (200mL * 3) extraction, merge organic phase, with the washing of 200mL saturated nacl aqueous solution, anhydrous magnesium sulfate drying filters; Filtrate decompression concentrates the faint yellow solid that obtains, and adds 50mL ETHYLE ACETATE, 80 ℃ of dissolvings down, adds the 50mL normal hexane, crystal seed; Be cooled under the room temperature, after 0.5 hour, add the 100mL normal hexane, place refrigerator overnight, suction filtration; Obtain title product 3-amino-4-(2,4,5-three fluoro-phenyl)-but-2-ene acetoacetic ester 1c (19.5g, white solid), yield: 80%.
MS?m/z(ESI)：260.1[M+1]
The 4th step
(R)-3-t-butoxycarbonyl amino-4-(2,4,5-three fluoro-phenyl)-ethyl n-butyrate
(4.1g 15.8mmol) adds in the autoclave, adds 70mL methyl alcohol (logical nitrogen used after 1 hour) again with 3-oxo-4-(2,4,5-three fluoro-phenyl)-ethyl n-butyrate 1c; Tert-Butyl dicarbonate (3.8g, 17.4mmol), chlorine (1, the 5-cyclooctadiene) rhodium (I) dimer (32mg, 0.0632mmol) with (R)-1-[(S)-2-(diphenylphosphino) ferrocenyl]-ethyl-tertiary butyl phosphine (68mg; 0.126mmol), under 30 ℃, reaction is 24 hours in the hydrogen of 90Psi, filters; Solvent evaporated adds 34mL methyl alcohol down at 50 ℃, and the dissolving back adds 12mL water fully, in refrigerator overnight; Filter, with methanol (v: v=3: 2) mixed solvent wash solids product, drain solvent, obtain title product (R)-3-t-butoxycarbonyl amino-4-(2; 4,5-three fluoro-phenyl)-ethyl n-butyrate 1d (4g, faint yellow solid), yield: 70%.
MS?m/z(ESI)：362.4[M+1]。
The 5th step
(R)-3-t-butoxycarbonyl amino-4-(2,4,5-three fluoro-phenyl)-butyric acid
With (R)-3-t-butoxycarbonyl amino-4-(2,4,5-three fluoro-phenyl)-ethyl n-butyrate 1d (10g, 27.7mmol) and sodium hydroxide (3.32g; 83mmol) stirring is dissolved in the mixed solvent of 100mL methyl alcohol and 50mL water down, and reaction is after 4 hours down at 30 ℃, and concentrating under reduced pressure is removed partial solvent, adds less water; The sodium bisulfate regulator solution pH of adding 10% is 2.5 under ice bath, with ETHYLE ACETATE (200mL * 3) extraction, merges organic phase, washs with the 200mL saturated nacl aqueous solution; Use anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure filtrating; With ETHYLE ACETATE/normal hexane recrystallization 2 times, obtain title product (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-and butyric acid 1e (9.7g, white solid), directly be used for next step reaction.
MS?m/z(ESI)：332.3[M-1]。
The 6th step
2,2,2-three fluoro-N-pyrazine-2-methyl-methane amides
(1.0g 9.2mmol) joins in the reaction flask, and ice bath is cooled to 0 ℃, drips the 10mL trifluoroacetic anhydride with C-pyrazine-2-methylamine 1f; Stirred 2 hours under the room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears, the reaction solution concentrating under reduced pressure; Use the silica gel column chromatography purifying, obtain title product 2,2; 2-three fluoro-N-pyrazines-2-methyl-methane amide 1g (2.0g, brown oil), yield: 69%.
MS?m/z(ESI)：206.1[M+1]。
The 7th step
3-trifluoromethyl-imidazo [1,5-a] pyrazine
Under the room temperature condition, with 2,2,2-three fluoro-N-pyrazines-2-methyl-methane amide 1g (21.0g; 100mmol) add in the reaction flask, add the 100mL POCl3, stirring at room added Vanadium Pentoxide in FLAKES (17.8g after 30 minutes; 125mmol), heating reflux reaction 5 hours, thin-layer chromatography are followed the tracks of and are reacted to the raw material disappearance, remove the phosphorus trichloride that desolvates; Reaction system is used 20% sodium hydroxide solution in ice bath, to regulate pH again and is 5-6 with slowly cancellation reaction of deionized water, with ETHYLE ACETATE (250mL * 4) extraction, merges organic phase; Use anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure filtrating is used the silica gel column chromatography purifying; Obtain title product 3-trifluoromethyl-imidazo [1,5-a] pyrazine 1h (12.0g, yellow solid), yield: 65%.
MS?m/z(ESI)：188.0[M+1]。
The 8th step
3-trifluoromethyl-imidazo [1,5-a] piperazine
(12.0g 64.2mmol) is dissolved in the 150mL absolute ethyl alcohol under the stirring, adds 500mg 10% palladium/carbon, substitutes gas three times, stirred overnight under nitrogen atmosphere with 3-trifluoromethyl-imidazo [1,5-a] pyrazine 1h.With reacting liquid filtering, remove catalyzer with thick silica gel, evaporated under reduced pressure filtrating obtains title product 3-trifluoromethyl-imidazo [1,5-a] piperazine 1i (12.2g, brown solid), yield: 99%.
The 9th step
(R)-[3-oxo-1-(2,4, the 5-trifluoro-benzyl)-3-(3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-propyl group]-t-butyl carbamate
Under the nitrogen atmosphere, with 3-t-butoxycarbonyl amino-4-(2,4,5-three fluoro-phenyl)-butyric acid 1e (8.6g; 45mmol) (preparation gets according to WO03004498), 9.4mL triethylamine are dissolved in the 300mL methylene dichloride under stirring, and stir after 5 minutes under the room temperature, add 3-trifluoromethyl-imidazo [1,5-a] piperazine 1i (15.0g more respectively successively; (17.1g 67.3mmol), reacted 2 hours under the room temperature, and thin-layer chromatography is followed the tracks of reaction raw materials and disappeared 45mmol) to reach two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides; Revolve the steaming reaction solution, remove and desolvate, with silica gel column chromatography purifying gained resistates; Obtain title product (R)-[3-oxo-1-(2,4, the 5-trifluoro-benzyl)-3-(3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl)-propyl group]-t-butyl carbamate 1j (20.0g, white solid), yield: 88%.
The tenth step
(R)-3-amino-1-(3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-[3-oxo-1-(2,4, the 5-trifluoro-benzyl)-3-(3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-propyl group]-t-butyl carbamate 1j (300mg; 0.59mmol) stir the 4.3N hydrogen chloride methanol solution that is dissolved in 10mL down, stirred overnight under the room temperature, thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and solvent evaporated is used the silica gel column chromatography purifying; Obtain title product (R)-3-amino-1-(3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4; The 5-trifluorophenyl)-and Ding-1-keto hydrochloride 1 (260mg, white solid), yield: 99%.
1HNMR(400MHz，CD 3OD)：δ7.08(s，1H)，7.06(s，1H)，6.80(t，1H)，4.51-4.59(m，2H)，4.09(s，1H)，3.97(s，1H)，3.70(d，2H)，3.56(s，1H)，2.75-2.78(m，2H)，2.59-2.64(d，2H)
Embodiment 2
(R)-3-amino-1-(1-amino-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-ketone dihydrochloride
Figure GPA00000755172000211
The first step
1-nitro-3-trifluoromethyl-imidazo [1,5-a] pyrazine
(2g 10.7mmol) joins in the single port flask of 25mL, stirs to add the 5mL nitrosonitric acid and the 5mL vitriol oil down with 3-trifluoromethyl-imidazo [1,5-a] pyrazine 1h; The mixture heating up to 110 of gained ℃, 1.5 hours afterreactions of stirring reaction finish, reaction solution is cooled to room temperature after, pour in the ice bath refrigerative 50mL strong aqua; Stir the back with ethyl acetate extraction (250mL * 3), and the organic phase of merging is used anhydrous magnesium sulfate drying, filters; Concentrating under reduced pressure with silica gel column chromatography purifying gained resistates, obtains title product 1-nitro-3-trifluoromethyl-imidazo [1; 5-a] pyrazine 2a (250mg, brown oily liquids), yield: 10%.
MS?m/z(ESI)：233[M+1]
Second step
3-trifluoromethyl-imidazoles [1,5-a] piperazine-1-amine
(250mg 1.05mmol) is dissolved in the 30mL absolute ethyl alcohol under the stirring, adds 100mg 10%Pd/C with 1-nitro-3-trifluoromethyl-imidazo [1,5-a] pyrazine 2a; Substitute gas three times, stirred overnight at room temperature under nitrogen atmosphere, with zeyssatite with reacting liquid filtering; Evaporated under reduced pressure filtrating is used the silica gel column chromatography purifying, obtains title product 3-trifluoromethyl-imidazoles [1; 5-a] piperazine-1-amine 2b (65mg, white solid), yield: 31.6%.
MS?m/z(ESI)：207[M+1]
The 3rd step
(R)-[3-(1-amino-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group 1]-t-butyl carbamate
Under the nitrogen atmosphere, with 3-trifluoromethyl-imidazoles [1,5-a] piperazine-1-amine 2b (60mg; 0.29mmol) be dissolved in the 20mL methylene dichloride under stirring, add successively under the room temperature diisopropylethylamine (85 μ L, 0.486mmol); (R)-3-t-butoxycarbonyl amino-4-(2,4,5-three fluoro-phenyl)-butyric acid 1e (81mg; 0.243mmol) and two (2-oxo-3-oxazolidinyl) inferior phosphonyl chloride (92mg, 0.36mmol).Stirred overnight under the room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; With the reaction solution concentrating under reduced pressure, use the silica gel column chromatography purifying, obtain title product (R)-[3-(1-amino-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group 1]-t-butyl carbamate 2c (125mg; White solid), yield: 98%.
MS?m/z(ESI)：522[M+1]
The 4th step
(R)-3-amino-1-(1-amino-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-ketone dihydrochloride
With (R)-[3-(1-amino-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group 1]-t-butyl carbamate 2c (125mg; 0.24mmol) stir down and be dissolved in 10mL 4.3N hydrogen chloride methanol solution, stirred overnight under the room temperature, thin-layer chromatography is followed the tracks of and is reacted; Raw material disappears, and solvent evaporated is used the silica gel column chromatography purifying; Obtain title product (R)-3-amino-1-(1-amino-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4; The 5-trifluorophenyl)-and Ding-1-ketone dihydrochloride 2 (117mg, white solid), yield: 98%.
MS?m/z(ESI)：422[M+1]
1HNMR(400MHz，CD 3OD)：δ7.35(m，1H)，7.18(m，1H)，5.15(m，2H)，4.25(m，2H)，4.05(m，2H)，3.91(s，1H)，3.05(s，2H)，2.92(m，2H)
Embodiment 3
(R)-and 3-amino-1-(1-cyclopentyl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000221
Figure GPA00000755172000231
The first step
3-cyclopentyl-N*2*-ethylidene-N*1*-methylene radical-propylene-1,2, the 3-triamine
(6.3g 0.06mol) is dissolved in the 80mL toluene, and cooling solution slowly drips cyclopentyl bromination magnesium (33mL to-10 ℃ with 2 cyano pyrazine 3a; 66mmol), dropwise and stir after 30 minutes, in reaction solution, drip the 40mL Virahol, stirred 30 minutes; Continue to drip 40mL ethanol, under 0 ℃, in reaction solution, add Peng Qinghuana (3.18g, 84mmol); Stirred overnight under the room temperature adds acetone, first alcohol and water quencher reaction in reaction solution, produce until no bubble, and concentrating under reduced pressure steams most of organic solvent; Water merges organic phase with ethyl acetate extraction (250mL * 3), uses anhydrous magnesium sulfate drying, filters; Concentrating under reduced pressure with silica gel column chromatography purifying gained resistates, obtains title product 3-cyclopentyl-N*2*-ethylidene-N*1*-methylene radical-propylene-1,2; 3-triamine 3b (1.5g, brown oily liquids), yield: 15%.
MS?m/z(ESI)：178[M+1]
Second step
N-(cyclopentyl pyrazine-2-methyl)-2,2, the 2-trifluoroacetamide
With 3-cyclopentyl-N*2*-ethylidene-N*1*-methylene radical-propylene-1,2, (5.2g 29mmol) joins in the reaction flask 3-triamine 3b; Ice bath is cooled to 0 ℃, drips the 40mL trifluoroacetic anhydride, stirs 2 hours under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, reaction solution concentrating under reduced pressure, the dark oil thing N-that obtains (cyclopentyl pyrazine-2-methyl)-2; 2,2-trifluoroacetamide 3c directly carries out next step reaction without separating.
The 3rd step
1-cyclopentyl-3-trifluoromethyl-imidazo [1,5-a] pyrazine
Under the ice bath cooling, with N-(cyclopentyl pyrazine-2-methyl)-2,2,2-trifluoroacetamide 3c is added dropwise in the 10mL POCl3, adds Vanadium Pentoxide in FLAKES (2g rapidly; 14.6mmol), 4 hours afterreactions of reflux finish, and the reaction solution concentrating under reduced pressure adds 5mL water; Transfer pH=9 with strong aqua,, merge organic phase, wash with the 20mL saturated nacl aqueous solution with ETHYLE ACETATE (150mL * 4) extraction; Use anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure filtrating is used the silica gel column chromatography purifying; Obtain title product 1-cyclopentyl-3-trifluoromethyl-imidazo [1,5-a] pyrazine 3d (166mg, red oil), yield: 25.7%.
MS?m/z(ESI)：256[M+1]。
The 4th step
1-cyclopentyl-3-trifluoromethyl-imidazo [1,5-a] piperazine
(166mg 0.65mmol) is dissolved in the 10mL absolute ethyl alcohol under the stirring, adds 40mg 10%Pd/C with 1-cyclopentyl-3-trifluoromethyl-imidazo [1,5-a] pyrazine 3d; Substitute gas three times, stirred overnight at room temperature under nitrogen atmosphere, with zeyssatite with reacting liquid filtering; Concentrating under reduced pressure filtrating with silica gel column chromatography purifying gained resistates, obtains title product 1-cyclopentyl-3-trifluoromethyl-imidazo [1; 5-a] piperazine 3e (110mg, red oily liquids), yield: 65%.
MS?m/z(ESI)：260[M+1]
The 5th step
(R)-[3-(1-cyclopentyl 1-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate
Under the nitrogen atmosphere, (156mg 0.47mmol) is dissolved in the 20mL methylene dichloride under the stirring with 1-cyclopentyl-3-trifluoromethyl-imidazo [1,5-a] piperazine 3e; Add successively under the room temperature diisopropylethylamine (0.29mL, 0.63mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (156mg, 0.47mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (160mg, 0.63mmol), stirred overnight under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, with the reaction solution concentrating under reduced pressure, with silica gel column chromatography purifying gained resistates; Obtain title product (R)-[3-(1-cyclopentyl 1-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 3f (254mg, white solid), yield: 94%.
MS?m/z(ESI)：575[M+1]
The 6th step
(R)-and 3-amino-1-(1-cyclopentyl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-[3-(1-cyclopentyl 1-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-(254mg 0.44mmol) is dissolved in the 10mL 4.3N hydrogen chloride methanol solution under the stirring t-butyl carbamate 3f, stirs 2 hours afterreactions under the room temperature and finishes; Solvent evaporated with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-(1-cyclopentyl-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 3 (216mg; White solid), yield: 96%.
MS?m/z(ESI)：475[M+1]
1HNMR(400MHz，CD 3OD)：δ7.39(q，1H)，7.18-7.23(m，1H)，4.27-4.37(d，2H)，3.66-4.05(m，5H)，3.07-3.12(m，3H)，2.89-2.96(m，2H)，2.06(s，2H)，1.86(s，2H)，1.71(s，4H)
Embodiment 4
(R)-3-amino-1-(1-phenyl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000241
Figure GPA00000755172000251
The first step
N*2*-ethylidene-N*1*-methylene radical-3-phenyl-propylene-1,2, the 3-triamine
With 2 cyano pyrazine 3a (3.15g 0.03mol) is dissolved in the 100mL toluene, and cooling solution is to-10 ℃, slowly drip phenyl-magnesium-bromide (11mL, 33mmol); Dropwise after 40 minutes, stir after 1 hour, in reaction solution, drip the 40mL Virahol, stir and continue to add Peng Qinghuana (1.59g down; 42mmol), stirred overnight under the room temperature adds acetone, first alcohol and water quencher reaction in reaction solution, produce until no bubble; Concentrating under reduced pressure steams most of organic solvent, and water merges organic phase with ethyl acetate extraction (250mL * 3), uses anhydrous magnesium sulfate drying; Filter, concentrating under reduced pressure with silica gel column chromatography purifying gained resistates, obtains title product N*2*-ethylidene-N*1*-methylene radical-3-phenyl-propylene-1; 2,3-triamine 4a (1.38g, brown oil), yield: 25%.
MS?m/z(ESI)：186[M+1]
Second step
2,2,2-three fluoro-N-(phenyl pyrazines-2-methyl)-trifluoroacetamide
With N*2*-ethylidene-N*1*-methylene radical-3-phenyl-propylene-1,2, (650mg 3.5mmol) joins in the reaction flask 3-triamine 4a; Ice bath is cooled to 0 ℃, and Dropwise 5 mL trifluoroacetic anhydride stirred 1 hour under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the reaction solution concentrating under reduced pressure obtains title product 2,2; 2-three fluoro-N-(phenyl pyrazines-2-methyl)-trifluoroacetamide 4b (950mg, brown solid) directly carry out next step reaction without separating.
The 3rd step
1-phenyl-3-trifluoromethyl-imidazo [1,5-a] pyrazine
Under the ice bath cooling, with 2,2,2-three fluoro-N-(phenyl pyrazines-2-methyl)-trifluoroacetamide 4b (940mg; 3.5mmol) put into reaction flask, to wherein dripping the 10mL POCl3, add rapidly Vanadium Pentoxide in FLAKES (994mg, 7mmol); 4 hours afterreactions of reflux finish, and the reaction solution concentrating under reduced pressure adds 5mL water, transfers pH=9 with strong aqua; With ETHYLE ACETATE (150mL * 4) extraction, merge organic phase, with the washing of 20mL saturated nacl aqueous solution, collect organic phase; Use anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure filtrating is with silica gel column chromatography purifying gained resistates; Obtain title product 1-phenyl-3-trifluoromethyl-imidazo [1,5-a] pyrazine 4c (700mg, yellow solid), yield: 76%.
MS?m/z(ESI)：264[M+1]。
The 4th step
1-phenyl-3-trifluoromethyl-imidazo [1,5-a] piperazine
(300mg 1.14mmol) is dissolved in the 5mL absolute ethyl alcohol under the stirring with 1-phenyl-3-trifluoromethyl-imidazo [1,5-a] pyrazine 4c; Add 90mg 10%Pd/C, substitute gas three times, stirred overnight at room temperature under nitrogen atmosphere; With reacting liquid filtering, evaporated under reduced pressure filtrating obtains bullion title product 1-phenyl-3-trifluoromethyl-imidazo [1 with zeyssatite; 5-a] piperazine 4d (290mg, white solid), directly carry out next step reaction without separating.
MS?m/z(ESI)：268[M+1]
The 5th step
(R)-[3-oxo-3-(1-phenyl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate
Under the nitrogen atmosphere, (150mg 0.5mmol) is dissolved in the 5mL methylene dichloride under the stirring with 1-phenyl-3-trifluoromethyl-imidazo [1,5-a] piperazine 4d; Add successively diisopropylethylamine (0.35mL, 2mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (167mg, 0.5mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (191mg, 0.75mmol), stirred overnight under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, with the reaction solution concentrating under reduced pressure; Obtain bullion title product (R)-[3-oxo-3-(1-phenyl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 4e (310mg, white solid), directly carry out next step reaction without separating.
MS?m/z(ESI)：583[M+1]
The 6th step
(R)-3-amino-1-(1-phenyl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-[3-oxo-3-(1-phenyl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-(300mg 0.52mmol) is dissolved in the 10mL 4.3N hydrogen chloride methanol solution under the stirring t-butyl carbamate 4e, stirs 2 hours afterreactions under the room temperature and finishes; Solvent evaporated with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-(1-phenyl-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 4 (200mg; White solid), yield: 74.3%.
MS?m/z(ESI)：483[M+1]
1HNMR(400MHz，CD 3OD)：δ7.61(d，2H)，7.45(m，2H)，7.36(m，2H)，7.08-7.22(m，1H)，4.96-5.05(m，2H)，4.27-4.36(m，2H)，3.90-4.10(m，3H)，2.90-3.09(m，4H)
Embodiment 5
(R)-3-amino-1-(1-methyl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000271
The first step
N*2*-ethylidene-N*1*-methylene radical-but-1-ene-1,2, the 3-triamine
(1.05g 10mmol) is dissolved in the 30mL toluene, and cooling solution slowly drips methyl-magnesium-bromide (7.9mL to-10 ℃ with 2 cyano pyrazine 3a; 11mmol), dropwise after 30 minutes, stirring reaction is after 30 minutes; In reaction solution, drip 12mL ethanol, and continuation adding Peng Qinghuana under stirring (530mg, 14mmol); Stirred overnight under the room temperature adds acetone, first alcohol and water quencher reaction in reaction solution, produce until no bubble.Decompression steams most of organic solvent down, and water is with dichloromethane extraction (50mL * 3), and the organic phase of merging is used anhydrous magnesium sulfate drying; Filter, concentrating under reduced pressure is with silica gel column chromatography purifying gained resistates; Obtain title product N*2*-ethylidene-N*1*-methylene radical-but-1-ene-1,2,3-triamine 5a (290mg; Yellow oil), yield: 25%.
MS?m/z(ESI)：124[M+1]
Second step
2,2,2-three fluoro-N-(1-pyrazine-2-ethyl)-ethanamide
With N*2*-ethylidene-N*1*-methylene radical-but-1-ene-1,2, (2.6g 21.1mmol) joins in the reaction flask 3-triamine 5a; Ice bath is cooled to 0 ℃, drips the 20mL trifluoroacetic anhydride, and stirring reaction is 3 hours under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the reaction solution concentrating under reduced pressure with silica gel column chromatography purifying gained resistates, obtains title product 2; 2,2-three fluoro-N-(1-pyrazine-2-ethyl)-ethanamide 5b (1.8g, red-brown oily liquids), yield: 38.9%.
MS?m/z(ESI)：220[M+1]
The 3rd step
1-methyl-3-trifluoromethyl-imidazo [1,5-a] pyrazine
Under the ice bath cooling, with 2,2,2-three fluoro-N-(1-pyrazine-2-ethyl)-ethanamide 5b (1.8g; 8.2mmol) put in the reaction flask, to wherein dripping the 20mL POCl3, add rapidly Vanadium Pentoxide in FLAKES (2.3g, 16.4mmol); 5 hours afterreactions of reflux finish, and the reaction solution concentrating under reduced pressure adds 5mL water, transfers pH=9 with strong aqua; With ETHYLE ACETATE (50mL * 5) extraction, merge organic phase, with the washing of 20mL saturated nacl aqueous solution, collect organic phase; Use anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure filtrating is with silica gel column chromatography purifying gained resistates; Obtain title product 1-methyl-3-trifluoromethyl-imidazo [1,5-a] pyrazine 5c (130mg, brown oily liquids), yield: 76%.
MS?m/z(ESI)：202[M+1]。
The 4th step
1-methyl-3-trifluoromethyl-imidazo [1,5-a] piperazine
(170mg 0.85mmol) is dissolved in the 10mL absolute ethyl alcohol under the stirring, adds 35mg 10%Pd/C with 1-methyl-3-trifluoromethyl-imidazo [1,5-a] pyrazine 5c; Substitute gas three times, stirring at room reaction is spent the night under nitrogen atmosphere, with zeyssatite with reacting liquid filtering; Concentrating under reduced pressure filtrating with silica gel column chromatography purifying gained resistates, obtains title product 1-methyl-3-trifluoromethyl-imidazo [1; 5-a] piperazine 5d (40mg, white solid), yield: 23.1%.
MS?m/z(ESI)：206[M+1]
The 5th step
(R)-[3-(1-methyl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate
Under the nitrogen atmosphere, (40mg 0.2mmol) is dissolved in the 5mL methylene dichloride under the stirring with 1-methyl-3-trifluoromethyl-imidazo [1,5-a] piperazine 5d; Add successively under the room temperature diisopropylethylamine (0.07mL, 0.4mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (100mg, 0.3mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (100mg, 0.4mmol); Stir reaction in 2 hours under the room temperature and finish, with the reaction solution concentrating under reduced pressure, with silica gel column chromatography purifying gained resistates; Obtain title product (R)-[3-(1-methyl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 5e (310mg, yellow oily liquid), yield: 76.9%.
MS?m/z(ESI)：521[M+1]
The 6th step
(R)-3-amino-1-(1-methyl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-[3-(1-methyl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-(80mg 0.15mmol) is dissolved in the 5mL 4.3N hydrogen chloride methanol solution under the stirring t-butyl carbamate 5e, stirs 2 hours afterreactions under the room temperature and finishes; Solvent evaporated with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-(1-methyl-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 5 (30mg; White solid), yield: 43.9%.
MS?m/z(ESI)：421[M+1]
1HNMR(400MHz，CD 3OD)：δ7.39(m，1H)，7.20(m，1H)，4.82(m，2H)，4.40(s，1H)，4.31(s，1H)，3.91-4.06(t，3H)，3.10(m，2H)，2.94(m，2H)，2.31(m，3H)
Embodiment 6
(R)-3-amino-1-[1-(4-aminophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-ketone dihydrochloride
Figure GPA00000755172000291
The first step
1-(4-nitrophenyl)-3-trifluoromethyl-imidazo [1,5-a] pyrazine
Under the ice bath cooling, in the flask of 50mL, add the 2mL concentrated nitric acid successively, the 2mL vitriol oil and 1-phenyl-3-trifluoromethyl-imidazo [1,5-a] pyrazine 4c (220mg; 0.836mmol), ice bath stirs 1 hour afterreaction down and finishes, and reaction solution is dropped in the 100mL strong aqua under the ice bath cooling; With ethyl acetate extraction (25mL * 3), merge organic phase, use anhydrous magnesium sulfate drying; Filter, concentrating under reduced pressure filtrating obtains bullion title product 1-(4-nitrophenyl)-3-trifluoromethyl-imidazo [1; 5-a] pyrazine 6a (240mg, yellow solid), directly carry out next step reaction without separating.
MS?m/z(ESI)：309[M+1]
Second step
4-(3-trifluoromethyl--imidazo [1,5-a] piperazine-1-yl)-aniline
(240mg 0.779mmol) is dissolved in the 5mL absolute ethyl alcohol under the stirring, adds 72mg 10%Pd/C with bullion 1-(4-nitrophenyl)-3-trifluoromethyl-imidazo [1,5-a] pyrazine 6a; Substitute gas three times, stirred overnight at room temperature under nitrogen atmosphere, with zeyssatite with reacting liquid filtering; Concentrating under reduced pressure filtrating with silica gel column chromatography purifying gained resistates, obtains title product 4-(3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl)-aniline 6b (150mg, white solid), yield: 68.5%.
MS?m/z(ESI)：283[M+1]
The 3rd step
(R)-{ 3-[1-(4-aminophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
Under the nitrogen atmosphere, (150mg 0.5mmol) is dissolved in the 5mL methylene dichloride under the stirring with 4-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-aniline 6b; Add successively diisopropylethylamine (0.35mL, 2mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (167mg, 0.5mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (191mg, 0.75mmol), stirring reaction spends the night under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, with the reaction solution concentrating under reduced pressure, with silica gel column chromatography purifying gained resistates; Obtain title product (R)-{ 3-[1-(4-aminophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 6c (150mg, white solid), yield: 50.1%.
MS?m/z(ESI)：598[M+1]
The 4th step
(R)-3-amino-1-[1-(4-aminophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-ketone dihydrochloride
With (R)-{ 3-[1-(4-aminophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(250mg 0.42mmol) is dissolved in the 5mL 4.3N hydrogen chloride methanol solution under the stirring t-butyl carbamate 6c, stirs 2 hours afterreactions under the room temperature and finishes; Solvent evaporated with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-(1-phenyl-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-ketone dihydrochloride 6 (150mg; White solid), yield: 62.5%.
MS?m/z(ESI)：498[M+1]
1HNMR(400MHz，CD 3OD)：δ7.80(d，2H)，7.48(m，2H)，7.40(m，1H)，7.19(m，1H)，4.97-5.07(m，2H)，4.27-4.37(m，2H)，3.85-4.09(m，3H)，2.93-3.10(m，4H)
Embodiment 7
(R)-3-amino-1-[1-(3-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000301
The first step
3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
(3.5g 18.7mmol) is dissolved in the 50mL ethanol, stirs to add 0.5g Pd/C down with 3-trifluoromethyl-imidazo [1,5-a] pyrazine 1h; Substitute gas three times, stirred overnight under nitrogen atmosphere, reaction finishes, with zeyssatite with reacting liquid filtering; Evaporated under reduced pressure filtrating, the residue that obtains is used the 100mL washing with alcohol, stirs in the solution that obtains, to drip tert-Butyl dicarbonate (6.2g down gradually; 28.1mmol) the 100mL ethanolic soln, after dropwising, continue to stir 30 minutes afterreactions and finish; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product 3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-carboxylic acid tert-butyl ester 7a (3.7g, white solid), yield: 68%.
Second step
1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
(300mg is 1.04mmol) with 50mL ethanol in 100mL exsiccant flask, to add 3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7a; After the stirring and dissolving, and adding N-bromine succinimide (369mg, 2.08mmol); The mixture that obtains at room temperature stirs, and afterreaction finished in 1 hour, the concentrating under reduced pressure reaction solution; With silica gel column chromatography purifying gained resistates, obtain title product 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (220mg; White solid), yield: 57.8%.
The 3rd step
1-(3-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (300mg, 0.81mmol), 3-methoxyphenylboronic acid (133.6mg; 0.89mmol), four triphenylphosphine palladiums (92.8mg, 0.083mmol), salt of wormwood (220.8mg; 1.62mmol), 3mL glycol dimethyl ether and 3mL water are put into 20mL microwave reaction pipe, under argon shield; 120 ℃, reaction is after 15 minutes under microwave, and reaction finishes; Reaction solution is under reduced pressure concentrated,, obtain title product 1-(3-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1 with silica gel column chromatography purifying gained resistates; 5-a] piperazine-7-carboxylic acid tert-butyl ester 7c (300mg, white solid), yield: 93.5%.
MS?m/z(ESI)：398[M+1]
The 4th step
1-(3-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine trifluoroacetate
With 1-(3-p-methoxy-phenyl)-(300mg 0.756mmol) is dissolved in the 30mL methylene dichloride 3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7c; Stir and drip trifluoroacetic acid (2.6g down; 22.6mmol), the solution of gained continues to stir 5 hours afterreactions and finishes the concentrating under reduced pressure reaction solution; Obtain bullion title product 1-(3-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine trifluoroacetate 7d (300mg, yellow oil), directly carry out next step reaction without separating.
The 5th step
(R)-{ 3-[1-(3-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
Under the nitrogen atmosphere, (271mg 0.81mmol) is dissolved in the 30mL methylene dichloride under the stirring with 1-(3-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine trifluoroacetate 7d; Add successively diisopropylethylamine (0.49g, 4.9mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (310mg, 0.81mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (200mg, 1.21mmol), stirring reaction spends the night under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-{ 3-[1-(3-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 7e (215mg, white solid), yield: 45%.
MS?m/z(ESI)：613[M+1]
The 6th step
(R)-3-amino-1-[1-(3-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(3-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(215mg 0.35mmol) is dissolved in the 4mL 4.3N hydrogen chloride methanol solution t-butyl carbamate 7e, and 2 hours afterreactions of stirring reaction finish; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-[1-(3-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 7 (140mg; Yellow solid), yield: 72.6%.
MS?m/z(ESI)：513[M+1]
1HNMR(400MHz，CD 3OD)：δ6.91-7.37(m，6H)，4.82-5.04(m，2H)，4.26-4.34(t，3H)，3.84-3.98(m，6H)，1.28-1.32(m，3H)
Embodiment 8
(R)-3-amino-1-[1-(4-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000321
The first step
1-(4-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (200mg, 0.54mmol), 4-fluorobenzoic boric acid (83mg; 0.594mmol), four triphenylphosphine palladiums (62mg, 0.054mmol), salt of wormwood (149mg; 1.08mmol), 1.5mL glycol dimethyl ether and 1.5mL water are put into 20mL microwave reaction pipe, under argon shield, and 120 ℃; Reaction is after 10 minutes under microwave, and reaction finishes, and reaction solution merges organic phase with ethyl acetate extraction (15mL * 3); Use anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure filtrating is with silica gel column chromatography purifying gained resistates; Obtain title product 1-(4-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 8a (250mg, white solid), yield: 60%.
MS?m/z(ESI)：386[M+1]
Second step
1-(4-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine trifluoroacetate
With 1-(4-fluorophenyl)-(250mg 0.649mmol) is dissolved in the 5mL methylene dichloride 3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 8a; Stir adding 11mL trifluoroacetic acid down, stir 1.5 hours afterreactions under the room temperature and finish the concentrating under reduced pressure reaction solution; Obtain bullion title product 1-(4-fluorophenyl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine trifluoroacetate 8b (450mg, yellow solid), directly carry out next step reaction without separating.
The 3rd step
(R)-{ 3-[1-(4-fluorophenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
Under the nitrogen atmosphere, (450mg 0.649mmol) is dissolved in the 10mL methylene dichloride under the stirring with 1-(4-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine trifluoroacetate 8b; Add successively diisopropylethylamine (0.51g, 3.9mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (216mg, 0.65mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (248mg, 0.975mmol), stirring reaction is after 1 hour under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-{ 3-[1-(4-fluorophenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 8c (330mg, white solid), yield: 84%.
MS?m/z(ESI)：601[M+1]
The 4th step
(R)-3-amino-1-[1-(4-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(4-fluorophenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(330mg 0.55mmol) is dissolved in the 5mL 4.3N hydrogen chloride methanol solution t-butyl carbamate 8c, and 2 hours afterreactions of stirring reaction finish; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-[1-(4-fluorophenyl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 8 (60mg; Yellow solid), yield: 20.3%
MS?m/z(ESI)：501[M+1]
1HNMR(400MHz，CD 3OD)：δ7.63(d，2H)，7.35(m，1H)，7.19(m，3H)，4.94-5.08(m，2H)，4.27-4.35(m，2H)，3.90-4.10(m，3H)，2.95-3.08(m，4H)
Embodiment 9
(R)-3-amino-1-[1-(4-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000331
The first step
1-(4-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (370mg, 1mmol), 4-methoxyphenylboronic acid (167mg; 1.7mmol), four triphenylphosphine palladiums (116mg, 0.1mmol), salt of wormwood (276mg; 2mmol), 3mL glycol dimethyl ether and 3mL water are put into 20mL microwave reaction pipe, under argon shield, and 120 ℃; Reaction is after 12 minutes down for microwave, and reaction finishes, and reaction solution merges organic phase with ethyl acetate extraction (15mL * 3); Use anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure filtrating is with silica gel column chromatography purifying gained resistates; Obtain title product 1-(4-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 9a (250mg, white solid), yield: 63%.
MS?m/z(ESI)：398[M+1]
Second step
1-(4-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine
With 1-(4-p-methoxy-phenyl)-(250mg 0.629mmol) is dissolved in the 5mL methylene dichloride 3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 9a; Stir and drip trifluoroacetic acid (1.5mL down; 18.9mmol), the solution of gained continues to stir 1 hour afterreaction and finishes the concentrating under reduced pressure reaction solution; Obtain title product 1-(4-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine trifluoroacetate 9b (400mg, yellow solid), product directly carries out next step reaction without separating.
The 3rd step
(R)-{ 3-[1-(4-p-methoxy-phenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
Under the nitrogen atmosphere, (400mg 0.63mmol) is dissolved in the 10mL methylene dichloride under the stirring with 1-(4-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine trifluoroacetate 9b; Add successively diisopropylethylamine (0.49g, 3.78mmol), (R)-3-t-butoxycarbonyl amino-4-(2; 4,5-three fluoro-phenyl)-(210mg is 0.63mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chloride (240mg for butyric acid 1e; 0.945mmol), stirring reaction is 1 hour under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, with the reaction solution concentrating under reduced pressure, with silica gel column chromatography purifying gained resistates; Obtain title product (R)-{ 3-[1-(4-p-methoxy-phenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 9c (280mg, yellow solid), yield: 72.7%.
MS?m/z(ESI)：613[M+1]
The 4th step
(R)-3-amino-1-[1-(4-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(4-p-methoxy-phenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(280mg 0.45mmol) is dissolved in the 5mL 4.3N hydrogen chloride methanol solution t-butyl carbamate 9c, and solution under agitation reacts 2 hours afterreactions and finishes; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-[1-(4-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 9 (120mg; Yellow solid), yield: 48%
MS?m/z(ESI)：513[M+1]
1HNMR(400MHz，CD 3OD)：δ7.53(d，2H)，7.10-7.45(m，2H)，7.03(m，2H)，4.92-5.01(m，2H)，4.28-4.37(m，2H)，3.83-4.10(m，6H)，2.90-3.10(m，4H)
Embodiment 10
(R)-3-amino-1-[1-(2-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000351
The first step
1-(2-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (370mg, 1mmol), 2-methoxyphenylboronic acid (167mg; 1.1mmol), four triphenylphosphine palladiums (116mg, 0.1mmol), salt of wormwood (276mg; 2mmol), 3mL glycol dimethyl ether and 3mL water are put into 20mL microwave reaction pipe, under the argon shield, and 120 ℃; Reaction is after 50 minutes under microwave, and reaction finishes, and reaction solution merges organic phase with ethyl acetate extraction (15mL * 3); Use anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure filtrating is with silica gel column chromatography purifying gained resistates; Obtain title product 1-(2-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 10a (300mg, white solid), yield: 75%.
MS?m/z(ESI)：398[M+1]
Second step
1-(2-p-methoxy-phenyl)-3-trifluoromethyl--imidazo [1,5-a] piperazine
With 1-(2-p-methoxy-phenyl)-(300mg 0.756mmol) is dissolved in the 5mL methylene dichloride 3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 10a; Dropping trifluoroacetic acid under stirring (2.6g, 22.6mmol), the solution of gained continues to stir 1 hour afterreaction and finishes; The concentrating under reduced pressure reaction solution; Obtain yellow thick title product 1-(2-p-methoxy-phenyl)-3-trifluoromethyl-5 imidazo [1,5-a] piperazine trifluoroacetate 10b, product directly carries out next step reaction without separating.
The 3rd step
(R)-{ 3-[1-(2-p-methoxy-phenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
Under the nitrogen atmosphere, with 1-(2-p-methoxy-phenyl)-3-trifluoromethyl--(308mg 0.75mmol) is dissolved in the 10mL methylene dichloride under the stirring imidazo [1,5-a] piperazine trifluoroacetate 10b; Add successively triethylamine (303mg, 3mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-and butyric acid 1e (250mg, 0.75mmol) (286mg 1.12mmol), stirs after 1.5 hours under the room temperature with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, with the reaction solution concentrating under reduced pressure, with silica gel column chromatography purifying gained resistates; Obtain title product (R)-{ 3-[1-(2-p-methoxy-phenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 10c (380mg, yellow solid), yield: 82.8%.
MS?m/z(ESI)：613[M+1]
The 4th step
(R)-3-amino-1-[1-(2-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(2-p-methoxy-phenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(380mg 0.62mmol) is dissolved in the 4mL4.3N hydrogen chloride methanol solution t-butyl carbamate 10c, and solution under agitation reacts 2 hours afterreactions and finishes; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-[1-(2-p-methoxy-phenyl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 10 (100mg; Yellow solid), yield: 31%.
MS?m/z(ESI)：513[M+1]
1HNMR(400MHz，DMSO-d 6)：δ8.33(bs，2H)，7.57(m，1H)，7.47(m，2H)，7.38(m，1H)，7.11(m，1H)，7.03(m，1H)，4.65(m，2H)，4.18-4.32(m，2H)，3.84-3.95(m，5H)，3.73(s，1H)，2.76-3.17(m，4H)
Embodiment 11
(R)-3-amino-1-[1-(2, the 3-dichlorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
The first step
1-(2, the 3-dichlorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (370mg, 1mmol), 2,3-dichlorobenzene boric acid (210mg; 1.1mmol), four triphenylphosphine palladiums (116mg, 0.1mmol), salt of wormwood (276mg, 2mmol); 3mL glycol dimethyl ether and 3mL water are put into 20mL microwave reaction pipe, and under the argon shield, 120 ℃, reaction is after 15 minutes under microwave; Reaction finishes, and reaction solution merges organic phase with ethyl acetate extraction (15mL * 3), uses anhydrous magnesium sulfate drying; Suction filtration, concentrating under reduced pressure filtrating with silica gel column chromatography purifying gained resistates, obtains title product 1-(2; The 3-dichlorophenyl)-and 3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 11a (220mg, yellow solid), yield: 50%.
MS?m/z(ESI)：398[M+1]
Second step
1-(2, the 3-dichlorophenyl)-3-trifluoromethyl--imidazo [1,5-a] piperazine
With 1-(2, the 3-dichlorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 11a (220mg; 0.504mmol) be dissolved in the 5mL methylene dichloride, dropping trifluoroacetic acid under stirring (1.72g, 15.1mmol); The solution of gained continues to stir 1 hour afterreaction and finishes, and the concentrating under reduced pressure reaction solution obtains yellow thick title product 1-(2; The 3-dichlorophenyl)-and 3-trifluoromethyl-imidazo [1,5-a] piperazine trifluoroacetate 11b, product directly carries out next step reaction without separating.
The 3rd step
(R)-{ 3-[1-(2, the 3-dichlorophenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
Under the nitrogen atmosphere, with 1-(2, the 3-dichlorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine trifluoroacetate 11b (225mg; 0.5mmol) be dissolved in the 8mL methylene dichloride under stirring, add successively triethylamine (202mg, 2mmol), (R)-3-t-butoxycarbonyl amino-4-(2; 4,5-three fluoro-phenyl)-butyric acid 1e (167mg, 0.5mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (191mg, 0.75mmol); Stirred 1.5 hours under the room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears, with the reaction solution concentrating under reduced pressure; With silica gel column chromatography purifying gained resistates, obtain title product (R)-{ 3-[1-(2, the 3-dichlorophenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 11c (290mg, yellow solid), yield: 89.2%.
MS?m/z(ESI)：651[M+1]
The 4th step
(R)-3-amino-1-[1-(2, the 3-dichlorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(2, the 3-dichlorophenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(290mg 0.45mmol) is dissolved in the 4mL4.3N hydrogen chloride methanol solution t-butyl carbamate 11c, and solution under agitation reacts 2 hours afterreactions and finishes; The concentrating under reduced pressure reaction solution, with silica gel column chromatography purifying gained resistates, [1-(2 to obtain title product (R)-3-amino-1-; The 3-dichlorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4; The 5-trifluorophenyl)-and Ding-1-keto hydrochloride 11 (100mg, yellow solid), yield: 38%
MS?m/z(ESI)：551[M+1]
1HNMR(400MHz，DMSO-d 6)：δ8.21(bs，2H)，7.72(d，2H)，7.43-7.56(m，3H)，4.68(d，2H)，4.36(m，2H)，3.95(s，2H)，3.62(s，1H)，2.90-3.10(m，4H)
Embodiment 12
(R)-3-amino-1-[1-(3-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000381
The first step
1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine trifluoroacetate
(2.6g 7.02mmol) is dissolved in the 40mL methylene dichloride with 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b; Adding trifluoroacetic acid under stirring (16mL, 211mmol), gained solution at room temperature stirs 30 minutes afterreactions and finishes; The concentrating under reduced pressure reaction solution; Obtain yellow thick title product 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine trifluoroacetate 12a, directly carry out next step reaction without separating.
MS?m/z(ESI)：272[M+1]
Second step
(R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate
Piperazine trifluoroacetate 12a is dissolved in the 70mL methylene dichloride with bullion 1-bromo-3-trifluoromethyl-imidazo [1,5-a], adds triethylamine (4.9mL successively; 35.1mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (2.34g, 7.02mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (2.68g, 10.5mmol); Stir reaction in 1 hour under the room temperature and finish, the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (3g, white solid), yield: 70%.
The 3rd step
(R)-{ 3-[1-(3-fluorophenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (100mg, 0.171mmol); The 3-fluorobenzoic boric acid (26mg, 0.188mmol), four triphenylphosphine palladiums (20mg, 0.0171mmol); Salt of wormwood (47mg, 0.342mmol), 2mL glycol dimethyl ether and 2mL water are put into 10mL microwave reaction pipe, under the argon shield; 140 ℃, reaction is after 15 minutes under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Concentrating under reduced pressure filtrating with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(3-fluorophenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 12c (84mg, white solid), yield: 81%.
MS?m/z(ESI)：601[M+1]
The 4th step
(R)-3-amino-1-[1-(3-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(3-fluorophenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 12c (84mg; 0.2mmol) be dissolved in the 3mL 3.1N hydrogen chloride methanol solution, stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-3-amino-1-[1-(3-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4; The 5-trifluorophenyl)-and Ding-1-keto hydrochloride 12 (70mg, white solid), yield: 93.3%.
MS?m/z(ESI)：501[M+1]
1HNMR(400MHz，CD 3OD)：δ7.07-7.48(m，6H)，4.97-5.10(m，2H)，4.27-4.35(m，2H)，3.89-4.10(m，3H)，2.84-3.08(m，4H)
Embodiment 13
(R)-3-amino-1-[1-(2,4 difluorobenzene base)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000391
The first step
(R)-{ 3-[1-(2,4 difluorobenzene base)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
Under argon shield, with (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (100mg; 0.171mmol), 2,4 difluorobenzene boric acid (30mg, 0.188mmol), four triphenylphosphine palladium (20mg; 0.0171mmol), salt of wormwood (47mg, 0.342mmol), 1mL glycol dimethyl ether and 1mL water are put into 10mL microwave reaction pipe, 120 ℃; Reaction is after 20 minutes under microwave, and reaction finishes, and in reaction solution, adds 5mL water, with ethyl acetate extraction (15mL * 3); Merge organic phase, use anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates; With silica gel column chromatography purifying gained resistates, obtain title product (R)-{ 3-[1-(2,4 difluorobenzene base)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 13a (50mg, white solid), yield: 48%.
MS?m/z(ESI)：619[M+1]
Second step
(R)-3-amino-1-[1-(2,4 difluorobenzene base)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(2,4 difluorobenzene base)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(50mg 0.08mmol) is dissolved in the 3mL methylene dichloride t-butyl carbamate 13a, adds in the 2.5mL 3.1N hydrogen chloride methanol solution; Stirring reaction is 1 hour under the room temperature, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears; The concentrating under reduced pressure reaction solution, with silica gel column chromatography purifying gained resistates, [1-(2 to obtain title product (R)-3-amino-1-; The 4-difluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4; The 5-trifluorophenyl)-and Ding-1-keto hydrochloride 13 (40mg, white solid), yield: 81%.
MS?m/z(ESI)：519[M+1]
1HNMR(400MHz，CD 3OD)：δ7.62(m，2H)，7.38(m，2H)，7.05-7.18(m，3H)，4.75-4.80(m，2H)，4.28-4.37(m，2H)，3.98-4.07(m，2H)，3.87(s，1H)，2.75-3.23(m，4H)
Embodiment 14
(R)-4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the benzonitrile trifluoroacetate
The first step
4-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-benzonitrile trifluoroacetate
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (370mg, 1mmol), 4-cyanophenylboronic acid (161.7mg; 1.1mmol), four triphenylphosphine palladiums (116mg, 0.1mmol), salt of wormwood (276mg; 2mmol), 3mL glycol dimethyl ether and 3mL water are put into 20mL microwave reaction pipe, under the argon shield, and 120 ℃; Reaction is after 30 minutes under microwave, and reaction finishes, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; The yellow oil that obtains is dissolved in the 30mL methylene dichloride, and dropping trifluoroacetic acid under stirring (2.6g, 22.6mmo1); The solution of gained continues stirring afterreaction half a hour and finishes, and the concentrating under reduced pressure reaction solution obtains bullion title product 4-(3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl)-benzonitrile trifluoroacetate 14a (270mg, yellow oil), directly carry out next step reaction without separating.
Second step
(R)-{ 3-[1-(4-cyano-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
Under the nitrogen atmosphere, (251mg 0.85mmol) is dissolved in the 20mL methylene dichloride under the stirring with 4-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-benzonitrile trifluoroacetate 14a; Add successively diisopropylethylamine (404mg, 4mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (283mg, 0.85mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (323mg, 1.28mmol), stirring reaction is 3 hours under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and the concentrating under reduced pressure reaction solution is used the silica gel column chromatography purifying; Obtain title product (R)-{ 3-[1-(4-cyano-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 14b (400mg, white solid), yield: 77.5%.
MS?m/z(ESI)：608[M+1]
The 3rd step
(R)-4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the benzonitrile trifluoroacetate
With (R)-{ 3-[1-(4-cyano-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(400mg 0.66mmol) is dissolved in the 4mL methylene dichloride t-butyl carbamate 14b, stirs to add the 5mL trifluoroacetic acid down; Half hour,, afterreaction finished, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl }-benzonitrile trifluoroacetate 14 (200mg, white solid), yield: 48.9%.
MS?m/z(ESI)：509[M+1]
1HNMR(400MHz，CD 3OD)：δ7.79-7.85(m，4H)，7.21-7.32(m，2H)，5.01-5.10(m，2H)，4.27-4.35(m，2H)，3.98-4.10(m，3H)，3.02-3.30(m，3H)，2.82(m，1H)
Embodiment 15
(R)-3-amino-1-[1-(4-methyl-thiene-3-yl-)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000411
Figure GPA00000755172000421
The first step
1-(4-thiotolene-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (370mg, 1mmol), 5-thiotolene-2-ylboronic acid (170mg; 1.2mmol), four triphenylphosphine palladiums (116mg, 0.1mmol), salt of wormwood (276mg; 2mmol), 3mL glycol dimethyl ether and 3mL water are put into 20mL microwave reaction pipe, under the argon shield, and 120 ℃; Reaction is after 20 minutes under microwave, and reaction finishes, and reaction solution is under reduced pressure concentrated, with silica gel column chromatography purifying gained resistates; Obtain title product 1-(4-thiotolene-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 15a (250mg, yellow oil), yield: 67.6%.
MS?m/z(ESI)：388[M+1]
Second step
1-(4-thiotolene-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine
With 1-(4-thiotolene-3-yl)-(250mg 0.65mmol) is dissolved in the 10mL methylene dichloride 3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 15a; Dropping trifluoroacetic acid under stirring (1.2mL, 16mmol), the solution of gained continues to stir 3 hours afterreactions and finishes; The concentrating under reduced pressure reaction solution; Obtain yellow oily liquid crude article title product 1-(4-thiotolene-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine 15b, directly carry out next step reaction without separating.
The 3rd step
(R)-{ 3-[1-(4-thiotolene-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
Under the nitrogen atmosphere, (187mg 0.65mmol) is dissolved in the 10mL methylene dichloride under the stirring with 1-(4-thiotolene-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine 15b; Add successively diisopropylethylamine (0.57mL, 3.25mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (217mg, 0.65mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (254mg, 1mmol), stirring reaction is 6 hours under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying; Obtain title product (R)-{ 3-[1-(4-thiotolene-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 15c (220mg, colourless oil liquid), yield: 56.2%.
MS?m/z(ESI)：603[M+1]
The 4th step
(R)-3-amino-1-[1-(4-methyl-thiene-3-yl-)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(4-thiotolene-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(220mg 0.36mmol) is dissolved in the 5mL3.1N hydrogen chloride methanol solution t-butyl carbamate 15c, and stirring reaction spends the night under the room temperature; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-[1-(4-methyl-thiene-3-yl-)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 15 (100mg; White solid), yield: 50%.
MS?m/z(ESI)：504[M+1]
1HNMR(400MHz，CD 3OD)：δ7.37(dd，1H)，7.17(dd，1H)，7.10-7.36(m，2H)，4.80-4.92(m，2H)，4.52(t，1H)，4.29(t，1H)，4.01-4.10(m，2H)，3.50-3.64(m，1H)，2.86(m，2H)，2.63-2.70(m，1H)，2.31(s，3H)，2.07(m，1H)
Embodiment 16
(R)-3-amino-1-[1-(1H-pyrazoles-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000431
The first step
1-(1H-pyrazoles-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (740mg, 2mmol), 4-pyrazoles boric acid (246mg, 2.2mmol); Four triphenylphosphine palladiums (232mg, 0.2mmol), salt of wormwood (540mg, 4mmol); 5mL glycol dimethyl ether and 5mL water are put into 20mL microwave reaction pipe, and under the argon shield, 140 ℃, reaction is after 50 minutes under microwave; Reaction finishes, and in reaction solution, adds 5mL water, with ethyl acetate extraction (15mL * 3), merges organic phase; Use anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrating is with silica gel column chromatography purifying gained resistates; Obtain title product 1-(1H-pyrazoles-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 16a (80mg, white solid), yield: 11.2%.
MS?m/z(ESI)：358[M+1]
Second step
1-(1H-pyrazoles-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine hydrochloride
(80mg 0.224mmol) is dissolved in the 5mL 4.1N hydrogen chloride methanol solution with 1-(1H-pyrazoles-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 16a; Stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears; The concentrating under reduced pressure reaction solution; Obtain yellow oily liquid crude article title product 1-(1H-pyrazoles-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine hydrochloride 16b, directly carry out next step reaction without separating.
The 3rd step
(R)-{ 3-oxo-3-[1-(1H-pyrazoles-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
Under the nitrogen atmosphere, (64.6mg 0.22mmol) is dissolved in the 10mL methylene dichloride under the stirring with 1-(1H-pyrazoles-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine hydrochloride 16b; Add successively diisopropylethylamine (113.7mg, 0.88mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (73.3mg, 0.22mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (84mg, 0.33mmol), stirring reaction spends the night under the room temperature; Reaction finishes, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-{ 3-oxo-3-[1-(1H-pyrazoles-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 16c (60mg, white solid), yield: 47.7%.
MS?m/z(ESI)：573[M+1]
The 4th step
(R)-3-amino-1-[1-(1H-pyrazoles-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-oxo-3-[1-(1H-pyrazoles-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(60mg 0.1mmol) is dissolved in the 5mL3.1N hydrogen chloride methanol solution t-butyl carbamate 16c, and stirring reaction spends the night under the room temperature; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-[1-(1H-pyrazoles-4-yl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 16 (30mg; Colourless oil liquid), yield: 63.5%.
MS?m/z(ESI)：473[M+1]
1HNMR(400MHz，DMSO-d 6)：δ8.26(s，3H)，7.95(s，1H)，7.86(s，1H)，7.50-7.60(m，2H)，4.74-4.91(m，2H)，4.27(m，1H)，4.12(m，1H)，3.94(m，2H)，3.75(m，1H)，3.09(m，1H)，2.98(m，2H)，2.84(m，1H)
Embodiment 17
(R)-3-amino-1-[1-(pyridin-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000441
The first step
(R)-[3-oxo-3-(1-pyridin-3-yl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (204mg, 0.171mmol); 3-pyridine boric acid (47mg, 0.382mmol), four triphenylphosphine palladiums (38mg, 0.035mmol); Salt of wormwood (96mg, 0.348mmol), 2.5mL glycol dimethyl ether and 2.5mL water are put into 10mL microwave reaction pipe, under the argon shield; 140 ℃, reaction is after 20 minutes under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-[3-oxo-3-(1-pyridin-3-yl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-1-(2; 4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 17a (120mg, yellow solid), yield: 60%.
MS?m/z(ESI)：584[M+1]
Second step
(R)-3-amino-1-(1-pyridin-4-yl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-[3-oxo-3-(1-pyridin-3-yl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-(120mg 0.2mmol) is dissolved in the 5mL 3.1N hydrogen chloride methanol solution t-butyl carbamate 17a, and stirring reaction spends the night under the room temperature; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-[1-(pyridin-3-yl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 17 (50mg; Yellow solid), yield: 48.2%.
MS?m/z(ESI)：484[M+1]
1HNMR(400MHz，CD 3OD)：δ9.10(d，1H)，8.72(m，2H)，8.05(m，1H)，7.39(m，1H)，7.18(m，1H)，5.14(m，2H)，4.34(m，2H)，4.05(m，2H)，3.91(s，1H)，2.86-3.11(m，4H)
Embodiment 18
(R)-3-amino-1-[1-(pyridin-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000451
The first step
(R)-[3-oxo-3-(1-pyridin-4-yl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (102mg, 0.174mmol); 4-pyridine boric acid (23.5mg, 0.191mmol), four triphenylphosphine palladiums (19mg, 0.0174mmol); Salt of wormwood (48mg, 0.348mmol), 2mL glycol dimethyl ether and 2mL water are put into 10mL microwave reaction pipe, under the argon shield; 140 ℃, reaction is after 20 minutes under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-[3-oxo-3-(1-pyridin-4-yl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-1-(2; 4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 18a (90mg, white solid), yield: 90%.
MS?m/z(ESI)：584[M+1]
Second step
(R)-3-amino-1-(1-pyridin-4-yl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-[3-oxo-3-(1-pyridin-4-yl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-1-(2,4; The 5-trifluoro-benzyl)-propyl group 1]-(90mg 0.15mmol) is dissolved in the 5mL 3.1N hydrogen chloride methanol solution t-butyl carbamate 18a, and stirring reaction spends the night under the room temperature; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-[1-(pyridin-4-yl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 18 (20mg; Colourless oil liquid), yield: 25.6%.
MS?m/z(ESI)：484[M+1]
1HNMR(400MHz，CD 3OD)：δ8.66(d，2H)，7.94(d，2H)，7.34(m，2H)，5.12-5.19(m，2H)，4.29-4.37(m，2H)，3.91-4.10(m，3H)，3.65(s，2H)，3.06(m，2H)，2.88-2.96(m，2H)
Embodiment 19
(R)-3-amino-1-[1-(2-chlorothiophene-3-yl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-ketone trifluoroacetate
Figure GPA00000755172000461
The first step
1-(2-chlorothiophene-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (370mg, 1mmol), 2-chlorothiophene-3-ylboronic acid (195mg, 1.2mmol); Four triphenylphosphine palladiums (116mg, 0.1mmol), salt of wormwood (276mg, 2mmol), 3mL glycol dimethyl ether and 3mL water are put into 20mL microwave reaction pipe; Under the nitrogen protection, seal after stirring, 140 ℃, reaction is after 20 minutes under microwave; Reaction finishes, and in reaction solution, adds 5mL water, with ethyl acetate extraction (15mL * 3), merges organic phase; Use anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrating is with silica gel column chromatography purifying gained resistates; Obtain title product 1-(2-chlorothiophene-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 19a (285mg, yellow oily liquid), yield: 70%.
MS?m/z(ESI)：408[M+1]
Second step
1-(2-chlorothiophene-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine hydrochloride
(285mg 0.7mmol) is dissolved in 5mL 3.1N hydrogen chloride methanol solution with 1-(2-chlorothiophene-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 19a; Mixed solution is stirred overnight at room temperature; Reaction finishes, and the concentrating under reduced pressure reaction solution obtains title product 1-(2-chlorothiophene-3-yl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine hydrochloride 19b, directly carry out next step reaction without separating.
The 3rd step
(R)-{ 3-[1-(2-chlorothiophene-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
Under the nitrogen atmosphere, (240mg 0.22mmol) is dissolved in the 10mL methylene dichloride under the stirring with 1-(2-chlorothiophene-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine hydrochloride 19b; Add successively triethylamine (282.8mg, 2.8mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (233.3mg, 0.7mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (267mg, 1.05mmol), stirring reaction spends the night under the room temperature; Reaction finishes, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-{ 3-[1-(2-chlorothiophene-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 19c (100mg, yellow solid), yield: 22.9%.
MS?m/z(ESI)：622[M-1]
The 4th step
(R)-3-amino-1-[1-(2-chlorothiophene-3-yl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-ketone trifluoroacetate
With (R)-[3-[1-(2-chlorothiophene-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 19c (100mg, 0.16mmol) solution is in 3mL trifluoroacetic acid and 15mL methylene dichloride, and the solution of gained at room temperature stirs 3 hours afterreactions and finishes; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-[1-(2-chlorothiophene-3-yl)-3-trifluoromethyl-imidazoles [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-ketone trifluoroacetate 19 (20mg; Colourless oil liquid), yield: 22.5%.
MS?m/z(ESI)：522[M-1]
1HNMR(400MHz，CD 3OD)：δ7.43(m，1H)，7.29(m，1H)，7.14(m，2H)，4.78-4.93(m，4H)，4.14-4.31(m，2H)，4.01-4.10(m，2H)，3.53(m，1H)，2.78-2.84(m，2H)，2.57-2.65(m，2H)
Embodiment 20
(R)-3-amino-1-{1-[1-(3-methylbutyl)-1H-pyrazoles-4-yl]-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl }-4-(2,4, the 5-trifluorophenyl)-Ding-1-ketone trifluoroacetate
Figure GPA00000755172000481
The first step
(R)-[3-{1-[1-(3-methylbutyl)-1H-pyrazoles-4-yl]-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl }-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (181mg, 0.31mmol); 1-isopentyl-1H-pyrazoles-4-ylboronic acid (62mg, 0.34mmol), four triphenylphosphine palladiums (36mg, 0.03mmol); Salt of wormwood (85mg, 0.616mmol), 2mL glycol dimethyl ether and 2mL water are put into 10mL microwave reaction pipe, under the argon shield; 140 ℃, reaction is after 15 minutes under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Concentrating under reduced pressure filtrating, with silica gel column chromatography purifying gained resistates, obtain title product (R)-[3-{1-[1-(3-methylbutyl)-1H-pyrazoles-4-yl]-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl }-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 20a (160mg, faint yellow solid), yield: 80%.
MS?m/z(ESI)：643[M+1]
Second step
(R)-3-amino-1-{1-[1-(3-methylbutyl)-1H-pyrazoles-4-yl]-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl }-4-(2,4, the 5-trifluorophenyl)-Ding-1-ketone trifluoroacetate
With (R)-[3-{1-[1-(3-methylbutyl)-1H-pyrazoles-4-yl]-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl }-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-(160mg 0.25mmol) is dissolved in the 5mL methylene dichloride t-butyl carbamate 20a, stirs to add trifluoroacetic acid (0.5mL down; 6.67mmol), stir 6 hours afterreactions under the room temperature and finish the concentrating under reduced pressure reaction solution; With silica gel column chromatography purifying gained resistates, obtain title product (R)-3-amino-1-{1-[1-(3-methylbutyl)-1H-pyrazoles-4-yl]-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl }-4-(2; 4; The 5-trifluorophenyl)-and Ding-1-ketone trifluoroacetate 20 (100mg, yellow solid), yield: 61%.
MS?m/z(ESI)：543[M+1]
1HNMR(400MHz，CD 3OD)：δ7.93(dd，1H)，7.74(s，1H)，7.32(m，2H)，4.89-4.94(m，2H)，4.20-4.28(m，4H)，3.94-4.19(m，3H)，3.05(t，2H)，2.94(m，1H)，2.82(dd，1H)，1.78(m，2H)，1.56(m，1H)，1.29(d，2H)，0.96(t，6H)
Embodiment 21
(R)-3-amino-1-[3-Trifluoromethyl-1-(2-trifluoromethyl)-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
The first step
3-Trifluoromethyl-1-(2-trifluoromethyl)-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (370mg, 1mmol), 2-trifluoromethyl phenylo boric acid (209mg; 1.1mmol), four triphenylphosphine palladiums (116mg, 0.1mmol), salt of wormwood (276mg; 2mmol), 3mL glycol dimethyl ether and 3mL water are put into 20mL microwave reaction pipe, under the argon shield, and 120 ℃; Reaction is after 30 minutes under microwave, and reaction finishes, and with ethyl acetate extraction reaction solution (10mL * 3), merges organic phase; Use anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure filtrating is with silica gel column chromatography purifying gained resistates; Obtain title product 3-Trifluoromethyl-1-(2-trifluoromethyl)-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 21a (323mg, yellow solid), yield: 74%.
MS?m/z(ESI)：436[M+1]
Second step
3-Trifluoromethyl-1-(2-trifluoromethyl)-imidazo [1,5-a] piperazine hydrochloride
With the 3-Trifluoromethyl-1-(323mg 0.74mmol) is dissolved in the 2mL methyl alcohol (2-trifluoromethyl)-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 21a; Stir and drip 3mL 4.3N hydrogen chloride methanol solution down; The solution of gained continues to stir 1 hour afterreaction and finishes, and the concentrating under reduced pressure reaction solution obtains title product 3-Trifluoromethyl-1-(2-trifluoromethyl)-imidazo [1; 5-a] piperazine hydrochloride 21b, directly carry out next step reaction without separating.
The 3rd step
(R)-{ 3-oxo-1-(2,4, the 5-trifluoro-benzyl)-3-[3-Trifluoromethyl-1-(2-trifluoromethyl)-imidazo [1,5-a] piperazine-7-yl]-propyl group }-t-butyl carbamate
(276mg 0.74mmol) is dissolved in the 30mL methylene dichloride under the stirring, adds triethylamine (300mg successively with 3-Trifluoromethyl-1-(2-trifluoromethyl)-imidazo [1,5-a] piperazine trifluoroacetate 21b; 2.97mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4,5-three fluoro-phenyl)-butyric acid 1e (247mg; 0.74mmol) and two (2-oxo-3-oxazolidinyl) inferior phosphonyl chloride (282mg, 1.11mmol), stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution is used the silica gel column chromatography purifying; Obtain title product (R)-{ 3-oxo-1-(2,4, the 5-trifluoro-benzyl)-3-[3-Trifluoromethyl-1-(2-trifluoromethyl)-imidazo [1; 5-a] piperazine-7-yl]-propyl group }-t-butyl carbamate 21c (420mg, yellow solid), yield: 87%.
MS?m/z(ESI)：651[M+1]
The 4th step
(R)-3-amino-1-[3-Trifluoromethyl-1-(2-trifluoromethyl)-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-oxo-1-(2,4, the 5-trifluoro-benzyl)-3-[3-Trifluoromethyl-1-(2-trifluoromethyl)-imidazo [1; 5-a] piperazine-7-yl]-propyl group }-(420mg 0.65mmol) is dissolved in the 5mL 3.1N hydrogen chloride methanol solution t-butyl carbamate 21c, and 30 minutes afterreactions of stirring reaction finish; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-[3-Trifluoromethyl-1-(2-trifluoromethyl)-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 21 (200mg; White solid), yield: 57%.
MS?m/z(ESI)：551[M+1]
1HNMR(400MHz，CD 3OD)：δ7.76(m，1H)，7.69(m，2H)，7.36(d，1H)，7.03(m，1H)，6.87(m，1H)，4.65(m，1H)，4.51(s，1H)，3.88-4.29(m，5H)，2.30-2.73(m，4H)
Embodiment 22
(R)-3-amino-1-[1-morpholine-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000501
The first step
1-morpholine-4-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (200mg, 0.54mmol), morpholine (56mg, 0.65mmol); Three (dibenzalacetones), two palladiums (2.4mg, 0.0026mmol), 2-(di-t-butyl phosphine) biphenyl (3.2mg, 0.022mmol); Sodium tert-butoxide (78mg, 0.81mmol), 2mL exsiccant toluene is put into 20mL microwave reaction pipe, 100 ℃; Reaction is after 70 minutes under microwave, and reaction finishes, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product 1-morpholine-4-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 22a (100mg, white solid), yield: 49%.
MS?m/z(ESI)：377[M+1]
Second step
1-morpholine-4-base-3-trifluoromethyl-imidazo [1,5-a] piperazine trifluoroacetate
With the 1-morpholine-(150mg 0.40mmol) is dissolved in the 10mL methylene dichloride 4-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 22a; Dropping trifluoroacetic acid under stirring (2.76g, 24mmol), the solution of gained continues to stir 2 hours afterreactions and finishes; The concentrating under reduced pressure reaction solution; Obtain bullion title product 1-morpholine-4-base-3-trifluoromethyl-imidazo [1,5-a] piperazine trifluoroacetate 22b, directly carry out next step reaction without separating.
The 3rd step
(R)-[3-(1-morpholine-4-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate
Under the nitrogen atmosphere,, add triethylamine (0.40g successively with being dissolved in the 20mL methylene dichloride under 1-morpholine-4-base-3-trifluoromethyl-imidazo [1,5-a] piperazine trifluoroacetate 22b stirring; 4mmol) with (R)-3-t-butoxycarbonyl amino-4-(2,4,5-three fluoro-phenyl)-butyric acid 1e (147mg, 0.44mmol); Stir after 10 minutes, and two (2-oxo-3-oxazolidinyl) the inferior phosphonyl chlorides of adding (152mg, 0.6mmol), stirring reaction is 2 hours under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and the concentrating under reduced pressure reaction solution is used the silica gel column chromatography purifying; Obtain title product (R)-[3-(1-morpholine-4-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 22c (200mg, light yellow oil), yield: 84%.
MS?m/z(ESI)：592[M+1]
The 4th step
(R)-3-amino-1-(1-morpholine-4-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-[3-(1-morpholine-4-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-(200mg 0.34mmol) is dissolved in the 4mL 4.3N hydrogen chloride methanol solution t-butyl carbamate 22c, and 2 hours afterreactions of stirring reaction finish; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-(1-morpholine-4-base-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 22 (42mg; Yellow solid), yield: 25%.
MS?m/z(ESI)：492[M+1]
1HNMR(400MHz，CD 3OD)：δ7.28(m，2H)，4.72-4.83(m，4H)，3.59-4.24(m，8H)，2.68-3.03(m，2H)
Embodiment 23
(R)-3-amino-1-[1-(4-dimethylamino-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-ketone trifluoroacetate
Figure GPA00000755172000521
The first step
(R)-{ 3-[1-(4-dimethylamino-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 4-dimethylamino phenylo boric acid (62mg, 0.376mmol), four triphenylphosphine palladiums (39.4mg, 0.034mmol); Salt of wormwood (94.3mg, 0.683mmol), 3mL glycol dimethyl ether and 3mL water are put into 10mL microwave reaction pipe, under the argon shield; 130 ℃, reaction is after 30 minutes under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction reaction solution (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, suction filtration; Concentrating under reduced pressure filtrating with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(4-dimethylamino-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 23a (150mg, light yellow solid), yield: 70%.
MS?m/z(ESI)：626[M+1]
Second step
(R)-3-amino-1-[1-(4-dimethylamino-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-ketone trifluoroacetate
With (R)-{ 3-[1-(4-dimethylamino-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(150mg 0.24mmol) is dissolved in the 5mL methylene dichloride t-butyl carbamate 23a, stirs to add the 2mL trifluoroacetic acid down; Stir 3 hours afterreactions under the room temperature and finish, the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-3-amino-1-[1-(4-dimethylamino phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4; The 5-trifluorophenyl)-and Ding-1-ketone trifluoroacetate 23 (90mg, white solid), yield: 59%.
MS?m/z(ESI)：526[M+1]
1HNMR(400MHz，CD 3OD)：δ7.55(m，2H)，7.10-7.40(m，4H)，7.34(m，2H)，4.95-5.01(m，2H)，4.27(m，2H)，3.81-4.10(m，3H)，3.63(m，3H)，3.05(m，7H)
Embodiment 24
(R)-N-[4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-phenyl]-acetamide hydrochloride
Figure GPA00000755172000531
The first step
(R)-{ 3-[1-(4-acetylamino phenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (146mg, 0.25mmol); 4-kharophen phenylo boric acid (67mg, 0.375mmol), two (dibenzalacetone) palladium (2.3mg, 0.005mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (4.8mg, 0.01mmol); Potassiumphosphate (106mg, 0.5mmol), the 1.5mL trimethyl carbinol joins in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 30 minutes under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction reaction solution (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Concentrating under reduced pressure filtrating with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(4-acetylamino phenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 24a (100mg, white solid), yield: 62%.
MS?m/z(ESI)：640[M+1]
Second step
(R)-N-[4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-phenyl]-acetamide hydrochloride
With (R)-{ 3-[1-(4-acetylamino phenyl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 24a (100mg; 0.156mmol) be dissolved in the 2mL ETHYLE ACETATE, adding 2mL 2N hydrogenchloride ethyl acetate solution, the adularescent solid is separated out; Stir after 10 minutes under the room temperature, add 2mL 2N hydrogenchloride ethyl acetate solution, continue reaction 1 hour; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and filters; Obtain title product (R)-N-[4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl }-phenyl]-acetamide hydrochloride 24 (62mg, light yellow solid), yield: 69%.
MS?m/z(ESI)：540[M+1]
1HNMR(400MHz，CD 3OD)：δ7.69(m，2H)，7.56(m，2H)，7.20(m，1H)，7.13(m，1H)，5.04(m，2H)，4.41(m，2H)，3.89(s，1H)，2.86-3.08(m，4H)，2.14(s，3H)
Embodiment 25
(R)-3-amino-1-[1-(2,4-two trifluoromethyls-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000541
The first step
(R)-{ 3-[1-(2,4-two trifluoromethyls-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
Under argon shield, with (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg; 0.342mmol), 2, and 4-two trifluoromethyl phenylo boric acids (97mg, 0.376mmol), four triphenylphosphine palladium (40mg; 0.0342mmol), salt of wormwood (94mg, 0.684mmol), 2mL glycol dimethyl ether and 2mL water are put into 10mL microwave reaction pipe, 130 ℃; Reaction is after 35 minutes under microwave, and reaction finishes, and in reaction solution, adds 5mL water, with ethyl acetate extraction reaction solution (15mL * 3); Merge organic phase, use anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates; With silica gel column chromatography purifying gained resistates, obtain title product (R)-{ 3-[1-(2,4-two trifluoromethyls-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 25a (70mg, light yellow solid), yield: 30%.
MS?m/z(ESI)：719[M+1]
Second step
(R)-3-amino-1-[1-(2,4-two trifluoromethyls-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(2,4-two trifluoromethyls-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(70mg 0.097mmol) is dissolved in the 2mL methylene dichloride t-butyl carbamate 25a, stirs to add 2mL 3.1N hydrogen chloride methanol solution down, stirs 2 hours under the room temperature; Reaction finishes, the concentrating under reduced pressure reaction solution, and [1-(2 to obtain title product (R)-3-amino-1-; 4-two trifluoromethyls-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4; The 5-trifluorophenyl)-and Ding-1-keto hydrochloride 25 (60mg, yellow solid), yield: 100%.
MS?m/z(ESI)：619[M+1]
1HNMR(400MHz，CD 3OD)：δ8.28(s，4H)，8.17(s，1H)，7.75(dd，1H)，7.52(m，2H)，4.70(d，2H)，4.15-4.40(m，2H)，3.95(m，2H)，3.73(s，1H)，2.70-3.11(m，4H)
Embodiment 26
(R)-3-amino-1-[1-(6-amino-pyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-ketone dihydrochloride
The first step
(R)-{ 3-[1-(6-amino-pyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (293mg, 0.5mmol); 6-EL-970-3-ylboronic acid (165mg, 0.75mmol), two (dibenzalacetone) palladium (5.8mg, 0.01mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (9.5mg, 0.02mmol); Potassiumphosphate (212mg, 1mmol), the 2mL trimethyl carbinol joins in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 30 minutes under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction reaction solution (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Concentrating under reduced pressure filtrating with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(6-amino-pyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 26a (130mg, light yellow solid), yield: 43%.
MS?m/z(ESI)：599[M+1]
Second step
(R)-3-amino-1-[1-(6-amino-pyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-ketone dihydrochloride
With (R)-{ 3-[1-(6-amino-pyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(130mg 0.21mmol) is dissolved in the mixed solvent of 2mL methylene dichloride and 2mL methyl alcohol t-butyl carbamate 26a, stirs to add 10mL 2N hydrogenchloride ethyl acetate solution down; Stirred 2 hours under the room temperature, reaction finishes, the concentrating under reduced pressure reaction solution; Obtain title product (R)-3-amino-1-[1-(6-amino-pyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4; The 5-trifluorophenyl)-and Ding-1-ketone dihydrochloride 26 (120mg, yellow solid), yield: 100%.
MS?m/z(ESI)：499[M+1]
1HNMR(400MHz，CD 3OD)：δ8.15-8.40(m，6H)，7.55(m，2H)，7.18(m，1H)，4.89-5.05(m，2H)，3.70-4.40(m，5H)，2.75-3.20(m，4H)
Embodiment 27
(R)-3-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the benzyl cyanide hydrochloride
Figure GPA00000755172000561
The first step
(R)-{ 3-[1-(3-cyano-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); The 3-cyanophenylboronic acid (75.4mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol joins in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 30 minutes under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction reaction solution (15mL * 4), merge organic phase, use anhydrous magnesium sulfate drying, filter; Concentrating under reduced pressure filtrating with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(3-cyano-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 27a (187mg, white solid), yield: 90%.
MS?m/z(ESI)：630[M+23]
Second step
(R)-3-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the benzyl cyanide hydrochloride
With (R)-{ 3-[1-(3-cyano-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 27a (187mg; 0.308mmol) be dissolved in the 2mL ETHYLE ACETATE, adding 2mL2N hydrogenchloride ethyl acetate solution, the adularescent solid is separated out; Stirring reaction was added 2mL 2N hydrogenchloride ethyl acetate solution after 10 minutes under the room temperature, and stirring reaction spends the night under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and filters; Obtain title product (R)-3-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl }-benzyl cyanide hydrochloride 27 (110mg, yellow solid), yield: 66%.
MS?m/z(ESI)：508[M+1]
1HNMR(400MHz，CD 3OD)：δ7.97(m，2H)，7.65(m，2H)，7.10-7.40(m，2H)，5.07(m，2H)，4.28-4.36(m，2H)，3.92-4.10(m，3H)，3.09(m，4H)
Embodiment 28
(R)-3-amino-1-[1-(furans-3-yl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000571
The first step
(R)-[3-(1-furans-3-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (293mg, 0.5mmol); Furans-3-ylboronic acid (84mg, 0.75mmol), two (dibenzalacetone) palladium (5.8mg, 0.01mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (8.2mg, 0.02mmol); Potassiumphosphate (212mg, 1mmol), the 1.5mL trimethyl carbinol adds in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 30 minutes under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction reaction solution (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Concentrating under reduced pressure filtrating with silica gel column chromatography purifying gained resistates, obtains title product (R)-[3-(1-furans-3-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 28a (200mg, light yellow solid), yield: 70%.
MS?m/z(ESI)：573[M+1]
Second step
(R)-3-amino-1-(1-furans-3-base-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-[3-(1-furans-3-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-(200mg 0.349mmol) is dissolved in the 2mL ETHYLE ACETATE t-butyl carbamate 28a, adds 10mL 2N hydrogenchloride ethyl acetate solution; Stirred 1.5 hours under the room temperature, reaction finishes, the concentrating under reduced pressure reaction solution; Obtain title product (R)-3-amino-1-[1-(furans-3-yl)-3-trifluoromethyl-imidazoles [1,5-a] piperazine-7-yl]-4-(2,4; The 5-trifluorophenyl)-and Ding-1-keto hydrochloride 28 (150mg, yellow solid), yield: 91%.
MS?m/z(ESI)：473[M+1]
1HNMR(400MHz，CD 3OD)：δ6.96(m，1H)，6.73(s，1H)，6.33(m，1H)，6.30(m，1H)，5.95(m，1H)，4.01(m，2H)，3.45(m，2H)，3.14(m，3H)，2.14(m，4H)
Embodiment 29
(R)-2-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the benzyl cyanide hydrochloride
Figure GPA00000755172000581
The first step
(R)-{ 3-[1-(2-cyano-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); The 2-cyanophenylboronic acid (75.4mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol joins in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction reaction solution (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Concentrating under reduced pressure filtrating with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(2-cyano-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 29a (100mg, white solid), yield: 51%.
MS?m/z(ESI)：630[M+23]
Second step
(R)-2-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the benzyl cyanide hydrochloride
With (R)-{ 3-[1-(2-cyano-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 29a (100mg; 0.165mmol) be dissolved in the 2mL ETHYLE ACETATE, adding 2mL 2N hydrogenchloride ethyl acetate solution, stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution is used the silica gel column chromatography purifying; Obtain title product (R)-2-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl }-benzyl cyanide hydrochloride 29 (40mg, yellow solid), yield: 48%.
MS?m/z(ESI)：508[M+1]
1HNMR(400MHz，CD 3OD)：δ7.86(m，2H)，7.76(m，2H)，7.20-7.33(m，2H)，4.92(m，2H)，4.40(m，2H)，4.08(m，2H)，3.85(s，1H)，2.92-3.07(m，4H)
Embodiment 30
(R)-3-amino-1-[1-(2-chloro-3-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000591
The first step
(R)-{ 3-[1-(2-chloro-3-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 2-chloro-3-fluorine pyridin-4-yl boric acid (89.8mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol joins in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 30 minutes under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction reaction solution (15mL * 4), merge organic phase, use anhydrous magnesium sulfate drying, filter; Concentrating under reduced pressure filtrating with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(2-chloro-3-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 30a (120mg, light yellow solid), yield: 55%.
MS?m/z(ESI)：636[M+1]
Second step
(R)-3-amino-1-[1-(2-chloro-3-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(2-chloro-3-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(120mg 0.189mmol) is dissolved in the 2mL ETHYLE ACETATE t-butyl carbamate 30a, adds 2mL 2N hydrogenchloride ethyl acetate solution; Stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-[1-(2-chloro-3-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 30 (80mg; Yellow solid), yield: 80%.
MS?m/z(ESI)：536[M+1]
Embodiment 31
(R)-3-amino-1-[1-(6-Dimethylamino pyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000601
The first step
(R)-{ 3-[1-(6-Dimethylamino pyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 6-Dimethylamino pyridine-3-ylboronic acid (85mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol joins in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction reaction solution (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Concentrating under reduced pressure filtrating with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(6-Dimethylamino pyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 31a (115mg, light yellow solid), yield: 53%.
MS?m/z(ESI)：627[M+1]
Second step
(R)-3-amino-1-[1-(6-Dimethylamino pyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(6-Dimethylamino pyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(115mg 0.183mmol) is dissolved in the 2mL ETHYLE ACETATE t-butyl carbamate 31a, adds 2mL 2N hydrogenchloride ethyl acetate solution; Stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-[1-(6-Dimethylamino pyridine-3-yl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 31 (70mg; Yellow solid), yield: 73%.
MS?m/z(ESI)：527[M+1]
1HNMR(400MHz，CD 3OD)：δ8.26(m，2H)，7.42(m，2H)，7.23(m，1H)，5.10(m，2H)，4.34(m，2H)，4.05(m，3H)，3.15(m，3H)，2.04(s，1H)，1.24(m，1H)
Embodiment 32
(R)-3-amino-1-[1-(3-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000611
The first step
(R)-{ 3-[1-(3-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 3-fluorine pyridin-4-yl boric acid (72.3mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Concentrating under reduced pressure filtrating with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(3-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 32a (125mg, light yellow solid), yield: 60%.
MS?m/z(ESI)：602[M+1]
Second step
(R)-3-amino-1-[1-(3-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(3-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(125mg 0.21mmol) is dissolved in the 2mL ETHYLE ACETATE t-butyl carbamate 32a, adds 2mL 2N hydrogenchloride ethyl acetate solution; Stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-[1-(3-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 32 (80mg; Yellow solid), yield: 77%.
MS?m/z(ESI)：502[M+1]
Embodiment 33
(R)-3-amino-1-[1-(pyrimidine-5-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000621
The first step
(R)-[3-(1-pyrimidine-5-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); Pyrimidine-5-ylboronic acid (63.6mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction reaction solution (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-[3-(1-pyrimidine-5-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 33a (110mg, light yellow solid), yield: 55%.
MS?m/z(ESI)：585[M+1]
Second step
(R)-3-amino-1-(1-pyrimidine-5-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-[3-(1-pyrimidine-5-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 33a (110mg; 0.188mmol) be dissolved in the 2mL ETHYLE ACETATE, add 2mL 2N hydrogenchloride ethyl acetate solution, stirred overnight at room temperature, thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying; Obtain title product (R)-3-amino-1-[1-(pyrimidine-5-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4; The 5-trifluorophenyl)-and Ding-1-keto hydrochloride 33 (75mg, yellow solid), yield: 82%.
MS?m/z(ESI)：485[M+1]
Embodiment 34
(R)-3-amino-1-[1-(2,3-dichloropyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000631
The first step
(R)-{ 3-[1-(2,3-dichloropyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 2, and 3-dichloropyridine-4-ylboronic acid (98mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol), potassiumphosphate (145mg; 0.684mmol), the 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe, under the argon shield, and 100 ℃; Reaction is after 1.5 hours under microwave, and reaction finishes, and in reaction solution, adds 5mL water, with ethyl acetate extraction (15mL * 3); Merge organic phase, use anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates; With silica gel column chromatography purifying gained resistates, obtain title product (R)-{ 3-[1-(2,3-dichloropyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 34a (140mg, light yellow solid), yield: 63%.
MS?m/z(ESI)：652[M+1]
Second step
(R)-3-amino-1-[1-(2,3-dichloropyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(2,3-dichloropyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 34a (140mg, 0,214mmol) be dissolved in the 2mL ETHYLE ACETATE, add 2mL 2N hydrogenchloride ethyl acetate solution; Stirred overnight at room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; With the reaction solution concentrating under reduced pressure, use the silica gel column chromatography purifying, [1-(2 to obtain title product (R)-3-amino-1-; 3-dichloropyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4; The 5-trifluorophenyl)-and Ding-1-keto hydrochloride 34 (90mg, yellow solid), yield: 78%.
MS?m/z(ESI)：552[M+1]
Embodiment 35
(R)-3-amino-1-[1-(3-chloropyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000641
The first step
(R)-{ 3-[1-(3-chloropyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 3-chloropyridine-4-ylboronic acid (80.5mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(3-chloropyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 35a (130mg, light yellow solid), yield: 63%.
MS?m/z(ESI)：618[M+1]
Second step
(R)-3-amino-1-[1-(3-chloropyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(3-chloropyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 35a (130mg; 0.21mmol) be dissolved in the 2mL ETHYLE ACETATE, add 2mL 2N hydrogenchloride ethyl acetate solution, stirred overnight at room temperature, thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying; Obtain title product (R)-3-amino-1-[1-(3-chloropyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4; The 5-trifluorophenyl)-and Ding-1-keto hydrochloride 35 (80mg, yellow solid), yield: 72%.
MS?m/z(ESI)：518[M+1]
Embodiment 36
(R)-3-amino-1-[1-(6-chloropyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000651
The first step
(R)-{ 3-[1-(6-chloropyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 6-chloropyridine-3-ylboronic acid (80.5mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol);-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(6-chloropyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 36a (130mg, light yellow solid), yield: 61%.
MS?m/z(ESI)：618[M+1]
Second step
(R)-3-amino-1-[1-(6-chloropyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(6-chloropyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 36a (130mg; 0.21mmol) be dissolved in the 2mL ETHYLE ACETATE, add 2mL 2N hydrogenchloride ethyl acetate solution, stirred overnight at room temperature, thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying; Obtain title product (R)-3-amino-1-[1-(6-chloropyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4; The 5-trifluorophenyl)-and Ding-1-keto hydrochloride 36 (100mg, yellow solid), yield: 92%.
MS?m/z(ESI)：518[M+1]
Embodiment 37
(R)-3-amino-1-[1-(2-chloropyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
The first step
(R)-{ 3-[1-(2-chloropyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg; 0.342mmol), 2-chloropyridine-4-ylboronic acid (80.5mg, 0.513mmol), two (dibenzalacetone) palladium (4mg; 0.0068mmol), 2-dicyclohexyl phosphino--2 ', 4 ', 6 '-tri isopropyl biphenyl (6.52mg; 0.014mmol), potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe; Under the argon shield, 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes; In reaction solution, add 5mL water,, merge organic phase, use anhydrous magnesium sulfate drying with ethyl acetate extraction (15mL * 3); Filter, filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(6-amino-pyridine-3-yl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-3-oxo-1-(2-chloropyridine-4-yl)-propyl group }-t-butyl carbamate 37a (145mg, light yellow solid), yield: 68%.
MS?m/z(ESI)：618[M+1]
Second step
(R)-3-amino-1-[1-(2-chloropyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(2-chloropyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 37a (145mg; 0.239mmol) be dissolved in the 2mL ETHYLE ACETATE, add 2mL 2N hydrogenchloride ethyl acetate solution, stirred overnight at room temperature, thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying; Obtain title product (R)-3-amino-1-[1-(2-chloropyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4; The 5-trifluorophenyl)-and Ding-1-keto hydrochloride 37 (85mg, yellow solid), yield: 71%.
MS?m/z(ESI)：518[M+1]
Embodiment 38
(R)-3-amino-1-[1-(2-fluorine pyridin-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
The first step
(R)-{ 3-[1-(2-fluorine pyridin-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 2-fluorine pyridin-3-yl boric acid (72.3mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, anhydrous magnesium sulfate drying filters; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(2-fluorine pyridin-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 38a (100mg, light yellow solid), yield: 48%.
MS?m/z(ESI)：602[M+1]
Second step
(R)-3-amino-1-[1-(2-fluorine pyridin-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(2-fluorine pyridin-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 38a (100mg; 0.166mmol) be dissolved in the 2mL ETHYLE ACETATE, add 2mL 2N hydrogenchloride ethyl acetate solution, stirred overnight at room temperature, thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying; Obtain title product (R)-3-amino-1-[1-(2-fluorine pyridin-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4; The 5-trifluorophenyl)-and Ding-1-keto hydrochloride 38 (55mg, yellow solid), yield: 66%.
MS?m/z(ESI)：502[M+1]
1HNMR(400MHz，CD 3OD)：δ8.23-8.29(m，2H)，7.18-7.50(m，3H)，4.87-4.95(m，2H)，3.93-4.43(m，5H)，2.79-3.11(m，4H)。
Embodiment 39
(R)-3-amino-1-[1-(6-fluorine pyridin-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000681
The first step
(R)-{ 3-[1-(6-fluorine pyridin-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 6-fluorine pyridin-3-yl boric acid (72.3mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(6-fluorine pyridin-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 39a (150mg, light yellow solid), yield: 73%.
MS?m/z(ESI)：602[M+1]
Second step
(R)-3-amino-1-[1-(6-fluorine pyridin-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(6-fluorine pyridin-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 39a (150mg; 0.249mmol) be dissolved in the 2mL ETHYLE ACETATE, add 2mL 2N hydrogenchloride ethyl acetate solution, stirred overnight at room temperature, thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying; Obtain title product (R)-3-amino-1-[1-(6-fluorine pyridin-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4; The 5-trifluorophenyl)-and Ding-1-keto hydrochloride 39 (90mg, yellow solid), yield: 72%.
MS?m/z(ESI)：502[M+1]
Embodiment 40
(R)-3-amino-1-[1-(2-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000691
The first step
(R)-{ 3-[1-(2-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 2-fluorine pyridin-4-yl boric acid (72.3mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(2-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 40a (130mg, light yellow solid), yield: 63%.
MS?m/z(ESI)：602[M+1]
Second step
(R)-3-amino-1-[1-(2-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(2-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 40a (130mg; 0.215mmol) be dissolved in the 2mL ETHYLE ACETATE, add 2mL 2N hydrogenchloride ethyl acetate solution, stirred overnight at room temperature, thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying; Obtain title product (R)-3-amino-1-[1-(2-fluorine pyridin-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4; The 5-trifluorophenyl)-and Ding-1-keto hydrochloride 40 (80mg, yellow solid), yield: 76%.
MS?m/z(ESI)：502[M+1]
Embodiment 41
(R)-3-amino-1-[1-(6-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000701
The first step
(R)-{ 3-[1-(6-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 6-methoxypyridine-3-ylboronic acid (78.5mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(6-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 41a (155mg, light yellow solid), yield: 74%.
MS?m/z(ESI)：614[M+1]
Second step
(R)-3-amino-1-[1-(6-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(6-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(155mg 0.252mmol) is dissolved in the 2mL ETHYLE ACETATE t-butyl carbamate 41a, adds 2mL 2N hydrogenchloride ethyl acetate solution; Stirred overnight at room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; With the reaction solution concentrating under reduced pressure, use the silica gel column chromatography purifying, obtain title product (R)-3-amino-1-[1-(6-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 41 (100mg; Yellow solid), yield: 77%.
MS?m/z(ESI)：514[M+1]
1HNMR(400MHz，CD 3OD)：δ8.50(m，1H)，8.38(m，1H)，7.39(m，1H)，7.23(m，1H)，5.12(m，2H)，4.35(m，2H)，4.18(m，4H)，3.95(m，2H)，3.14(m，2H)，2.95(m，2H)，2.04(m，1H)，2.02(m，1H)
Embodiment 42
(R)-3-amino-1-[1-(4-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
The first step
(R)-{ 3-[1-(4-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 4-methoxypyridine-3-ylboronic acid (78.5mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(4-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 42a (125mg, light yellow solid), yield: 60%.
MS?m/z(ESI)：614[M+1]
Second step
(R)-3-amino-1-[1-(4-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(4-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(125mg 0.204mmol) is dissolved in the 2mL ETHYLE ACETATE t-butyl carbamate 42a, adds 2mL 2N hydrogenchloride ethyl acetate solution; Stirred overnight at room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; With the reaction solution concentrating under reduced pressure, use the silica gel column chromatography purifying, obtain title product (R)-3-amino-1-[1-(4-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 42 (70mg; Yellow solid), yield: 68%.
MS?m/z(ESI)：514[M+1]
1HNMR(400MHz，CD 3OD)：δ8.86-8.77(m，2H)，7.81-7.79(m，1H)，7.43-7.42(m，1H)，7.23-7.19(m，1H)，4.43-4.32(m，4H)，4.13-3.95(m，3H)，3.14-2.97(m，4H)
Embodiment 43
(R)-3-amino-1-[1-(2-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000721
The first step
(R)-{ 3-[1-(2-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 2-methoxypyridine-3-ylboronic acid (78.5mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(2-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 43a (130mg, light yellow solid), yield: 62%.
MS?m/z(ESI)：614[M+1]
Second step
(R)-3-amino-1-[1-(2-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(2-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(130mg 0.211mmol) is dissolved in the 2mL ETHYLE ACETATE t-butyl carbamate 43a, adds 2mL 2N hydrogenchloride ethyl acetate solution; Stirred overnight at room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; With the reaction solution concentrating under reduced pressure, use the silica gel column chromatography purifying, obtain title product (R)-3-amino-1-[1-(2-methoxypyridine-3-yl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 43 (60mg; Yellow solid), yield: 56%.
MS?m/z(ESI)：514[M+1]
Embodiment 44
(R)-3-amino-1-[1-(3-Methoxy Pyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000731
The first step
(R)-{ 3-[1-(3-Methoxy Pyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 3-Methoxy Pyridine-4-ylboronic acid (78.5mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(3-Methoxy Pyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 44a (110mg, light yellow solid), yield: 52%.
MS?m/z(ESI)：614[M+1]
Second step
(R)-3-amino-1-[1-(3-Methoxy Pyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(3-Methoxy Pyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(110mg 0.179mmol) is dissolved in the 2mL ETHYLE ACETATE t-butyl carbamate 44a, adds 2mL 2N hydrogenchloride ethyl acetate solution; Stirred overnight at room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; With the reaction solution concentrating under reduced pressure, use the silica gel column chromatography purifying, obtain title product (R)-3-amino-1-[1-(3-Methoxy Pyridine-4-yl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 44 (80mg; Yellow solid), yield: 86%.
MS?m/z(ESI)：514[M+1]
Embodiment 45
(R)-3-amino-1-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4,5-three fluoro-phenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000741
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (0.38g; 0.65mmol) stirring following being dissolved in the ethyl acetate solution of 2mL 3N hydrogenchloride, stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-3-amino-1-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4; 5-three fluoro-phenyl)-and Ding-1-keto hydrochloride 45 (0.25g, faint yellow solid), yield: 73.5%.
MS?m/z(ESI)：485.2[M+1]
1HNMR(400MHz，CD 3OD)：δ7.35(m，1H)，7.18(m，1H)，4.71(m，2H)，4.31(m，1H)，4.20(m，1H)，4.02(m，2H)，3.74(m，1H)，3.00(m，2H)，2.78(m，2H)
Embodiment 46
(R)-3-amino-1-[1-(2H-pyrazole-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000742
The first step
(R)-{ 3-[1-(2H-pyrazole-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 2H-pyrazole-3-yl boric acid (65mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(2H-pyrazole-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 46a (110mg, light yellow solid), yield: 56%.
MS?m/z(ESI)：573[M+1]
Second step
(R)-3-amino-1-[1-(2H-pyrazole-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(1H-pyrazoles-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 46a (110mg; 0.192mmol) be dissolved in the 2mL ETHYLE ACETATE, add 2mL 2N hydrogenchloride ethyl acetate solution, stirred overnight at room temperature, thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying; Obtain title product (R)-3-amino-1-[1-(2H-pyrazole-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4; The 5-trifluorophenyl)-and Ding-1-keto hydrochloride 46 (50mg, yellow solid), yield: 56%.
MS?m/z(ESI)：473[M+1]
Embodiment 47
(R)-3-amino-1-[1-(4-5-flumethiazine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000751
The first step
(R)-{ 3-[1-(4-5-flumethiazine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 4-5-flumethiazine-3-ylboronic acid (98mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(4-5-flumethiazine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 47a (145mg, light yellow solid), yield: 65%.
MS?m/z(ESI)：652[M+1]
Second step
(R)-3-amino-1-[1-(4-5-flumethiazine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(4-5-flumethiazine-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(145mg 0.222mmol) is dissolved in the 2mL ETHYLE ACETATE t-butyl carbamate 47a, adds 2mL 2N hydrogenchloride ethyl acetate solution; Stirred overnight at room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; With the reaction solution concentrating under reduced pressure, use the silica gel column chromatography purifying, obtain title product (R)-3-amino-1-[1-(4-5-flumethiazine-3-yl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 47 (90mg; Yellow solid), yield: 74%.
MS?m/z(ESI)：552[M+1]
Embodiment 48
(R)-3-amino-1-[1-(2,6-difluoro pyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000761
The first step
(R)-{ 3-[1-(2,6-difluoro pyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 2, and 6-difluoro pyridine-4-ylboronic acid (81.5mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol); Potassiumphosphate (145mg, 0.684mmol), the 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe, under the argon shield; 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(2,6-difluoro pyridine-4-yl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-3-oxo-1-(2,6-difluoro pyridine-4-yl)-propyl group }-t-butyl carbamate 48a (125mg, light yellow solid), yield: 60%.
MS?m/z(ESI)：620[M+1]
Second step
(R)-3-amino-1-[1-(2,6-difluoro pyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(2,6-difluoro pyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(125mg 0.2mmol) is dissolved in the 2mL ETHYLE ACETATE t-butyl carbamate 48a, adds 2mL 2N hydrogenchloride ethyl acetate solution; Stirred overnight at room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; With the reaction solution concentrating under reduced pressure, use the silica gel column chromatography purifying, [1-(2 to obtain title product (R)-3-amino-1-; 6-difluoro pyridine-4-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4; The 5-trifluorophenyl)-and Ding-1-keto hydrochloride 48 (85mg, yellow solid), yield: 76%.
MS?m/z(ESI)：520[M+1]
Embodiment 49
(R)-1-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-piperidines-2-keto hydrochloride
Figure GPA00000755172000771
The first step
1-(2-oxo-piperidine-1-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (300mg, 0.81mmol), piperidines-2-ketone (96mg; 0.97mmol), cuprous iodide (46mg, 0.24mmol), trans-N; N '-dimethyl cyclohexane-1, and the 2-diamines (23mg, 0.16mmol), salt of wormwood (224mg; 1.6mmol), 5mL toluene adds in the 20mL microwave reaction pipe, under the argon shield, and 135 ℃; Reaction is after 2 hours under microwave, and reaction finishes, with the reaction solution concentrating under reduced pressure, with silica gel column chromatography purifying gained resistates; Obtain title product 1-(2-oxo-piperidine-1-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 49a (120mg, yellow oil), yield: 38%.
MS?m/z(ESI)：389[M+1]
Second step
1-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-piperidines-2-keto hydrochloride
(120mg 0.31mmol) is dissolved in the 2mL 2.4N hydrogenchloride ethyl acetate solution with 1-(2-oxo-piperidine-1-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 49a; Stir after 40 minutes under the room temperature, add 2mL 2.4N hydrogenchloride ethyl acetate solution, continue reaction 1 hour; Thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution obtains yellow oily liquid crude article title product 1-(3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl)-piperidines-2-keto hydrochloride 49b, directly carry out next step reaction without separating.
The 3rd step
(R)-{ 3-[1-(2-oxo-piperidine-1-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
Under the nitrogen atmosphere, (100mg 0.31mmol) is dissolved in the 5mL methylene dichloride under the stirring with 1-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-piperidines-2-keto hydrochloride 49b; Add successively triethylamine (0.21mL, 1.54mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (102mg, 0.31mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (117.6mg, 0.46mmol), stirring reaction spends the night under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying; Obtain title product (R)-{ 3-[1-(2-oxo-piperidine-1-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 49c (105mg, colourless oil liquid), yield: 56.2%.
MS?m/z(ESI)：603[M+1]
The 4th step
(R)-1-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-piperidines-2-keto hydrochloride
With (R)-{ 3-[1-(2-oxo-piperidine-1-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(105mg 0.17mmol) is dissolved in the 5mL3.1N hydrogen chloride methanol solution stirred overnight under the room temperature to t-butyl carbamate 49c; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-1-{7-[3-amino-4-(2; 4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-piperidines-2-keto hydrochloride 49 (44mg; White solid), yield: 50%.
MS?m/z(ESI)：503[M+1]
1HNMR(400MHz，CD 3OD)：δ7.40(m，1H)，7.26(m，1H)，4.65(m，2H)，4.33(m，1H)，4.25(d，1H)，4.08(d，1H)，3.98(m，2H)，3.81(d，2H)，3.12(s，2H)，2.98(m，1H)，2.85(m，1H)，2.60(m，2H)，2.03(m，4H)。
Embodiment 50
(R)-1-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-acetamide hydrochloride
Figure GPA00000755172000791
The first step
1-acetylaminohydroxyphenylarsonic acid 3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (300mg, 0.81mmol), ethanamide (57.4mg, 0.97mmol); Cuprous iodide (30.85mg, 0.162mmol) trans-N, N '-dimethyl cyclohexane-1,2-diamines (23mg; 0.16mmol), salt of wormwood (224mg, 1.6mmol), 5mL toluene adds in the 20mL microwave reaction pipe, under the argon shield; 130 ℃, reaction is after 2 hours under microwave, and reaction finishes, and adds 10mL water, with ethyl acetate extraction (15mL * 4); Merge organic phase, with the washing of 20mL saturated nacl aqueous solution, anhydrous magnesium sulfate drying filters, and filtrate decompression concentrates; With silica gel column chromatography purifying gained resistates, obtain title product 1-acetylaminohydroxyphenylarsonic acid 3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 50a (200mg, white solid), yield: 71%.
MS?m/z(ESI)：349[M+1]
1HNMR(400MHz，CDCl 3)：δ8.08(s，1H)，4.68(s，2H)，4.11(m，2H)，3.86(m，2H)，2.13(s，3H)，1.49(s，9H)
Second step
N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-ethanamide trifluoroacetate
(190mg 0.545mmol) is dissolved in the 5mL methylene dichloride with 1-acetylaminohydroxyphenylarsonic acid 3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 50a; Slow dropping trifluoroacetic acid (1.26mL, 16.36mmol), stirring at room 2 hours; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, the concentrating under reduced pressure reaction solution; Obtain yellow oily liquid crude article title product N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-ethanamide trifluoroacetate 50b, directly carry out next step reaction without separating.
The 3rd step
(R)-[3-(1-acetylaminohydroxyphenylarsonic acid 3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate
Under the nitrogen atmosphere, (190mg 0.545mmol) is dissolved in the 5mL methylene dichloride under the stirring with N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-ethanamide trifluoroacetate 50b; Add successively triethylamine (0.38mL, 2.72mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (181.6mg, 0.545mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (208mg, 0.818mmol), stirring reaction is 2 hours under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and adds 10mL water, with dichloromethane extraction (15mL * 4); Merge organic phase, with the washing of 20mL saturated nacl aqueous solution, anhydrous magnesium sulfate drying filters; Filtrate decompression concentrates, and uses the silica gel column chromatography purifying, obtains title product (R)-[3-(1-acetylaminohydroxyphenylarsonic acid 3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 50c (160mg, colourless oil liquid), yield: 52%.
MS?m/z(ESI)：564[M+1]
The 4th step
(R)-1-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-acetamide hydrochloride
With (R)-[3-(1-acetylaminohydroxyphenylarsonic acid 3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-(160mg 0.28mmol) is dissolved in the 5mL 3.1N hydrogen chloride methanol solution stirred overnight under the room temperature to t-butyl carbamate 50c; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-1-{7-[3-amino-4-(2; 4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-acetamide hydrochloride 50 (156mg; Yellow solid), yield: 95%.
MS?m/z(ESI)：464[M+1]
1HNMR(400MHz，CD 3OD)：δ7.37-7.31(m，1H)，7.23-7.12(m，1H)，4.90-4.66(m，2H)，4.36-4.23(m，2H)，4.12-3.97(m，2H)，3.57-3.56(m，1H)，2.91-2.81(m，2H)，2.72-2.57(m，2H)，2.21-2.19(s，3H)
Embodiment 51
(R)-1-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-carboxamide hydrochloride
Figure GPA00000755172000801
The first step
1-formamido group-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (300mg, 0.81mmol), methane amide (43mg, 0.97mmol); Cuprous iodide (46mg, 0.24mmol) trans-N, N '-dimethyl cyclohexane-1,2-diamines (23mg; 0.16mmol), salt of wormwood (224mg, 1.6mmol), 5mL toluene adds in the 20mL microwave reaction pipe, under the argon shield; 135 ℃, reaction is after 2 hours under microwave, and reaction finishes, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product 1-formamido group-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 51a (190mg, white solid), yield: 70%.
MS?m/z(ESI)：335[M+1]
Second step
N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-carboxamide hydrochloride
(190mg 0.57mmol) is dissolved in the 4mL 2.4N hydrogenchloride ethyl acetate solution with 1-formamido group-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 51a; Stirred 2 hours under the room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; The concentrating under reduced pressure reaction solution; Obtain title product N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-carboxamide hydrochloride 51b, directly carry out next step reaction without separating.
The 3rd step
(R)-[3-(1-formamido group-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate
Under the nitrogen atmosphere, (154mg 0.57mmol) is dissolved in the 5mL methylene dichloride under the stirring with N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-carboxamide hydrochloride 51b; Add successively triethylamine (0.38mL, 1.54mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (187mg, 0.58mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (216mg, 0.85mmol), stirring reaction spends the night under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying; Obtain title product (R)-[3-(1-formamido group-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 51c (163mg, colourless oil liquid), yield: 52%.
MS?m/z(ESI)：550[M+1]
The 4th step
(R)-1-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-carboxamide hydrochloride
With (R)-[3-(1-formamido group-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-(163mg 0.29mmol) is dissolved in the 5mL 3.1N hydrogen chloride methanol solution stirred overnight under the room temperature to t-butyl carbamate 51c; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-1-{7-[3-amino-4-(2; 4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-carboxamide hydrochloride 51 (79mg; White solid), yield: 55%.
MS?m/z(ESI)：450[M+1]
Embodiment 52
(R)-1-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the pyrrolidin-2-one hydrochloride
Figure GPA00000755172000821
The first step
1-(2-oxo-pyrrolidine-1-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (300mg, 0.81mmol), pyrrolidin-2-one (82mg; 0.97mmol), cuprous iodide (46mg, 0.24mmol), trans-N; N '-dimethyl cyclohexane-1, and the 2-diamines (23mg, 0.16mmol), salt of wormwood (224mg; 1.6mmol), 5mL toluene adds in the 20mL microwave reaction pipe, under the argon shield, and 135 ℃; Reaction is after 2 hours under microwave, and reaction finishes, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product 1-(2-oxo-pyrrolidine-1-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 52a (180mg, white solid), yield: 61%.
MS?m/z(ESI)：361[M+1]
Second step
1-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-pyrrolidin-2-one hydrochloride
(180mg 0.50mmol) is dissolved in the 4mL 2.4N hydrogenchloride ethyl acetate solution with 1-(2-oxo-pyrrolidine-1-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 52a; Stirred 2 hours under the room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; The concentrating under reduced pressure reaction solution; Obtain title product 1-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-pyrrolidin-2-one hydrochloride 52b, directly carry out next step reaction without separating.
The 3rd step
(R)-{ 3-[1-(2-oxo-pyrrolidine-1-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
Under the nitrogen atmosphere, (148mg 0.5mmol) is dissolved in the 5mL methylene dichloride under the stirring with 1-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-pyrrolidin-2-one hydrochloride 52b; Add successively triethylamine (0.34mL, 2.48mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (164mg, 0.5mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (189mg, 0.74mmol), stirred overnight under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying; Obtain title product (R)-{ 3-[1-(2-oxo-pyrrolidine-1-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 52c (144mg, colourless oil liquid), yield: 50%.
MS?m/z(ESI)：576[M+1]
The 4th step
(R)-1-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the pyrrolidin-2-one hydrochloride
With (R)-{ 3-[1-(2-oxo-pyrrolidine-1-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(144mg 0.25mmol) is dissolved in the 5mL3.1N hydrogen chloride methanol solution stirred overnight under the room temperature to t-butyl carbamate 52c; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-1-{7-[3-amino-4-(2; 4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-pyrrolidin-2-one hydrochloride 52 (69mg; White solid), yield: 55%.
MS?m/z(ESI)：476[M+1]
Embodiment 53
(R)-and 3-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-1,1-dimethyl urea hydrochloride
Figure GPA00000755172000831
The first step
1-(3,3-dimethyl--urea groups)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (500mg, 1.35mmol), 1,1-dimethyl urea (143mg; 1.62mmol), cuprous iodide (51.3mg, 0.27mmol) trans-N, N '-dimethyl cyclohexane-1; The 2-diamines (39mg, 0.27mmol), salt of wormwood (347mg, 2.71mmol); 5mL YLENE adds in the 20mL microwave reaction pipe, and under the argon shield, 135 ℃, reaction is after 2 hours under microwave; Reaction finishes, and the concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product 1-(3; 3-dimethyl--urea groups)-and 3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 53a (77mg, light yellow solid), yield: 15%.
MS?m/z(ESI)：378[M+1]
Second step
1,1-dimethyl--3-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-urea hydrochloride
With 1-(3,3-dimethyl--urea groups)-(77mg 0.2mmol) is dissolved in the 5mL ETHYLE ACETATE 3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 53a; Add 5mL 2.4N hydrogenchloride ethyl acetate solution, stirred 2 hours under the room temperature, thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution obtains title product 1; 1-dimethyl--3-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-urea hydrochloride 53b directly carries out next step reaction without separating.
The 3rd step
(R)-{ 3-[1-(3,3-dimethyl--urea groups)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
Under the nitrogen atmosphere, with 1,1-dimethyl--3-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-urea hydrochloride 53b (70mg; 0.22mmol) be dissolved in the 5mL methylene dichloride under stirring, add successively triethylamine (89mg, 0.88mmol), (R)-3-t-butoxycarbonyl amino-4-(2; 4,5-three fluoro-phenyl)-butyric acid 1e (73mg, 0.22mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (84mg, 0.33mmol); Stirred overnight under the room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears, with the reaction solution concentrating under reduced pressure; Use the silica gel column chromatography purifying, obtain title product (R)-{ 3-[1-(3,3-dimethyl--urea groups)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 53c (78mg, light yellow oily liquid), yield: 60%.
MS?m/z(ESI)：593[M+1]
The 4th step
(R)-and 3-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-1,1-dimethyl urea hydrochloride
With (R)-{ 3-[1-(3,3-dimethyl--urea groups)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(78mg 0.13mmol) is dissolved in the 5mL 3.1N hydrogen chloride methanol solution t-butyl carbamate 53c, and stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-{7-[3-amino-4-(2; 4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-1; 1-dimethyl urea hydrochloride 53 (41mg, white solid), yield: 59%.
MS?m/z(ESI)：493[M+1]
1HNMR(400MHz，CD 3OD)：δ7.39(m，1H)，7.24(m，1H)，4.76(m，2H)，4.32(m，2H)，4.02(m，4H)，2.85-3.10(m，9H)，
Embodiment 54
(R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-N-methylacetamide hydrochloride
Figure GPA00000755172000851
The first step
1-(ethanoyl methylamino)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (300mg, 0.81mmol), N-methyl-ethanamide (71mg; 0.97mmol), cuprous iodide (46mg, 0.24mmol), trans-N; N ' dimethyl cyclohexane-1, and the 2-diamines (23mg, 0.16mmol), salt of wormwood (224mg; 1.6mmol), 5mL toluene adds in the 20mL microwave reaction pipe, under the argon shield, and 135 ℃; Reaction is after 2 hours under microwave, and reaction finishes, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product 1-(ethanoyl methylamino)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 54a (206mg, white solid), yield: 70%.
MS?m/z(ESI)：363[M+1]
Second step
N-methyl-N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-acetamide hydrochloride
(206mg 0.57mmol) is dissolved in the 4mL 2.4N hydrogenchloride ethyl acetate solution with 1-(ethanoyl methylamino)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 54a; Stirring reaction is 2 hours under the room temperature, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears; The concentrating under reduced pressure reaction solution; Obtain title product N-methyl-N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-acetamide hydrochloride 54b, directly carry out next step reaction without separating.
The 3rd step
(R)-{ 3-[1-(ethanoyl methylamino)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
Under the nitrogen atmosphere, (171mg 0.57mmol) is dissolved in the 5mL methylene dichloride under the stirring with N-methyl-N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-acetamide hydrochloride 54b; Add successively triethylamine (0.39mL, 2.83mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (187mg, 0.57mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (216mg, 0.85mmol), stirring reaction spends the night under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and the concentrating under reduced pressure reaction solution is used the silica gel column chromatography purifying; Obtain title product (R)-{ 3-[1-(ethanoyl methylamino)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 54c (171mg, colourless oil liquid), yield: 52%.
MS?m/z(ESI)：578[M+1]
The 4th step
(R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-N-methylacetamide hydrochloride
With (R)-{ 3-[1-(ethanoyl methylamino)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 54c (171mg; 0.3mmol) be dissolved in the 5mL 3.1N hydrogen chloride methanol solution, stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl }-N-methylacetamide hydrochloride 54 (84mg, white solid), yield: 55%.
MS?m/z(ESI)：478[M+1]
Embodiment 55
(R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the Toluidrin hydrochloride
Figure GPA00000755172000861
Figure GPA00000755172000871
The first step
1-methanesulfonamido-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (300mg, 0.81mmol), Toluidrin (92mg; 0.97mmol), cuprous iodide (46mg, 0.24mmol), trans-N; N '-dimethyl cyclohexane-1, and the 2-diamines (23mg, 0.16mmol), salt of wormwood (224mg; 1.6mmol), 5mL toluene adds in the 20mL microwave reaction pipe, under the argon shield, and 135 ℃; Reaction is after 2 hours under microwave, and reaction finishes, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product 1-methanesulfonamido-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 55a (158mg, white solid), yield: 75%.
MS?m/z(ESI)：385[M+1]
Second step
N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-Toluidrin hydrochloride
(158mg 0.41mmol) is dissolved in the 4mL 2.4N hydrogenchloride ethyl acetate solution with 1-methanesulfonamido-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 55a; Stirred 2 hours under the room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; The concentrating under reduced pressure reaction solution; Obtain title product N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-Toluidrin hydrochloride 55b, directly carry out next step reaction without separating.
The 3rd step
(R)-[3-(1-methanesulfonamido-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate
Under the nitrogen atmosphere, (131mg 0.41mmol) is dissolved in the 5mL methylene dichloride under the stirring with N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-Toluidrin hydrochloride 55b; Add successively triethylamine (0.28mL, 2.03mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (135mg, 0.41mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (155mg, 0.61mmol), stirring reaction spends the night under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying; Obtain title product (R)-[3-(1-methanesulfonamido-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 55c (133mg, colourless oil liquid), yield: 54%.
MS?m/z(ESI)：600[M+1]
The 4th step
(R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the Toluidrin hydrochloride
With (R)-[3-(1-methanesulfonamido-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 55c (133mg; 0.22mmol) be dissolved in the 5mL 3.1N hydrogen chloride methanol solution, stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl }-Toluidrin hydrochloride 55 (71mg, white solid), yield: 60%.
MS?m/z(ESI)：500[M+1]
Embodiment 56
(R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-benzene Toluidrin hydrochloride
Figure GPA00000755172000881
The first step
1-phenylsulfonamido-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
Under the nitrogen atmosphere, with 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (300mg, 0.81mmol), benzsulfamide (152mg; 0.97mmol), cuprous iodide (46mg, 0.24mmol) trans-N, N '-dimethyl cyclohexane-1; The 2-diamines (23mg, 0.16mmol), salt of wormwood (224mg, 1.6mmol), 5mL toluene adds in the tube sealing; 135 ℃, to react after 16 hours, reaction finishes, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product 1-phenylsulfonamido-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 56a (253mg, white solid), yield: 70%.
MS?m/z(ESI)：447[M+1]
Second step
N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-benzsulfamide hydrochloride
(253mg 0.57mmol) is dissolved in the 4mL 2.4N hydrogenchloride ethyl acetate solution with 1-phenylsulfonamido-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 56a; Stirred 2 hours under the room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; The concentrating under reduced pressure reaction solution; Obtain title product N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-benzsulfamide hydrochloride 56b, directly carry out next step reaction without separating.
The 3rd step
(R)-[3-(1-phenylsulfonamido-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate
Under the nitrogen atmosphere, (218mg 0.57mmol) is dissolved in the 5mL methylene dichloride under the stirring with N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-benzsulfamide hydrochloride 56b; Add successively triethylamine (0.39mL, 2.83mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (187mg, 0.57mmol) with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides (216mg, 0.85mmol), stirred overnight under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying; Obtain title product (R)-[3-(1-phenylsulfonamido-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 56c (146mg, colourless oil liquid), yield: 52%.
MS?m/z(ESI)：662[M+1]
The 4th step
(R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the benzsulfamide hydrochloride
With (R)-[3-(1-phenylsulfonamido-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 56c (146mg; 0.22mmol) be dissolved in the 5mL 3.1N hydrogen chloride methanol solution, stirred overnight under the room temperature, thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl }-benzsulfamide hydrochloride 56 (73mg, white solid), yield: 55%.
MS?m/z(ESI)：562[M+1]
Embodiment 57
(R)-3-amino-1-(1-dimethylamino-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172000891
Figure GPA00000755172000901
The first step
1-dimethylamino-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (200mg, 0.54mmol), n n dimetylaniline (29mg; 0.65mmol), three (dibenzalacetones), two palladiums (2.4mg, 0.0026mmol), 2-(di-t-butyl phosphine) biphenyl (3.2mg; 0.022mmol), sodium tert-butoxide (78mg, 0.81mmol), 2mL exsiccant toluene is put into 20mL microwave reaction pipe; Under the argon shield, 100 ℃, reaction is after 70 minutes under microwave, and reaction finishes; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product 1-dimethylamino-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-carboxylic acid tert-butyl ester 57a (90mg, white solid), yield: 50%.
MS?m/z(ESI)：335[M+1]
Second step
Dimethyl--(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-amine trifluoroacetate
(90mg 0.27mmol) is dissolved in the 10mL methylene dichloride with 1-dimethylamino-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 57a; Dropping trifluoroacetic acid under stirring (1.84g, 16mmol), the solution of gained continues to stir 2 hours afterreactions and finishes; The concentrating under reduced pressure reaction solution; Obtain title product dimethyl--(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-amine trifluoroacetate 57b, directly carry out next step reaction without separating.
The 3rd step
(R)-[3-(1-dimethylamino-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate
Under the nitrogen atmosphere,, add triethylamine (0.40g successively with being dissolved in the 20mL methylene dichloride under dimethyl--(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-amine trifluoroacetate 57b stirring; 4mmol) with (R)-3-t-butoxycarbonyl amino-4-(2,4,5-three fluoro-phenyl)-butyric acid 1e (147mg, 0.44mmol); Stir after 10 minutes, (152mg 0.6mmol), stirs after 2 hours under the room temperature to add two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying; Obtain title product (R)-[3-(1-dimethylamino-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 57c (111mg, colourless oil liquid), yield: 75%.
MS?m/z(ESI)：550[M+1]
The 4th step
(R)-3-amino-1-(1-dimethylamino-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride
With (R)-[3-(1-dimethylamino-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-(111mg 0.2mmol) is dissolved in the 4mL 4.3N hydrogen chloride methanol solution t-butyl carbamate 57c, and solution under agitation reacts 2 hours afterreactions and finishes; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-3-amino-1-(1-dimethylamino-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl) 4-(2,4, the 5-trifluorophenyl)-Ding-1-keto hydrochloride 57 (27mg; White solid), yield: 30%.
MS?m/z(ESI)：450[M+1]
Embodiment 58
(R)-N-(5-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-pyridine-2 base)-acetamide hydrochloride
Figure GPA00000755172000911
The first step
(R)-{ 3-[1-(6-kharophen pyridin-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-{ 3-[1-(6-EL-970-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 56a (155mg; 0.252mmol) be dissolved in the 2mL pyridine, add the 0.5mL diacetyl oxide, stirred overnight at room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, with the reaction solution concentrating under reduced pressure; Obtain title product (R)-{ 3-[1-(6-kharophen pyridin-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 58a (155mg, yellow solid), yield: 97%.
MS?m/z(ESI)：641[M+1]
Second step
(R)-N-(5-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-pyridine-2 base)-acetamide hydrochloride
With (R)-{ 3-[1-(6-kharophen pyridin-3-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(155mg 0.242mmol) is dissolved in 6mL methylene dichloride and the 2mL methyl alcohol t-butyl carbamate 58a, stirs to add 5mL2N hydrogenchloride ethyl acetate solution down; Room temperature reaction 2 hours, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; With the reaction solution concentrating under reduced pressure, use the silica gel column chromatography purifying, obtain title product (R)-N-(5-{7-[3-amino-4-(2; 4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-pyridine-2 base)-acetamide hydrochloride 58 (125mg; Yellow solid), yield: 90%.
MS?m/z(ESI)：541[M+1]
1HNMR(400MHz，CD 3OD)：δ8.70(m，2H)，7.63(m，1H)，7.43(m，1H)，7.24(m，1H)，5.16(m，2H)，4.31-4.41(d，2H)，3.96-4.14(d，2H)，3.96(s，1H)，3.02-3.14(m，4H)，2.38(s，3H)
Embodiment 59
(R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-benzamide hydrochloride salt
Figure GPA00000755172000921
The first step
1-benzamido--3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (300mg, 0.81mmol), BM (117.8mg; 0.97mmol), cuprous iodide (46.3mg, 0.24mmol), trans-N; N '-dimethyl cyclohexane-1, and the 2-diamines (23mg, 0.16mmol), salt of wormwood (224mg; 1.6mmol), 5mL toluene adds in the 20mL microwave reaction pipe, under the argon shield, and 135 ℃; Reaction is after 2 hours under microwave, and reaction finishes, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product 1-benzamido--3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 59a (170mg, white solid), yield: 52%.
MS?m/z(ESI)：411[M+1]
Second step
N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-benzamide hydrochloride salt
(90mg 0.27mmol) is dissolved in the 4mL 2.1N hydrogenchloride ethyl acetate solution with 1-benzamido--3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 59a; Stirred overnight under the room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; The concentrating under reduced pressure reaction solution; Obtain title product N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-benzamide hydrochloride salt 59b, directly carry out next step reaction without separating.
The 3rd step
(R)-[3-(1-benzamido--3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate
Under the nitrogen atmosphere, (140mg 0.4mmol) is dissolved in the 10mL methylene dichloride under the stirring with N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-benzamide hydrochloride salt 59b; Add successively triethylamine (204mg, 2.02mmol) with (R)-3-t-butoxycarbonyl amino-4-(2,4,5-three fluoro-phenyl)-butyric acid 1e (206mg; 0.81mmol), stir after 10 minutes, and two (2-oxo-3-oxazolidinyl) the inferior phosphonyl chlorides of adding (152mg, 0.6mmol); Stirred overnight under the room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears, with the reaction solution concentrating under reduced pressure; Use the silica gel column chromatography purifying, obtain title product (R)-[3-(1-benzamido--3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 59c (170mg, white solid), yield: 67%.
MS?m/z(ESI)：626[M+1]
The 4th step
(R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-benzamide hydrochloride salt
With (R)-[3-(1-benzamido--3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group]-(170mg 0.27mmol) is dissolved in the 5mL ETHYLE ACETATE t-butyl carbamate 59c, adds 5mL 2.1N hydrogenchloride ethyl acetate solution; Stirred overnight under the room temperature, reaction finishes, the concentrating under reduced pressure reaction solution; Obtain title product (R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl }-benzamide hydrochloride salt 59 (150mg, white solid), yield: 98%.
MS?m/z(ESI)：526[M+1]
1HNMR(400MHz，CD 3OD)：δ8.01(m，2H)，7.65(m，1H)，7.55(m，2H)，7.40(m，1H)，7.17(m，1H)，4.87(m，2H)，4.27-4.36(m，2H)，3.94-4.12(m，3H)，2.85-3.24(m，4H)，
Embodiment 60
(R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-4-methylbenzene Toluidrin hydrochloride
Figure GPA00000755172000931
Figure GPA00000755172000941
The first step
1-(toluene-4-sulfonamido)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
Under the nitrogen atmosphere, with 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b (370mg, 1mmol), para toluene sulfonamide (206mg; 1.2mmol), cuprous iodide (38mg, 0.2mmol) trans-N, N '-dimethyl cyclohexane-1; The 2-diamines (28mg, 0.2mmol), salt of wormwood (276mg, 2mmol), 5mL toluene adds in the tube sealing; Under 135 ℃, react after 16 hours, reaction finishes, with the reaction solution concentrating under reduced pressure, with silica gel column chromatography purifying gained resistates; Obtain title product 1-(toluene-4-sulfonamido)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 60a (280mg, white solid), yield: 61%.
MS?m/z(ESI)：461[M+1]
Second step
4-methyl-N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-benzsulfamide hydrochloride
(280mg 0.61mmol) is dissolved in the 5mL 2.1N hydrogenchloride ethyl acetate solution with 1-(toluene-4-sulfonamido)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 60; Stirred overnight under the room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; The concentrating under reduced pressure reaction solution; Obtain title product 4-methyl-N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-benzsulfamide hydrochloride 60b, directly carry out next step reaction without separating.
The 3rd step
(R)-{ 3-[1-(toluene-4-sulfonamido)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
Under the nitrogen atmosphere, (250mg 0.63mmol) is dissolved in the 10mL methylene dichloride under the stirring with 4-methyl-N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-benzsulfamide hydrochloride 60b; Add successively triethylamine (0.2mL, 1.26mmol), (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-and butyric acid 1e (210mg, 0.63mmol) (240mg 0.95mmol), stirred 3 hours under the room temperature with two (2-oxo-3-oxazolidinyl) inferior phosphonyl chlorides; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying; Obtain title product (R)-{ 3-[1-(toluene-4-sulfonamido)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 60c (100mg, colourless oil liquid), yield: 23.5%.
MS?m/z(ESI)：676[M+1]
The 4th step
(R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-4-methylbenzene Toluidrin hydrochloride
With (R)-{ 3-[1-(toluene-4-sulfonamido)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(100mg 0.148mmol) is dissolved in the 5mL2.1N hydrogenchloride ethyl acetate solution t-butyl carbamate 60c, stirs 5 hours under the room temperature; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-N-{7-[3-amino-4-(2; 4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-4-methylbenzene Toluidrin hydrochloride 60 (80mg; White solid), yield: 88%.
MS?m/z(ESI)：576[M+1]
1HNMR(400MHz，CD 3OD)：δ7.64(t，2H)，7.34(d，2H)，7.18(m，2H)，4.80(m，2H)，4.23(d，2H)，4.03(m，2H)，3.76(s，1H)，2.99(s，2H)，2.80(m，2H)，2.44(s，3H)
Embodiment 61
(R)-N-(4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the 2-fluorophenyl)-acetamide hydrochloride
The first step
2-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) aniline
Under the nitrogen atmosphere, with 4-bromo-2-fluoroaniline (570mg, 3mmol), dichloro diacetonitrile palladium (23.3mg, 0.09mmol), 2-dicyclohexyl phosphino--2 '; (73.9mg 0.18mmol) is dissolved in the 15mL toluene 6 '-dimethoxy-biphenyl, and (758mg is 7.5mmol) with 4,4,5 to add triethylamine under stirring; 5-tetramethyl--1,3, and 2-dioxy boron penta ring (461mg, 3.6mmol), 90 ℃ were stirred 5 hours down, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying, obtains title product 2-fluoro-4-(4,4,5; 5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) aniline 61a (400mg, colourless oil liquid), yield: 56%.
MS?m/z(ESI)：238[M+1]
Second step
(R)-{ 3-[1-(4-amino-3-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 2-fluoro-4-(4,4,5,5-tetramethyl--1,3; 2-dioxy boron penta ring-2-yl) aniline 61a (122mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol), 2-dicyclohexyl phosphino--2 '; 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol), potassiumphosphate (145mg, 0.684mmol); The 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe, and under the argon shield, 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes; In reaction solution, add 5mL water,, merge organic phase, use anhydrous magnesium sulfate drying, filter with ethyl acetate extraction (15mL * 3); Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(4-amino-3-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 61b (120mg, light yellow solid), yield: 57%.
MS?m/z(ESI)：616[M+1]
The 3rd step
(R)-{ 3-[1-(4-acetylaminohydroxyphenylarsonic acid 3-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-{ 3-[1-(4-amino-3-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 61b (120mg; 0.19mmol) be dissolved in the 2mL pyridine, add the 0.5mL diacetyl oxide, stirred overnight at room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, with the reaction solution concentrating under reduced pressure; Obtain title product (R)-{ 3-[1-(4-acetylaminohydroxyphenylarsonic acid 3-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 61c (115mg, yellow solid), yield: 93%.
MS?m/z(ESI)：658[M+1]
The 4th step
(R)-N-(4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the 2-fluorophenyl)-acetamide hydrochloride
With (R)-{ 3-[1-(4-acetylaminohydroxyphenylarsonic acid 3-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(115mg 0.174mmol) is dissolved in the 2mL ETHYLE ACETATE t-butyl carbamate 61c, adds 2mL 2N hydrogenchloride ethyl acetate solution; Stirred overnight at room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; With the reaction solution concentrating under reduced pressure, use the silica gel column chromatography purifying, obtain title product
(R)-N-(4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the 2-fluorophenyl)-acetamide hydrochloride 61 (70mg, yellow solid), yield: 72%.
MS?m/z(ESI)：558[M+1]
1HNMR(400MHz，CD 3OD)：δ8.06(m，1H)，7.40(m，4H)，5.10(m，2H)，4.38(m，2H)，4.05(m，3H)，3.05(m，4H)，2.20(s，3H)
Embodiment 62
(R)-N-(4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the 2-fluorophenyl)-acetamide hydrochloride
Figure GPA00000755172000971
The first step
4-fluoro-3-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) aniline
Under the nitrogen atmosphere, with 3-bromo-4-fluoroaniline (570mg, 3mmol), dichloro diacetonitrile palladium (23.3mg, 0.09mmol), 2-dicyclohexyl phosphino--2 '; (73.9mg 0.18mmol) is dissolved in the 15mL toluene 6 '-dimethoxy-biphenyl, and (758mg is 7.5mmol) with 4,4,5 to add triethylamine under stirring; 5-tetramethyl--1,3, and 2-dioxy boron penta ring (461mg, 3.6mmol), 90 ℃ were stirred 5 hours down, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and with the reaction solution concentrating under reduced pressure, uses the silica gel column chromatography purifying, obtains title product 4-fluoro-3-(4,4,5; 5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) aniline 62a (400mg, colourless oil liquid), yield: 56%.
MS?m/z(ESI)：238[M+1]
Second step
(R)-{ 3-[1-(5-amino-2-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (200mg, 0.342mmol); 4-fluoro-3-(4,4,5,5-tetramethyl--1,3; 2-dioxy boron penta ring-2-yl) aniline 62a (122mg, 0.513mmol), two (dibenzalacetone) palladium (4mg, 0.0068mmol), 2-dicyclohexyl phosphino--2 '; 4 ', 6 '-tri isopropyl biphenyl (6.52mg, 0.014mmol), potassiumphosphate (145mg, 0.684mmol); The 2mL trimethyl carbinol adds in the 10mL microwave reaction pipe, and under the argon shield, 100 ℃, reaction is after 1.5 hours under microwave, and reaction finishes; In reaction solution, add 5mL water,, merge organic phase, use anhydrous magnesium sulfate drying, filter with ethyl acetate extraction (15mL * 3); Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(5-amino-2-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 62b (120mg, light yellow solid), yield: 57%.
MS?m/z(ESI)：616[M+1]
The 3rd step
(R)-{ 3-[1-(5-acetylaminohydroxyphenylarsonic acid 2-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-{ 3-[1-(5-amino-2-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 62b (120mg; 0.19mmol) be dissolved in the 2mL pyridine, add the 0.5mL diacetyl oxide, stirred overnight at room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, with the reaction solution concentrating under reduced pressure; Obtain title product (R)-{ 3-[1-(5-acetylaminohydroxyphenylarsonic acid 2-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 62c (115mg, yellow solid), yield: 93%.
MS?m/z(ESI)：658[M+1]
The 4th step
(R)-N-(4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the 2-fluorophenyl)-acetamide hydrochloride
With (R)-{ 3-[1-(5-acetylaminohydroxyphenylarsonic acid 2-fluorophenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(115mg 0.174mmol) is dissolved in the 2mL ETHYLE ACETATE t-butyl carbamate 62c, adds 2mL 2N hydrogenchloride ethyl acetate solution; Stirred overnight at room temperature, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; With the reaction solution concentrating under reduced pressure, use the silica gel column chromatography purifying, obtain title product (R)-N-(4-{7-[3-amino-4-(2; 4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the 2-fluorophenyl)-acetamide hydrochloride 62 (70mg; Yellow solid), yield: 72%.
MS?m/z(ESI)：558[M+1]
Embodiment 63
(R)-4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-benzamide hydrochloride salt
Figure GPA00000755172000981
In the 25mL eggplant-shape bottle, add compound (R) 4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-benzonitrile trifluoroacetate 14 (50mg; 0.08mmol), add 1mL trifluoroacetic acid/vitriol oil (v: v=4: mixed solvent 1), stirred overnight at room temperature, thin-layer chromatography tracking reaction; Raw material disappears, and reaction solution cools off with ice bath, and slowly dropping ammonia accent pH is 8-9, with ethyl acetate extraction (20mL * 3); Merge organic phase, use anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure filtrating; In residue, add 4mL 4.3N hydrogen chloride methanol solution, stir after 10 minutes concentrating under reduced pressure; Obtain title product (R)-4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl }-benzamide hydrochloride salt 63 (30mg, yellow solid), yield: 67%.
MS?m/z(ESI)：525[M+1]
1HNMR(400MHz，CD 3OD)：δ8.34(s，2H)，7.97-8.05(m，2H)，7.56-7.74(m，2H)，4.97-5.05(m，2H)，4.33-4.35(s，1H)，3.95-3.98(m，2H)，3.76(m，1H)，3.17(s，1H)，2.99-3.16(m，3H)，1.24(s，3H)
Embodiment 64
(R)-3-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-benzamide hydrochloride salt
Figure GPA00000755172000991
In the 25mL eggplant-shape bottle, add compound (R)-3-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-benzonitrile hydrochloride 27 (60mg; 0.11mmol), add 1mL trifluoroacetic acid/vitriol oil (v: v=4: mixed solvent 1), stirred overnight at room temperature, thin-layer chromatography tracking reaction; Raw material disappears, and reaction solution cools off with ice bath, and slowly dropping ammonia accent pH is 8-9, with ethyl acetate extraction (20mL * 3); Merge organic phase, use anhydrous magnesium sulfate drying, suction filtration, concentrating under reduced pressure filtrating; In residue, add 4mL 4.3N hydrogen chloride methanol solution, stir after 10 minutes concentrating under reduced pressure; Obtain title product (R)-3-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl }-benzamide hydrochloride salt 64 (40mg, yellow solid), yield: 65%.
MS?m/z(ESI)：525[M+1]
1HNMR(400MHz，CD 3OD)：δ8.15(d，1H)，7.84(m，2H)，7.57(m，1H)，7.49(m，1H)，7.19(m，1H)，5.09(m，1H)，4.36(d，2H)，4.06(m，2H)，3.60(m，2H)，3.09(m，2H)，2.91(m，2H)。
Embodiment 65
(R)-N-(4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-phenyl)-the Toluidrin hydrochloride
Figure GPA00000755172001001
The first step
(R)-{ 3-[1-(4-methanesulfonamido-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (150mg, 0.256mmol); 4-(methanesulfonamido) phenylo boric acid (83.8mg, 0.282mmol), four triphenylphosphine palladiums (30mg, 0.0256mmol); Salt of wormwood (70.8mg, 0.512mmol), 2mL glycol dimethyl ether and 2mL water are put into 10mL microwave reaction pipe, under the argon shield; 130 ℃, reaction is after 30 minutes under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(4-methanesulfonamido-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 65a (120mg, white solid), yield: 70%.
MS?m/z(ESI)：676[M+1]
Second step
(R)-N-(4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-phenyl)-the Toluidrin hydrochloride
With (R)-{ 3-[1-(4-methanesulfonamido-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 65a (150mg; 0.222mmol) be dissolved in 5mL2N hydrogenchloride ethyl acetate solution, separate out white solid, stirring at room 2 hours, thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and with reacting liquid filtering, obtains white solid, vacuum-drying; Obtain title product (R)-N-(4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl }-phenyl)-Toluidrin hydrochloride 65 (100mg, yellow solid), yield: 73%.
MS?m/z(ESI)：576[M+1]
1HNMR(400MHz，CD 3OD)：δ7.66-7.62(m，2H)，7.43-7.37(m，3H)，7.27-7.16(m，1H)，5.11-4.93(m，2H)，4.40-4.31(m，2H)，4.15-3.92(m，3H)，3.12-2.82(m，7H)
Embodiment 66
(R)-3-amino-1-(1-thiene-3-yl--3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4,5-three fluoro-phenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172001011
The first step
(R)-[3-oxo-3-(1-thiene-3-yl--3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-1-(2,4,5-three fluoro-phenyl)-propyl group]-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (293mg, 0.5mmol); Thiene-3-yl-boric acid (96mg, 0.75mmol), four triphenylphosphine palladiums (58mg, 0.05mmol); Salt of wormwood (138mg, 1mmol), 3mL glycol dimethyl ether and 3mL water are put into 20mL microwave reaction pipe, under the argon shield; 120 ℃, reaction is after 30 minutes under microwave, and reaction finishes, and in reaction solution, adds 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, use anhydrous magnesium sulfate drying, filter; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-[3-oxo-3-(1-thiene-3-yl--3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-1-(2; 4,5-three fluoro-phenyl)-propyl group]-t-butyl carbamate 66a (200mg, light yellow solid), yield: 68%.
MS?m/z(ESI)：589[M+1]
Second step
(R)-3-amino-1-(1-thiene-3-yl--3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4,5-three fluoro-phenyl)-Ding-1-keto hydrochloride
With (R)-[3-oxo-3-(1-thiene-3-yl--3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-1-(2,4,5-three fluoro-phenyl)-propyl group]-t-butyl carbamate 66a (0.2g; 0.34mmol) put into reaction flask, add 2mL ETHYLE ACETATE, stir and make its dissolving, add the hydrogenchloride ethyl acetate solution of 3mL 2.0N again; Stirring reaction is 1.5 hours under the room temperature, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears; Filtering reacting liquid is collected solid, vacuum-drying; Obtain title product (R)-3-amino-1-(1-thiene-3-yl--3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4; 5-three fluoro-phenyl)-and Ding-1-keto hydrochloride 66 (0.13g, yellow solid), yield: 72.9%.
MS?m/z(ESI)：489.2[M+1]
Embodiment 67
(R)-3-amino-1-[1-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4,5-three fluoro-phenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172001021
The first step
(R)-{ 3-[1-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (0.3g; 0.5mmol), 4-(methylsulfonyl) phenylo boric acid (123mg, 0.6mmol), 2-dicyclohexyl phosphino--2 '; 4 ', 6 '-tri isopropyl biphenyl (9.53mg, 0.02mmol), two (dibenzalacetone) two palladium (0.006g; 0.01mmol) and potassiumphosphate (0.22g 1mmol) is dissolved in the 10mL propyl carbinol under the stirring, under the argon shield, and 130 ℃; Reaction is after 30 minutes under microwave, and reaction finishes, filtering reacting liquid, and solid is with methylene chloride (v: v=10: 1) washing; Collect washings, drain, obtain title product (R)-{ 3-[1-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4, the 5-trifluoro-benzyl)-propyl group }-t-butyl carbamate 67a (150mg, white solid), yield: 44%.
MS?m/z(ESI)：661.2[M+1]
Second step
With (R)-{ 3-[1-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; The 5-trifluoro-benzyl)-propyl group }-(150mg 0.227mmol) is dissolved in 5mL dichloromethane/ethyl acetate (v: v=1: 1) in the mixed solvent, add 10mL 2N hydrogenchloride ethyl acetate solution to t-butyl carbamate 67a under the stirring; Reacted 1 hour, thin-layer chromatography is followed the tracks of reaction, and raw material disappears; Drain solvent, obtain title product (R)-3-amino-1-[1-(4-methylsulfonyl-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2; 4; 5-three fluoro-phenyl)-and Ding-1-keto hydrochloride 67 (0.12g, white solid), yield: 88.6%.
MS?m/z(ESI)：561.3[M+1]
1HNMR(400MHz，CD 3OD)：δ8.01-7.97(m，2H)，7.88-7.85(m，2H)，7.31-7.29(m，1H)，7.11-7.20(m，1H)，5.00-5.08(m，2H)，4.24-4.32(m，2H)，2.85-3.08(m，3H)，2.80-3.12(m，5H)，2.64-2.80(m，2H)。
Embodiment 68
(R) N-[4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-2-fluoro-phenyl]-cyclopropyl carboxamide hydrochloride
The first step
(R)-[3-{1-[4-(cyclopropyl formamido group)-3-fluoro-phenyl]-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl }-3-oxo-1-(2,4,5-three fluoro-benzyls)-propyl group]-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (0.292g, 0.5mmol); The cyclopropyl formyl [3-fluoro-5-(4,4,5-trimethylammonium-[1,3; 2] dioxy boron penta ring-2-yl)-phenyl]-amine (123mg, 0.6mmol), two (dibenzalacetones), two palladiums (5.75mg, 0.01mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (9.53mg, 0.02mmol) and potassiumphosphate (0.22g; 1mmol) put into the microwave reaction pipe, be dissolved in the 10mL propyl carbinol under stirring, under the argon shield, 130 ℃; Reaction is after 30 minutes under microwave, and reaction finishes, filtering reacting liquid, and solid is with methylene chloride (v: v=10: 1) washing; Collect washings, concentrating under reduced pressure, obtain title product (R)-[3-{1-[4-(cyclopropyl formamido group)-3-fluoro-phenyl]-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl }-3-oxo-1-(2; 4,5-three fluoro-benzyls)-propyl group]-t-butyl carbamate 68a (150mg, white solid), yield: 44%.
MS?m/z(ESI)：661.2[M+1]
Second step
(R)-N-[4-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-2-fluoro-phenyl]-the cyclopropyl carboxamide hydrochloride
With (R)-[3-{1-[4-(cyclopropyl formamido group)-3-fluoro-phenyl]-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl }-3-oxo-1-(2,4; 5-three fluoro-benzyls)-propyl group]-(0.1g 0.146mmol) together puts into reaction flask with the ethyl acetate solution of the hydrogenchloride of 4mL 6.5N to t-butyl carbamate 68a, and stirring reaction is 4 hours under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, the concentrating under reduced pressure reaction solution; Obtain title product (R)-N-[4-{7-[3-amino-4-(2; 4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-2-fluoro-phenyl]-cyclopropyl carboxamide hydrochloride 68 (0.085g; Faint yellow solid), yield: 94%.
MS?m/z(ESI)：584.1[M+1]。
Embodiment 69
(R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the cyclopropyl carboxamide hydrochloride
Figure GPA00000755172001041
The first step
1-(cyclopropyl carboxamide base)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
(0.555g 1.5mmol) puts in the reaction tubes with salt of wormwood and 5mL toluene with 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 7b; Add again cyclopropyl carboxamide (0.255g, 3mmol), cuprous iodide (0.057g; 0.3mmol) and (1R, 2R)-N 1, N 2-Dimethylcyclohexyl-1, and the 2-diamines (0.042g, 0.3mmol), under the argon shield; Tube sealing, 125 ℃ of stirring reactions of temperature spend the night outside the control in oil bath, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product 1-(cyclopropyl carboxamide base)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-carboxylic acid tert-butyl ester 69a (0.25g, yellow solid), yield: 44.6%.
MS?m/z(ESI)：375.0[M+1]。
Second step
N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl) cyclopropyl carboxamide hydrochloride
With 1-(cyclopropyl carboxamide base)-3-trifluoromethyl-imidazo [1,5-a] piperazine-(0.25g 0.67mmol) puts into reaction flask to 7-carboxylic acid tert-butyl ester 69a; Add the ethyl acetate solution of the hydrogenchloride of 5mL2.3N, stirring reaction is 4 hours under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution obtains title product N-(3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl) cyclopropyl carboxamide hydrochloride 69b (0.2g, yellow solid), yield: 95.8%.
MS?m/z(ESI)：275.2[M+1]。
The 3rd step
(R)-{ 3-[1-(cyclopropyl formamido group)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4,5-three fluoro-phenyl)-propyl group }-t-butyl carbamate
(0.2g 0.67mmol) puts in the reaction flask, adds the 10mL methylene dichloride with N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl) cyclopropyl carboxamide hydrochloride 69b; (0.30mL 1.34mmol), stirs under the room temperature and makes its dissolving triethylamine, adds (R)-3-t-butoxycarbonyl amino-4-(2 again; 4,5-three fluoro-phenyl)-butyric acid 1e (0.223g, 0.67mmol), and two (2-oxo-3-oxazolidinyl) inferior phosphoryl chloride (0.254g; 1mmol), stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-{ 3-[1-(cyclopropyl formamido group)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; 5-three fluoro-phenyl)-propyl group }-t-butyl carbamate 69c (0.23g, white solid), yield: 58.3%.
MS?m/z(ESI)：589.9[M+1]。
The 4th step
(R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-the cyclopropyl carboxamide hydrochloride
With (R)-{ 3-[1-(cyclopropyl formamido group)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; 5-three fluoro-phenyl)-propyl group }-(0.23g 0.39mmol) puts in the reaction flask t-butyl carbamate 69c, adds the ethyl acetate solution of the hydrogenchloride of 5mL 2.3N; Stirring reaction is 4 hours under the room temperature, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears; Revolve dry reaction liquid,, obtain title product (R)-N-{7-[3-amino-4-(2 with silica gel column chromatography purifying gained resistates; 4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-cyclopropyl carboxamide hydrochloride 69 (0.15g; White solid), yield: 73.1%.
MS?m/z(ESI)：490.2[M+1]。
1HNMR(400MHz，CD 3OD)：δ7.31(m，1H)，7.16(m，1H)，4.58(m，2H)，4.31(t，1H)，4.21(t，1H)，3.99(m，2H)，3.62(m，1H)，2.88(m，2H)，2.72(m，1H)，2.61(m，1H)，1.94(s，1H)，1.83(m，1H)，1.36(m，1H)，0.94(m，4H)
Embodiment 70
(R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-1-methylsulfonyl-piperidines-4-carboxamide hydrochloride
Figure GPA00000755172001051
The first step
1-methylsulfonyl-piperidines-4-methane amide
(1.025g 8mmol) is dissolved in the 80mL exsiccant acetonitrile, adds salt of wormwood (4.42g with piperidines-4-methane amide 70a; 32mmol), (2075g 24mmol) splashes in the reaction solution with methylsulfonyl chloride under ice bath; Stirring reaction rises to room temperature reaction 2 hours gradually under the ice bath after 2 hours, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears; Filter, filtrate decompression concentrates, with silica gel column chromatography purifying gained resistates; Obtain title product 1-methylsulfonyl-piperidines-4-methane amide 70b (1.27g, white solid), yield: 77.0%.
MS?m/z(ESI)：207.1[M+1]。
Second step
1-[(1-methylsulfonyl-piperidines-4-carbonyl)-amino]-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-(370mg 1mmol) puts into reaction tubes to 7-carboxylic acid tert-butyl ester 7b, adds potassiumphosphate (424mg successively; 2mmol), the 5mL o-Xylol, 1-methylsulfonyl-piperidines-4-methane amide 70b (412.5mg, 2mmol); Cuprous iodide (38mg, 0.2mmol) and (1R, 2R)-N1, N2-Dimethylcyclohexyl-1; The 2-diamines (28.4mg, 0.2mmol), tube sealing under the argon shield, 125 ℃ of stirring reactions of temperature control spend the night in oil bath; Thin-layer chromatography is followed the tracks of reaction, and the raw material unreacted is intact, and temperature control stirs to send out and answered 8 hours in 140 ℃ of oil baths, and thin-layer chromatography is followed the tracks of reaction; The raw material major part has been reacted, revolves dry reaction liquid, with silica gel column chromatography purifying gained resistates, obtains title product 1-[(1-methylsulfonyl-piperidines-4-carbonyl)-amino]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-carboxylic acid tert-butyl ester 70c (95mg, yellow solid), yield: 19.2%.
MS?m/z(ESI)：496.0[M+1]。
The 3rd step
1-methylsulfonyl-N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-piperidines-4-carboxamide hydrochloride
With 1-[(1-methylsulfonyl-piperidines-4-carbonyl)-amino]-3-trifluoromethyl-imidazo [1,5-a] piperazine-(190mg 0.38mmol) puts into reaction flask to 7-carboxylic acid tert-butyl ester 70c; Add the ethyl acetate solution of the hydrogenchloride of 3mL 2.3N, stirring reaction is 4 hours under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears; The concentrating under reduced pressure reaction solution obtains title product 1-methylsulfonyl-N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-piperidines-4-carboxamide hydrochloride 70d (150mg; Yellow solid), yield: 91.5%.
MS?m/z(ESI)：396.3[M+1]。
The 4th step
(R)-[3-{1-[(1-methylsulfonyl-piperidines-4-carbonyl)-amine]-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl }-3-oxo-1-(2,4,5-three fluoro-phenyl)-propyl group]-t-butyl carbamate
(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-(165.6mg 0.38mmol) is dissolved in the 8mL methylene dichloride piperidines-4-carboxamide hydrochloride 70d with 1-methylsulfonyl-N-; Add the 0.2mL triethylamine again, (R)-3-t-butoxycarbonyl amino-4-(2,4; 5-three fluoro-phenyl)-butyric acid 1e (127.8mg, 0.38mmol) and two (2-oxo-3-oxazolidinyl) inferior phosphoryl chloride (144.8mg, 0.57mmol); Stirring reaction is 2 hours under the room temperature, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-[3-{1-[(1-methylsulfonyl-piperidines-4-carbonyl)-amine]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl }-3-oxo-1-(2,4,5-three fluoro-phenyl)-propyl group]-t-butyl carbamate 70e (100mg; White solid), yield: 37.1%.
MS?m/z(ESI)：710.9[M+1]。
The 5th step
(R)-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-1-methylsulfonyl-piperidines-4-carboxamide hydrochloride
With (R)-[3-{1-[(1-methylsulfonyl-piperidines-4-carbonyl)-amine]-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl }-3-oxo-1-(2,4; 5-three fluoro-phenyl)-propyl group]-(100mg 0.14mmol) puts into reaction flask to t-butyl carbamate 70e, adds the ethyl acetate solution of the hydrogenchloride of 4mL 2.3N; Stirring reaction is 3 hours under the room temperature, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears; The concentrating under reduced pressure reaction solution obtains title product (R)-N-{7-[3-amino-4-(2,4; The 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl }-1-methylsulfonyl-piperidines-4-carboxamide hydrochloride 70 (80mg, white solid), yield: 88.4%.
MS?m/z(ESI)：611.2[M+1]。
1HNMR(400MHz，CD 3OD)：δ7.36(m，1H)，7.20(m，1H)，4.75(m，2H)，4.23(m，2H)，4.01(m，2H)，3.83(m，3H)，3.02(m，2H)，2.90(m，5H)，2.62(m，1H)，2.50(m，1H)，2.01(m，2H)，1.85(m，2H)，1.30(m，2H)
Embodiment 71
(R)-1-ethanoyl-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-piperidines-4-carboxamide hydrochloride
Figure GPA00000755172001071
The first step
1-ethanoyl-piperidines-4-methane amide
(1.025g 8mmol) is dissolved in the exsiccant acetonitrile, adds salt of wormwood (4.4g with piperidines-4-methane amide 71a; 32mmol), and dripping acetyl chloride in ice bath downhill reaction liquid (1.9g, 24mmol); Stirring reaction slowly rises to room temperature reaction 4 hours under the ice bath after 2 hours, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears; Filter, concentrating under reduced pressure filtrating is with silica gel column chromatography purifying gained resistates; Obtain title product 1-ethanoyl-piperidines-4-methane amide 71b (1.14g, white solid), yield: 83.8%.
MS?m/z(ESI)：171.2[M+1]。
Second step
1-[(1-ethanoyl-piperidines-4-carbonyl)-amine]-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester
With 1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-(740mg 2mmol) puts into reaction tubes to 7-carboxylic acid tert-butyl ester 7b, adds salt of wormwood (550mg successively; 4mmol), the 8mL o-Xylol, 1-ethanoyl-piperidines-4-methane amide 71b (680mg, 4mmol); Cuprous iodide (76mg, 0.4mmol) and (1R, 2R)-N1, N2-Dimethylcyclohexyl-1; The 2-diamines (56mg, 0.4mmol), tube sealing after the argon replaces, 145 ℃ of stirring reactions of temperature control are 6 hours in oil bath; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product 1-[(1-ethanoyl-piperidines-4-carbonyl)-amine]-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 71c (560mg, faint yellow oily thing), yield: 60.9%.
MS?m/z(ESI)：460.3[M+1]。
The 3rd step
1-ethanoyl-N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-piperidines-4-carboxamide hydrochloride
(560mg 1.21mmol) is dissolved in the ethyl acetate solution of hydrogenchloride of 5mL 2.3N with 1-[(1-ethanoyl-piperidines-4-carbonyl)-amine]-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-carboxylic acid tert-butyl ester 71c; Stirring reaction spends the night under the room temperature, separates out a large amount of yellow solids, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears; The concentrating under reduced pressure reaction solution obtains title product 1-ethanoyl-N-(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-piperidines-4-carboxamide hydrochloride 71d (480mg; Yellow solid), yield: 100%.
MS?m/z(ESI)：360.5[M+1]。
The 4th step
(R)-[3-{1-[(1-ethanoyl-piperidines-4-carbonyl)-amine]-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl }-3-oxo-1-(2,4,5-three fluoro-benzyls)-propyl group]-t-butyl carbamate
(3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl)-(200mg 0.56mmol) is dissolved in the 6mL methylene dichloride piperidines-4-carboxamide hydrochloride 71d with 1-ethanoyl-N-; Add again triethylamine (112mg, 0.84mmol), (R)-3-t-butoxycarbonyl amino-4-(2; 4,5-three fluoro-phenyl)-and butyric acid 1e (186mg, 0.56mmol) and two (2-oxo-3-oxazolidinyl) inferior phosphoryl chloride (213mg; 0.84mmol), stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-[3-{1-[(1-ethanoyl-piperidines-4-carbonyl)-amine]-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl }-3-oxo-1-(2,4; 5-three fluoro-benzyls)-propyl group]-t-butyl carbamate 71e (270mg, faint yellow solid), yield: 71.4%.
MS?m/z(ESI)：675.0[M+1]。
The 5th step
(R)-1-ethanoyl-N-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-piperidines-4-carboxamide hydrochloride
With (R)-[3-{1-[(1-ethanoyl-piperidines-4-carbonyl)-amine]-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl }-3-oxo-1-(2,4; 5-three fluoro-benzyls)-propyl group]-(150mg 0.22mmol) puts into reaction flask to t-butyl carbamate 71e, adds the ethyl acetate solution of 5mL 2.3N hydrogenchloride; Stirring reaction is 3 hours under the room temperature, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears; The concentrating under reduced pressure reaction solution obtains title product (R)-1-ethanoyl-N-{7-[3-amino-4-(2,4; The 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl }-piperidines-4-carboxamide hydrochloride 71 (133mg, faint yellow solid), yield: 99.3%.
MS?m/z(ESI)：575.1[M+1]。
1HNMR(400MHz，CD 3OD)：δ7.37(m，1H)，7.22(m，1H)，4.76(m，1H)，4.60(m，1H)，4.52(m，1H)，4.36(m，1H)，4.21(m，1H)，4.05(m，4H)，3.27(m，1H)，3.12(m，2H)，2.95(m，1H)，2.77(m，3H)，2.18(s，3H)，1.94(m，3H)，1.73(m，2H)
Embodiment 72
(R)-3-amino-1-(1-thiophene-2-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4,5-three fluoro-phenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172001091
The first step
(R)-[3-oxo-3-(1-thiophene-2-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-1-(2,4,5-three fluoro-benzyls)-propyl group]-t-butyl carbamate
Under argon shield, with compound (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (0.293g; 0.5mmol) with thiophene-2-ylboronic acid (0.096g, 0.75mmol) and four triphenylphosphine palladiums (0.058g, 0.05mmol), salt of wormwood (0.138g; 1mmol), 3mL glycol dimethyl ether, 3mL water are together put into the microwave reaction pipe of 20mL, tube sealing; In 120 ℃ of following microwave reactions 30 minutes, thin-layer chromatography was followed the tracks of reaction, and raw material disappears, and in reaction solution, added 5mL water; With ethyl acetate extraction (15mL * 3), merge organic phase, anhydrous magnesium sulfate drying filters; Filtrate decompression concentrates, and with silica gel column chromatography purifying gained resistates, obtains title product (R)-[3-oxo-3-(1-thiophene-2-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-1-(2; 4,5-three fluoro-benzyls)-propyl group]-t-butyl carbamate 72a (0.2g, faint yellow solid), yield: 68%.
MS?m/z(ESI)：589[M+1]。
Second step
With (R)-[3-oxo-3-(1-thiophene-2-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-1-(2,4,5-three fluoro-benzyls)-propyl group]-t-butyl carbamate 72a (0.2g; 0.34mmol) put in the reaction flask with 2mL ETHYLE ACETATE, adding the ethyl acetate solution of 3mL 2.0N hydrogenchloride again, stirring reaction spends the night under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, the concentrating under reduced pressure reaction solution; Obtain title product (R)-3-amino-1-(1-thiophene-2-base-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4; 5-three fluoro-phenyl)-and Ding-1-keto hydrochloride 72 (0.13g, yellow solid), yield: 72.9%.
MS?m/z(ESI)：489.2[M+1]。
Embodiment 73
(R)-N-[3-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-phenyl]-acetamide hydrochloride
Figure GPA00000755172001101
The first step
(R)-{ 3-[1-(3-amino-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4,5-three fluoro-benzyls)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (0.3g, 0.51mmol); 3-(4,4,5,5-tetramethyl--[1,3; 2] dioxy boron penta ring-2-yl)-and aniline (0.128g, 0.76mmol), potassiumphosphate (0.218g, 1.03mmol), two (dibenzalacetone) palladium (0.006g; 0.01mmol) and 2-dicyclohexyl phosphino--2 ', (0.01g 0.02mmol) puts into reaction flask to 4 ', 6 '-tri isopropyl biphenyl, is dissolved in the 3mL propyl carbinol under stirring; Under the argon shield, 100 ℃, microwave reacted 30 minutes down, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears; The concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains title product (R)-{ 3-[1-(3-amino-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4,5-three fluoro-benzyls)-propyl group }-t-butyl carbamate 73a (0.2g, yellow solid), yield: 65.4%.
Second step
(R)-{ 3-[1-(3-ethanamide-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4,5-three fluoro-benzyls)-propyl group }-t-butyl carbamate
With (R)-{ 3-[1-(3-amino-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; 5-three fluoro-benzyls)-propyl group }-(0.2g 0.33mmol) puts into reaction flask to t-butyl carbamate 73a, adds the 2mL diacetyl oxide; Be dissolved in the 4mL pyridine under stirring, stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-{ 3-[1-(3-ethanamide-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; 5-three fluoro-benzyls)-propyl group }-t-butyl carbamate 73b (0.14g, white solid), yield: 65.4%.
MS?m/z(ESI)：662.2[M+23]
The 3rd step
(R)-N-[3-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-phenyl]-acetamide hydrochloride
With (R)-{ 3-[1-(3-ethanamide-phenyl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4,5-three fluoro-benzyls)-propyl group }-t-butyl carbamate 73b (0.14g; 0.11mmol) be dissolved in the 2mL methyl alcohol, in reaction solution, adding the methanol solution of 7mL hydrogenchloride, stirring reaction is 5 hours under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, concentrating under reduced pressure reaction solution, vacuum-drying; Obtain title product (R)-N-[3-{7-[3-amino-4-(2,4, the 5-trifluorophenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl }-phenyl]-acetamide hydrochloride 73 (0.12g, yellow solid), yield: 96.5%.
MS?m/z(ESI)：540.2[M+1]
Embodiment 74
(R)-3-amino-1-[1-(2-methoxyl group-pyrimidine-5-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4,5-three fluoro-phenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172001111
The first step
(R)-{ 3-[1-(2-methoxyl group-pyrimidine-5-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4,5-three fluoro-benzyls)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (0.293g, 0.5mmol); 2-methoxy pyrimidine-5-ylboronic acid (118mg, 0.75mmol), two (dibenzalacetone) palladium (5.8mg, 0.01mmol); 2-dicyclohexyl phosphino--2 ', and 4 ', 6 '-tri isopropyl biphenyl (9.5mg, 0.02mmol); Potassiumphosphate (0.212g 1mmol) is dissolved in the 2.5mL propyl carbinol under the stirring, under the argon shield, and 100 ℃; Reaction is after 30 minutes under microwave, and reaction finishes, and has a large amount of solids to separate out, and the cooling back adds the 15mL normal hexane; Filter, remove filtrating, solid is with methylene chloride (v: v=10: 1) mixed solution dissolving, filtration once more; Remove residue, filtrate decompression concentrates, and obtains title product (R)-{ 3-[1-(2-methoxyl group-pyrimidine-5-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2; 4,5-three fluoro-benzyls)-propyl group }-t-butyl carbamate 74a (220mg, tawny solid), yield: 71.7%.
MS?m/z(ESI)：615.1[M+1]
Second step
(R)-3-amino-1-[1-(2-methoxyl group-pyrimidine-5-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-4-(2,4,5-three fluoro-phenyl)-Ding-1-keto hydrochloride
With (R)-{ 3-[1-(2-methoxyl group-pyrimidine-5-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; 5-three fluoro-benzyls)-propyl group }-(220mg 0.36mmol) is dissolved in the 3mL ETHYLE ACETATE under the stirring t-butyl carbamate 74a, adds 5mL 2.7N hydrogenchloride ethyl acetate solution; Reaction is 1 hour under the room temperature, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears; Solvent evaporated is used the silica gel column chromatography purifying, obtains title product (R)-3-amino-1-[1-(2-methoxyl group-pyrimidine-5-yl)-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl]-4-(2,4,5-three fluoro-phenyl)-Ding-1-keto hydrochloride 74 (80mg; Faint yellow solid), yield: 41.6%.
MS?m/z(ESI)：515.2[M+1]
1HNMR(400MHz，CD 3OD)：δ8.92(m，2H)，7.40(m，1H)，7.23(m，1H)，5.06(m，2H)，4.35(m，2H)，4.35(m，2H)，4.13(m，3H)，4.00(m，2H)，3.47(s，2H)，2.98(m，3H)，
Embodiment 75
(R)-5-{7-[3-amino-4-(2,4,5-three fluoro-phenyl)-butyl]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-furans-2-formaldehyde hydrochloride
Figure GPA00000755172001121
The first step
(R)-{ 3-[1-(5-formyl radical-furans-2-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4,5-three fluoro-benzyls)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (0.123g; 0.21mmol), 5-formylfuran-2-ylboronic acid (35.3mg, 0.252mmol), tetrakis triphenylphosphine palladium (12.1mg; 0.01mmol), four butyl bromation amine (13.5mg, 0.042mmol), salt of wormwood (87.12mg; 0.63mmol), be dissolved in 1.5mL1 under stirring, in the mixed solvent of 4-dioxane and 0.75mL water, under the argon atmospher; 100 ℃, reaction is after 30 minutes under microwave, and reaction finishes, solvent evaporated; Use the silica gel column chromatography purifying, obtain title product (R)-{ 3-[1-(5-formyl radical-furans-2-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; 5-three fluoro-benzyls)-propyl group }-t-butyl carbamate 75a (65mg, yellow solid), yield: 51.6%.
MS?m/z(ESI)：623.1[M+23]
Second step
(R)-5-{7-[3-amino-4-(2,4,5-three fluoro-phenyl)-butyl]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-furans-2-formaldehyde hydrochloride
With (R)-{ 3-[1-(5-formyl radical-furans-2-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; 5-three fluoro-benzyls)-propyl group }-(65mg 0.11mmol) is dissolved in the 1mL ETHYLE ACETATE under the stirring t-butyl carbamate 75a, adds 1mL2.7N hydrogenchloride ethyl acetate solution; Reaction is 4 hours under the room temperature, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears; Solvent evaporated is used the silica gel column chromatography purifying, obtains title product (R)-5-{7-[3-amino-4-(2; 4,5-three fluoro-phenyl)-butyl]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-furans-2-formaldehyde hydrochloride 75 (80mg; Faint yellow solid), yield: 41.6%.
MS?m/z(ESI)：515.2[M+1]
Embodiment 76
(R)-7-[3-amino-4-(2,4,5-three fluoro-phenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-nitrile hydrochloride
Figure GPA00000755172001131
The first step
(R)-7-[uncle's 3-fourth oxanamide-4-(2,4,5-three fluoro-phenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-carboxylate methyl ester
With cobalt octacarbonyl (3.5g, 10.23mmol), ethyl chloroacetate (0.62g, 5.12mmol); Salt of wormwood (1.41g, 10.23mmol) and 10mL methyl alcohol put into reaction flask, stirring reaction is 5 minutes under the room temperature, adds (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1; 5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (2.0g, 3.41mmol); 60 ℃ of reactions of temperature control are spent the night in oil bath, and thin-layer chromatography is followed the tracks of reaction, and raw material disappears, the concentrating under reduced pressure reaction solution; With silica gel column chromatography purifying gained resistates, obtain title product (R)-7-[uncle's 3-fourth oxanamide-4-(2,4,5-three fluoro-phenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-carboxylate methyl ester 76a (1.1g, white solid), yield: 57.3%.
MS?m/z(ESI)：565.0[M+1]
Second step
(R)-7-[uncle's 3-fourth oxanamide-4-(2,4,5-three fluoro-phenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-carboxylic acid
With (R)-7-[uncle's 3-fourth oxanamide-4-(2,4,5-three fluoro-phenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-carboxylate methyl ester 76a (1.0g; 1.77mmol) be dissolved in the 10mL methyl alcohol, adding the sodium hydroxide solution 13.25mL of 4N, stirring reaction is 30 minutes under the room temperature, and reaction finishes; The hydrochloric acid soln adjust pH that adds 2N is 4-5, with ethyl acetate extraction (20mL * 3), collects organic phase, with the washing of 20mL saturated common salt once; Merge organic phase, use anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates; With silica gel column chromatography purifying gained resistates, obtain title product (R)-7-[uncle's 3-fourth oxanamide-4-(2,4,5-three fluoro-phenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-carboxylic acid 76b (0.78g, faint yellow solid), yield: 80.1%.
MS?m/z(ESI)：573.1[M+23]
The 3rd step
(R)-[3-(1-carbamyl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4,5-three fluoro-benzyls)-propyl group]-t-butyl carbamate
With (R)-7-[uncle's 3-fourth oxanamide-4-(2,4,5-three fluoro-phenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-carboxylic acid 76b (0.3g; 0.54mmol), amine carbonate (0.156g, 1.62mmol), two (2-oxo-3-oxazolidinyl) inferior phosphoryl chloride (0.412g; 1.62mmol) put into reaction flask, add 30mL THF and 0.5mL triethylamine, stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-[3-(1-carbamyl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; 5-three fluoro-benzyls)-propyl group]-t-butyl carbamate 76c (284mg, white solid), yield: 95.0%.
MS?m/z(ESI)：549.9[M+1]
The 4th step
(R)-[3-(1-cyanic acid-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4,5-three fluoro-benzyls)-propyl group]-t-butyl carbamate
Under the nitrogen protection, with (R)-[3-(1-carbamyl-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; 5-three fluoro-benzyls)-propyl group]-t-butyl carbamate 76c (0.35g, 0.636mmol), (0.091g 1.34mmol) puts in the exsiccant reaction flask imidazoles; Add the dissolving of 10mL pyridine, bathe with dry ice-propanone and be chilled to-35 ℃, keep-35 ℃ in reaction solution, drip POCl3 (0.4g, 2.6mmol); Finish, temperature control-35 ℃ reaction 1 hour, after rise to room temperature reaction and spend the night, thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and revolves the pyridine in the dry reaction liquid, adds the dissolving of 5mL saturated nacl aqueous solution, with ethyl acetate extraction (10mL * 4); Merge organic phase, wash (5mL * 2) with copper/saturated copper sulphate solution successively, the 5mL saturated sodium bicarbonate solution is washed, and the 5mL saturated nacl aqueous solution is washed; Collect organic phase, use anhydrous magnesium sulfate drying, filter, filtrate decompression concentrates; With silica gel column chromatography purifying gained resistates, obtain title product (R)-[3-(1-cyanic acid-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; 5-three fluoro-benzyls)-propyl group]-t-butyl carbamate 76d (0.12g, white solid), yield: 35.5%.
MS?m/z(ESI)：554.0[M+23]
The 5th step
(R)-7-[3-amino-4-(2,4,5-three fluoro-phenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-nitrile hydrochloride
With (R)-[3-(1-cyanic acid-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4,5-three fluoro-benzyls)-propyl group]-t-butyl carbamate 76d (0.12g; 0.23mmol) stir down and be dissolved in the 4mL 2.0N hydrogenchloride ethyl acetate solution, stirring reaction is 4 hours under the room temperature, and thin-layer chromatography is followed the tracks of and is reacted; Raw material disappears, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-7-[3-amino-4-(2,4,5-three fluoro-phenyl)-butyryl radicals]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-nitrile hydrochloride 76 (0.06g, white solid), yield: 56.7%.
MS?m/z(ESI)：432.1[M+1]
1HNMR(400MHz，CD 3OD)：δ7.43-7.39(m，1H)，7.30-7.26(m，1H)，5.01(m，2H)，4.36-4.28(m，2H)，4.12-4.09(m，1H)，4.02-3.94(m，2H)，3.12-3.10(m，2H)，3.03-2.99(m，1H)，2.88-2.81(m，1H)
Embodiment 77
(R)-5-{7-[3-amino-4-(2,4, the 5-trifluorophenyl) butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-N-methyl furan-2-carboxamide hydrochloride
Figure GPA00000755172001151
The first step
(R)-{ 3-[1-(5-aldehyde radical-furans-2-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4,5-three fluoro-benzyls)-propyl group }-t-butyl carbamate
With (R)-[3-(1-bromo-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4, the 5-trifluoro-benzyl)-propyl group]-t-butyl carbamate 12b (1.308g; 2.23mmol), 5-aldehyde radical furans-2-ylboronic acid (0.469g, 3.35mmol), four triphenyl phosphatization palladium (0.127g; 0.11mmol), four butyl bromation amine (0.145g, 0.45mmol) and salt of wormwood (0.925g 6.69mmol) puts into the microwave reaction pipe; Add 7mL dme and 3.5mL water again, tube sealing after the argon replaces, 140 ℃, microwave reacted 70 minutes down; Thin-layer chromatography is followed the tracks of reaction, and the small number of materials unreacted is arranged, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-{ 3-[1-(5-aldehyde radical-furans-2-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; 5-three fluoro-benzyls)-propyl group }-t-butyl carbamate 77a (0.8g, yellow solid), yield: 59.7%.
MS?m/z(ESI)：623.0[M+23]
Second step
(R)-5-{7-[uncle's 3-fourth oxanamide-4-(2,4,5-three fluoro-phenyl)-butyryl]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-furans-2-carboxylic acid
With (R)-{ 3-[1-(5-aldehyde radical-furans-2-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; 5-three fluoro-benzyls)-propyl group }-t-butyl carbamate 77a (0.85g, 1.42mmol) stirring is dissolved in the mixing solutions of 30mL THF and 15mL water down, adds two hypophosphite monohydrate sodium dihydrogens (0.663g then successively; 4.25mmol), Textone (0.384g, 4.25mmol) and 2-methyl-2-butene (0.298g; 4.25mmol), stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction; The small number of materials unreacted is arranged, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-5-{7-[uncle's 3-fourth oxanamide-4-(2,4,5-three fluoro-phenyl)-butyryl]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl }-furans-2-carboxylic acid 77b (0.13g, yellow oily solid), yield: 14.9%.
MS?m/z(ESI)：615.2[M-1]
The 3rd step
(R)-{ 3-[1-(5-methyl carboxamide-furans-2-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4,5-three fluoro-benzyls)-propyl group }-t-butyl carbamate
With 5-{7-[uncle's 3-fourth oxanamide-4-(2,4,5-three fluoro-phenyl)-butyryl]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl }-(0.13g 0.21mmol) is dissolved in the 5mL methylene dichloride under the stirring furans-2-carboxylic acid 77b, adds Monomethylamine hydrochloride (0.029g successively; 0.42mmol), two (2-oxo-3-oxazolidinyl) inferior phosphoryl chloride (0.107g, 0.42mmol) and triethylamine (0.064g; 0.63mmol), stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-{ 3-[1-(5-methyl carboxamide-furans-2-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4; 5-three fluoro-benzyls)-propyl group }-t-butyl carbamate 77c (0.05g, white solid), yield: 37.9%.
MS?m/z(ESI)：652.2[M+23]
The 4th step
(R)-5-{7-[3-amino-4-(2,4, the 5-trifluorophenyl) butyryl radicals]-3-trifluoromethyl-imidazo [1,5-a] piperazine-1-yl }-N-methyl furan-2-carboxamide hydrochloride
With (R)-{ 3-[1-(5-methyl carboxamide-furans-2-yl)-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl]-3-oxo-1-(2,4,5-three fluoro-benzyls)-propyl group }-t-butyl carbamate 77c (0.05g; 0.08mmol) be dissolved in the 3mL ETHYLE ACETATE under stirring, adding the ethyl acetate solution of 2mL 3N hydrogenchloride again, stirring reaction spends the night under the room temperature; Thin-layer chromatography is followed the tracks of reaction, and raw material disappears, and filters; Solid is washed (2mL * 3) with ETHYLE ACETATE, collects solid, vacuum-drying; Obtain title product (R)-5-{7-[3-amino-4-(2,4, the 5-trifluorophenyl) butyryl radicals]-3-trifluoromethyl-imidazo [1; 5-a] piperazine-1-yl }-N-methyl furan-2-carboxamide hydrochloride 77 (0.036g, yellow solid), yield: 80.0%.
MS?m/z(ESI)：530.2[M+1]
Embodiment 78
(R)-3-amino-1-(1-chloro-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4,5-three fluoro-phenyl)-Ding-1-keto hydrochloride
Figure GPA00000755172001171
The first step
(R)-[3-(1-chloro-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4,5-three fluoro-benzyls)-propyl group]-t-butyl carbamate
With (R)-[3-oxo-1-(2,4, the 5-trifluoro-benzyl)-3-(3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-propyl group]-t-butyl carbamate 1j (0.11g; 0.217mmol) stir down and be dissolved in the 15mL absolute ethyl alcohol adding 1-chloro-Pyrrolidine-2,5-diketone (0.058g; 0.435mmol), stirring reaction spends the night under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-[3-(1-chloro-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4; 5-three fluoro-benzyls)-propyl group]-t-butyl carbamate 78a (0.06g, white solid), yield: 51.3%.
MS?m/z(ESI)：540.8[M+1]
Second step
(R)-3-amino-1-(1-chloro-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4,5-three fluoro-phenyl)-Ding-1-keto hydrochloride
With (R)-[3-(1-chloro-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-3-oxo-1-(2,4,5-three fluoro-benzyls)-propyl group]-t-butyl carbamate 78a (55mg; 0.1mmol) put into reaction flask, add 6mL ETHYLE ACETATE, stir and make its dissolving; Add 3mL 3N hydrogenchloride ethyl acetate solution again, stirring reaction is 2 hours under the room temperature, and thin-layer chromatography is followed the tracks of reaction; Raw material disappears, and the concentrating under reduced pressure reaction solution is with silica gel column chromatography purifying gained resistates; Obtain title product (R)-3-amino-1-(1-chloro-3-trifluoromethyl-imidazo [1,5-a] piperazine-7-yl)-4-(2,4; 5-three fluoro-phenyl)-and Ding-1-keto hydrochloride 78 (40mg, faint yellow solid), yield: 85.1%.
1HNMR(400MHz，CD 3OD)：δ7.37(m，1H)，7.23(m，1H)，4.76(m，2H)，4.30(m，2H)，3.93(m，3H)，3.10(m，2H)，2.85(m，2H)，2.00(s，2H)。
Test case:
Biological assessment
DPP IV suppresses active mensuration
Following method is to be used for measuring the ability that The compounds of this invention suppresses the DPPIV enzymic activity.The inhibiting rate of each compound or 503nhibiting concentration IC 50(suppressing enzymic activity to 50% o'clock compound concentrations of surveying) is to measure with the enzyme mixing substrate of fixed amount and the testing compound of different concns.
DPP IV suppresses active mensuration
Material and method:
Material:
A. white 96 orifice plates (BMG)
The b.Tris damping fluid: the Tris damping fluid of preparation 100mL 2mM is dissolved in about 90mLdH with 0.0242g Tris 2Among the O, regulate pH to 8.00, add dH at last with HCl and NaOH 2O to 100mL.
C.DPPIV enzyme (CalBiochem Catalog no.317630) is dissolved in the Tris damping fluid to 2mM.
D.DPPIV-Glo TMSubstrate (Promega Catalog no.G8350) is dissolved in dH 2Among the O to 1mM.
E.DPPIV-Glo. damping fluid (Promega Catalog no.G8350)
F. resorcinolphthalein detection reagent (Promega Catalog no.G8350)
g.DMSO
h.dH 2O
Operation:
Undertaken by following working order:
1. before using, the DPPIV-Glo. that thaws cushions and equilibrates to room temperature.
2. the frozen resorcinolphthalein detection reagent of buffering before using.
3. suspension DPPIV-Glo. adds in substrate after ultrapure water slightly mixes, and processes the substrate of 1mM.
4. the resorcinolphthalein detection reagent is put into amber bottle, add DPPIV-Glo..The resorcinolphthalein detection reagent should be dissolved in 1 minute.
With the DMSO dissolving institute compound of surveying to finally operating 50 times of concentration.
6. the compound of the surveying 2 μ L of institute that add 50 times of concentration in each test tube close adding 2 μ LDMSO in the blank in negative control.
7. in each test tube, add 46 μ L Tris damping fluids, in blank, add 48 μ L Tris damping fluids.
8. in each test tube of negative control and test specimens, add 2 μ LDPPIV enzymes.
9. vibration mixes and centrifuge tube.Material in the test tube is all transferred on the 96-well flat board.
10. mixing substrate and DPPIV-Glo. ratio is 1: 49.Vibration is mixed to thorough mixing.At room temperature left standstill before the use 30-60 minute.
11. in each 96-well plate well, add the mixed solution of 50 μ L DPPIV-Glo. and substrate, seal flat board with the envelope film.
12. under 300-500rpm/30s, slowly mix material in 96 holes with oscillator plate.At room temperature cultivated 30 minutes to 3 hours.
13. write down luminous.
Inhibiting rate definition: [1-(S-B)/(N-B)] * 100%
S: sample
B: blank
N: negative control
IC 50Value
The embodiment numbering IC 50(DPPIV)(μM)
MK-0431 0.023
1 0.14
2 0.15
3 0.07
4 0.037
5 0.023
6 0.004
7 0.23
8 0.2
9 0.42
10 0.22
11 0.8
12 0.1
13 0.38
14 0.16
15 0.47
16 0.019
17 0.027
18 0.009
19 0.06
20 0.06
21 0.52
22 0.18
23 0.13
24 0.011
25 0.87
26 0.027
27 0.015
28 0.015
29 0.076
38 0.197
42 0.147
45 0.039
49 0.73
50 0.12
55 0.133
59 0.304
60 0.054
63 0.19
64 0.089
65 0.051
66 0.051
67 0.061
68 0.06
69 1.46
70 0.11
71 0.046
72 0.011
76 0.011
77 0.025
78 0.036

Claims (17)

1. compound or pharmacy acceptable salt by general formula (I) expression:
Figure FSB00000789632300011
Wherein:
Ar is a phenyl, and this phenyl is further replaced by 1～5 halogen;
R 1Be C 1-10Alkyl, wherein C 1-10Alkyl is further replaced by one or more halogen;
R 2Be selected from Wasserstoffatoms, halogen, cyanic acid, amino, C 1-10Alkyl, C 3-8Monocyclic cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-NR 3R 4,-NR 3C (O) R 4, C wherein 3-8Monocyclic cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl are further by one or more halogen, amino, cyanic acid, nitro, hydroxyl, C of being selected from 1-10Alkyl, C 1-10Alkoxyl group, C 1-10Tri haloalkyl ,-NR 3R 4,-NR 3C (O) R 4,-C (O) NR 3R 4,-COR 5Or-SO 2R 6Substituting group replace;
R 3And R 4Be selected from Wasserstoffatoms, C independently of one another 1-10Alkyl, C 3-8Monocyclic cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or-SO 2R 6, C wherein 1-10Alkyl, C 3-8Monocyclic cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are further by one or more halogen, hydroxyl, amino, C of being selected from 1-10Alkoxyl group, C 1-10Alkyl ,-COR 5,-SO 2R 6, carboxyl or carboxylic acid ester groups substituting group replace, wherein carboxylicesters refers to (C 1-10Alkyl) C (=O) O (C 1-10Alkyl);
Perhaps, R 3And R 4Form 4～8 yuan of heterocyclic radicals together, wherein 4～8 yuan of heterocycles contain one or more N, O, S atom, and on 4～8 yuan of heterocycles further by one or more halogen, C of being selected from 1-10Alkyl, hydroxyl, cyanic acid, C 1-10Alkoxyl group, C 1-10The substituting group of hydroxyalkyl replaces;
R 5Be selected from Wasserstoffatoms or C 1-10Alkyl;
R 6Be selected from C 1-10Alkyl or aryl, wherein aryl is further by one or more C 1-10Alkyl replaces;
Described " aryl " is phenyl;
Described " heteroaryl " is selected from oxygen, sulphur and nitrogen heteroatom for having 1～3, and other annular atoms is the 5-6 unit hetero-aromatic ring of carbon;
Described " Heterocyclylalkyl " is selected from the heteroatomic monocyclic groups of nitrogen, oxygen or S (O) n for having 1～2, and wherein n is 0～2 integer, and other annular atoms is a carbon, and has 5～9 yuan of rings of one or more pairs of keys.
2. compound according to claim 1 or its pharmacy acceptable salt, wherein R 1Be trifluoromethyl.
3. a compound or its pharmacy acceptable salt, wherein this compound pharmacy acceptable salt is selected from:
Figure FSB00000789632300021
Figure FSB00000789632300031
Figure FSB00000789632300041
Figure FSB00000789632300051
4. a compound or its pharmacy acceptable salt, wherein this compound is selected from:
Figure FSB00000789632300052
Figure FSB00000789632300061
Figure FSB00000789632300071
Figure FSB00000789632300081
Figure FSB00000789632300091
5. compound according to claim 1 or its pharmacy acceptable salt, described salt are said compound and the salt that is selected from following acid formation: oxysuccinic acid, lactic acid, toxilic acid, hydrochloric acid, methylsulfonic acid, sulfuric acid, phosphoric acid, Hydrocerol A, tartrate, acetate or trifluoroacetic acid.
6. general formula compound (IA), said compound is the midbody of synthetic general formula according to claim 1 (I) compound:
Figure FSB00000789632300092
Wherein:
R 1Be C 1-10The wherein said C of alkyl 1-10Alkyl is further replaced by one or more halogen;
R 2Be selected from Wasserstoffatoms, halogen, cyanic acid, amino, C 1-10Alkyl, C 3-8Monocyclic cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-NR 3R 4,-NR 3C (O) R 4, C wherein 3-8Monocyclic cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl are further by one or more halogen, amino, cyanic acid, nitro, hydroxyl, C of being selected from 1-10Alkyl, C 1-10Alkoxyl group, C 1-10Tri haloalkyl ,-NR 3R 4,-NR 3C (O) R 4,-C (O) NR 3R 4,-COR 5Or-SO 2R 6Substituting group replace;
Condition is to work as R 2During for Wasserstoffatoms, R 1Be selected from trifluoromethyl;
R 3And R 4Be selected from Wasserstoffatoms, C independently of one another 1-10Alkyl, C 3-8Monocyclic cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or-SO 2R 6, C wherein 1-10Alkyl, C 3-8Monocyclic cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are further by one or more halogen, hydroxyl, amino, C of being selected from 1-10Alkoxyl group, C 1-10Alkyl ,-COR 5,-SO 2R 6, carboxyl or carboxylic acid ester groups substituting group replace, wherein carboxylicesters refers to (C 1-10Alkyl) C (=O) O (C 1-10Alkyl);
Perhaps, R 3And R 4Form 4～8 yuan of heterocyclic radicals together, wherein 4～8 yuan of heterocycles contain one or more N, O, S atom, and on 4～8 yuan of heterocycles further by one or more halogen, C of being selected from 1-10Alkyl, hydroxyl, cyanic acid, C 1-10Alkoxyl group, C 1-10The substituting group of hydroxyalkyl replaces;
R 5Be selected from Wasserstoffatoms or C 1-10Alkyl;
R 6Be selected from C 1-10Alkyl or aryl, wherein aryl is further by one or more C 1-10Alkyl replaces;
Described " aryl " is phenyl;
Described " heteroaryl " is selected from oxygen, sulphur and nitrogen heteroatom for having 1～3, and other annular atoms is the 5-6 unit hetero-aromatic ring of carbon;
Described " Heterocyclylalkyl " is selected from the heteroatomic monocyclic groups of nitrogen, oxygen or S (O) n for having 1～2, and wherein n is 0～2 integer, and other annular atoms is a carbon, and has 5～9 yuan of rings of one or more pairs of keys.
7. general formula compound according to claim 6 (IA), wherein R 1It is trifluoromethyl.
8. the preparation method of general formula compound according to claim 6 (IA), this method comprises:
Figure FSB00000789632300101
With raw material R 2Substituted pyrazine 2-methylamine and acid anhydrides react, and the amide product of generation adds Vanadium Pentoxide in FLAKES with after POCl3 at room temperature mixes stirring, generates imidazo [1,5-a] pyrazine ring, and under Pd/C catalysis, hydro-reduction generates general formula compound (IA) then.
9. the preparation method of general formula compound according to claim 6 (IA), this method comprises:
Figure FSB00000789632300102
With general formula compound (IB) under the catalysis of palladium class reagent; React under microwave with boric acid or boric acid ester, carry out the Suzuki coupling, or under catalytic condition, carry out the Buchwald coupling with substitutional amine-group; Obtain the protection base of product desamidizate under acidic conditions, obtain general formula compound (IA);
R 1Be C 1-10Alkyl, wherein said C 1-10Alkyl is further replaced by one or more halogen;
R 2Be selected from halogen, cyanic acid, amino, C 1-10Alkyl, C 3-8Monocyclic cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-NR 3R 4Or-NR 3C (O) R 4, C wherein 3-8Monocyclic cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl are further by one or more halogen, amino, cyanic acid, nitro, hydroxyl, C of being selected from 1-10Alkyl, C 1-10Alkoxyl group, C 1-10Tri haloalkyl ,-NR 3R 4,-NR 3C (O) R 4,-C (O) NR 3R 4,-COR 5Or-SO 2R 6Substituting group replace;
R 3And R 4Be selected from Wasserstoffatoms, C independently of one another 1-10Alkyl, C 3-8Monocyclic cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or-SO 2R 6, C wherein 1-10Alkyl, C 3-8Monocyclic cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are further by one or more halogen, hydroxyl, amino, C of being selected from 1-10Alkoxyl group, C 1-10Alkyl ,-COR 5,-SO 2R 6, carboxyl or carboxylic acid ester groups substituting group replace, wherein carboxylicesters refers to (C 1-10Alkyl) C (=O) O (C 1-10Alkyl);
Perhaps, R 3And R 4Form 4～8 yuan of heterocyclic radicals together, wherein 4～8 yuan of heterocycles contain one or more N, O, S atom, and on 4～8 yuan of heterocycles further by one or more halogen, C of being selected from 1-10Alkyl, hydroxyl, cyanic acid, C 1-10Alkoxyl group, C 1-10The substituting group of hydroxyalkyl replaces;
R 5Be selected from Wasserstoffatoms or C 1-10Alkyl;
R 6Be selected from C 1-10Alkyl or aryl, wherein aryl is further by one or more C 1-10Alkyl replaces;
Described " aryl " is phenyl;
Described " heteroaryl " is selected from oxygen, sulphur and nitrogen heteroatom for having 1～3, and other annular atoms is the 5-6 unit hetero-aromatic ring of carbon;
Described " Heterocyclylalkyl " is selected from the heteroatomic monocyclic groups of nitrogen, oxygen or S (O) n for having 1～2, and wherein n is 0～2 integer, and other annular atoms is a carbon, and has 5～9 yuan of rings of one or more pairs of keys.
X is selected from halogen.
10. the preparation method of general formula according to claim 1 (I) compound, this method comprises:
General formula compound according to claim 6 (IA) carries out condensation with 3-tert-butoxycarbonyl amino-4-aryl-butyric acid under the condition of two (2-oxo-3-oxazolidinyl) the inferior phosphonyl chlorides of condensation reagent; The product that obtains is desamidizate protection base under acidic conditions, obtains general formula compound (I).
11. the preparation method of general formula according to claim 1 (I) compound, this method comprises:
Figure FSB00000789632300112
React under the condition of two (2-oxo-3-oxazolidinyl) the inferior phosphonyl chlorides of condensation reagent with 3-tert-butoxycarbonyl amino-4-aryl-butyric acid behind general formula compound (IB) the deprotection base; The condensation product that obtains is under the catalysis of palladium class reagent; Further under microwave, react with boric acid or boric acid ester; Carry out the Suzuki coupling, obtain general formula compound (I); Condensation product also can with substitutional amine-group under catalytic condition, carry out the Buchwald coupling, obtain general formula compound (I); Condensation product also can be in oil bath; As catalyzer, with the alcohol reaction, the substituted carboxylic acid ester cpds that obtains further is hydrolyzed into carboxylic acid under carbon monoxide atmosphere with cobalt octacarbonyl and ethyl chloroacetate; With the acid amides that the volatile salt reaction generates, further dehydration generates R 2General formula compound (I) for cyanic acid;
X is selected from halogen, R 1Definition such as claim 1 described in.
12. according to each described preparation method in the claim 10～11, wherein also comprise the purified back of the general formula that obtains (I) compound reacted in methyl alcohol, methylene dichloride or the ethyl acetate solution of acid, obtain its sour adduct salt.
13. preparation method according to claim 12, wherein said acid is selected from oxysuccinic acid, lactic acid, toxilic acid, hydrochloric acid, methylsulfonic acid, sulfuric acid, phosphoric acid, Hydrocerol A, tartrate, acetate or trifluoroacetic acid.
14. a pharmaceutical composition, its contain the treatment effective dose according to any one described compound or its pharmacy acceptable salt in the claim 1～4, and pharmaceutically acceptable carrier or vehicle.
15. compound according to claim 1 or its pharmacy acceptable salt purposes in the medicine of preparation treatment type ii diabetes, hyperglycemia, obesity or insulin resistant disease.
16. the method for a vitro inhibition DPP IV catalytic activity is comprising any one described compound in described DPP IV and the claim 1～4 or salt are contacted.
17. the purposes of pharmaceutical composition according to claim 14 in the medicine of preparation treatment type ii diabetes, hyperglycemia, obesity or insulin resistant disease.
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