CN106478631A - The preparation method of long-acting dipeptidyl peptidase-iv inhibitor, purposes and its intermediate - Google Patents

The preparation method of long-acting dipeptidyl peptidase-iv inhibitor, purposes and its intermediate Download PDF

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CN106478631A
CN106478631A CN201510522308.7A CN201510522308A CN106478631A CN 106478631 A CN106478631 A CN 106478631A CN 201510522308 A CN201510522308 A CN 201510522308A CN 106478631 A CN106478631 A CN 106478631A
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amino
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CN106478631B (en
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谢益农
游泽金
宋占波
苏瑞飞
邓智文
王亚君
陈兴
曾宏
宋宏梅
齐伟
王利春
王晶翼
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Sichuan Kelun Botai biological pharmaceutical Limited by Share Ltd
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Sichuan Kelun Pharmaceutical Research Institute Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The present invention relates to the preparation method of long-acting inhibitors of dipeptidyl IV, purposes and its intermediate, in particular it relates to below general formula（1）Shown compound and preparation method thereof, described compound include diabetes, the application especially in DPP 4 relevant disease of type ii diabetes treating and preventing, and containing the pharmaceutical composition of described formula (1) compound and pharmaceutical preparation, in formula the definition of each symbol with identical in description.

Description

The preparation method of long-acting dipeptidyl peptidase-iv inhibitor, purposes and its intermediate
Technical field
The present invention relates to compound as dipeptidyl peptidase-IV (DPP-4) inhibitor and its treating and preventing the application including in the treatment diabetes especially DPP-4 relevant disease of II patients with type Ⅰ DM.The invention still further relates to preparing the preparation method of above-claimed cpd and its intermediate.The invention still further relates to comprising the pharmaceutical composition of these compounds, and purposes in the prevention or treatment of this kind of disease relevant with dipeptidyl peptidase-IV for these compositionss.
Background technology
Diabetes are the chronic metabolic diseases being caused by the effect of the various virulence factor such as inherited genetic factorss, immunologic function disorder, microorganism infection and its toxin, free radical toxin, Nervous and Mental Factors, clinically with hyperglycemia as cardinal symptom.It can be divided into type i diabetes (insulin-dependent), the diabetes of type ii diabetes (non-insulin-depending type), gestational diabetes and other specific types.In diabeticss, the ratio shared by II patients with type Ⅰ DM is about 90%.
Traditional oral antidiabetic drug species is various, including sulphanylureas (SU), biguanides etc., but typically all with body weight increase, toleration is limited, the problems such as side effect such as hypoglycemia and drug effect are gradually lowered, therefore, people are look for new medicine, just under study for action, the achievement that the drug research wherein with dipeptidyl peptidase-IV (DPP-4) as target spot obtains is especially prominent for many new therapy target（Non-patent literature 1）.
DPP IV (DPP-4) is a kind of serine protease. there are some researches show that DPP-4 can stop the secretion of glucagon-like peptide (GLP) -1, especially, it can crack group-the third dipeptidase of N- end in GLP-1 so as to be degraded to inactive GLP-1 (9-36) NH2 (non-patent literature 2) from GLP-1 (7-36) NH2 of activity form.Glucagon-like-peptide-1 (GLP-1) is that the effect having glucose dependency insulin secretion accelerating and increasing biological insulin synthesis, therefore using GLP-1 by a kind of hormone of islets of langerhans A cells and the secretion of intestinal L- cell Treatment diabetes cause scientist's great interest.GLP-1, in addition to having and promoting insulin secretion effect, also has promotion beta cell hypertrophy, the generation of anti-beta cell apoptosis, glucagon suppression and glycogen, appetite-suppressing, reduces the physiological functions such as gastrointestinal emptying speed, protection neurocyte.These features of GLP-1 become preferable Remedies for diabetes.However, the GLP-1 only several minutes of half-life in vivo, rapidly by endogenouss dipeptidyl peptidase-IV (DPP-4) Degraded（Remove N end dipeptides）, and lose insulin secretion accelerating activity (non-patent literature 3).
DPP-4 is widely distributed in human body, is the main metabolic enzyme of GLP-1, in regulation and control GLP-1 Play an important role in activity.The reactive compound of therefore suppression DPP-4 is DPP-4 inhibitor, can strengthen the effect of GLP-1.In addition, DPP-4 inhibitor also has promotion β-hyperplasia, the generation of anti-β-apoptosis, glucagon suppression and glycogen, appetite-suppressing, does not put on weight, and reduces the effects such as gastrointestinal emptying speed, protection neurocyte.Therefore, DPP-4 inhibitor can be additionally used in the treatment (non-patent literature 4) of various the diseases such as obesity and hyperlipidemia related to dipeptidyl peptidase.
From after the crystal structure report of DPP-4 in 2003, the DPP-4 inhibitor of multiple new construction types lists in succession in recent years, such as sitagliptin phosphate (the sitagliptin of Merck ＆ Co., Inc.'s research and development Phosphate, in October, 2006 lists in the U.S.) etc..
In addition, patent documentation 1 also discloses that the DPP-4 inhibitor of the structure types such as substituted amino tetrahydro pyran class compound.
However, despite the presence of above-mentioned some DPP-4 inhibitor, but these compounds are satisfactory not enough to the inhibitory activity of DPP-4, lack the selectivity to DPP-2/8/9 enzyme, and also lack long-acting medicine at present.Therefore, the property of people's highly desirable exploitation drug metabolism etc. is improved, activity is higher, toxic and side effects are less, can be used for the novel DPP-4 inhibitor of long-acting structure, so that the treatment various diseases related to DPP-4.
Prior art literature
Non-patent literature
[non-patent literature 1] Medicinal Research Review,2009,29(1),125-195
[non-patent literature 2] Endocrinology, 1999,140：5356～5363
[non-patent literature 3] Expert Opin.Investing.Drugs,2004,13(9):1091-1102
[non-patent literature 4]
Diabetologia,2007,50(6):1148-1155;RegulPept,2008,31(1):108-113
Patent documentation
[patent documentation 1] WO 2007/136603 Al.
Content of the invention
It is an object of the invention to provide a kind of compound as dipeptidyl peptidase-iv inhibitor, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, they can be used for treating and preventing the DPP-4 relevant disease including treatment diabetes, especially II patients with type Ⅰ DM.In further detail, the present invention provides the 3- amino tetrahydro pyran structure with new substituted, has high inhibitory activity and the new compound with excellent pharmacokinetic properties to dipeptidyl peptidase-IV.
In addition, the object of the invention also resides in the Pharmaceutical composition providing for treatment various diseases the, the compounds of this invention containing therapeutically effective amount related to dipeptidyl peptidase-IV and pharmaceutically acceptable carrier or excipient.
In addition, the present invention also aims to providing the therapeutic agent containing this compound pharmaceutically acceptable salt, particularly dipeptidyl peptidase-iv inhibitor, this salifie form has the activity of excellent treatment diabetes, dissolubility is obviously improved, and activity in animal body and its bioavailability are well, toxicity is low it is adaptable to the preparation of diabetes is treated in preparation.
The present inventor is in depth studied to achieve these goals, it is found that：There is the specific compound, i.e. of 3- amino tetrahydro pyran structure, compound shown in aftermentioned logical formula (I) is compared with prior art, have and work through glucose dependency mechanism, the advantage therefore reducing hypoglycemic risk, in addition compared with existing DPP-4 inhibitor, the described compound of the present invention has a more favourable pharmacokinetics performance, more long persistent period, thus completing the present invention.
Specifically, embodiments of the present invention can enumerate content below.
Following formulas（1）Compound, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug representing,
In formula, A ring is unsaturation ring, and A1And A2Connected with singly-bound；
A1、A2、A3、A4And A5It is each independently selected from carbon or nitrogen, and A1、A2、A3、A4And A5In at least 2 be carbon；
R1And R2Independently of one another with A3、A4Or A5In conjunction with, and independently selected from hydrogen atom, cyano group, nitro ,-S (=O)2R3、-R4-COOH、-R4COOR5, optionally it is selected from the sulfydryl of the substituent group replacing basis set a, optionally it is selected from the amino of the substituent group replacing basis set a, optionally it is selected from the sulfinyl of the substituent group replacing basis set a, optionally it is selected from the C1-6 alkyl of the substituent group replacing basis set a, optionally it is selected from the C1-6 alkoxyl of the substituent group replacing basis set a, optionally it is selected from the C2-6 alkanoyl of the substituent group replacing basis set a, optionally it is selected from the C3-8 cycloalkyl of the substituent group replacing basis set a, optionally it is selected from the C6-10 aryl of the substituent group replacing basis set a, optionally it is selected from the 5-11 circle heterocycles base of the substituent group replacing basis set a, or-R8(C=O)-N R6R7；
Wherein R3Selected from hydroxyl, optionally it is selected from the alkyl of the substituent group replacing basis set a, optionally it is selected from the cycloalkyl of the substituent group replacing basis set a, optionally it is selected from the amino of the substituent group replacing basis set a, optionally it is selected from the amino C2-6 alkanoyl of the substituent group replacing basis set a, optionally it is selected from the amino carbonyl amino of the substituent group replacing basis set a, optionally it is selected from the C6-10 aryl of the substituent group replacing basis set a, optionally it is selected from the 5-11 circle heterocycles base of the substituent group replacing basis set a；
R4For singly-bound or C1-6 alkylidene, C2-6 alkenylene or C2-6 alkynylene；
R5For amino, C1-6 alkyl, C2-6 thiazolinyl or C2-6 alkynyl；
R6And R7It is each independently hydrogen, hydroxyl, be optionally selected from the C1-6 alkyl of the substituent group replacing basis set a, be optionally selected from the C3-8 cycloalkyl of the substituent group replacing basis set a, be optionally selected from the amino of the substituent group replacing basis set a；
R8For singly-bound, C1-6 alkylidene, C2-6 alkenylene or C2-6 alkynylene,
Premise is to work as A1、A2、A3And A4In 2 be nitrogen when, if R1And R2In a side be hydrogen atom, then R1And R2In the opposing party be not hydrogen atom and the alkyl being substituted with halogen atoms；Ar is the C6-10 aryl being optionally selected from, by 1～5, the substituent group replacing basis set a；
Replace basis set a：By C1-6 alkyl, C2-6 thiazolinyl, C2-6 alkynyl, the C1-6 alkyl of halogenation, halogen ,-CN, NHOH ,-OH ,-O-C1-6 alkyl ,-NH-C1-6 alkyl ,-N (C1-6 alkyl)2、-NH2、-C(=NH)-NH-CH3、-C(=NH)-N(CH3)2、-C(=NH)-NH2、-C(=NH)-NH 2、-C(O)NH2,-C (O) NH-C1-6 alkyl ,-C (O) N (C1-6 alkyl)2、 - NHC (O)-C1-6 alkyl ,-NHC (O)-C3-8 cycloalkyl ,-N (C1-6 alkyl) C (O) H ,-N (C1-6 alkyl) C (O)-C1-6 alkyl ,-NHC (O) NH2Composition.
Compound of the present invention, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein,
(1)A1For N, A2For C, A3For N, A4For C, A5For N, or
(2)A1For N, A2For C, A3For C, A4For C, A5For N, or
(3)A1For N, A2For C, A3For N, A4For N, A5For C, or
(4)A1For N, A2For C, A3For C, A4For N, A5For C, or
(5)A1For N, A2For C, A3For N, A4For C, A5For C, or
(6)A1For C, A2For C, A3For N, A4For N, A5For C, or
(7) A1For C, A2For C, A3For C, A4For N, A5For N.
Compound of the present invention, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein, under the either case of above-mentioned (1)～(5), A2With A3Between and A4With A5Between be double bond,
In the case of above-mentioned (6) or (7), A2With A3Between and A1With A5Between be double bond.
Compound of the present invention, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein,
R1、R2It is separately hydrogen atom ,-S (=O)2- C1-6 alkyl ,-S (=O)2- C3-8 cycloalkyl ,-S (=O)2-N（C1-6 alkyl）2、-S(=O)2- C2-6 alkanoyl, C6-10 aryl C1-6 the alkyl ,-S (=O) being replaced by C1-6 alkyl2- amino carbonyl amino ,-COO-C1-6 alkyl, the amino being replaced by C1-6 alkyl, the C1-6 alkyl being substituted with halogen atoms, C1-6 alkoxyl, C3-8 cycloalkyl, C6-10 aryl, C6-10 aryl C1-8 alkoxyl, C1-6 alkylthio group, 5-11 circle heterocycles base ,-(C=O)-NH-C1-6 alkyl ,-(C=O)-N（C1-6 alkyl）2,-(C=O)-NH-C3-8 cycloalkyl ,-(C=O)-N（C3-8 cycloalkyl）2, C1-6 alkyl sulphinyl or single C1-6 alkyl amino-carbonyl or two C1-6 alkyl amino-carbonyls.
Compound of the present invention, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein, R1、R2It is separately hydrogen atom, amino ,-S (=O)2-CH3、-S(=O)2-CH2CH3、-S(=O)2-CH(CH3)2、-S(=O)2-OH、-S(=O)2- cyclopropyl ,-S (=O)2-NH2、-S(=O)2-N（CH3）2、-S(=O)2- NH -C(=NH)-NH-CH3、-S(=O)2- NH -C(=O)-NH-( CH2)2CH3、-S(=O)2- NH -C(=NH)-NH2、- NH -C(=NH)-NH-CH3、-S(=O)2- NH -C(=NH)-N（CH3）2、-COOH、-COOCH3、-COOCH2CH3、-NH2、-CF3、-N(CH3)2、-COONH2Or-(C=O)-NH2.
Compound of the present invention, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein, Ar is the phenyl optionally being replaced by 1～5 halogen atom.
Compound of the present invention, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein, described compound be selected from following formula (a),（b）、（c）、（d）、（e）、（f）、（g）, and（h）In any one compound,
Wherein, Ar is the phenyl optionally being replaced by 1～5 halogen atom,
R9、R10, and R11It is each independently selected from hydrogen atom, cyano group, nitro ,-S (=O)2R3、-R4-COOH、-R4COOR5, optionally it is selected from the sulfydryl of the substituent group replacing basis set a, optionally it is selected from the amino of the substituent group replacing basis set a, optionally it is selected from the sulfinyl of the substituent group replacing basis set a, optionally it is selected from the C1-6 alkyl of the substituent group replacing basis set a, optionally it is selected from the C1-6 alkoxyl of the substituent group replacing basis set a, optionally it is selected from the C2-6 alkanoyl of the substituent group replacing basis set a, optionally it is selected from the C3-8 cycloalkyl of the substituent group replacing basis set a, optionally it is selected from the C6-10 aryl of the substituent group replacing basis set a, optionally it is selected from the 5-11 circle heterocycles base of the substituent group replacing basis set a, or-R6(C=O)-N R6R7,
Wherein R3、R4、R5、R6、R7、R8Basis set a is identical with the definition in claim 1 with replacing.
Compound of the present invention, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein, R9、R10, and R11It is each independently selected from hydrogen atom ,-S (=O)2- C1-6 alkyl ,-S (=O)2- C3-8 cycloalkyl ,-S (=O)2-N（C1-6 alkyl）2、-S(=O)2- C2-6 alkanoyl, C6-10 aryl C1-6 the alkyl ,-S (=O) being replaced by C1-6 alkyl2- amino carbonyl amino ,-COO-C1-6 alkyl, the amino being replaced by C1-6 alkyl, the C1-6 alkyl being substituted with halogen atoms, C1-6 alkoxyl, C3-8 cycloalkyl, C6-10 aryl, C6-10 aryl C1-8 alkoxyl, C1-6 alkylthio group, 5-11 circle heterocycles base ,-(C=O)-NH-C1-6 alkyl ,-(C=O)-N（C1-6 alkyl）2,-(C=O)-NH-C3-8 cycloalkyl ,-(C=O)-N（C3-8 cycloalkyl）2, C1-6 alkyl sulphinyl or single C1-6 alkyl amino-carbonyl or two C1-6 alkyl amino-carbonyls.
Compound of the present invention, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein, R9、R10, and R11It is each independently selected from hydrogen atom, amino ,-S (=O)2-CH3、-S(=O)2-CH2CH3、-S(=O)2-CH(CH3)2、-S(=O)2-OH、-S(=O)2- cyclopropyl ,-S (=O)2-NH2、-S(=O)2-N（CH3）2、-S(=O)2- NH -C(=NH)-NH-CH3、-S(=O)2- NH -C(=O)-NH-( CH2)2CH3、-S(=O)2- NH -C(=NH)-NH2、- NH -C(=NH)-NH-CH3、-S(=O)2- NH -C(=NH)-N（CH3）2、-COOH、-COOCH3、-COOCH2CH3、-NH2、-CF3、-N(CH3)2、-COONH2Or-(C=O)-NH2.
Compound of the present invention, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein, described compound is selected from following compounds,
.
Compound of the present invention, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, it is used as dipeptidyl peptidase-IV inhibitor.
Pharmaceutical composition, it contains described compound, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, and pharmaceutically acceptable carrier or excipient.
Pharmaceutical composition of the present invention, wherein, comprising further can be with described compound, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or other active substance associated with its prodrug.
Pharmaceutical composition of the present invention, wherein, described other active substance is metformin or its salt or pioglitazone etc..
Pharmaceutical composition of the present invention contains compound 0.01-1000mg of the present invention, is suitably 0.5-800mg, preferably 1-400mg, more preferably 5-200mg, particularly preferred 10-100mg, most preferably 15-50mg.Pharmaceutical preparation of the present invention etc. can be unit dosage form, and unit dose contains compound 0.01-1000mg of the present invention, is suitably 0.5-800mg, it is preferably 1-400mg, more preferably 5-200mg, particularly preferred 10-100mg, most preferably 15-50mg, such as 20mg, 25mg, 30mg.
One kind is suitable for administration to animal, the pharmaceutical preparation of especially mammal, wherein, said preparation comprises compound of the present invention, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug as effective ingredient, and said preparation includes solid preparation, semi-solid preparation, liquid preparation, gaseous state preparation etc..
The treatment of the disease related to dipeptidyl peptidase-IV or preventive, it contains described compound, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug as effective ingredient.
Compound of the present invention, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, or itself and application in the medicine of the disease related with dipeptidyl peptidase-IV for preparation treatment for the mixture associated with other active substances.
The compound of the present invention has very high inhibitory activity and selectivity to dipeptidyl peptidase-IV, has very excellent pharmacokinetic properties and toxic and side effects are less, can be used as long-acting dipeptidyl peptidase-iv inhibitor, to treat the various diseases related to dipeptidyl peptidase-IV.
Application of the present invention, wherein related to dipeptidyl peptidase-IV disease includes diabetes, obesity, insulin resistance or hyperlipidemia.
Compound of the present invention, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, or itself and the method for treating the disease related with dipeptidyl peptidase-IV for the mixture associated with other active substances.
Method of the present invention, containing compound 0.01-1000mg of the present invention, is suitably 0.5-800mg, preferably 1-400mg, more preferably 5-200mg, particularly preferred 10-100mg, most preferably 15-50mg.Pharmaceutical preparation of the present invention etc. can be unit dosage form, and unit dose contains compound 0.01-1000mg of the present invention, is suitably 0.5-800mg, preferably 1-400mg, more preferably 5-200mg, particularly preferred 10-100mg, most preferably 15-50mg.
Specific embodiment
The meaning of each term using in this manual is below described.Each term is used with the unified meaning, when being used alone, or when being applied in combination with other terms, is all looked like with identical and uses.
In the present invention, " being optionally selected from the substituent group replacing basis set a " refers to be replaced with the identical or different substituent group selected from replace basis set a more than 1 or 2 in arbitrary position.
In the present invention, " being replaced by C1-6 alkyl " refers to be replaced with the identical or different substituent group selected from more than 1 or 2 of C1-6 alkyl in arbitrary position.
In the present invention, " halogen atom " represents fluorine atom, chlorine atom, bromine atoms or atomic iodine.
In the present invention, the carbon number of " C1-6 alkyl " expression straight-chain or branched is 1～6 alkyl, can enumerate the group of methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl, tertiary pentyl etc..
In the present invention, the carbon number of " C2-6 thiazolinyl " expression straight-chain or branched is 2～6 thiazolinyl, can enumerate the group of vinyl, positive acrylic, isopropenyl, n-butene base, isobutenyl, secondary cyclobutenyl, tertiary cyclobutenyl, n-pentene base, isopentene group, new pentenyl, tertiary amylene base etc..
In the present invention, the carbon number of " C2-6 alkynyl " expression straight-chain or branched is 2～6 alkynyl, can enumerate the group of acetenyl, positive propinyl, isopropynyl, positive butynyl, butynyl, secondary butynyl, tertiary butynyl, positive pentynyl, isoamyl alkynyl, new pentynyl, tertiary pentynyl etc..
In the present invention, " C3-8 cycloalkyl " can enumerate the group of cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl etc..
In the present invention, " C1-6 alkoxyl " refers to the alkoxyl that the carbon number of straight-chain or branched is 1～6, can enumerate the group of methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyl epoxide, isopentyl epoxide, neopentyl epoxide, tertiary pentyl epoxide etc..
In the present invention, " C1-6 alkylidene ", " C2-6 alkenylene ", " C2-6 alkynylene " refer respectively to eliminate the divalent group of 1 hydrogen atom from above-mentioned " C1-6 alkyl ", " C2-6 thiazolinyl ", " C2-6 alkynyl ".
In the present invention, " C2-6 alkanoyl " refers to the alkanoyl that the carbon number of straight-chain or branched is 2～6, can enumerate the group of acetyl group, propiono, bytyry, isobutyryl, valeryl, isovaleryl, pivaloyl group etc..
In the present invention, " single C1-6 alkyl amino-carbonyl " refers to, with the carbonyl that instead of of amino having 1 above-mentioned " C1-6 alkyl " as substituent group, to enumerate methylaminocarbonyl, ethyl aminocarbonyl, n-propyl amino carbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylamino carbonyl, s-butylamino carbonyl, tert-butylamino carbonyl, n-pentyl amino carbonyl, isopentylaminocarbonyl, neopentyl amino carbonyl etc..
In the present invention, " two C1-6 alkyl amino-carbonyls " refers to the carbonyl that instead of of amino with having 2 identical or different above-mentioned " C1-6 alkyl " as substituent group, can enumerate Dimethylaminocarbonyl, diethylaminocarbonyl, two（N-pro-pyl）Amino carbonyl, two（Isopropyl）Amino carbonyl, ethylmethylaminocarbonyl, methyl（N-pro-pyl）Amino carbonyl, methyl（Isopropyl）Amino carbonyl etc..
In the present invention, " C6-10 aryl " refers to the aryl that monocyclic or multi-ring carbon number is 6-10.When wherein, for polyaromatic, in addition to completely unsaturated, also comprise the group of fractional saturation.Phenyl, naphthyl, base, indenyl, indanyl, tetrahydro naphthyl etc. for example can be enumerated.
In the present invention, " C6-10 aryl C1-6 alkyl " refers to following C6-10 aryl group alkyl linked with above-mentioned C1-6.Benzyl, phenethyl, 3- phenyl-n-pro-pyl, 4- phenyl-n-butyl, 5- phenyl-n-pentyl, 8- phenyl-n-hexyl, menaphthyl etc. for example can be enumerated.
In the present invention, " 5-11 circle heterocycles base " refers to：As the atom constituting ring, also comprise 1～4 heteroatomic 5～7 yuan of aromatic heterocycle selected from nitrogen-atoms, oxygen atom and sulphur atom, saturated heterocyclic, unsaturated heterocycle or these heterocycles outside carbon atom and phenyl ring condenses the annelated heterocycles obtaining.For example can enumerate：2- furyl、3- furyl、2- thienyl、3- thienyl、Pyrroles's -1- base、Pyrroles's -2- base、Pyrroles's -3- base、Pyridine -2- base、Pyridin-3-yl、Pyridin-4-yl、Pyrazine -2- base、Pyrazine -3- base、Pyrimidine -2-base、Pyrimidine-4-yl、Pyrimidine -5- base、Pyrimidine -6- base、Pyridazine -3- base、Pyridazine -4- base、1,3- benzodioxole -4- base、1,3- benzodioxole -5- base、2,3- Dihydrobenzofuranes -4- base、2,3- Dihydrobenzofuranes -5- base、2,3- Dihydrobenzofuranes -6- base、2,3- Dihydrobenzofuranes -7- base、Benzofuran -2- base、Benzofuran -3- base、Benzofuran -4- base、Benzofuran -5- base、Benzofuran -6- base、Benzofuran -7- base、Benzothiophene -2- base、Benzothiophene -3- base、Benzothiophene -4- base、Benzothiophene -5- base、Benzothiophene -6- base、Benzothiophene -7- base、Quinoxaline -2- base、Quinoxaline -5- base、Quinoxalin-6-yl、Indole -1- base、Indole -2- base、Indol-3-yl、Indole -4- base、Indole -5- base、Indole -6- base、Indole -7- base、Iso-indoles -1- base、Iso-indoles -2- base、Iso-indoles -4- base、Iso-indoles -5- base、Iso-indoles -6- base、Iso-indoles -7- base、Isobenzofuran -1- base、Isobenzofuran -4- base、Isobenzofuran -5- base、Isobenzofuran -6- base、Isobenzofuran -7- base、Chromene -2- base、Chromene -3- base、Chromene -4- base、Chromene -5- base、Chromene -6- base、Chromene -7- base、Chromene -8- base、Imidazoles -1- base、Imidazoles -2- base、Imidazol-4 yl、Imidazoles -5- base、Pyrazol-1-yl、Pyrazole-3-yl、Pyrazoles -4- base、Pyrazoles -5- base、Thiazol-2-yl、Thiazole-4-yl、Thiazole -5- base、Azoles -2- base,Azoles -4- base,Azoles -5- base, differentAzoles -3- base, differentAzoles -4- base, differentAzoles -5- base, pyrrolidin-2-yl, pyrrolidin-3-yl, benzimidazole -1- base, benzimidazolyl-2 radicals-base, benzimidazole -4- base, benzimidazole -5- base, benzothiazole -2- base, benzothiazole -4- base, benzothiazole -5- base, benzoAzoles -2- base, benzoAzoles -4- base, benzoAzoles -5- base、Quinoline -2- base、Quinoline -3- base、Quinolyl-4、Quinoline -5- base、Quinoline -6- base、Quinoline -7- base、Quinoline-8-yl、Isoquinolyl-1、Isoquinolin -3- base、Isoquinolin -4- base、Isoquinolin -5- base、Isoquinolin -6- base、Isoquinolin -7- base、Isoquinolin -8- base、1,3,4- thiadiazoles -2- base、Morpholino base、1,2,3- triazol-1-yl、1,2,3- triazole-4-yl、1,2,3- triazole -5- base、1,2,4- triazol-1-yl、1,2,4- triazole -3- base、1,2,4- triazole -5- base、Tetrazolium -1- base、Tetrazolium -2- base、Indoline -4- base、Indoline -5- base、Indoline -6- base、Indoline -7- base、1,2,3,4- tetrahydroquinoline -5- base、1,2,3,4- tetrahydroquinoline -6- base、1,2,3,4- tetrahydroquinoline -7- base、1,2,3,4- tetrahydroquinoline -8- base、1,2,3,4- tetrahydroisoquinoline -5- base、1,2,3,4- tetrahydroisoquinoline -6- base、1,2,3,4- tetrahydroisoquinoline -7- base、1,2,3,4- tetrahydroisoquinoline -8- base etc..
In the present invention, " C6-10 aryl C1-6 alkoxyl " refers to the group of above-mentioned " C6-10 aryl C1-6 alkyl " and oxygen atoms bond.Benzyl epoxide, phenethyl epoxide, menaphthyl epoxide etc. for example can be enumerated.
In the present invention, " C1-6 alkylthio group " for example can enumerate methyl mercapto, ethylmercapto group, positive rosickyite base, isopropyisulfanyl, positive butylthio, isobutylthio, secondary butylthio, tertiary butylthio, positive penta sulfenyl, isopentylthio, new penta sulfenyl, 1- methylbutylthio, 1- ethyl rosickyite base, just own sulfenyl, isohexylthio, 3- methyl penta sulfenyl, 2- methyl penta sulfenyl, 1- methyl penta sulfenyl, 3, 3- dimethyl butyrate sulfenyl, 2, 2- dimethyl butyrate sulfenyl, 1, 1- dimethyl butyrate sulfenyl, 1, 2- dimethyl butyrate sulfenyl, 1, 3- dimethyl butyrate sulfenyl, 2, 3- dimethyl butyrate sulfenyl, 1- ethyl butylthio, 2- ethyl butylthio etc..
In the present invention, " C1-6 alkyl sulphinyl " for example can be enumerated：Methylsulfinyl、Ethylsulfinyl、N-pro-pyl sulfinyl、Isopropylsulphinyl、N-butylsulfinyl、Isobutyl group sulfinyl、Sec-butyl sulfinyl、Terf-butylsulfinyl、N-pentyl sulfinyl、Isopentyl sulfinyl、Neopentyl sulfinyl、1- methyl butyl sulfinyl、1- ethyl propyl sulfinyl、N-hexyl sulfinyl、Isohesyl sulfinyl、3- methyl amyl sulfinyl、2- methyl amyl sulfinyl、1- methyl amyl sulfinyl、3,3- dimethylbutyl sulfinyl、2,2- dimethylbutyl sulfinyl、1,1- dimethylbutyl sulfinyl、1,2- dimethylbutyl sulfinyl、1,3- dimethylbutyl sulfinyl、2,3- dimethylbutyl sulfinyl、1- ethyl-butyl sulfinyl、2- ethyl-butyl sulfinyl etc..
In addition, here undefined group in accordance with common definition.
Currently preferred mode can enumerate in the following manner.
Formula（I）In, as R1、R2- S (=O)2R3In, R3The preferably C3-8 cycloalkyl of the C1-6 alkyl of methyl, ethyl, isopropyl etc., cyclopropyl etc., hydroxyl, amino, the amino being replaced by 1 or 2 C1-6 alkyl ,-NH-C (=O)-NH- (CH2)2CH3、- NH -C(=NH)-NH2、- NH -C(=NH)-N（CH3）2.
Formula（I）In, as R1、R2- R4In-COOH, R4Preferably singly-bound.
Formula（I）In, as R1、R2- R4COOR5In, R4Preferably singly-bound, R5Preferably C1-6 alkyl, more preferably methyl or ethyl.
Formula（I）In, as R1、R2- R8(C=O)-N R6R7In, R8Preferably singly-bound, R6And R7It is preferably hydrogen atom or C1-6 alkyl, more preferably hydrogen atom independently of one another.
Formula（I）In, preferably A1For N, A2For C, A3For N, A4For C, A5For N.
Formula（I）In, preferably A1For N, A2For C, A3For C, A4For C, A5For N.
Formula（I）In, preferably A1For N, A2For C, A3For N, A4For N, A5For C.
Formula（I）In, preferably A1For N, A2For C, A3For C, A4For N, A5For C.
Formula（I）In, preferably A1For N, A2For C, A3For N, A4For C, A5For C.
Formula（I）In, preferably in A1For C, A2For C, A3For N, A4For N, A5For C；Or A1For C, A2For C, A3For C, A4For N, A5For N；Or A1For N, A2For C, A3For N, A4For C, A5For N；Or
A1For N, A2For C, A3For C, A4For C, A5For N；Or A1For N, A2For C, A3For N, A4For N, A5In the case of C, A2With A3Between and A4With A5Between be double bond.
Formula（I）In, preferably in A1For N, A2For C, A3For C, A4For N, A5For C；Or A1For N, A2For C, A3For N, A4For C, A5In the case of C, A2With A3Between and A1With A5Between be double bond.
Formula（I）In, preferably Ar is the phenyl optionally being replaced by 1～5 halogen atom, the phenyl that the phenyl being preferably replaced by fluorine atoms more preferably is replaced by 2 fluorine atoms.
As the example of the preferred compound in the compounds of this invention, following compounds can be enumerated：
.
" pharmaceutically acceptable salt " in this specification comprises and sulphuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, or the salt of the mineral acid such as nitric acid, or and acetic acid, benzoic acid, oxalic acid, lactic acid, malic acid, tartaric acid, fumaric acid, maleic acid, citric acid, malonic acid, mandelic acid, gluconic acid, galactosaccharic acid, glucoheptonic acid, glycolic, glutamic acid, trifluoracetic acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, camphorsulfonic acid, or the salt of the organic acid such as naphthalene-2-sulfonic acid, with lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, the salt of one or more metal ions such as aluminium ion, with ammonia, arginine, lysine, piperazine, gallbladder alkali, diethylamide, 4- phenylcyclohexylamine, 2- ethylaminoethanol, the salt of the amine such as benzathine benzylpenicillin.As long as pharmaceutically acceptable salt, it is not particularly limited.Can be carried out with existing method from episome to the conversion of this salt.
Should illustrate, the compound of the present invention also can exist as various solvates.In addition, from the point of view of the suitability as medicine, the situation of promising hydrate.
The compound of the present invention can contain one or more asymmetric centers, thus, it is possible to presented in racemate, racemic mixture, single enantiomer, non-enantiomer mixture and single diastereoisomer etc..Term " crystal formation " includes any crystal formation of the compounds of this invention, such as monocrystalline, polymorphic etc..
The compound of the present invention can combine and to form pharmaceutical preparation with the pharmaceutically acceptable carrier of or more than two, excipient or diluent.Refer to not cause obvious zest to organism as above-mentioned carrier, excipient and diluent and do not disturb given compound the pharmaceutical composition of the property of biological activity in non-active ingredient.
As above-mentioned carrier, excipient and diluent, comprise various oil of water, Lactose, glucose, Fructose, sucrose, Sorbitol, Mannitol, Polyethylene Glycol, propylene glycol, starch, rubber, gel, alginate, calcium silicates, calcium phosphate, cellulose, aqueous syrup, methylcellulose, polyvinyl pyrrolidone, para hydroxybenzene Pyrusussuriensiss acid alkyl ester, Talcum, magnesium stearate, stearic acid, glycerol, Oleum sesami, olive oil, soybean oil etc. etc..
In addition, the additive of the extender generally using, binding agent, disintegrating agent, pH adjusting agent, lytic agent etc. can be mixed as needed in above-mentioned carrier, excipient or diluent, it is possible to use conventional preparation technique to be prepared as the oral of tablet, pill, capsule, granule, powder, liquor, Emulsion, suspending agent, ointment, injection, skin patch etc. or non-oral administration thing.The compound of the present invention is for adult patient, can with oral or parenteral being given, the oral drugs of the present invention are generally administered once for every 3-12 days, are preferably often administered once within 5-10 days, it is administered once within more preferably 1 week, and be administered total amount 0.01～1000mg/ time.Should illustrate, the dosage of the compound of the present invention suitably can increase and decrease according to the species of the disease as treatment target, the age of patient, body weight, symptom etc..
The compound of the present invention also comprises more than one hydrogen atom, fluorine atom, carbon atom, nitrogen-atoms, oxygen atom, sulphur atom are replaced into the compound of radiosiotope or stable isotope.These labelled compounds can be used for metabolism or pharmacokinetic, the part etc. as receptor carries out biological analysiss etc..
The compound of the present invention can be with one or more other medicines（Such as metformin）Combine for treating, preventing, suppress or improve disease or condition of illness, wherein medicine be used in combination more safer or more effectively than being used alone of any medicine.This other medicines simultaneously or sequentially can be administered with the compound of the present invention with the approach that this is usually used and amount.When the compound of the present invention is used with one or more other medicines simultaneously, in unit dosage forms, the pharmaceutical composition containing this other medicines and the compound of the present invention is preferred, particularly combines with pharmaceutically acceptable carrier.However, therapeutic alliance is additionally may included in different overlapping schedules gives the compound of the present invention and the treatment of one or more other medicines.It is also contemplated that when using with one or more other active ingredient combination, the compounds of this invention and other active component can be used with the dosage lower than when being each used alone.Therefore, except the chemical combination beyond the region of objective existence of the present invention, pharmaceutical composition of the present invention also includes those compositionss containing one or more other active component.
The compound of the present invention for example can be manufactured according to following shown methods.
Formula（1）Shown the compounds of this invention can be with the synthetic method manufacture shown in Utilization plan 1.
<Scheme 1>
（In formula, A1～A5、Ar、R1And R2All with aforementioned, there is the identical meaning）.
Make formula（2）Shown ketone and formula（3）Shown amine carries out 0.5-30 hour, the reduction amination of preferred 1-24 hour at a temperature of 0-50 DEG C, preferred 10-40 DEG C, obtains formula（4）Shown reduced aminate, by the described product obtaining further pH be 2～6 acid condition under slough amino protecting group, obtain general formula compound（1）.
Above-mentioned<Scheme 1>In formula（3）Shown amines are Formula（8）When, it is possible to use the synthetic method manufacture shown in scheme 2.
<Scheme 2>
（In formula, R1And R2All with aforementioned, there is the identical meaning）.
Formula（5）In the solvent of carbon tetrachloride etc., carry out bromo with bromine, then carry out the ring closure reaction of 0.5-20 hour, preferred 1-12 hour with 2- Aminopyrazine at a temperature of 0-40 DEG C, preferred 10-30 DEG C, obtain Formula（7）.By this Formula（7）Pass through palladium carbon catalytic hydrogenation at a temperature of 0-40 DEG C, preferred 20-30 DEG C, obtain Formula（8）.
Above-mentioned<Scheme 1>In formula（3）Shown amines areWhen, it is possible to use the synthetic method manufacture shown in scheme 3.
<Scheme 3>
C- pyrazine -2- base-methylamine and the halo anhydride of trifluoroacetic anhydride etc. are stirred at room temperature overnight, obtain compound 1b.By this compound 1b in the presence of phosphorus oxychloride with phosphorus pentoxide, obtain cyclization product 1c.Then protect amino with Boc, carry out bromo with NBS.Bromo-derivative 1e is carried out with cobalt octacarbonyl in organic solvent, preferred methanol insert carbonyl, after slotting carbonyl product 1f takes off Boc-, obtain target compound.
Formula（1）When shown compound is ester type compound, hydrolysis and ammonolysis can be passed through respectively, and obtain corresponding carboxylic acid and amide target product.
Embodiment
It is exemplified below embodiment and test example, and then explains the present invention, but they do not limit the present invention, in addition can be changed without departing from the scope of the invention.
The structure of the compound described in below example pass through nuclear magnetic resonance, NMR (1) or mass spectrum (MS) is determining HNMR.
Nuclear magnetic resonance, NMR (1HNMR determining instrument) uses JEOL Eclipse 400 nuclear magnetic resonance spectrometer；Mensure solvent is deuterated methanol (CD3OD), deuterochloroform (CDCl3), hexadeuterated dimethyl sulfoxide (DMSO-d6)；Internal standard substance is tetramethylsilane (TMS).
Nuclear magnetic resonance, NMR used in embodiment（NMR）Abbreviation in collection of illustrative plates is shown in following.
s：Unimodal, d：Doublet, t：Triplet, q：Quartet, dd：Double doublet, qd：Four doublets, ddd：Doublet, ddt in pairs：Triplet, dddd in pairs：Double doublet, m in pairs：Multiplet, br：Broad peak（broad）、J：Coupling constant, Hz：Hertz, DMSO-d6：Deuterodimethylsulfoxide.
Whole δ-value are represented with ppm value.
The determining instrument of mass spectrum (MS) uses Agilent (ESI) mass spectrograph, model Agilent 6120B.
In conventional synthetic method and embodiment and intermediate synthesis example, the meaning of each abbreviation is as shown below.
DMF：DMF
DMA：N,N-dimethylacetamide
NMP：N-Methyl pyrrolidone
THF：Oxolane
Boc：Tert-butoxycarbonyl
NBS；N- bromine butanimide
m-CPBA：Metachloroperbenzoic acid
TFA：Trifluoracetic acid
Et2O：Anaesthetie Ether,
EtOH：Ethanol
Dioxane：Isosorbide-5-Nitrae-dioxane
TLC：Thin layer chromatography
HATU：O-（7- azepine benzo triazol-1-yl）- N, N, N ', N '-tetramethylurea hexafluorophosphate
Me：Methyl
DCM:Dichloromethane
EA：Ethyl acetate
DDQ:The chloro- 5,6- dicyan -1,4- benzoquinone of 2,3- bis-.
Should illustrate, in herein below, compound n represents the salt form of compound n.
Embodiment 1 ： 7-((3R,5S,6R)-5- Amino -6-(2,5- Difluorophenyl ) 2H- Pentamethylene oxide. -3- Base )-3- Trifluoromethyl -5,6,7,8- Tetrahydrochysene - Imidazo [1,5-a] Pyrazine -1- Carboxylate methyl ester and its preparation of two trifluoroacetates
The first step：The synthesis of trifluoroacetyl pyrazine -2- methylamine
At 0 DEG C, C- pyrazine -2- base-methylamine (5 g, 45.9 mmol) is added in reaction bulb, it is slowly added dropwise 9.8 mL trifluoroacetic anhydride, stir 12 hours under room temperature, reactant liquor concentrating under reduced pressure, obtain title product trifluoroacetyl pyrazine -2- methylamine (15 G crude product, brown oil), it is directly used in next step reaction.
Second step：The synthesis of 3- trifluoromethyl imidazoles simultaneously [1,5-a] pyrazine
Under room temperature condition, 2,2,2- tri- fluoro- N- pyrazine -2- methyl-Methanamide (15 g) are added in reaction bulb, sequentially add 80 mL phosphorus oxychloride and phosphorus pentoxide (10 g, 73 Mmol), heating reflux reaction 6 hours, remove solvent phosphorus oxychloride, reaction system deionized water is slowly quenched reaction, then to adjust pH in ice bath with 20% sodium hydroxide solution be 5-6, with ethyl acetate (250 mL × 4) extraction, merge organic faciess, be dried with anhydrous magnesium sulfate, sucking filtration, concentrating under reduced pressure filtrate, purified with column chromatography, be concentrated to give title product 3- trifluoromethyl-imidazole simultaneously [1,5-a] pyrazine (5.0 g, yellow solid), two step yields：58.3%.
3rd step：The synthesis of 3- trifluoromethyl -7- tert-butoxycarbonyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine
To be dissolved in 50 mL oxolanes under 3- trifluoromethyl-imidazole simultaneously [1,5-a] pyrazine (3.53 g, 18.88 mmol) stirring, sequentially add triethylamine (2.48 g), Boc2O (4.94 g, 22.65 mmol）, and 350 Mg 10% palladium/carbon, stirs 13 hours under hydrogen shield.Remove catalyst, evaporated under reduced pressure filtrate, column chromatography purification obtains title product 3- trifluoromethyl -7- tert-butoxycarbonyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine (4.4 g, brown solid), yield：80%.
4th step：The synthesis of 1- bromo- 3- trifluoromethyl -7- tert-butoxycarbonyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine
Under room temperature, by 3- trifluoromethyl -7- tert-butoxycarbonyl -5, simultaneously [1,5-a] pyrazine (4.7 g, 16.1 mmol) is dissolved in 80 mL ethanol 6,7,8- tetrahydro-imidazo, be subsequently adding NBS (4.3 g, 24.2 Mmol after) reacting 7 hours, concentration of reaction solution, add water 80 mL, separates out white solid, filter, filtering residue washes post-drying with water and obtains target product 1- bromo- 3- trifluoromethyl -7- tert-butoxycarbonyl -5, and 6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine (4 g, white solid), yield：50%.
5th step：The synthesis of 3- trifluoromethyl -7- tert-butoxycarbonyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester
By cobalt octacarbonyl (5.56 g, 16.26 Mmol), ethyl chloroacetate (1 g, 8.13 Mmol) and potassium carbonate (2.24 g, 16.26 Mmol lower addition 30 mL methanol) are stirred, after stirring 10 minutes, add 1- bromo- 3- trifluoromethyl -7- tert-butoxycarbonyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine (2.0 g, 5.42 mmol), react 24 hours at 60 DEG C, be evaporated reactant liquor, residue is through column chromatography purification, it is concentrated to give title product 3- trifluoromethyl -7- tert-butoxycarbonyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester (1.3 g, white solid), yield：68.7%.
6th step：The synthesis of 3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester
By 7-Boc-3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester (1.1 g, 3.5 mmol) is dissolved in 10 mL dichloromethane, and add trifluoroacetic acid (1 mL) under room temperature and stir 13 hours, methanol dissolving after concentration, adjust pH=8, column chromatography purification with triethylamine, be concentrated to give target product 3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester (0.5 g, brown solid), yield：63%.
7th step：7-((3R,5S,6R)-5-（Tert-butoxycarbonyl）Amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester synthesis
Under room temperature, to (3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- Pentamethylene oxide. -3- ketone (387 mg, 1.18 mmol) and 3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester（310 mg, 1.24 mmol）Oxolane (15 mL) solution in add acetic acid (149 mg, 2.48 mmol), stirring 6 hours after, reactant liquor is cooled to 0 DEG C, add NaBH3CN (156 mg, 2.48 mmol) simultaneously stir 12 hours.After reactant liquor is quenched with water, concentrate, TLC separates and obtains 7- ((3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester (180 mg, white solid), yield：27%.
8th step：The synthesis of 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester two trifluoroacetate
Under room temperature, to 7- ((3R, 5S, 6R) -5-（Tert-butoxycarbonyl）Amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester (40 mg) 1 mL dichloromethane solution in add 0.3 mL trifluoroacetic acid, be stirred at room temperature 15 hours.Concentration of reaction solution, again add methyl tertiary butyl ether(MTBE) after being dissolved with ethyl acetate dissolving and separate out product, after filtration, obtain target product 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester two trifluoroacetate (11 mg, brown solid), yield：33%.
9th step：Free cpds 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester（Compound 1）Preparation
By 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester two trifluoroacetate use 2M aqueous sodium carbonate supersound washing, filtration can obtain free cpds 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester.
Embodiment 2 ： 7-((3R,5S,6R)-5- Amino -6-(2,5- Difluorophenyl ) 2H- Pentamethylene oxide. -3- Base )-3- Trifluoromethyl -5,6,7,8- Tetrahydrochysene - Imidazo [1,5-a] Pyrazine -1- Carboxylic acid and its preparation of two trifluoroacetates
The first step：The synthesis of 7- ((3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acid
Under room temperature, to 7- ((3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7, the oxolane (1 of 8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester (80 mg, 0.14 mmol) ML) in solution add Lithium hydrate (15 mg, 0.28 Mmol 1 mL aqueous solution), after stirring 8 hours.Adjust the pH=6 of reaction with 1 N dilute hydrochloric acid, be then concentrated to dryness, crude product is directly used in next step reaction.
Second step：The synthesis of 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acid two trifluoroacetate
Under room temperature, by 7- ((3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7, simultaneously [1,5-a] pyrazine -1- crude carboxylic acid is dissolved in dichloromethane (2 mL) 8- tetrahydro-imidazo, adds trifluoroacetic acid (0.5 ) and stir 12 hours mL.Crude product is obtained after concentration of reaction solution, crude product recrystallization purifying is obtained 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acid two trifluoroacetate (15 mg, faint yellow solid), two step yields 23%.
3rd step：Free cpds 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acid（Compound 2）Preparation
By 7- ((3R,5S,6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acid two trifluoroacetate is dissolved in water，It has been adjusted to research of chaotic phenomenon with 2M sodium carbonate，Now pH value is 6.5，Then extracted three times with dichloromethane，Be washed once with saturated sodium-chloride after dichloromethane phase is merged，Dichloromethane solution anhydrous sodium sulfate drying after washing，It is filtered to remove desiccant，Revolving removes dichloromethane and obtains free cpds 7- ((3R,5S,6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acid.
Embodiment 3 ： 7-((3R,5S,6R)-5- Amino -6-(2,5- Difluorophenyl ) 2H- Pentamethylene oxide. -3- Base )-3- Trifluoromethyl -5,6,7,8- Tetrahydrochysene - Imidazo [1, 5-a] Pyrazine -1- The preparation of carboxylic acid amide two trifluoroacetate
The first step：The synthesis of 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acid amide
By 7- ((3R, 5S, 6R) -5-Boc- amino -6- (2, 5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5, 6, 7, 8- tetrahydro-imidazo simultaneously [1, 5-a] pyrazine -1- carboxylate methyl ester (70 mg) add 2 mL ammonia in, 100 DEG C of vexed tanks are reacted 15 hours, after reactant liquor concentrates, TLC isolates and purifies and obtains sterling 7- ((3R, 5S, 6R) -5- amino -6- (2, 5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5, 6, 7, 8- tetrahydro-imidazo simultaneously [1, 5-a] pyrazine -1- carboxylic acid amide (30 mg, white solid), yield：68%.
Second step：The synthesis of 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acid amide two trifluoroacetate
Under room temperature，To 7- ((3R,5S,6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acid amide (30 mg) dichloromethane (2 mL) solution in add trifluoroacetic acid (0.5 mL),After stirring 3 hours，Reactant liquor is concentrated to give crude product，Crude product washs to obtain sterling 7- ((3R,5S,6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acid amide two trifluoroacetate (21 mg，Off-white powder)，Yield 56%.
Embodiment 4 ： 7-((3R,5S,6R)-5- Amino -6-(2,5- Difluorophenyl ) Tetrahydrochysene -2H- Pyrans -3- Base )-5,6,7,8- Tetrahydrochysene -[1,2,4] Triazole is simultaneously [4,3-a] Pyrazine -3- The preparation of carboxylic acid, ethyl ester two trifluoroacetate
The first step：7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- tetrahydrochysene-[1,2,4] synthesis of triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid, ethyl ester
Except using 5,6,7,8- tetrahydrochysenes-[1,2,4] triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid, ethyl ester replacement 3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester, makes 5,6,7,8- tetrahydrochysenes-[1,2,4] triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid, ethyl ester consumption be 1g outside, other is equally operated with embodiment 1 the 7th step, obtains title product 480mg, and yield is 18.6%.
Second step：7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- tetrahydrochysene-[1,2,4] synthesis of triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid, ethyl ester two trifluoroacetate
Except using 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- tetrahydrochysene-[1,2,4] triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid, ethyl ester replacement 7- ((3R, 5S, 6R) -5-（Tert-butoxycarbonyl）Amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester, make 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- tetrahydrochysenes-[1,2,4] triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid, ethyl ester consumption be 60 mg outside, other equally operate with embodiment 1 the 8th step, obtain title product 40mg, yield is 53.3%.
Embodiment 5 ： 7-((3R,5S,6R)-5- Amino -6-(2,5- Difluorophenyl ) Tetrahydrochysene -2H- Pyrans -3- Base )-5,6,7,8- Tetrahydrochysene -[1,2,4] Triazole is simultaneously [4,3-a] Pyrazine -3- The preparation of carboxylic acid amide two trifluoroacetate
The first step：7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- tetrahydrochysene-[1,2,4] synthesis of triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid amide
Except using 7- ((3R,5S,6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- tetrahydrochysene-[1,2,4] triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid, ethyl ester replacement 7- ((3R,5S,6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester，Make 7- ((3R,5S,6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- tetrahydrochysene-[1,2,4] triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid, ethyl ester consumption be 150mg outside，Other is equally operated with embodiment 3 first step，Obtain title product 100mg，Yield is 70.9%.
Second step：7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- tetrahydrochysene-[1,2,4] synthesis of triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid amide two trifluoroacetate
Except using 7- ((3R,5S,6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- tetrahydrochysene-[1,2,4] triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid amide replacement 7- ((3R,5S,6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acid amide，Make 7- ((3R,5S,6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- tetrahydrochysene-[1,2,4] triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid amide consumption be 100mg outside，Other is equally operated with embodiment 3 second step，Obtain title product 51mg，Yield is 40.3%.
Embodiment 6 ： 7-((3R,5S,6R)-5- Amino -6-(2,5- Difluorophenyl ) Tetrahydrochysene -2H- Pyrans -3- Base )-5,6,7,8- Imidazolidine is simultaneously [1,2-a] Pyrazine -2- The preparation of carboxylic acid, ethyl ester two trifluoroacetate
The first step：The synthesis of 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester
Except using 5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester replacement 3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester, make 5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester consumption be 1.5g outside, other equally operate with embodiment 1 the 7th step, obtain title product 0.7g, yield is 27.2%.
Second step：The synthesis of 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester two trifluoroacetate
Except using 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester replacement 7- ((3R, 5S, 6R) -5-（Tert-butoxycarbonyl）Amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester, makes 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester consumption be 150mg outside, other equally operate with embodiment 1 the 8th step, obtain title product 100mg, yield is 53.3%.
Embodiment 7 ： 7-((3R,5S,6R)-5- Amino -6-(2,5- Difluorophenyl ) Tetrahydrochysene -2H- Pyrans -3- Base )-5,6,7,8- Imidazolidine is simultaneously [1,2-a] Pyrazine -2- The preparation of carboxylic acid two trifluoroacetate
The first step：The synthesis of 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid
Except using 7- ((3R,5S,6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester replacement 7- ((3R,5S,6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester，Make 7- ((3R,5S,6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester consumption be 150mg outside，Other is equally operated with embodiment 2 first step，Obtain title product 110mg，Yield is 77.6%.
Second step：The synthesis of 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid two trifluoroacetate
Except using 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid replacement 7- ((3R, 5S, 6R) -5-（Tert-butoxycarbonyl）Amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester, makes 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid consumption be 110mg outside, other equally operate with embodiment 2 second step, obtain title product 100mg, yield is 71.9%.
Embodiment 8 ： 7-((3R,5S,6R)-5- Amino -6-(2,5- Difluorophenyl ) Tetrahydrochysene -2H- Pyrans -3- Base )-5,6,7,8- Imidazolidine is simultaneously [1,2-a] Pyrazine -2- The preparation of carboxylic acid amide two trifluoroacetate
The first step：The synthesis of 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid amide
Except using 7- ((3R,5S,6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester replacement 7- ((3R,5S,6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester，Make 7- ((3R,5S,6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester consumption be 250mg outside，Other is equally operated with embodiment 3 first step，Obtain title product 100mg，Yield is 42.4%.
Second step：The synthesis of 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid amide two trifluoroacetate
Except using 7- ((3R,5S,6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid amide replacement 7- ((3R,5S,6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acid amide，Make 7- ((3R,5S,6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid amide consumption be 100mg outside，Other is equally operated with embodiment 3 second step，Obtain title product 65mg，Yield is 51.3%.
Embodiment 9 ： 7-((3R,5S,6R)-5- Amino -6-(2,5- Difluorophenyl ) Tetrahydrochysene -2H- Pyrans -3- Base )-2-( Trifluoromethyl )-5,6,7,8- Imidazolidine is simultaneously [1,2-a] Pyrazine -3- The preparation of carboxylic acid, ethyl ester dihydrochloride
The first step：The synthesis of 2- bromo- 2- trifluoroacetyl ethyl
By trifluoroacetic ethyl acetoacetate (10 g, 54.3 Mmol) it is added in reaction bulb with carbon tetrachloride 20ml, be slowly added dropwise bromine under room temperature and obtain carbon tetrachloride solution（8.7,54.4 mmol/30ml）Afterwards, stirring reaction 3 hours.Reactant liquor concentrating under reduced pressure, obtains title product compound 2- bromo- 2- trifluoroacetyl ethyl (12.1 g crude products, yield：84.6%, yellow liquid), it is directly used in next step reaction.
Second step：The synthesis of 2- trifluoromethyl imidazoles simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester
Successively by bromo- for compound 2- 2- trifluoroacetyl ethyl (10g, 38mmol), ethanol 100ml, 2- Aminopyrazine（3.95g, 41.5mmol）Add in reaction bulb, N2Protection, 90 DEG C of stirring reactions 12 hours, concentrating under reduced pressure, residue column chromatography is purified, and obtains title product compound 2- trifluoromethyl imidazoles simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester (2.5g, yield：25.5%, off-white powder).
3rd step：The synthesis of 2- trifluoromethyl -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester
To be dissolved in 30mL methanol under compound 2- trifluoromethyl imidazoles simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester (1.5 g, 5.9 mmol) stirring, add 10% palladium carbon 750mg, under hydrogen shield, be stirred at room temperature 13 hours.Remove catalyst, be concentrated under reduced pressure to give title product compound 2- trifluoromethyl -5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester (1.3 g, yield：85.0%, brown solid).
4th step：- 2- (trifluoromethyl) -5,6,7,8- imidazolidine is simultaneously [1,2-a] for 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) The synthesis of pyrazine -3- carboxylic acid, ethyl ester
Under room temperature, to (3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- Pentamethylene oxide. -3- ketone (1050 mg, 3.21 mmol) and compound 2- trifluoromethyl -5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester（820 mg, 3.12 mmol）Dichloromethane (50 mL) solution in add tetraisopropyl titanate (1.1g, 3.87 Mmol), it is stirred at room temperature 12 hours.Reactant liquor is cooled to after 0 DEG C, adds NaBH3CN (384 mg, 6.09 ) and 10mL ethanol mmol, intensification room temperature stirring reaction is after 8 hours, after reactant liquor is quenched with water, concentrating under reduced pressure, purified with column chromatography, obtain title product compound 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -2- (trifluoromethyl) -5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester (800 mg, off-white powder), yield：44.7%.
5th step：- 2- (trifluoromethyl) -5,6,7,8- imidazolidine is simultaneously [1,2-a] for 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) The synthesis of pyrazine -3- carboxylic acid, ethyl ester dihydrochloride
Under room temperature, to compound 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2, 5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -2- (trifluoromethyl) -5, 6, 7, 8- imidazolidine simultaneously [1, 2-a] pyrazine -3- carboxylic acid, ethyl ester (110 mg) 5 mL ethyl acetate solutions in be passed through dry HCl gas, after reaction completely, concentrate, washing, it is dried, obtain target product 7- ((3R, 5S, 6R) -5- amino -6- (2, 5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -2- (trifluoromethyl) -5, 6, 7, 8- imidazolidine simultaneously [1, 2-a] pyrazine -3- carboxylic acid, ethyl ester dihydrochloride (75 mg, class solid), yield：71.6%.
Embodiment 10 ： 7-((3R,5S,6R)-5- Amino -6-(2,5- Difluorophenyl ) 2H- Pentamethylene oxide. -3- Base )-3- Trifluoromethyl -5,6,7,8- Tetrahydrochysene - Imidazo [1,2-a] Pyrazine -3- The preparation of carboxylic acid dihydrochloride
The first step：7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -2- (trifluoromethyl) -5,6,7, the synthesis of 8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid
Under room temperature, to compound 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -2- (trifluoromethyl) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester（110 mg, 0.19 mmol) oxolane (5mL) in solution add Lithium hydrate (15 mg, 0.36 Mmol 1 mL aqueous solution), after stirring 5 hours, adjusts the pH=3 of reaction with 1 N dilute hydrochloric acid, then concentrate and remove organic solvent, residual reaction liquid adds purified water, filter, obtain target compound 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -2- (trifluoromethyl) -5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine -3- carboxylic acid 95mg, yield：90%.
Second step：The synthesis of 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,2-a] pyrazine -3- carboxylic acid dihydrochloride
Under room temperature, by compound 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -2- (trifluoromethyl) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid（95mg, 0.17mmol）It is dissolved in ethyl acetate (5 mL), be passed through dry HCl gas, after the completion of reaction, concentrate, wash, being dried to obtain target product 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,2-a] pyrazine -3- carboxylic acid dihydrochloride (80 mg, white group solid), yield：81.0%.
Embodiment 11 ： 7-((3R,5S,6R)-5- Amino -6-(2,5- Difluorophenyl ) Tetrahydrochysene -2H- Pyrans -3- Base )-2- Trifluoromethyl -5,6,7,8- Tetrahydrochysene - Imidazo [1,2-a] Pyrazine -3- The preparation of carboxylic acid amide dihydrochloride
The first step：7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -2- (trifluoromethyl) -5,6,7, the synthesis of 8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid amide
Except using 7- ((3R,5S,6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -2- (trifluoromethyl) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester replacement 7- ((3R,5S,6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester，Make 7- ((3R,5S,6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -2- (trifluoromethyl) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester consumption be 100mg outside，Other is equally operated with embodiment 3 first step，Obtain title product 90mg，Yield is 90%.
Second step：The synthesis of 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -2- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,2-a] pyrazine -3- carboxylic acid amide dihydrochloride
Except using 7- ((3R,5S,6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -2- (trifluoromethyl) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid amide amine replacement 7- ((3R,5S,6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acid amide，Make 7- ((3R,5S,6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -2- (trifluoromethyl) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid amide consumption be 90mg outside，Other is equally operated with embodiment 3 second step，Obtain title product 38mg，Yield is 48%.
Embodiment 12 ： (2R,3S,5R)-2-(2,5- Difluorophenyl )-5-(2- Methyl sulphonyl -4,5- Dihydro -2H- Pyrrolo- [3,4-c] Pyridine -6(7H)- Base ) Tetrahydrochysene -2H- Pyrans -3- The preparation of ammonia two trifluoroacetate
The first step：The synthesis of 4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine two trifluoroacetate
Under room temperature, to Isosorbide-5-Nitrae, 5,7- tetrahydrochysene -6H- pyrazolo [3,4-C] pyridine -6- carboxylic acid tert-butyl esters（300 mg）Dichloromethane (5mL) solution in add trifluoroacetic acid (2 mL), stirring 16 hours after, reactant liquor is concentrated to give crude product 4,5,6,7- tetrahydrochysene -2H- pyrazolos [3,4-c] pyridine two trifluoroacetate (500 mg, pale solid), yield：105.9 %.
Second step：The synthesis of ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (4,5- dihydro-2 h-pyrrole simultaneously [3,4-c] pyridine -6 (7H)-yl) tetrahydrochysene -2H- pyrans -3- amino) t-butyl formate
Under room temperature, to 4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine two trifluoroacetate (265 Mg, 1.12 mmol) 8 mL methanol systems in add (3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- Pentamethylene oxide. -3- ketone (370 mg, 1.12 mmol), stirring reaction 3 hours, is then dividedly in some parts NaBH at 0 DEG C3CN (351 mg, 5.59 mmol), warm naturally to room temperature and stir 12 hours.Reactant liquor concentrates, column chromatography purification obtains target product ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (4,5- dihydro-2 h-pyrroles simultaneously [3,4-c] pyridine -6 (7H)-yl) tetrahydrochysene -2H- pyrans -3- amino) t-butyl formate (100 mg, white solid), yield：30.5 %.
3rd step：((2R; 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- methyl sulphonyl -4; 5- dihydro-2 h-pyrrole simultaneously [3,4-c] pyridine -6 (7H)-yl) tetrahydrochysene -2H- pyrans -3- amino) t-butyl formate synthesis
Under room temperature, to ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (4,5- dihydro-2 h-pyrroles simultaneously [3,4-c] pyridine -6 (7H)-yl) tetrahydrochysene -2H- pyrans -3- amino) t-butyl formate（100 mg, 0.23 mmol）6 mL dichloromethane solutions in sequentially add triethylamine（47 mg, 0.46 mmol）And methylsufonyl chloride（40 mg, 0.35 mmol）, under nitrogen protection, reaction 6 hs are stirred at room temperature.After reactant liquor is quenched with water; concentrate; TLC isolates and purifies and obtains ((2R; 3S; 5R) -2- (2; 5- difluorophenyl) -5- (2- methyl sulphonyl -4,5- dihydro-2 h-pyrrole simultaneously [3,4-c] pyridine -6 (7H)-yl) tetrahydrochysene -2H- pyrans -3- amino) t-butyl formate（27 mg）, yield is 23 %.
4th step：The synthesis of (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- methyl sulphonyl -4,5- dihydro-2 h-pyrrole simultaneously [3,4-c] pyridine -6 (7H)-yl) tetrahydrochysene -2H- pyrans -3- ammonia two trifluoroacetate
Under room temperature; to ((2R; 3S; 5R) -2- (2; 5- difluorophenyl) -5- (2- methyl sulphonyl -4; 5- dihydro-2 h-pyrrole simultaneously [3,4-c] pyridine -6 (7H)-yl) tetrahydrochysene -2H- pyrans -3- amino) t-butyl formate dichloromethane (3 mL) solution in add trifluoroacetic acid (1 mL), stirring reaction is after 16 hours.Reactant liquor is concentrated, washs, dry sterling (2R; 3S; 5R) -2- (2; 5- difluorophenyl) -5- (2- methyl sulphonyl -4; 5- dihydro-2 h-pyrrole simultaneously [3; 4-c] pyridine -6 (7H)-yl) tetrahydrochysene -2H- pyrans -3- ammonia two trifluoroacetate (26 mg, white solid), yield：77 %.
Embodiment 13 ： (2R,3S,5R)-2-(2,5- Difluorophenyl )-5-(2- Methyl sulphonyl -6,7- Dihydro -2H- Pyrrolo- [4,3-c] Pyridine -5(4H)- Base ) Tetrahydrochysene -2H- Pyrans -3- The preparation of amine two trifluoroacetate
The first step：The synthesis of 4,5,6,7- tetrahydrochysene -2H- pyrazolo [4,3-c] pyridine two trifluoroacetate
Under room temperature, to 6,7- dihydro -2H- pyrazolo [4,3-c] pyridine -5 (4H)-carboxylic acid tert-butyl ester（300 mg）Dichloromethane (5mL) solution in add trifluoroacetic acid (2 mL), stirring reaction is after 16 hours.Reactant liquor is concentrated to give crude product 4,5,6,7- tetrahydrochysene -2H- pyrazolo [4,3-c] pyridine two trifluoroacetate (467 Mg, pale solid), yield：99.1%.
Second step：The synthesis of ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (6,7- dihydro-2 h-pyrrole simultaneously [4,3-c] pyridine -5 (4H)-yl) tetrahydrochysene -2H- pyrans -3- amino) t-butyl formate
Under room temperature, to 4,5,6,7- tetrahydrochysene -2H- pyrazolo [4,3-c] pyridine two trifluoroacetate (294 Mg, 1.24 mmol) 8 mL methanol systems in add (3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- Pentamethylene oxide. -3- ketone (405 mg, 1.24 mmol), reaction 3 hour is stirred at room temperature, then at 0 DEG C, is dividedly in some parts NaBH3CN (389 mg, 6.2 mmol), are warming up to room temperature and stir 12 hours after adding.After reactant liquor concentrates, purified with column chromatography and obtain target product ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (6,7- dihydro-2 h-pyrroles simultaneously [4,3-c] pyridine -5 (4H)-yl) tetrahydrochysene -2H- pyrans -3- amino) t-butyl formate (120 mg, white solid), yield：30.5 %.
3rd step：((2R; 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- methyl sulphonyl -6; 7- dihydro-2 h-pyrrole simultaneously [4,3-c] pyridine -5 (4H)-yl) tetrahydrochysene -2H- pyrans -3- amino) t-butyl formate synthesis
Under room temperature, to ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (6,7- dihydro-2 h-pyrroles simultaneously [4,3-c] pyridine -5 (4H)-yl) tetrahydrochysene -2H- pyrans -3- amino) t-butyl formate（120 mg, 0.28 mmol）6 mL dichloromethane solutions in sequentially add triethylamine（56 mg, 0.55 mmol）And methylsufonyl chloride（47 mg, 0.41 mmol）, under nitrogen protection, 6 hs are stirred at room temperature.After reactant liquor is quenched with water; concentrate; TLC isolates and purifies and obtains ((2R; 3S; 5R) -2- (2; 5- difluorophenyl) -5- (2- methyl sulphonyl -6,7- dihydro-2 h-pyrrole simultaneously [4,3-c] pyridine -5 (4H)-yl) tetrahydrochysene -2H- pyrans -3- amino) t-butyl formate（104mg, white solid）, yield 73 %.
4th step：(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- methyl sulphonyl -6,7- dihydro-2 h-pyrrole simultaneously [4,3-c] pyridine -5 (4H)-yl) tetrahydrochysene -2H- pyrans -3- amine two trifluoroacetate
Under room temperature, to ((2R, 3S; 5R) -2- (2; 5- difluorophenyl) -5- (2- methyl sulphonyl -6,7- dihydro-2 h-pyrrole simultaneously [4,3-c] pyridine -5 (4H)-yl) tetrahydrochysene -2H- pyrans -3- amino) t-butyl formate（100 mg）Dichloromethane (6 mL) solution in add trifluoroacetic acid (2 mL), stirring reaction is after 16 hours.Reactant liquor is concentrated, washs, TLC isolates and purifies and obtains (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2-Methyl sulphonyl- 6,7- dihydro-2 h-pyrrole simultaneously [4,3-c] pyridine -5 (4H)-yl) tetrahydrochysene -2H- pyrans -3- amine two trifluoroacetate (31 Mg, white solid), yield：24.8 %.
Embodiment 14 ： 7-((3R,5S,6R)-5- Amino -6-(2,5- Difluorophenyl ) 2H- Pentamethylene oxide. -3- Base )-3- Trifluoromethyl -5,6,7,8- Tetrahydrochysene - Imidazo [1, 5-a] Pyrazine -1- The preparation of carboxylic acyloxy methylamine dihydrochloride
The first step：7- ((3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acyloxy methylamine
Except using 7- ((3R,5S,6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester replacement 7- ((3R,5S,6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester，Make 7- ((3R,5S,6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester consumption be 50mg outside，Other is equally operated with embodiment 3 first step，Obtain title product 45mg，Yield is 90%.
Second step：7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acyloxy methylamine dihydrochloride
Except using 7- ((3R,5S,6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acyloxy methylamine replacement 7- ((3R,5S,6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acid amide，Make 7- ((3R,5S,6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acyloxy methylamine consumption be 45mg outside，Other is equally operated with embodiment 3 second step，Obtain title product 38mg，Yield is 96%.
Embodiment 15 ： 7-((3R,5S,6R)-5- Amino -6-(2,5- Difluorophenyl )-2H- Pentamethylene oxide. -3- Base )-3- Trifluoromethyl -5,6,7,8- Tetrahydrochysene - Imidazo [1, 5-a] Pyrazine -1- The preparation of carboxylic acyloxy dimethylamine
The first step：7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) -2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acyloxy dimethylamine
By compound 1 ' under room temperature（40 mg, 0.069 mmol）It is dissolved in 1,4 dioxane（1 ml）In, add methylamine water solution（1 ml）, it is warming up to 100 DEG C, vexed tank is reacted 8 hours.Reactant liquor saturated sodium-chloride is dissolved, ethyl acetate（2 ml×2）Extraction, organic faciess HPLC prepare the title product that purification obtains white solid（6 mg, 0.013 mmol）, yield is 19%.MS(ESI)m/z：474（M+1）+.
Embodiment 16 ： (2R,3S,5R)-2-(2,5- Difluorophenyl )-5-(5,6- Dihydro -[1,2,4] Triazole is simultaneously [4,3-a] Pyrazine -7(8H)- Base ) Tetrahydrochysene -2H- Pyrans -3- The preparation of amine two trifluoroacetate
The first step：(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (5,6- dihydro-[1,2,4] triazole simultaneously [4,3-a] pyrazine -7 (8H)-yl) tetrahydrochysene -2H- pyrans -3- t-butyl carbamate
Under room temperature, to 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- tetrahydrochysenes-[1,2,4] oxolane (1 of triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid, ethyl ester (80 mg, 0.14 mmol) ML) in solution add Lithium hydrate (15 mg, 0.28 Mmol 1 mL aqueous solution), after stirring 16 hours, adjust the pH=6 of reaction with 1 N dilute hydrochloric acid, be then concentrated to dryness, crude product (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (5,6- dihydro-[1,2,4] triazole simultaneously [4,3-a] pyrazine -7 (8H)-yl) tetrahydrochysene -2H- pyrans -3- t-butyl carbamate be directly used in next step reaction.
Second step：(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (5,6- dihydro-[1,2,4] triazole simultaneously [4,3-a] pyrazine -7 (8H)-yl) tetrahydrochysene -2H- pyrans -3- amine two trifluoroacetate
Under room temperature, by (2R, 3S, 5R) -2- (2, 5- difluorophenyl) -5- (5, 6- dihydro-[1, 2, 4] triazole simultaneously [4, 3-a] pyrazine -7 (8H)-yl) tetrahydrochysene -2H- pyrans -3- t-butyl carbamate crude product is dissolved in dichloromethane (2 mL), add trifluoroacetic acid (0.5 mL) and be stirred overnight, concentration of reaction solution obtains crude product, recrystallization purifying obtains (2R, 3S, 5R) -2- (2, 5- difluorophenyl) -5- (5, 6- dihydro-[1, 2, 4] triazole simultaneously [4, 3-a] pyrazine -7 (8H)-yl) tetrahydrochysene -2H- pyrans -3- amine two trifluoroacetate (52 Mg, off-white powder), two step yields 57.4%.
Embodiment 17 ： (2R,3S,5R)-2-(2,5- Difluorophenyl )-5-(4,5- Dihydro -2H- Pyrazolo [3,4-c] Pyridine -6(7H)- Base ) Tetrahydrochysene -2H- Pyrans -3- The preparation of amine three trifluoroacetate
Under room temperature, to (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (4,5- dihydro -2H- pyrazolo [3,4-c] pyridine -6 (7H)-yl) tetrahydrochysene -2H- pyrans -3- t-butyl carbamate（60 mg,0.14 nnol）Dichloromethane (3 mL) solution in add trifluoroacetic acid (1 mL), after stirring 16 hours, reactant liquor is concentrated, washs to obtain sterling (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (4,5- dihydro -2H- pyrazolo [3,4-c] pyridine -6 (7H)-yl) tetrahydrochysene -2H- pyrans -3- amine three trifluoroacetate (50 Mg, faint yellow solid), yield：54 %.
Embodiment 18 ： 6-((3R,5S,6R)-5- Amino -6-(2,5- Difluorophenyl ) Tetrahydrochysene -2H- Pyrans -3- Base )-4,5,6,7- Tetrahydrochysene -2H- Pyrazolo [3,4-c] Pyridine -3- The preparation of carboxylate methyl ester dihydrochloride
The first step：4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl ester
At 0 DEG C, by compound 6-BOC-4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acids（500 mg, 1.87 mmol）It is dissolved in methanol（12 ml）In, add thionyl chloride（1 g, 9.3 mmol）, after reactant liquor temperature rising reflux reacts 6 hours, reactant liquor concentrates, and uses methanol（50 ml）Dissolving, triethylamine adjusts PH=7-8, concentrates, then wash with dichloromethane, filtration, dry compound as white solid 4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl ester（280 mg, 1.54 mmol）, yield is 82%.
Second step：6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl ester
Under room temperature, by compound 4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl ester（1.5 g, 8 mmol）, compound (3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- Pentamethylene oxide. -3- ketone（2.7 g, 8 mmol）, isopropyl titanate（7 g, 24mmol）It is dissolved in dichloromethane（30 ml）And methanol（3 ml）Mixed solvent in, be stirred overnight, by sodium cyanoborohydride（1.5 g, 24 mmol）Add, room temperature reaction, after 6 hours, adds water（2 ml）And kieselguhr（10 g）After filter, filtrate concentrates, column chromatography for separation, obtains faint yellow compound 6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl ester（0.9 g, 1.8 mmol）, yield is 22%.
3rd step：6- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl ester dihydrochloride
Under room temperature, by compound 6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl ester（0.05 g, 0.1 mmol）Add to 4mol/L HCl/ dioxane（1 ml）In, react 1 hour.LCMS monitoring reaction is complete, by reactant liquor ether（2 ml）Dilution, remove supernatant, solid is dried, and obtains compound as white solid 6- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl ester dihydrochloride（40 mg, 0.086mmol）, yield is 86%.
Embodiment 19 ： 6-((3R,5S,6R)-5- Amino -6-(2,5- Difluorophenyl ) Tetrahydrochysene -2H- Pyrans -3- Base )-4,5,6,7- Tetrahydrochysene -2H- Pyrazolo [3,4-c] Pyridine -3- The preparation of carboxylic acid dihydrochloride
The first step：6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -4,5,6, the synthesis of 7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid
By compound 6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2 under room temperature, 5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl ester（0.3 g, 0.6 mmol）, Lithium hydrate（51 mg, 1.2m mol）, be dissolved in oxolane（3 ml）And water（3 ml）Mixed solution in, room temperature reaction is overnight.Reactant liquor is adjusted PH=5-6 with 1N hydrochloric acid, it is concentrated to give crude Compound 6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid（Faint yellow solid, 0.4 g, 0.8mmol）.
Second step：The synthesis of 6- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid dihydrochloride
By compound 6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2 under room temperature, 5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid（0.4 g, 0.6 mmol）Add 4mol/L HCl/ dioxane（4 ml）In solvent, react 1 hour, reactant liquor is concentrated, HPLC preparative separation, processed with dilute hydrochloric acid after concentration, obtain 6- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid dihydrochloride（50 mg）, two step total recoverys are 16%.
Embodiment 20 ： 6-((3R,5S,6R)-5- Amino -6-(2,5- Difluorophenyl ) Tetrahydrochysene -2H- Pyrans -3- Base )-4,5,6,7- Tetrahydrochysene -2H- Pyrazolo [3,4-c] Pyridine -3- The preparation of carboxylic acid amide dihydrochloride
The first step：6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -4,5,6, the synthesis of 7- tetrahydrochysene -2H- pyrazolo [3,4-c] Niacinamide
Under room temperature, by compound 6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl ester（0.1 g, 0.2 mmol）Add to dioxane（2 ml）, ammonia（2 ml）In, 100 DEG C of vexed tanks are reacted 5 hours, reactant liquor saturated sodium-chloride, ethyl acetate（5 ml）Extraction, organic faciess concentrate, and HPLC prepares purification, obtain compound as white solid 6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] Niacinamide (38 mg, 0.079 mmol), yield is 40%.
Second step：The synthesis of 6- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] Niacinamide dihydrochloride
Under room temperature, by compound 6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -4,5,6,7- tetrahydrochysene -2H- pyrazolo [3,4-c] Niacinamide（38 mg, 0.079 mmol）Add to 4M HCl/ dioxane（1 ml）In, room temperature reaction 3 hours, concentrate, dry compound as white solid/6- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -4,5,6,7- tetrahydrochysene -2H- pyrazolos [3,4-c] and Niacinamide dihydrochloride (20 mg, 0.044 Mmol), HPLC：95%, yield is 56%, MS (ESI) m/z：378（M+1）.
Embodiment 21 ： 7-((3R,5S,6R)-5- Amino -6-(2,5- Difluorophenyl ) Tetrahydrochysene -2H- Pyrans -3- Base )- 5,6,7,8- Imidazolidine is simultaneously [1,2-a] Pyrazine -3- The preparation of Ethyl formate two trifluoroacetate
The first step：The synthesis of 5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester
It is dissolved in 20mL oxolane under imidazo [1,2-a] pyrazine -3- carboxylic acid, ethyl ester (780 mg, 4.08 mmol) is stirred; it is subsequently adding 10% palladium carbon 400mg; after the lower 35 DEG C of stirrings of hydrogen shield 12 hours, remove the reactant liquor of catalyst, concentrating under reduced pressure; column chromatography purification obtains 5; 6,7,8- imidazolidines simultaneously [1; 2-a] pyrazine -3- carboxylic acid, ethyl ester (600 mg, yield：75.3%, off-white powder).
Second step：7-((3R,5S,6R)-5-（Boc- amino）- 6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- Ethyl formate synthesis
Under room temperature, to (3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- Pentamethylene oxide. -3- ketone (1000 mg, 3.05 mmol) and 5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester（400 mg, 2.05 mmol）Dichloromethane (20 mL) solution in add tetraisopropyl titanate (800mg, 2.82 mmol), be stirred at room temperature 12 hours.Reactant liquor is cooled to after 0 DEG C, adds NaBH3CN (258 mg, 4.09 mmol) and 8mL ethanol, after 8 hours, reactant liquor is quenched with water intensification room temperature stirring reaction, concentrating under reduced pressure, column chromatography purification, obtains 7- ((3R, 5S, 6R) -5-（Boc- amino）- 6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine -3- Ethyl formate (60 mg, yield：5.8%, off-white powder).
The synthesis of the 3rd step 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- Ethyl formate two trifluoroacetate
Under room temperature, to 7- ((3R, 5S, 6R) -5-（Boc- amino）- 6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously adds trifluoroacetic acid 1ml in 3 mL dichloromethane solutions of [1,2-a] pyrazine -3- Ethyl formate (35 mg, 0.069 mmol), it is stirred at room temperature 2 hours, concentration of reaction solution, obtains target product 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydrochysene -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- Ethyl formate two trifluoroacetate (24 Mg, yield：58.5%, pale solid).
By preferred compounds of the invention1The measurement result of H-NMR, MS is shown in table 1.
Test example 1 ：Biological assessment
1. reagent：
Enzyme DPP-4：Recombinant Human DPP-4/CD26；Manufacturer：R＆D company；Article No.：1180-SE-010,
DPP-4 substrate：H-Gly-Pro-AMC·HBr；Manufacturer：Bachem；Article No.：I-1225.
2.DPP-4 inhibition of enzyme activity detection method：
Testing compound is dissolved in detection buffer by variable concentrations（25 mM Tris-HCl, 140 mM NaC1,10 mM KC1,0.1% BSA, pH 7.4）In.Add DPP-4 and testing compound in 384 orifice plates, mix latter 37 DEG C and be incubated 15 minutes.Add substrate（H-Gly-Pro-AMC·HBr）Start reaction.Orifice plate is put in microplate reader, under enzyme kineticss pattern, a length of 380 nm of selective exitation light wave, wavelength of transmitted light is that 460 nm read fluorescent value.Read 1 time within every 15 seconds, continuous 40 circulations of reading.Calculate each experimental group fluorescence value changes slope within the linear response phase, calculate suppression ratio or the half-inhibition concentration IC using SigmaPlot or GraphPad Prism 5 software matching compound50Value.
【Table 2】
Table 2：The inhibitory action to DPP-IV for the test compound
Compound DPP-IV IC50（nM）
1 2.05
1’ 2.45
2 1.13
2’ 1.33
3’ 5.66
5’ 6.54
16’ 8.3
6’ 5.37
7’ 5.83
8’ 5.01
12’ 6.34
13’ 4.89
10’ 8.37
11’ 6.96
From the test data in table 2, above-claimed cpd has good inhibitory action to DPP-4.
3.DPP-9 inhibition of enzyme activity detection method
Testing compound is dissolved in detection buffer by variable concentrations（25 mM Tris-HCl, 140 mM NaC1,10 mM KC1,0.1% BSA, pH 7.4）In.Add DPP-9 and testing compound in 384 orifice plates, mix latter 37 DEG C and be incubated 15 minutes.Add substrate（H-Gly-Pro-AMC·HBr）Start reaction.Orifice plate is put in microplate reader, under enzyme kineticss pattern, a length of 380 nm of selective exitation light wave, wavelength of transmitted light is that 460 nm read fluorescent value.Read 1 time within every 15 seconds, continuous 40 circulations of reading.Calculate each experimental group fluorescence value changes slope within the linear response phase, using SigmaPlot or GraphPad Prism 5 software matching compound IC50Value.
【Table 3】
Table 3：The inhibitory action to DPP-9 for the test compound
Compound DPP-9 IC50(μM)
1’ >100
2’ 100
5’ >30
13’ >30
4.DPP-8 enzyme activity suppresses detection method
Testing compound is dissolved in detection buffer by variable concentrations（25 mM Tris-HCl, 140 mM NaC1,10 mM KC1,0.1% BSA, pH 7.4）In.Add DPP-8 and testing compound in 384 orifice plates, mix latter 37 DEG C and be incubated 15 minutes.Add substrate（H-Gly-Pro-AMC·HBr）Start reaction.Orifice plate is put in microplate reader, under enzyme kineticss pattern, a length of 380 nm of selective exitation light wave, wavelength of transmitted light is that 460 nm read fluorescent value.Read 1 time within every 15 seconds, continuous 40 circulations of reading.Calculate each experimental group fluorescence value changes slope within the linear response phase, using SigmaPlot or GraphPad Prism 5 software matching compound IC50Value.
【Table 4】
Table 4：The inhibitory action to DPP-8 for the test compound
Compound DPP-8 IC50(μM)
1’ >300
2’ >30
3’ 300
12’ >30
13’ >30
From table 2-4, the compound of the present invention is different for the inhibitory action of different DPP, and for DPP-8 and DPP-9, above-claimed cpd of the present invention has significant selection inhibitory action to DPP-4.
Test example 2 ：Safety testing
In myocardial cell, the potassium channel that human Ether-a-go-go Related Gene (hERG) encodes mediates a kind of Delayed Rectifier Potassium Current (IKr).IKr suppression is that medicine leads to the most important mechanism of QT interval prolongation.In hERG test, if manual patch-clamp method criterion is compound IC50>30 μM, then judge that compound acts on to hERG unrestraint.
Test compound and comparison medicine are detected using manual patch-clamp（Ao Malieting）Effect to hERG potassium-channel, test concentrations are 0.1,0.3,1,3,10,30 μM.In myocardial cell, the potassium channel that human Ether-a-go-go Related Gene (hERG) encodes mediates a kind of Delayed Rectifier Potassium Current (IKr), and IKr suppression is that medicine leads to the most important mechanism of QT interval prolongation.
Test cell is that transfection has hERG cDNA and stably expresses the Chinese hamster ovary celI system of hERG passage.Cell is placed in the electrophysiological recording groove under inverted microscope.In track, continuous perfusion is made with extracellular fluid.Experimentation adopts conventional whole-cell patch-clamp electric current recording technique.Result of the test is as shown in table 5：
【Table 5】
Table 5：Test compound hERG experimental result：
Compound 1’ 2’ 7’ 13’
IC50(μM) >30 >30 >30 >30
From the test data in table 5, in this test, above-claimed cpd is for 50% inhibition concentration of hERG（IC50）Value is all higher than 30 μM, no leads to heart QT intervals to extend safety risks.
Test example 3. CYP Enzyme level is tested
The metabolic enzyme species that clinical commonly used drug passes through needed for liver metabolism is various.The suggestion of FDA drug interaction guideline is preclinical to be needed to investigate the inhibitory action to this 7 Main Subtype CYP enzymes of CYP1A2,2B6,2C8,2C9,2C19,2D6,3A4 for the compound, current study show that, in 7 main metabolic enzymes, CYP3A4 is maximum for the effect in metabolic process in medicine.As testing compound has inhibitory action to CYP3A4, then illustrate this compound clinically with during by the drug combination of CYP3A4 metabolism, the activity of CYP3A4 enzyme can be suppressed, and then so that the metabolism of combination medicine is weakened, exposing in prototype body increases, cause security risks, therefore CYP Inhibition test becomes the important indicator that preclinical druggability is evaluated.
178 μ L hepatomicrosome solution are added in 1.1mL centrifuge tube（Hepatomicrosome is in the final concentration of 0.2mg/mL of reaction system）.It is added without positive inhibitor and testing compound in blank sample, corresponding addition 2 μ LDMSO, add target methanol solution in 200 μ L, vortex mixed 1 min（I.e. minute）, it is eventually adding 20 μ L NADPH solution.Non-blank-white sample, adds the storing solution of 2 μ L inhibitor or testing compound in 1.1mL centrifuge tube（10μM）, after vortex mixed under the conditions of 37 °C preincubate 5min, add 20 μ L NADPH solution start react（NADPH is in final concentration of 1 mM of reaction system）, it is incubated 20min under conditions of 37 °C of shakings.It is incubated after terminating target methanol solution terminating reaction in adding, be centrifuged 5 min under sample 4000 rpm, take supernatant to be analyzed to LC/MS/MS.
LC-MS/MS analyzes：Mass spectrum is API4000Q-TRAP, and liquid phase is Shimadzu LC-20AD system.Chromatographic column is kinetex C18Post (3.0 mm * 50 mm, 2.6 μm)；Mobile phase A phase is water+0.1% formic acid, and B phase is acetonitrile+0.1% formic acid, and flow velocity is 0.8 mL/min, and column temperature is room temperature.It is ESI source using ion source, scan mode monitors (MRM) for multiple reaction.
【Table 6】
Table 6：The histamine result to different CYP hypotypes for the test compound
From the test data in table 6, compound each IC for above-mentioned different CYP hypotype of the invention described above50It is all higher than 10 μM, the overwhelming majority is more than 50 μM, shows that the compounds of this invention has excellent safety, the risk of drug interaction is low.
Preparation example 1
As the specific embodiment of combination of oral medication, manufacture the tablet of the 100mg potency consisting of the following composition.
The compound 100mg of composition embodiment 1
Microcrystalline Cellulose 268mg
Cross-linking sodium carboxymethyl cellulose 20mg
Magnesium stearate 4mg
Amount to 392mg
First, active substance, Microcrystalline Cellulose and cross-linked carboxymethyl cellulose are mixed, then being lubricated mixture and pressed with magnesium stearate is tablet.
Preparation example 2
Manufacture the capsule filling granule containing following component.
The compound 15mg of composition embodiment 2
Lactose 90mg
Semen Maydis powder 42mg
　　　　　HPC-L 　　　　　　　　　　3mg
Amount to 150mg
Make formula（1）Shown compound, Lactose pass through the sieve of 60 sieve meshes.Semen Maydis powder is made to pass through the sieve of 120 sieve meshes.They are mixed, in mixed-powder, add HPC-L solution, carry out mediating, pelletize, drying.After the dry particle granulate of gained, its 150mg is filled in No. 4 hard gelatin capsules.
Preparation example 3
Preparation example 1
Manufacture the granule containing following component.
The compound 10mg of composition embodiment 3
Lactose 700mg
Semen Maydis powder 274mg
　　　　　HPC-L　　　　　　　　　　16mg
Amount to 1000mg
By formula（1）The shown compound and Lactose sieve by 60 meshes.Semen Maydis powder is passed through the sieve of 120 meshes.They are utilized V-Mixer to mix.Add HPC-L in mixed-powder（Low-viscosity hydroxypropylcelluloand）Aqueous solution, carries out mediating, pelletize（Extruder grain aperture 0.5～1mm）, be dried step.Dry particle shaking screen by gained（12/60 sieve mesh）Sieve, obtain granule.
Industrial applicability
According to the present invention, compound as dipeptidyl peptidase-IV inhibitor can be provided, it has high inhibitory activity and have excellent pharmacokinetic properties to dipeptidyl peptidase-IV, can be used for treating and preventing the DPP-4 relevant disease including treatment diabetes, especially II patients with type Ⅰ DM.

Claims (24)

1. following formulas（1）Compound, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug representing,
In formula, A ring is unsaturation ring, and A1And A2Connected with singly-bound；
A1、A2、A3、A4And A5It is each independently selected from carbon or nitrogen, and A1、A2、A3、A4And A5In at least 2 be carbon；
R1And R2Independently of one another with A3、A4Or A5In conjunction with, and independently selected from hydrogen atom, cyano group, nitro ,-S (=O)2R3、-R4-COOH、-R4COOR5, optionally it is selected from the sulfydryl of the substituent group replacing basis set a, optionally it is selected from the amino of the substituent group replacing basis set a, optionally it is selected from the sulfinyl of the substituent group replacing basis set a, optionally it is selected from the C1-6 alkyl of the substituent group replacing basis set a, optionally it is selected from the C1-6 alkoxyl of the substituent group replacing basis set a, optionally it is selected from the C2-6 alkanoyl of the substituent group replacing basis set a, optionally it is selected from the C3-8 cycloalkyl of the substituent group replacing basis set a, optionally it is selected from the C6-10 aryl of the substituent group replacing basis set a, optionally it is selected from the 5-11 circle heterocycles base of the substituent group replacing basis set a, or-R8(C=O)-N R6R7；
Wherein R3Selected from hydroxyl, optionally it is selected from the alkyl of the substituent group replacing basis set a, optionally it is selected from the cycloalkyl of the substituent group replacing basis set a, optionally it is selected from the amino of the substituent group replacing basis set a, optionally it is selected from the amino C2-6 alkanoyl of the substituent group replacing basis set a, optionally it is selected from the amino carbonyl amino of the substituent group replacing basis set a, optionally it is selected from the C6-10 aryl of the substituent group replacing basis set a, optionally it is selected from the 5-11 circle heterocycles base of the substituent group replacing basis set a；
R4For singly-bound or C1-6 alkylidene, C2-6 alkenylene or C2-6 alkynylene；
R5For amino, C1-6 alkyl, C2-6 thiazolinyl or C2-6 alkynyl；
R6And R7It is each independently hydrogen, hydroxyl, be optionally selected from the C1-6 alkyl of the substituent group replacing basis set a, be optionally selected from the C3-8 cycloalkyl of the substituent group replacing basis set a, be optionally selected from the amino of the substituent group replacing basis set a；
R8For singly-bound, C1-6 alkylidene, C2-6 alkenylene or C2-6 alkynylene,
Premise is to work as A1、A2、A3And A4In 2 be nitrogen when, if R1And R2In a side be hydrogen atom, then R1And R2In the opposing party be not hydrogen atom and the alkyl being substituted with halogen atoms；
Ar is the C6-10 aryl being optionally selected from, by 1～5, the substituent group replacing basis set a；
Replace basis set a：By C1-6 alkyl, C2-6 thiazolinyl, C2-6 alkynyl, the C1-6 alkyl of halogenation, halogen ,-CN, NHOH ,-OH ,-O-C1-6 alkyl ,-NH-C1-6 alkyl ,-N (C1-6 alkyl)2、-NH2、-C(=NH)-NH-CH3、-C(=NH)-N(CH3)2、-C(=NH)-NH 2、-C(=NH)-NH2、-C(O)NH2,-C (O) NH-C1-6 alkyl ,-C (O) N (C1-6 alkyl)2,-NHC (O)-C1-6 alkyl ,-NHC (O)-C3-8 cycloalkyl ,-N (C1-6 alkyl) C (O) H ,-N (C1-6 alkyl) C (O)-C1-6 alkyl ,-NHC (O) NH2Composition.
2. compound according to claim 1, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein,
(1)A1For N, A2For C, A3For N, A4For C, A5For N, or
(2)A1For N, A2For C, A3For C, A4For C, A5For N, or
(3)A1For N, A2For C, A3For N, A4For N, A5For C, or
(4)A1For N, A2For C, A3For C, A4For N, A5For C, or
(5)A1For N, A2For C, A3For N, A4For C, A5For C, or
(6)A1For C, A2For C, A3For N, A4For N, A5For C, or
(7) A1For C, A2For C, A3For C, A4For N, A5For N.
3. compound according to claim 2, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein, under the either case of above-mentioned (1)～(5), A2With A3Between and A4With A5Between be double bond,
In the case of above-mentioned (6) or (7), A2With A3Between and A1With A5Between be double bond.
4. the compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein,
R1、R2It is separately hydrogen atom ,-S (=O)2- C1-6 alkyl ,-S (=O)2- C3-8 cycloalkyl ,-S (=O)2-N（C1-6 alkyl）2、-S(=O)2- C2-6 alkanoyl, C6-10 aryl, C1-6 the alkyl ,-S (=O) being replaced by C1-6 alkyl2- amino carbonyl amino ,-COO-C1-6 alkyl, the amino being replaced by C1-6 alkyl, the C1-6 alkyl being substituted with halogen atoms, C1-6 alkoxyl, C3-8 cycloalkyl, C6-10 aryl, C6-10 aryl C1-8 alkoxyl, C1-6 alkylthio group, 5-11 circle heterocycles base ,-(C=O)-NH-C1-6 alkyl ,-(C=O)-N（C1-6 alkyl）2,-(C=O)-NH-C3-8 cycloalkyl ,-(C=O)-N（C3-8 cycloalkyl）2, C1-6 alkyl sulphinyl or single C1-6 alkyl amino-carbonyl or two C1-6 alkyl amino-carbonyls.
5. the compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein, R1、R2It is separately hydrogen atom, amino ,-S (=O)2-CH3、-S(=O)2-CH2CH3、-S(=O)2-CH(CH3)2、-S(=O)2-OH、-S(=O)2- cyclopropyl ,-S (=O)2-NH2、-S(=O)2-N（CH3）2、-S(=O)2- NH -C(=NH)-NH-CH3、-S(=O)2- NH -C(=O)-NH-( CH2)2CH3、-S(=O)2- NH -C(=NH)-NH2、- NH -C(=NH)-NH-CH3、-S(=O)2- NH -C(=NH)-N（CH3）2、-COOH、-COOCH3、-COOCH2CH3、-NH2、-CF3、-N(CH3)2、-COONH2Or-(C=O)-NH2.
6. the compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein, Ar is the phenyl optionally being replaced by 1～5 halogen atom.
7. the compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein, described compound be selected from following formula (a),（b）、（c）、（d）、（e）、（f）、（g）、（h）With（i）In any one compound,
Wherein, Ar is the phenyl optionally being replaced by 1～5 halogen atom,
R9、R10, and R11It is each independently selected from hydrogen atom, cyano group, nitro ,-S (=O)2R3、-R4-COOH、-R4COOR5, optionally it is selected from the sulfydryl of the substituent group replacing basis set a, optionally it is selected from the amino of the substituent group replacing basis set a, optionally it is selected from the sulfinyl of the substituent group replacing basis set a, optionally it is selected from the C1-6 alkyl of the substituent group replacing basis set a, optionally it is selected from the C1-6 alkoxyl of the substituent group replacing basis set a, optionally it is selected from the C2-6 alkanoyl of the substituent group replacing basis set a, optionally it is selected from the C3-8 cycloalkyl of the substituent group replacing basis set a, optionally it is selected from the C6-10 aryl of the substituent group replacing basis set a, optionally it is selected from the 5-11 circle heterocycles base of the substituent group replacing basis set a, or-R6(C=O)-N R6R7,
Wherein R3、R4、R5、R6、R7、R8Basis set a is identical with the definition in claim 1 with replacing.
8. compound according to claim 7, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein, R9、R10, and R11It is each independently selected from hydrogen atom ,-S (=O)2- C1-6 alkyl ,-S (=O)2- C3-8 cycloalkyl ,-S (=O)2-N（C1-6 alkyl）2、-S(=O)2- C2-6 alkanoyl, C6-10 aryl C1-6 the alkyl ,-S (=O) being replaced by C1-6 alkyl2- amino carbonyl amino ,-COO-C1-6 alkyl, the amino being replaced by C1-6 alkyl, the C1-6 alkyl being substituted with halogen atoms, C1-6 alkoxyl, C3-8 cycloalkyl, C6-10 aryl, C6-10 aryl C1-8 alkoxyl, C1-6 alkylthio group, 5-11 circle heterocycles base ,-(C=O)-NH-C1-6 alkyl ,-(C=O)-N（C1-6 alkyl）2,-(C=O)-NH-C3-8 cycloalkyl ,-(C=O)-N（C3-8 cycloalkyl）2, C1-6 alkyl sulphinyl or single C1-6 alkyl amino-carbonyl or two C1-6 alkyl amino-carbonyls.
9. compound according to claim 7, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein, R9、R10, and R11It is each independently selected from hydrogen atom, amino ,-S (=O)2-CH3、-S(=O)2-CH2CH3、-S(=O)2-CH(CH3)2、-S(=O)2-OH、-S(=O)2- cyclopropyl ,-S (=O)2-NH2、-S(=O)2-N（CH3）2、-S(=O)2- NH -C(=NH)-NH-CH3、-S(=O)2- NH -C(=O)-NH-( CH2)2CH3、-S(=O)2- NH -C(=NH)-NH2、- NH -C(=NH)-NH-CH3、-S(=O)2- NH -C(=NH)-N（CH3）2、-COOH、-COOCH3、-COOCH2CH3、-NH2、-CF3、-N(CH3)2、-COONH2Or-(C=O)-NH2.
10. compound according to claim 1, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, wherein, described compound is selected from following compounds,
.
11. compounds according to any one of claims 1 to 3, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, it is used as dipeptidyl peptidase-IV inhibitor.
The manufacture method of 12. compounds according to claim 1, it includes the synthetic method shown in scheme 1,
In formula, A1～A5、Ar、R1And R2All with claim 1, there is the identical meaning,
Make formula（2）Shown ketone and formula（3）Shown amine carries out 0.5-30 hour, the reduction amination of preferred 1-24 hour at a temperature of 0-50 DEG C, preferred 10-40 DEG C, obtains formula（4）Shown reduced aminate, by the described product obtaining further pH be 2～6 acid condition under slough amino protecting group, obtain general formula compound（1）.
The manufacture method of 13. compounds according to claim 12, wherein, formula in such scheme 1（3）Shown amines are formula（8）Shown compound, this formula（8）The shown synthetic method manufacture shown in compound Utilization plan 2,
In formula, R1And R2All with aforementioned, there is the identical meaning,
Formula（5）In the solvent of carbon tetrachloride etc., carry out bromo with bromine, then with 2- Aminopyrazine in 0-40 DEG C, preferred 10-30 Carry out 0.5-20 hour, the ring closure reaction of preferred 1-12 hour at a temperature of DEG C, obtain Formula（7）, by this Formula（7）Pass through palladium carbon catalytic hydrogenation at a temperature of 0-40 DEG C, preferred 20-30 DEG C, obtain formula（8）Shown compound.
The manufacture method of 14. compounds according to claim 12, wherein, formula in such scheme 1（3）Shown amines are, the synthetic method manufacture shown in this compound 1g Utilization plan 3,
C- pyrazine -2- base-methylamine and the halo anhydride of trifluoroacetic anhydride etc. are stirred at room temperature overnight; obtain compound 1b; by this compound 1b in the presence of phosphorus oxychloride with phosphorus pentoxide; obtain cyclization product 1c; then protect amino with Boc, carry out bromo with NBS, bromo-derivative 1e is carried out with cobalt octacarbonyl in organic solvent, preferred methanol insert carbonyl reaction; after product 1f takes off Boc-, obtain target compound.
15. pharmaceutical compositions, it contains compound any one of claim 1～11, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, and pharmaceutically acceptable carrier or excipient.
16. pharmaceutical compositions according to claim 15, wherein, comprising further can be with the compound any one of claim 1～11, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or other active substance associated with its prodrug.
17. pharmaceutical compositions according to claim 16, wherein, described other active substance is metformin or its salt or pioglitazone etc..
18. pharmaceutical compositions according to claim 15 or 16, wherein, described compositionss contain unit dose 0.01-1000mg of the compound any one of claim 1～11, it is suitably 0.5-800mg, it is preferably 1-400mg, more preferably 5-200mg, particularly preferred 10-100mg, most preferably 15-50mg.
A kind of 19. pharmaceutical preparatioies being suitable for administration to mammal, wherein, comprise compound any one of claim 1～11, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug as effective ingredient, this pharmaceutical preparation includes solid preparation, semi-solid preparation, liquid preparation, gaseous state preparation.
The treatment of 20. diseases related to dipeptidyl peptidase-IV or preventive, it contains compound any one of claim 1～11, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug as effective ingredient.
Compound any one of 21. claim 1～11, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, or itself and application in the medicine of the disease related with dipeptidyl peptidase-IV for preparation treatment for the compositionss associated with other active substances.
22. applications according to claim 21, wherein related to dipeptidyl peptidase-IV disease includes diabetes, obesity, insulin resistance or hyperlipidemia.
Compound any one of 23. claim 1～11, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal formation or its prodrug, or itself and the method for treating the disease related with dipeptidyl peptidase-IV for the mixture associated with other active substances.
24. methods according to claim 23, wherein, the unit dose of the compound any one of claim 1～11 is 0.01-1000mg, it is suitably 0.5-800mg, preferably 1-400mg, more preferably 5-200mg, particularly preferably 10-100mg, most preferably 15-50mg.
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