CN106478631B - 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 PDFInfo
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Abstract
The present invention relates to the preparation methods of long-acting dipeptidyl peptidase-iv inhibitor, purposes and its intermediate, specifically, the present invention relates to following general formula (1) compound represented and preparation method thereof, the compounds to treat and prevent the application in the DPP-4 related disease for including diabetes, especially type-2 diabetes mellitus, and containing the pharmaceutical composition and pharmaceutical preparation of the general formula (1) compound, the definition of each symbol is identical as in specification in general formula.
Description
Technical field
Include the present invention relates to the compound as dipeptidyl peptidase-IV (DPP-4) inhibitor and its in treatment and prevention
Treat the application in the DPP-4 related disease of diabetes especially II patients with type Ⅰ DM.The invention further relates to preparation above compounds
And its preparation method of intermediate.The invention further relates to exist comprising the pharmaceutical composition of these compounds and these compositions
The prevention of this kind of disease related with dipeptidyl peptidase-IV or the purposes in treatment.
Background technique
Diabetes be by inherent cause, immunologic function disorder, microorganism infection and its toxin, free radical toxin, spirit because
Chronic metabolic diseases caused by the various virulence factor effects such as element, clinically using hyperglycemia as cardinal symptom.It can be divided into I type
Diabetes (insulin-dependent), type-2 diabetes mellitus (non-insulin-depending type), gestational diabetes mellitus and other specific types sugar
Urine disease.In diabetic, ratio shared by II patients with type Ⅰ DM is about 90%.
Traditional oral hypoglycemic agents is many kinds of, including sulfonylureas (SU), biguanides etc., but general all with body
Increase again, the problems such as tolerance is limited, and the side effects such as hypoglycemia and drug effect gradually decrease, therefore, people are look for new
Therapeutic agent, many new therapy targets just under study for action, wherein with dipeptidyl peptidase-IV (DPP-4) be target spot drug
It is especially prominent (non-patent literature 1) to study the achievement obtained.
DPP IV (DPP-4) is that some researches show that DPP-4 can prevent pancreas hyperglycemia by a kind of serine protease
The secretion of plain sample peptide (GLP) -1 makes it from active form in particular, it can crack the-the third dipeptidase of group of the end N- in GLP-1
GLP-1 (7-36) NH2 be degraded to inactive GLP-1 (9-36) NH2 (non-patent literature 2).Glucagon-like-peptide-1 (GLP-
1) be a kind of hormone secreted by pancreas islet A cells and enteron aisle L- cell, have glucose dependency insulin secretion accelerating with
And increase the effect of biological insulin synthesis, therefore cause scientist's great interest using GLP-1 treatment diabetes.GLP-1
Other than having and promoting insulin secretion effect, also has and promote beta cell hyperplasia, anti-beta cell apoptosis, glucagon suppression
The physiological functions such as generation, appetite-suppressing, reduction gastrointestinal emptying speed, protection nerve cell with glycogen.These features of GLP-1
Become ideal Remedies for diabetes.However, only several minutes of the half-life period of GLP-1 in vivo, rapidly by endogenous two
Peptidyl peptidase-IV (DPP-4) degradation (removes the end N dipeptides), and it is active (non-patent literature 3) to lose insulin secretion accelerating.
DPP-4 is widely distributed in human body, is the main metabolic enzyme of GLP-1, plays and focuses in regulation GLP-1 activity
It acts on.Therefore reactive compound, that is, DPP-4 the inhibitor for inhibiting DPP-4, can enhance the effect of GLP-1.In addition to this,
DPP-4 inhibitor also has the generation of promotion β-hyperplasia, anti-β-Apoptosis, glucagon suppression and glycogen, suppression
The effects of appetite processed is not put on weight, and gastrointestinal emptying speed, protection nerve cell are reduced.Therefore, DPP-4 inhibitor also can be used
In the treatment (non-patent literature 4) of relevant to dipeptidyl peptidase various diseases such as obesity and hyperlipidemia.
From after the crystal structure report of DPP-4 in 2003, the DPP-4 inhibitor phase of a variety of new construction types in recent years
After listing, (sitagliptin phosphate, in October, 2006 is in the U.S. for the sitagliptin phosphate researched and developed such as Merck & Co., Inc.
City) etc..
In addition, patent document 1 also discloses that the DPP-4 of the structure types such as substituted amino tetrahydro pyran class compound inhibits
Agent.
However, despite the presence of above-mentioned several DPP-4 inhibitor, but these compounds to the inhibitory activity of DPP-4 also not
It is enough satisfactory, lack the selectivity to DPP-2/8/9 enzyme, and also lack long-acting drug at present.Therefore, people are highly desirable
The property of exploitation drug metabolism etc. is improved, activity is higher, toxic side effect is smaller, can be used for the DPP- of long-acting structure novel
4 inhibitor, to treat various diseases relevant to DPP-4.
Existing technical 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 document
2007/136603 Al of [patent document 1] WO.
Summary of the invention
The compound that the object of the present invention is to provide a kind of as dipeptidyl peptidase-iv inhibitor, its is pharmaceutically acceptable
Salt or ester, solvate, hydrate, isomers, crystal form or its prodrug, they can be used for treat and prevent include treatment glycosuria
Disease, the DPP-4 related disease of especially II patients with type Ⅰ DM.In further detail, the present invention provides the 3- ammonia with new substituted
Base oxinane structure is new with high inhibitory activity and with excellent pharmacokinetic properties to dipeptidyl peptidase-IV
Compound.
In addition, the object of the invention also reside in provide for treat various diseases relevant to dipeptidyl peptidase-IV, contain
The compounds of this invention of therapeutically effective amount and the pharmaceutically Pharmaceutical composition of acceptable carrier or excipient.
In addition, the object of the invention is also to provide the therapeutic agents containing the compound pharmaceutically acceptable salt, especially
It is dipeptidyl peptidase-iv inhibitor, which has the activity of excellent treatment diabetes, and solubility is obviously improved, and
Activity and its bioavilability in animal body is good, and toxicity is low, suitable for preparing the preparation for the treatment of diabetes.
The present inventor is in depth studied to achieve the goals above, as a result, it has been found that: there is 3- amino tetrahydro pyran
The specific compound of structure, that is, aftermentioned logical formula (I) compound represented is compared with prior art, have through glucose dependency
Mechanism works, therefore the advantages of the risk of reduction hypoglycemia, in addition compared with existing DPP-4 inhibitor, institute of the invention
Compound is stated with more favorable pharmacokinetics performance, the more long duration, so as to complete the present invention.
Specifically, embodiments of the present invention can enumerate content below.
The compound that the following general formula (1) indicates, pharmaceutically acceptable salt or ester, solvate, hydrate, isomery
Body, crystal form or its prodrug,
In formula, A ring is unsaturated ring, and A1And A2It is connected with singly-bound；
A1、A2、A3、A4And A5It is each independently selected from carbon or nitrogen, and A1、A2、A3、A4And A5Middle at least two is carbon；
R1And R2Each independently with A3、A4Or A5In conjunction with, and independently selected from hydrogen atom, cyano, nitro ,-S (=O)2R3、-R4-COOH、-R4COOR5, the sulfydryl, optionally selected from substituent group a's that replaces of the optionally selected group from substituent group a
The amino of group substitution is optionally chosen the sulfinyl replaced from the group of substituent group a, is optionally chosen from substituent group a's
The C1-6 alkyl of group substitution is optionally chosen the C1-6 alkoxy replaced from the group of substituent group a, is optionally chosen from substituent group
The C2-6 alkanoyl of the group substitution of group a is optionally chosen the C3-8 naphthenic base replaced from the group of substituent group a, is optionally chosen
The 5-11 circle heterocyclic ring base of the C6-10 aryl, the optionally selected group substitution from substituent group a that replace from the group of substituent group a,
Or-R8(C=O)-N R6R7；
Wherein R3Selected from hydroxyl, the alkyl that the optionally selected group from substituent group a replaces, optionally it is chosen from substituent group
The naphthenic base of the group substitution of a is optionally chosen the amino replaced from the group of substituent group a, is optionally chosen from substituent group a's
The amino C2-6 alkanoyl of group substitution is optionally chosen the amino carbonyl amino replaced from the group of substituent group a, is optionally chosen
The 5-11 circle heterocyclic ring base that C6-10 aryl, the optionally selected group from substituent group a replaced from the group of substituent group a replaces；
R4For singly-bound or C1-6 alkylidene, C2-6 alkenylene or C2-6 alkynylene；
R5For amino, C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl；
R6And R7It is each independently hydrogen, hydroxyl, the C1-6 alkyl replaced from the group of substituent group a is optionally chosen, is optional
The amino of C3-8 naphthenic base, the optionally selected group substitution from substituent group a that the selected group from substituent group a replaces；
R8For singly-bound, C1-6 alkylidene, C2-6 alkenylene or C2-6 alkynylene,
On condition that working as A1、A2、A3And A4In 2 be nitrogen when, if R1And R2In a side be hydrogen atom, then R1And R2In
Another party be not hydrogen atom and the alkyl that is substituted with halogen atoms；Ar is the group that substituent group a is optionally selected from by 1~5
Substituted C6-10 aryl；
Substituent group a: by C1-6 alkyl, C2-6 alkenyl, 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)-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 naphthenic base ,-N (C1-6 alkyl) C (O) H ,-N (C1-6 alkyl) C (O)-C1-6 alkane
Base ,-NHC (O) NH2Composition.
Compound of the present invention, pharmaceutically acceptable salt or ester, solvate, hydrate, isomers, crystal form
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, pharmaceutically acceptable salt or ester, solvate, hydrate, isomers, crystal form
Or its prodrug, wherein under the either case of above-mentioned (1)~(5), A2With A3Between and A4With A5Between be double bond,
In the case where above-mentioned (6) or (7), A2With A3Between and A1With A5Between be double bond.
Compound of the present invention, pharmaceutically acceptable salt or ester, solvate, hydrate, isomers, crystal form
Or its prodrug, wherein
R1、R2It is separately hydrogen atom ,-S (=O)2- C1-6 alkyl ,-S (=O)2- C3-8 naphthenic base ,-S (=O)2-N
(C1-6 alkyl)2、-S(=O)2- C2-6 alkanoyl, C6-10 aryl C1-6 alkyl, by the alkyl-substituted-S of C1-6 (=O)2Amino
Carbonylamino ,-COO-C1-6 alkyl, by the alkyl-substituted amino of C1-6, the C1-6 alkyl being substituted with halogen atoms, C1-6 alcoxyl
Base, C3-8 naphthenic base, C6-10 aryl, C6-10 aryl C1-8 alkoxy, C1-6 alkylthio group, 5-11 circle heterocyclic ring base ,-(C=O)-
NH-C1-6 alkyl ,-(C=O)-N(C1-6 alkyl)2,-(C=O)-NH-C3-8 naphthenic base ,-(C=O)-N(C3-8 naphthenic base)2、C1-
6 alkyl sulphinyls or list C1-6 alkyl amino-carbonyl or two C1-6 alkyl amino-carbonyls.
Compound of the present invention, pharmaceutically acceptable salt or ester, solvate, hydrate, isomers, crystal form
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)2Cyclopropyl ,-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, pharmaceutically acceptable salt or ester, solvate, hydrate, isomers, crystal form
Or its prodrug, wherein Ar is the phenyl optionally replaced by 1~5 halogen atom.
Compound of the present invention, pharmaceutically acceptable salt or ester, solvate, hydrate, isomers, crystal form
Or its prodrug, wherein the compound be selected from following formula (a), (b), (c), (d), (e), (f), (g) and (h) in it is any
A kind of compound,
Wherein, Ar is the phenyl optionally replaced by 1~5 halogen atom,
R9 、R10And R11It is each independently selected from hydrogen atom, cyano, nitro ,-S (=O)2R3、-R4-COOH、-R4COOR5、
It is optionally chosen the sulfydryl replaced from the group of substituent group a, the amino replaced from the group of substituent group a is optionally chosen, is optional
The C1-6 alkyl of sulfinyl, the optionally selected group substitution from substituent group a that the selected group from substituent group a replaces,
The C2-6 that C1-6 alkoxy, the optionally selected group from substituent group a of the optionally selected group substitution from substituent group a replace
Alkanoyl is optionally chosen the C3-8 naphthenic base replaced from the group of substituent group a, is optionally chosen take from the group of substituent group a
The 5-11 circle heterocyclic ring base or-R that the C6-10 aryl in generation, the optionally selected group from substituent group a replace6(C=O)-N R6R7,
Wherein R3、R4、R5、R6、R7、R8It is identical as the definition in claim 1 with substituent group a.
Compound of the present invention, pharmaceutically acceptable salt or ester, solvate, hydrate, isomers, crystal form
Or its prodrug, wherein R9、R10And R11It is each independently selected from hydrogen atom ,-S (=O)2- C1-6 alkyl ,-S (=O)2- C3-8 ring
Alkyl ,-S (=O)2- N(C1-6 alkyl)2、-S(=O)2- C2-6 alkanoyl, C6-10 aryl C1-6 alkyl are replaced by C1-6 alkyl
- S (=O)2Amino carbonyl amino ,-COO-C1-6 alkyl, C1- C1-6 alkyl-substituted amino, be substituted with halogen atoms
6 alkyl, C1-6 alkoxy, C3-8 naphthenic base, C6-10 aryl, C6-10 aryl C1-8 alkoxy, C1-6 alkylthio group, 5-11 member are miscellaneous
Ring group ,-(C=O)-NH-C1-6 alkyl ,-(C=O)-N(C1-6 alkyl)2,-(C=O)-NH-C3-8 naphthenic base ,-(C=O)-N(C3-
8 naphthenic base)2, C1-6 alkyl sulphinyl or list C1-6 alkyl amino-carbonyl or two C1-6 alkyl amino-carbonyls.
Compound of the present invention, pharmaceutically acceptable salt or ester, solvate, hydrate, isomers, crystal form
Or its prodrug, wherein R9 、R10And 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)2Cyclopropyl ,-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, pharmaceutically acceptable salt or ester, solvate, hydrate, isomers, crystal form
Or its prodrug, wherein the compound is to be selected from following compounds,
。
Compound of the present invention, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomers, crystal form
Or its prodrug, it is used as dipeptidyl peptidase-IV inhibitor.
Pharmaceutical composition, contain compound, its pharmaceutically acceptable salt or the ester, solvate, hydrate,
Isomers, crystal form or its prodrug, and pharmaceutically acceptable carrier or excipient.
Pharmaceutical composition of the present invention, wherein further include can with the compound, its is pharmaceutically acceptable
Salt or ester, solvate, hydrate, isomers, crystal form or other active materials associated with its prodrug.
Pharmaceutical composition of the present invention, wherein other active materials are melbine or its salt or lattice column
Ketone 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.Drug of the present invention
Preparation etc. can be unit dosage form, and it is suitably 0.5- that unit dose, which contains compound 0.01-1000mg of the present invention,
800mg, preferably 1-400mg, more preferably 5-200mg, particularly preferred 10-100mg, most preferably 15-50mg, such as 20mg,
25mg、30mg。
One kind being suitable for administration to the pharmaceutical preparation of animal, especially mammal, wherein said preparation includes of the present invention
Compound, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomers, crystal form or its prodrug as effectively at
Point, said preparation includes solid pharmaceutical preparation, semisolid preparation, liquid preparation, gaseous state preparation etc..
The treatment or prevention agent of disease relevant to dipeptidyl peptidase-IV, contains that the compound, it pharmaceutically may be used
The salt or ester of receiving, solvate, hydrate, isomers, crystal form or its prodrug are as effective component.
Compound of the present invention, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomers, crystal form
Or its prodrug or its mixture associated with to other active materials are being used to prepare treatment disease relevant with dipeptidyl peptidase-IV
Application in the drug of disease.
The compound of the present invention is to dipeptidyl peptidase-IV with very high inhibitory activity and selectivity, with very excellent
Pharmacokinetic properties and toxic side effect it is smaller, can be used as long-acting dipeptidyl peptidase-iv inhibitor, with treatment with two peptidyls
The relevant various diseases of peptase-IV.
Application of the present invention, wherein disease relevant to dipeptidyl peptidase-IV includes diabetes, obesity, pancreas islet
Element resists disease or hyperlipidemia.
Compound of the present invention, its pharmaceutically acceptable salt or ester, solvate, hydrate, isomers, crystal form
Or its prodrug or its mixture associated with to other active materials are used to treat the side of disease relevant with dipeptidyl peptidase-IV
Method.
Method of the present invention is suitably 0.5-800mg containing compound 0.01-1000mg of the present invention, excellent
It is selected as 1-400mg, more preferably 5-200mg, particularly preferred 10-100mg, most preferably 15-50mg.Pharmaceutical preparation of the present invention etc. can
To be unit dosage form, it is suitably 0.5-800mg that unit dose, which contains compound 0.01-1000mg of the present invention, excellent
It is selected as 1-400mg, more preferably 5-200mg, particularly preferred 10-100mg, most preferably 15-50mg.
Specific embodiment
Illustrate the meaning of each term used in the present specification below.Each term is used with the unified meaning, is individually made
Used time, or when being applied in combination with other terms, all with the use of the identical meaning.
In the present invention, " the optionally selected group from substituent group a replaces " refers to use to be selected from arbitrary position and replace
The identical or different substituent group of 1 or 2 or more of base group a replaces.
In the present invention, " being replaced by C1-6 alkyl ", which refers to, uses 1 or 2 's or more selected from C1-6 alkyl in arbitrary position
Identical or different substituent group replaces.
In the present invention, " halogen atom " indicates fluorine atom, chlorine atom, bromine atom or iodine atom.
In the present invention, " C1-6 alkyl " indicates the alkyl that the carbon atom number of straight-chain or branched is 1~6, can enumerate
Methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, uncle penta
The group of base etc..
In the present invention, " C2-6 alkenyl " indicates the alkenyl that the carbon atom number of straight-chain or branched is 2~6, can enumerate
Vinyl, positive acrylic, isopropenyl, n-butene base, isobutenyl, secondary cyclobutenyl, tertiary cyclobutenyl, n-pentene base, iso-amylene
The group of base, new pentenyl, tertiary amylene base etc..
In the present invention, " C2-6 alkynyl " indicates the alkynyl that the carbon atom number of straight-chain or branched is 2~6, can enumerate
Acetenyl, positive propinyl, isopropynyl, positive butynyl, butynyl, secondary butynyl, tertiary butynyl, positive pentynyl, isopropyl-acetylene
The group of base, new pentynyl, tertiary pentynyl etc..
In the present invention, " C3-8 naphthenic base " can enumerate the base of cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl etc.
Group.
In the present invention, " C1-6 alkoxy " refers to that the carbon atom number of straight-chain or branched is 1~6 alkoxy, can be with
Enumerate methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, positive penta
The group of base oxygroup, isopentyl oxygroup, neopentyl epoxide, tertiary pentyl oxygroup etc..
In the present invention, " C1-6 alkylidene ", " C2-6 alkenylene ", " C2-6 alkynylene " are referred respectively to from above-mentioned " C1-6 alkane
Base ", " C2-6 alkenyl ", the bivalent group that 1 hydrogen atom is eliminated in " C2-6 alkynyl ".
In the present invention, " C2-6 alkanoyl " refers to that the carbon atom number of straight-chain or branched is 2~6 alkanoyl, can be with
Enumerate the group of acetyl group, propiono, bytyry, isobutyryl, valeryl, isovaleryl, pivaloyl group etc..
In the present invention, " single C1-6 alkyl amino-carbonyl " refer to use have 1 above-mentioned " C1-6 alkyl " as substituent group
Amino instead of carbonyl, methylaminocarbonyl, ethyl aminocarbonyl, n-propyl amino carbonyl, isopropylamino can be enumerated
Carbonyl, n-butylaminocarbonyl, isobutylamino carbonyl, s-butylamino carbonyl, tert-butylamino carbonyl, n-pentyl amino carbonyl
Base, isopentylaminocarbonyl, neopentyl amino carbonyl etc..
In the present invention, " two C1-6 alkyl amino-carbonyls " refers to with 2 identical or different above-mentioned " C1-6 alkyl "
As substituent group amino instead of carbonyl, Dimethylaminocarbonyl, diethylaminocarbonyl, two (n-propyls) can be enumerated
Amino carbonyl, two (isopropyl) amino carbonyls, ethylmethylaminocarbonyl, methyl (n-propyl) amino carbonyl, methyl (isopropyl
Base) amino carbonyl etc..
In the present invention, " C6-10 aryl " refers to monocycle or polycyclic carbon atom number is the aryl of 6-10.Wherein, for more
The case where cyclophane base also includes the group of fractional saturation other than unsaturation completely.Such as phenyl, naphthalene, Azulene can be enumerated
Base, indenyl, indanyl, tetrahydro naphthyl etc..
In the present invention, " C6-10 aryl C1-6 alkyl " refers to following C6-10 aryl and above-mentioned C1-6 alkyl linked base
Group.Such as benzyl, phenethyl, 3- phenyl-n-propyl, 4- phenyl-n-butyl, 5- phenyl-n-pentyl, 8- phenyl-can be enumerated just
Hexyl, menaphthyl etc..
In the present invention, " 5-11 circle heterocyclic ring base " refers to: also including to be selected from nitrogen except carbon atom as the atom for constituting ring
Atom, 1~4 heteroatomic 5~7 yuan of aromatic heterocycle of oxygen atom and sulphur atom, saturated heterocyclic, unsaturated heterocycle or these are miscellaneous
Ring and the condensed obtained annelated heterocycles of phenyl ring.Such as it can enumerate: 2- furyl, 3- furyl, 2- thienyl, 3- thienyl, pyrrole
Cough up -1- base, pyrroles -2- base, pyrroles -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- benzo dioxa
Cyclopentene -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, benzo thiophene
Pheno -3- base, benzothiophene -4- base, benzothiophene -5- base, benzothiophene -6- base, benzothiophene -7- base, quinoxaline -2- base,
Quinoxaline -5- base, quinoxalin-6-yl, indoles -1- base, indoles -2- base, indol-3-yl, indoles -4- base, indoles -5- base, Yin
Diindyl -6- base, indoles -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, pyrrole
Azoles -4- base, pyrazoles -5- base, thiazol-2-yl, thiazole-4-yl, thiazole -5- base,Azoles -2- base,Azoles -4- base,Azoles -5-
It is base, differentIt is azoles -3- base, differentIt is azoles -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, benzo
Thiazole -5- base, benzoAzoles -2- base, benzoAzoles -4- base, benzoAzoles -5- base, quinoline -2- base, quinoline -3- base, quinoline
Quinoline -4- base, quinoline -5- base, quinoline -6- base, quinoline -7- base, quinoline-8-yl, isoquinolyl-1, isoquinolin -3- base, isoquinoline
Quinoline -4- base, isoquinolin -5- base, isoquinolin -6- base, isoquinolin -7- base, isoquinolin -8- base, 1,3,4- thiadiazoles -2- base,
Quinoline is for 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, two
Hydrogen indoles -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- tetrahydro are different
Quinoline -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 alkoxy " refers to above-mentioned " C6-10 aryl C1-6 alkyl " and oxygen atoms bond
Group.Such as benzyl oxygroup, phenethyl oxygroup, menaphthyl oxygroup can be enumerated etc..
In the present invention, " C1-6 alkylthio group " can for example enumerate methyl mercapto, ethylmercapto group, positive rosickyite base, isopropyisulfanyl, positive fourth sulphur
Base, 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 " can for example be enumerated: methylsulfinyl, ethylsulfinyl, positive third
Base sulfinyl, isopropylsulphinyl, n-butylsulfinyl, isobutyl group sulfinyl, sec-butyl sulfinyl, tert-butyl
Sulfinyl, n-pentyl sulfinyl, isopentyl sulfinyl, neopentyl sulfinyl, 1- methyl butyl sulfinyl, 1- second
Base propylsulfenyl, n-hexyl sulfinyl, isohesyl sulfinyl, 3- methyl amyl sulfinyl, 2- methyl amyl are sub-
Sulfonyl, 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- dimethyl butyrate
Base sulfinyl, 1- ethyl-butyl sulfinyl, 2- ethyl-butyl sulfinyl etc..
In addition to this, here undefined group in accordance with common definition.
Currently preferred mode can enumerate following manner.
In logical formula (I), as R1、R2- S (=O)2R3In, R3The preferably C1-6 alkane of methyl, ethyl, isopropyl etc.
The C3-8 naphthenic base of base, cyclopropyl etc., hydroxyl, amino, by 1 or 2 C1-6 alkyl-substituted amino ,-NH-C (=O)-
NH-( CH2)2CH3、- NH -C(=NH)-NH2,-NH-C (=NH)-N(CH3)2。
In logical formula (I), as R1、R2- R4In-COOH, R4Preferably singly-bound.
In logical formula (I), as R1、R2- R4COOR5In, R4Preferably singly-bound, R5Preferably C1-6 alkyl, more preferably
Methyl or ethyl.
In logical formula (I), as R1、R2- R8(C=O)-N R6R7In, R8Preferably singly-bound, R6And R7It is excellent each independently
Choosing is hydrogen atom or C1-6 alkyl, more preferably hydrogen atom.
In logical formula (I), preferably A1For N, A2For C, A3For N, A4For C, A5For N.
In logical formula (I), preferably A1For N, A2For C, A3For C, A4For C, A5For N.
In logical formula (I), preferably A1For N, A2For C, A3For N, A4For N, A5For C.
In logical formula (I), preferably A1For N, A2For C, A3For C, A4For N, A5For C.
In logical formula (I), preferably A1For N, A2For C, A3For N, A4For C, A5For C.
In logical formula (I), 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 where C, A2
With A3Between and A4With A5Between be double bond.
In logical formula (I), preferably in A1For N, A2For C, A3For C, A4For N, A5For C；Or A1For N, A2For C, A3For N, A4For C,
A5In the case where C, A2With A3Between and A1With A5Between be double bond.
In logical formula (I), preferably Ar is the phenyl optionally replaced by 1~5 halogen atom, is preferably replaced by fluorine atoms
Phenyl is more preferably the phenyl 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 includes and the nothings such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid or nitric acid
The salt of machine acid or with 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, ethanesulfonic acid, benzene sulphur
The salt of the organic acids such as acid, p-methyl benzenesulfonic acid, camphorsulfonic acid or naphthalene-2-sulfonic acid, with lithium ion, sodium ion, potassium ion, calcium ion,
The salt of one or more metal ions such as magnesium ion, zinc ion, aluminium ion and ammonia, arginine, lysine, piperazine, choline, diethyl
The salt of the amine such as base amine, 4- phenylcyclohexylamine, 2- ethylaminoethanol, tardocillin.As long as pharmaceutically acceptable salt,
It is not particularly limited.Conversion by from episome to the salt can be carried out with existing method.
It should be noted that the compound of the present invention also can be used as various solvates and exist.In addition, from as the suitable of drug
From the point of view of property, the case where promising hydrate.
The compound of the present invention can be containing one or more asymmetric centers, and thus, it is possible to racemate, racemic
The form of mixture, single enantiomter, non-enantiomer mixture and single diastereoisomer etc. exists.Term
" crystal form " includes any crystal form, such as monocrystalline, polymorphic of the compounds of this invention etc..
The compound of the present invention can pharmaceutically acceptable carrier, excipient or diluent with one or two or more
Combination is to form pharmaceutical preparation.As above-mentioned carrier, excipient and diluent refer to that organism is not caused significantly to stimulate
Property and do not interfere given compound bioactivity property pharmaceutical composition in non-active ingredient.
As above-mentioned carrier, excipient and diluent, comprising water, lactose, glucose, fructose, sucrose, D-sorbite, sweet
Reveal alcohol, polyethylene glycol, propylene glycol, starch, rubber, gel, alginates, calcium silicates, calcium phosphate, cellulose, aqueous syrup, methyl
Cellulose, polyvinylpyrrolidone, para hydroxybenzene and sorb acid alkyl ester, talcum, magnesium stearate, stearic acid, glycerol, sesame
Various oil of oil, olive oil, soybean oil etc. etc..
In addition, the incremental agent generally used, bonding can be mixed as needed in above-mentioned carrier, excipient or diluent
The additive of agent, disintegrating agent, pH adjusting agent, lytic agent etc. can use common preparation technique as tablet, pill, capsule
The oral or non-oral administration object of agent, granule, pulvis, liquor, emulsion, suspending agent, ointment, injection, skin patch etc.
To prepare.The compound of the present invention for adult patient, can with it is oral or it is non-oral given, mouth of the invention
Medication object, which is generally every 3-12 days, to be administered once, and is administered once within preferably every 5-10 days, is administered once, and total amount is administered within more preferable 1 week
0.01~1000mg/ times.It should be noted that the dosage of the compound of the present invention can be according to the kind of the disease as treatment object
Class, the age of patient, weight, symptom etc. and suitably increase and decrease.
The compound of the present invention also includes more than one hydrogen atom, fluorine atom, carbon atom, nitrogen-atoms, oxygen atom, sulphur original
Son is replaced into the compound of radioactive isotope or stable isotope.These labeled compounds can be used for being metabolized or medicine is for power
It learns research, carry out biological analysis etc. as ligand of receptor etc..
The compound of the present invention can combine for treating, in advance with one or more other medicines (such as melbine)
Anti-, inhibition improves disease or symptom, and wherein the exclusive use of drug being used in combination than any drug is more pacified
It is complete or more effective.This other medicines can with to this usually used approach and amount with the compound of the present invention simultaneously or
Person is successively administered.When the compound of the present invention with one or more kinds of other medicines simultaneously in use, containing in unit dosage forms
The pharmaceutical composition of the other medicines and the compound of the present invention is preferably, especially to combine with pharmaceutically acceptable carrier.
However, combination therapy, which can also be included in different overlapping schedules, gives the compound of the present invention and one or more kinds of other medicines
The treatment of object.It is also contemplated that when with one or more kinds of other active ingredient combinations in use, the compounds of this invention and other
Active constituent lower dosage use when can be with than being respectively used alone.Therefore, other than the compound of the present invention, the present invention
Pharmaceutical composition further includes containing those of one or more kinds of other active constituents composition.
The compound of the present invention can for example be manufactured according to method shown in following.
The compounds of this invention shown in formula (1) can use the manufacture of synthetic method shown in scheme 1.
<scheme 1>
(in formula, A1~A5、Ar、R1And R2With the aforementioned meaning having the same).
Amine shown in ketone shown in formula (2) and formula (3) 0-50 DEG C, preferably 10-40 DEG C at a temperature of carried out
0.5-30 hours, preferably 1-24 hours reduction aminations obtain reduced aminate shown in formula (4), by the obtained production
Object further sloughs amino protecting group in the case where pH is 2~6 acid condition, obtains general formula compound (1).
When amine compounds shown in formula (3) in above-mentioned<scheme 1>are Formula (8), it can use shown in scheme 2
Synthetic method manufacture.
<scheme 2>
(in formula, R1And R2With the aforementioned meaning having the same).
Formula (5) carries out bromo in the solvent of carbon tetrachloride etc., with bromine, then with 2- Aminopyrazine in 0-40
DEG C, 0.5-20 hours, preferably 1-12 hours ring closure reactions are carried out at a temperature of preferably 10-30 DEG C, obtain Formula (7).
By the Formula (7) 0-40 DEG C, preferably 20-30 DEG C at a temperature of by palladium carbon catalytic hydrogenation, obtain Formula
(8).
Amine compounds shown in formula (3) in above-mentioned<scheme 1>areWhen, it can use shown in scheme 3
Synthetic method manufacture.
<scheme 3>
C- pyrazine -2- base-methylamine and the halogenated acid anhydrides of trifluoroacetic anhydride etc. are stirred at room temperature overnight, compound is obtained
1b.By the compound 1b under the action of phosphorus oxychloride and phosphorus pentoxide, cyclization product 1c is obtained.Then ammonia is protected with Boc
Base carries out bromo with NBS.Bromo-derivative 1e is carried out to insert carbonyl in organic solvent, preferably methanol with cobalt octacarbonyl, inserts carbonyl product
After 1f takes off Boc-, target compound is obtained.
When formula (1) compound represented is ester type compound, corresponding carboxylic can be obtained respectively by hydrolysis and ammonolysis
Acid and amide target product.
Embodiment
It is exemplified below embodiment and test example, and then explains the present invention in detail, but they do not limit the present invention, in addition exist
It can be changed without departing from the scope of the invention.
The structure for the compound recorded in embodiment below by nuclear magnetic resonance (1HNMR) or mass spectrum (MS) determines.
Nuclear magnetic resonance (1HNMR determining instrument) uses 400 nuclear magnetic resonance spectrometer of JEOL Eclipse；Measurement solvent is deuterated first
Alcohol (CD3OD), deuterated chloroform (CDCl3), hexadeuterated dimethyl sulfoxide (DMSO-d6)；Internal standard substance is tetramethylsilane (TMS).
Abbreviation in nuclear magnetic resonance used in embodiment (NMR) map is shown in following.
S: unimodal, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: four doublets, ddd: in pairs two
Weight peak, ddt: triplet, dddd in pairs: double doublet, m in pairs: multiplet, br: broad peak (broad), J: coupling constant, Hz:
Hertz, DMSO-d6: deuterodimethylsulfoxide.
Whole δ values are indicated 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 respectively abridged is as shown below.
DMF:N, dinethylformamide
DMA:N, N- dimethyl acetamide
NMP:N- methyl pyrrolidone
THF: tetrahydrofuran
Boc: tert-butoxycarbonyl
NBS；N- bromine succinimide
M-CPBA: metachloroperbenzoic acid
TFA: trifluoracetic acid
Et2O: Anaesthetie Ether,
EtOH: ethyl alcohol
Dioxane:1,4- dioxane
TLC: thin-layer chromatography
HATU:O-(7- azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethylurea hexafluorophosphate
Me: methyl
DCM: methylene chloride
EA: ethyl acetate
The chloro- 5,6- dicyan -1,4- benzoquinones of DDQ:2,3- bis-.
It should be noted that in the following contents, the salt form of compound n ' expression compound n.
Embodiment 1:7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- three
Methyl fluoride -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester and secondly trifluoroacetate preparation
Step 1: 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 flask, is slowly added dropwise 9.8
ML trifluoroacetic anhydride stirs 12 hours at room temperature, and reaction solution is concentrated under reduced pressure, and obtains title product trifluoroacetyl pyrazine -2- methylamine
(15 g crude products, brown oil) is directly used in and reacts in next step.
Step 2: the synthesis of 3- trifluoromethyl imidazoles simultaneously [1,5-a] pyrazine
Under room temperature, 2,2,2- tri- fluoro- N- pyrazine -2- methyl-formamide (15 g) is added in reaction flask, successively
80 mL phosphorus oxychloride and phosphorus pentoxide (10 g, 73 mmol) are added, heating reflux reaction 6 hours, remove solvent trichlorine oxygen
Phosphorus, reaction system deionized water slowly quenching reaction, then it is 5-6 that pH is adjusted in ice bath with 20% sodium hydroxide solution, is used
Ethyl acetate (250 mL × 4) extraction, merges organic phase, dry with anhydrous magnesium sulfate, filters, and filtrate is concentrated under reduced pressure, with column layer
Analysis purifying, is concentrated to get title product 3- trifluoromethyl-imidazole simultaneously [1,5-a] pyrazine (5.0 g, yellow solid), and two steps are received
Rate: 58.3%.
Step 3: the conjunction of 3- trifluoromethyl -7- tert-butoxycarbonyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine
At
50 mL will be dissolved under 3- trifluoromethyl-imidazole simultaneously [1,5-a] pyrazine (3.53 g, 18.88 mmol) stirring
In tetrahydrofuran, triethylamine (2.48 g), Boc are sequentially added2O (4.94 g, 22.65 mmol) and 350 mg, 10% palladium/
Carbon stirs 13 hours under hydrogen protection.Catalyst, evaporated under reduced pressure filtrate are removed, column chromatographic purifying obtains title product 3- tri-
Methyl fluoride -7- tert-butoxycarbonyl -5,6,7,8- tetrahydro-imidazos simultaneously [1,5-a] pyrazine (4.4 g, brown solid), yield:
80%.
Step 4: the bromo- 3- trifluoromethyl -7- tert-butoxycarbonyl -5,6,7,8- tetrahydro-imidazo of 1- simultaneously [1,5-a] pyrazine
Synthesis
At room temperature, by 3- trifluoromethyl -7- tert-butoxycarbonyl -5,6,7,8- tetrahydro-imidazos simultaneously [1,5-a] pyrazine
(4.7 g, 16.1 mmol) are dissolved in 80 mL ethyl alcohol, dense after NBS (4.3 g, 24.2 mmol) reaction being then added 7 hours
Contracting reaction solution adds 80 mL of water, white solid, filtering is precipitated, drying obtains the bromo- 3- tri- of target product 1- after filter residue is washed with water
Methyl fluoride -7- tert-butoxycarbonyl -5,6,7,8- tetrahydro-imidazos simultaneously [1,5-a] pyrazine (4 g, white solid), yield:
50%。
Step 5: 3- trifluoromethyl -7- tert-butoxycarbonyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic
The synthesis of sour methyl esters
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) are added with stirring 30 mL methanol, and after ten minutes, the bromo- 3- trifluoromethyl -7- uncle of 1- is added in stirring
Butoxy carbonyl -5,6,7,8- tetrahydro-imidazos simultaneously [1,5-a] pyrazine (2.0 g, 5.42 mmol), reaction 24 is small at 60 DEG C
When, it is evaporated reaction solution, residue is concentrated to get title product 3- trifluoromethyl -7- tert-butoxycarbonyl -5,6 through column chromatographic purifying,
7,8- tetrahydro-imidazos simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester (1.3 g, white solid), yield: 68.7%.
Step 6: 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-imidazos simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester (1.1 g,
3.5 mmol) it is dissolved in 10 mL methylene chloride, trifluoroacetic acid (1 mL) is added at room temperature and stirs 13 hours, methanol after concentration
Dissolution, with triethylamine tune pH=8, column chromatographic purifying is concentrated to get target product 3- trifluoromethyl -5,6,7,8- tetrahydro-imidazos
And [1,5-a] pyrazine -1- carboxylate methyl ester (0.5 g, brown solid), yield: 63%.
Step 7: 7- ((3R, 5S, 6R) -5-(tert-butoxycarbonyl) amino -6- (2,5- difluorophenyl) 2H- tetrahydro pyrrole
Mutter -3- base) synthesis of -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester
At room temperature, to (3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- oxinane -3- ketone (387
Mg, 1.18 mmol) and 3- trifluoromethyl -5,6,7,8- tetrahydro-imidazos simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester (310 mg,
1.24 mmol) tetrahydrofuran (15 mL) solution in be added acetic acid (149 mg, 2.48 mmol), stirring 6 hours after, will
Reaction solution is cooled to 0 DEG C, and NaBH is added3CN (156 mg, 2.48 mmol) is simultaneously stirred 12 hours.After reaction solution is quenched with water,
Concentration, the isolated 7- of TLC ((3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -
3- trifluoromethyl -5,6,7,8- tetrahydro-imidazos simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester (180 mg, white solid), yield:
27%。
Step 8: 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoro
The synthesis of methyl -5,6,7,8- tetrahydro-imidazo simultaneously two trifluoroacetate of [1,5-a] pyrazine -1- carboxylate methyl ester
At room temperature, to 7- ((3R, 5S, 6R) -5-(tert-butoxycarbonyl) amino -6- (2,5- difluorophenyl) 2H- tetrahydro
Pyrans -3- base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester (40 mg) 1
0.3 mL trifluoroacetic acid is added in mL dichloromethane solution, is stirred at room temperature 15 hours.Concentration of reaction solution dissolves weight with ethyl acetate
Methyl tertiary butyl ether(MTBE) being added after new dissolution, product being precipitated, target product 7- ((3R, 5S, 6R) -5- amino -6- is obtained after filtering
(2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1-
Two trifluoroacetate of carboxylate methyl ester (11 mg, brown solid), yield: 33%.
Step 9: free compound 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- oxinane -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 -
Simultaneously two trifluoroacetate of [1,5-a] pyrazine -1- carboxylate methyl ester is super using the aqueous sodium carbonate of 2M for 5,6,7,8- tetrahydro-imidazo
Sound washing, filters and can get free compound 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- oxinane -
3- yl) -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- tetrahydropyran -3-base) -3- three
Methyl fluoride -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acid and secondly trifluoroacetate preparation
Step 1: 7- ((3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3-
The synthesis of trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acid
At room temperature, to 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 (80 mg, 0.14 mmol) four
The 1 mL aqueous solution of lithium hydroxide (15 mg, 0.28 mmol) is added in hydrogen furans (1 mL) solution, after stirring 8 hours.With 1
N dilute hydrochloric acid adjusts pH=6 of reaction, is then concentrated to dryness, and crude product is directly used in react in next step.
Step 2: 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoro
The synthesis of methyl -5,6,7,8- tetrahydro-imidazo simultaneously two trifluoroacetate of [1,5-a] pyrazine -1- carboxylic acid
At room temperature, by 7- ((3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -
3- trifluoromethyl -5,6, simultaneously [1,5-a] pyrazine -1- crude carboxylic acid is dissolved in methylene chloride (2 mL) 7,8- tetrahydro-imidazos, is added
Enter trifluoroacetic acid (0.5 mL) and stirs 12 hours.After concentration of reaction solution crude product, by crude product recrystallization purifying obtain 7- ((3R,
5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo
And two trifluoroacetate (15 mg, faint yellow solid) of [1,5-a] pyrazine -1- carboxylic acid, two step yields 23%.
Step 3: free compound 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- oxinane -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 -
Simultaneously two trifluoroacetate of [1,5-a] pyrazine -1- carboxylic acid is dissolved in water to 5,6,7,8- tetrahydro-imidazos, has been adjusted to 2M sodium carbonate mixed
Turbid phenomenon, pH value is 6.5 at this time, is then extracted with dichloromethane three times, is washed after methylene chloride is mutually merged with saturated sodium-chloride
It washs once, the dichloromethane solution after washing dries, filters removing desiccant with anhydrous sodium sulfate, and revolving removes methylene chloride and is
Obtain free compound 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoro
Methyl -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- tetrahydropyran -3-base) -3- three
The preparation of methyl fluoride -5,6,7,8- tetrahydro-imidazo simultaneously two trifluoroacetate of [1,5-a] pyrazine -1- carboxylic acid amide
Step 1: 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoro
The synthesis of methyl -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- trifluoro
Methyl -5,6, simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester (70 mg) is added in 2 mL ammonium hydroxide 7,8- tetrahydro-imidazos, and 100 DEG C bored
Tank reacts 15 hours, and after reaction solution concentration, TLC isolates and purifies to obtain sterling 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluoros
Phenyl) 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%.
Step 2: 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoro
The synthesis of methyl -5,6,7,8- tetrahydro-imidazo simultaneously two trifluoroacetate of [1,5-a] pyrazine -1- carboxylic acid amide
At room temperature, to 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- three
The methylene chloride (2 mL) of methyl fluoride -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acid amide (30 mg) is molten
Trifluoroacetic acid (0.5 mL) is added in liquid, after stirring 3 hours, reaction solution 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- four
Two trifluoroacetate (21 mg, off-white powder) of hydrogen-imidazo [1,5-a] pyrazine -1- carboxylic acid amide, yield 56%.
Embodiment 4:7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -5,6,
The preparation of 7,8- tetrahydro-[1,2,4] triazole simultaneously two trifluoroacetate of [4,3-a] pyrazine -3- carboxylic acid, ethyl ester
Step 1: 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrrole
Mutter -3- base) synthesis of -5,6,7,8- tetrahydro-[1,2,4] triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid, ethyl ester
In addition to using 5,6,7,8- tetrahydro-[1,2,4] triazole, simultaneously [4,3-a] pyrazine -3- carboxylic acid, ethyl ester replaces 3- trifluoro
Methyl -5,6,7,8- tetrahydro-imidazos simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester, makes 5,6,7,8- tetrahydros-[1,2,4] triazole
And the dosage of [4,3-a] pyrazine -3- carboxylic acid, ethyl ester be 1g except, it is other it is same as the 7th step of embodiment 1 operate, obtain title
Product 480mg, yield 18.6%.
Step 2: 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -5,6,7,
The synthesis of 8- tetrahydro-[1,2,4] triazole simultaneously two trifluoroacetate of [4,3-a] pyrazine -3- carboxylic acid, ethyl ester
In addition to using 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrrole
Mutter -3- base) simultaneously [4,3-a] pyrazine -3- carboxylic acid, ethyl ester replaces 7- ((3R, 5S, 6R)-to -5,6,7,8- tetrahydro-[1,2,4] triazole
5-(tert-butoxycarbonyl) amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- four
Hydrogen-imidazo [1,5-a] pyrazine -1- carboxylate methyl ester makes 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5-
Difluorophenyl) tetrahydro -2H- pyrans -3- base) -5,6,7,8- tetrahydro-[1,2,4] triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid second
The dosage of ester be 60 mg except, it is other it is same as the 8th step of embodiment 1 operate, obtain title product 40mg, yield is
53.3%.
Embodiment 5:7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -5,6,
The preparation of 7,8- tetrahydro-[1,2,4] triazole simultaneously two trifluoroacetate of [4,3-a] pyrazine -3- carboxylic acid amide
Step 1: 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrrole
Mutter -3- base) synthesis of -5,6,7,8- tetrahydro-[1,2,4] triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid amide
In addition to using 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrrole
Mutter -3- base) simultaneously [4,3-a] pyrazine -3- carboxylic acid, ethyl ester replaces 7- ((3R, 5S, 6R)-to -5,6,7,8- tetrahydro-[1,2,4] triazole
5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo is simultaneously
[1,5-a] pyrazine -1- carboxylate methyl ester makes 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl)
Tetrahydro -2H- pyrans -3- base) dosage of -5,6,7,8- tetrahydro-[1,2,4] triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid, ethyl ester is
Except 150mg, it is other it is same as 3 first step of embodiment operate, obtain title product 100mg, yield 70.9%.
Step 2: 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -5,6,7,
The synthesis of 8- tetrahydro-[1,2,4] triazole simultaneously two trifluoroacetate of [4,3-a] pyrazine -3- carboxylic acid amide
In addition to using 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrrole
Mutter -3- base) simultaneously [4,3-a] pyrazine -3- carboxylic acid amide replaces 7- ((3R, 5S, 6R)-to -5,6,7,8- tetrahydro-[1,2,4] triazole
5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo is simultaneously
[1,5-a] pyrazine -1- carboxylic acid amide makes 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl)
Tetrahydro -2H- pyrans -3- base) dosage of -5,6,7,8- tetrahydro-[1,2,4] triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid amide is
Except 100mg, it is other it is same as 3 second step of embodiment operate, obtain title product 51mg, yield 40.3%.
Embodiment 6:7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -5,6,
The preparation of 7,8- imidazolidine simultaneously two trifluoroacetate of [1,2-a] pyrazine -2- carboxylic acid, ethyl ester
Step 1: 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrrole
Mutter -3- base) synthesis of -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester
In addition to using 5,6,7,8- imidazolidine, simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester replaces trifluoromethyl -5,6,7 3-,
8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester, makes 5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine -2- carboxylic acid second
The dosage of ester be 1.5g except, it is other it is same as the 7th step of embodiment 1 operate, obtain title product 0.7g, yield 27.2%.
Step 2: 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -5,6,7,
The synthesis of 8- imidazolidine simultaneously two trifluoroacetate of [1,2-a] pyrazine -2- carboxylic acid, ethyl ester
In addition to using 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrrole
Mutter -3- base) simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester replaces 7- (the tertiary fourth oxygen of (3R, 5S, 6R) -5-(to -5,6,7,8- imidazolidine
Base carbonyl) amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo is simultaneously
[1,5-a] pyrazine -1- carboxylate methyl ester makes 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl)
Tetrahydro -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester dosage be 150mg it
Outside, it is other it is same as the 8th step of embodiment 1 operate, obtain title product 100mg, yield 53.3%.
Embodiment 7:7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -5,6,
The preparation of 7,8- imidazolidine simultaneously two trifluoroacetate of [1,2-a] pyrazine -2- carboxylic acid
Step 1: 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrrole
Mutter -3- base) synthesis of -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid
In addition to using 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrrole
Mutter -3- base) simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester replaces 7- ((3R, 5S, 6R) -5-Boc- ammonia to -5,6,7,8- imidazolidine
Base -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo is simultaneously [1,5-a]
Pyrazine -1- carboxylate methyl ester makes 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H-
Pyrans -3- base) -5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester dosage be 150mg except, Qi Tayu
2 first step of embodiment equally operates, and obtains title product 110mg, yield 77.6%.
Step 2: 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -5,6,7,
The synthesis of 8- imidazolidine simultaneously two trifluoroacetate of [1,2-a] pyrazine -2- carboxylic acid
In addition to using 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H-
Pyrans -3- base) simultaneously [1,2-a] pyrazine -2- carboxylic acid replaces 7- ((3R, 5S, 6R) -5-(tert-butoxy to -5,6,7,8- imidazolidine
Carbonyl) amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo is simultaneously
[1,5-a] pyrazine -1- carboxylate methyl ester makes 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorobenzenes
Base) tetrahydro -2H- pyrans -3- base) -5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine -2- carboxylic acid dosage be 110mg except,
It is other it is same as 2 second step of embodiment operate, obtain title product 100mg, yield 71.9%.
Embodiment 8:7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -5,6,
The preparation of 7,8- imidazolidine simultaneously two trifluoroacetate of [1,2-a] pyrazine -2- carboxylic acid amide
Step 1: 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrrole
Mutter -3- base) synthesis of -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -2- carboxylic acid amide
In addition to using 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H-
Pyrans -3- base) simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester replaces 7- ((3R, 5S, 6R) -5-Boc- ammonia to -5,6,7,8- imidazolidine
Base -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo is simultaneously [1,5-a]
Pyrazine -1- carboxylate methyl ester makes 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -
2H- pyrans -3- base) -5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine -2- carboxylic acid, ethyl ester dosage be 250mg except, it is other
It is same as 3 first step of embodiment to operate, obtain title product 100mg, yield 42.4%.
Step 2: 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -5,6,7,
The synthesis of 8- imidazolidine simultaneously two trifluoroacetate of [1,2-a] pyrazine -2- carboxylic acid amide
In addition to using 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H-
Pyrans -3- base) simultaneously [1,2-a] pyrazine -2- carboxylic acid amide replaces 7- ((3R, 5S, 6R) -5-Boc- ammonia to -5,6,7,8- imidazolidine
Base -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo is simultaneously [1,5-a]
Pyrazine -1- carboxylic acid amide makes 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -
2H- pyrans -3- base) -5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine -2- carboxylic acid amide dosage be 100mg except, it is other
It is same as 3 second step of embodiment to operate, obtain title product 65mg, yield 51.3%.
Embodiment 9:7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -2- (three
Methyl fluoride) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester dihydrochloride preparation
Step 1: the synthesis of the bromo- 2- trifluoroacetyl ethyl of 2-
Trifluoroacetic ethyl acetoacetate (10 g, 54.3 mmol) and carbon tetrachloride 20ml are added in reaction flask, room temperature
Under be slowly added dropwise after bromine obtains carbon tetrachloride solution (8.7,54.4 mmol/30ml), be stirred to react 3 hours.Reaction solution decompression is dense
Contracting, obtain the bromo- 2- trifluoroacetyl ethyl of title product compound 2- (12.1 g crude products, yield: 84.6%, yellow liquid
Body), it is directly used in and reacts in next step.
Step 2: the synthesis of 2- trifluoromethyl imidazoles simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester
Successively by the bromo- 2- trifluoroacetyl ethyl (10g, 38mmol) of compound 2-, ethyl alcohol 100ml, 2- amino pyrrole
Piperazine (3.95g, 41.5mmol) is added in reaction flask, N2Protection, 90 DEG C are stirred to react 12 hours, are concentrated under reduced pressure, residue column layer
Analysis purifying, obtain title product compound 2- trifluoromethyl imidazoles simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester (2.5g, yield:
25.5%, off-white powder).
Step 3: the synthesis of 2- trifluoromethyl -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester
It will be under compound 2- trifluoromethyl imidazoles simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester (1.5 g, 5.9 mmol) stirring
It is dissolved in 30mL methanol, 10% palladium carbon 750mg is added, is stirred at room temperature 13 hours under hydrogen shield.Catalyst is removed, is depressurized dense
Contracting obtains title product compound 2- trifluoromethyl -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester (1.3
G, yield: 85.0%, brown solid).
Step 4: 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrrole
Mutter -3- base) synthesis of -2- (trifluoromethyl) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester
At room temperature, to (3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- oxinane -3- ketone
(1050 mg, 3.21 mmol) and compound 2- trifluoromethyl -5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine -3- carboxylic acid second
In methylene chloride (50 mL) solution of ester (820 mg, 3.12 mmol) be added tetraisopropyl titanate (1.1g, 3.87
Mmol), it is stirred at room temperature 12 hours.After reaction solution is cooled to 0 DEG C, NaBH is added3CN (384 mg, 6.09 mmol) and 10mL
Ethyl alcohol after heating room temperature is stirred to react 8 hours, after reaction solution is quenched with water, is concentrated under reduced pressure, with column chromatographic purifying, obtains title
Product Compound 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3-
Base) -2- (trifluoromethyl) -5, simultaneously (800 mg, off-white color are solid for [1,2-a] pyrazine -3- carboxylic acid, ethyl ester for 6,7,8- imidazolidines
Body), yield: 44.7%.
Step 5: 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -2- (three
Methyl fluoride) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester dihydrochloride synthesis
At room temperature, to compound 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) four
Hydrogen -2H- pyrans -3- base) -2- (trifluoromethyl) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester (110
Mg it is passed through dry HCl gas in 5 mL ethyl acetate solutions), after fully reacting, concentration, washing, drying obtain target production
Object 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -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- tetrahydropyran -3-base) -3- three
The preparation of methyl fluoride -5,6,7,8- tetrahydro-imidazo simultaneously [1,2-a] pyrazine -3- carboxylic acid dihydrochloride
Step 1: 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrrole
Mutter -3- base) synthesis of -2- (trifluoromethyl) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid
At room temperature, to compound 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) four
Hydrogen -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) tetrahydrofuran (5mL) solution in be added lithium hydroxide (15 mg, 0.36 mmol) 1 mL it is water-soluble
Liquid adjusts pH=3 of reaction with 1 N dilute hydrochloric acid after stirring 5 hours, and then concentration removes organic solvent, and residual reaction liquid is added
Purified water, filtering, obtains target compound 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) four
Hydrogen -2H- pyrans -3- base) -2- (trifluoromethyl) -5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine -3- carboxylic acid 95mg, yield:
90%。
Step 2: 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoro
The synthesis of methyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,2-a] pyrazine -3- carboxylic acid dihydrochloride
At room temperature, by compound 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) four
Hydrogen -2H- pyrans -3- base) -2- (trifluoromethyl) -5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine -3- carboxylic acid (95mg,
It 0.17mmol) is dissolved in ethyl acetate (5 mL), is passed through dry HCl gas, it is after the reaction was completed, concentration, washing, dry
To target product 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -
5,6,7,8- tetrahydro-imidazos 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) tetrahydro -2H- pyrans -3- base) -2-
The preparation of trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,2-a] pyrazine -3- carboxylic acid amide dihydrochloride
Step 1: 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrrole
Mutter -3- base) synthesis of -2- (trifluoromethyl) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid amide
In addition to using 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrrole
Mutter -3- base) -2- (trifluoromethyl) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester replace 7- ((3R, 5S,
6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro-miaow
Azoles simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester, makes 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluoros
Phenyl) tetrahydro -2H- pyrans -3- base) -2- (trifluoromethyl) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid second
The dosage of ester be 100mg except, it is other it is same as 3 first step of embodiment operate, obtain title product 90mg, yield 90%.
Step 2: 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -2- trifluoro
The synthesis of methyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,2-a] pyrazine -3- carboxylic acid amide dihydrochloride
In addition to using 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrrole
Mutter -3- base) -2- (trifluoromethyl) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid amide amine replace 7- ((3R,
5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoromethyl -5,6,7,8- tetrahydro -
Imidazo [1,5-a] pyrazine -1- carboxylic acid amide makes 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- bis-
Fluorophenyl) tetrahydro -2H- pyrans -3- base) -2- (trifluoromethyl) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid
The dosage of amide be 90mg except, it is other it is same as 3 second step of embodiment operate, obtain title product 38mg, yield 48%.
Embodiment 12:(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- methyl sulphonyl -4,5- dihydro-2 h-pyrrole
And [3,4-c] pyridine -6 (7H)-yl) tetrahydro -2H- pyrans -3- ammonia two trifluoroacetate preparation
Step 1: the synthesis of two trifluoroacetate of 4,5,6,7- tetrahydro -2H- pyrazolo [3,4-c] pyridine
At room temperature, to Isosorbide-5-Nitrae, the dichloro of 5,7- tetrahydro -6H- pyrazolo [3,4-C] pyridine -6- carboxylic acid tert-butyl esters (300 mg)
Trifluoroacetic acid (2 mL) is added in methane (5mL) solution, after stirring 16 hours, reaction solution is concentrated to give crude product 4,5,6,7-
Two trifluoroacetate (500 mg, pale solid) of tetrahydro -2H- pyrazolo [3,4-c] pyridine, yield: 105.9 %.
Step 2: ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (4,5- dihydro-2 h-pyrrole simultaneously [3,4-c] pyridine -
6 (7H)-yls) tetrahydro -2H- pyrans -3- amino) t-butyl formate synthesis
At room temperature, to 4,5,6,7- tetrahydro -2H- pyrazolo [3,4-c] pyridine, two trifluoroacetate (265 mg, 1.12
Mmol (3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- oxinane-is added in 8 mL methanol systems)
3- ketone (370 mg, 1.12 mmol), is stirred to react 3 hours, NaBH then is added portionwise at 0 DEG C3CN (351 mg, 5.59
Mmol), warm naturally to room temperature and stir 12 hours.Reaction solution concentration, column chromatographic purifying obtain target product ((2R, 3S,
5R) -2- (2,5- difluorophenyl) -5- (4,5- dihydro-2 h-pyrrole simultaneously [3,4-c] pyridine -6 (7H)-yl) tetrahydro -2H- pyrans -
3- amino) t-butyl formate (100 mg, white solid), yield: 30.5 %.
Step 3: ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- methyl sulphonyl -4,5- dihydro-2 h-pyrrole
And [3,4-c] pyridine -6 (7H)-yl) tetrahydro -2H- pyrans -3- amino) t-butyl formate synthesis
At room temperature, to ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (4,5- dihydro-2 h-pyrroles simultaneously [3,4-c] pyrrole
Pyridine -6 (7H)-yl) tetrahydro -2H- pyrans -3- amino) t-butyl formate (100 mg, 0.23 mmol) 6 mL methylene chloride it is molten
Sequentially add triethylamine (47 mg, 0.46 mmol) and methylsufonyl chloride (40 mg, 0.35 mmol) in liquid, under nitrogen protection,
6 h of reaction are stirred at room temperature.After reaction solution is quenched with water, concentration, TLC isolates and purifies to obtain ((2R, 3S, 5R) -2- (2,5- difluoros
Phenyl) -5- (2- methyl sulphonyl -4,5- dihydro-2 h-pyrrole simultaneously [3,4-c] pyridine -6 (7H)-yl) tetrahydro -2H- pyrans -3-
Amino) t-butyl formate (27 mg), yield is 23 %.
Step 4: (2- methyl sulphonyl -4,5- dihydro-2 h-pyrrole is simultaneously by (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5-
[3,4-c] pyridine -6 (7H)-yl) tetrahydro -2H- pyrans -3- ammonia two trifluoroacetate synthesis
At room temperature, to ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- methyl sulphonyl -4,5- dihydro -2H- pyrrole
Cough up simultaneously [3,4-c] pyridine -6 (7H)-yl) tetrahydro -2H- pyrans -3- amino) t-butyl formate methylene chloride (3 mL) solution
Middle addition trifluoroacetic acid (1 mL), after being stirred to react 16 hours.By reaction solution concentration, washing, 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)
Two trifluoroacetate (26 mg, white solid) of tetrahydro -2H- pyrans -3- ammonia, yield: 77 %.
Embodiment 13:(2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- methyl sulphonyl -6,7- dihydro-2 h-pyrrole
And [4,3-c] pyridine -5 (4H)-yl) tetrahydro -2H- pyrans -3- amine two trifluoroacetate preparation
Step 1: the synthesis of two trifluoroacetate of 4,5,6,7- tetrahydro -2H- pyrazolo [4,3-c] pyridine
At room temperature, to the dichloro of 6,7- dihydro -2H- pyrazolo [4,3-c] pyridine -5 (4H)-carboxylic acid tert-butyl ester (300 mg)
Trifluoroacetic acid (2 mL) is added in methane (5mL) solution, after being stirred to react 16 hours.Reaction solution is concentrated to give crude product 4,5,
6,7- tetrahydro -2H- pyrazolo [4,3-c] pyridine, two trifluoroacetate (467 mg, pale solid), yield: 99.1%.
Step 2: ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (6,7- dihydro-2 h-pyrrole simultaneously [4,3-c] pyridine -
5 (4H)-yls) tetrahydro -2H- pyrans -3- amino) t-butyl formate synthesis
At room temperature, to 4,5,6,7- tetrahydro -2H- pyrazolo [4,3-c] pyridine, two trifluoroacetate (294 mg, 1.24
Mmol (3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- oxinane-is added in 8 mL methanol systems)
3- ketone (405 mg, 1.24 mmol) is stirred at room temperature reaction 3 hours, NaBH then is added portionwise at 0 DEG C3CN (389 mg,
6.2 mmol), it is warming up to room temperature after adding and stirs 12 hours.After reaction solution concentration, target product is obtained with column chromatographic purifying
((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (6,7- dihydro-2 h-pyrrole simultaneously [4,3-c] pyridine -5 (4H)-yl) tetrahydro -
2H- pyrans -3- amino) t-butyl formate (120 mg, white solid), yield: 30.5 %.
Step 3: ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- methyl sulphonyl -6,7- dihydro-2 h-pyrrole
And [4,3-c] pyridine -5 (4H)-yl) tetrahydro -2H- pyrans -3- amino) t-butyl formate synthesis
At room temperature, to ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (6,7- dihydro-2 h-pyrroles simultaneously [4,3-c] pyrrole
Pyridine -5 (4H)-yl) tetrahydro -2H- pyrans -3- amino) t-butyl formate (120 mg, 0.28 mmol) 6 mL methylene chloride it is molten
Sequentially add triethylamine (56 mg, 0.55 mmol) and methylsufonyl chloride (47 mg, 0.41 mmol) in liquid, under nitrogen protection,
6 h are stirred at room temperature.After reaction solution is quenched with water, concentration, TLC isolates and purifies to obtain ((2R, 3S, 5R) -2- (2,5- difluorobenzenes
Base) -5- (2- methyl sulphonyl -6,7- dihydro-2 h-pyrrole simultaneously [4,3-c] pyridine -5 (4H)-yl) tetrahydro -2H- pyrans -3- ammonia
Base) t-butyl formate (104mg, white solid), 73 % of yield.
Step 4: (2- methyl sulphonyl -6,7- dihydro-2 h-pyrrole is simultaneously by (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5-
[4,3-c] pyridine -5 (4H)-yl) two trifluoroacetate of tetrahydro -2H- pyrans -3- amine
At room temperature, to ((2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2- methyl sulphonyl -6,7- dihydro -2H- pyrrole
Cough up simultaneously [4,3-c] pyridine -5 (4H)-yl) tetrahydro -2H- pyrans -3- amino) t-butyl formate (100 mg) methylene chloride (6
ML trifluoroacetic acid (2 mL)) is added in solution, after being stirred to react 16 hours.By reaction solution concentration, washing, TLC is isolated and purified
Obtain (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (2-Methyl sulphonyl- 6,7- dihydro-2 h-pyrrole simultaneously [4,3-c] pyrrole
Pyridine -5 (4H)-yl) two trifluoroacetate (31 mg, white solid) of tetrahydro -2H- pyrans -3- amine, yield: 24.8 %.
Embodiment 14:7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- three
The preparation of methyl fluoride -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acyloxy methylamine dihydrochloride
Step 1: 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
In addition to using 7- ((3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -
Simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester replaces 7- ((3R, 5S, 6R) -5-Boc- to 3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo
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- oxinane -3-
Base) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazos simultaneously [1,5-a] pyrazine -1- carboxylate methyl ester dosage be 50mg except,
It is same as 3 first step of embodiment to operate, and obtains title product 45mg, yield 90%.
Step 2: 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -3- trifluoro
Methyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acyloxy methylamine dihydrochloride
In addition to using 7- ((3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- tetrahydropyran -3-base) -
Simultaneously [1,5-a] pyrazine -1- carboxylic acyloxy methylamine replaces 7- ((3R, 5S, 6R) -5- to 3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo
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- oxinane -
3- yl) -3- trifluoromethyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acyloxy methylamine dosage be 45mg it
Outside, it is other it is same as 3 second step of embodiment operate, obtain title product 38mg, yield 96%.
Embodiment 15:7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) -2H- tetrahydropyran -3-base) -3- three
The preparation of methyl fluoride -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acyloxy dimethylamine
Step 1: 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) -2H- tetrahydropyran -3-base) -3- trifluoro
Methyl -5,6,7,8- tetrahydro-imidazo simultaneously [1,5-a] pyrazine -1- carboxylic acyloxy dimethylamine
Compound 1 ' (40 mg, 0.069 mmol) is dissolved in Isosorbide-5-Nitrae dioxane (1 ml) at room temperature, methylamine water is added
Solution (1 ml) is warming up to 100 DEG C, and vexed tank is reacted 8 hours.Reaction solution is dissolved with saturated sodium-chloride, ethyl acetate (2 ml ×
2) extract, organic phase HPLC preparation purify white solid title product (6 mg, 0.013 mmol), yield 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 simultaneously [4,3-
A] pyrazine -7 (8H)-yl) tetrahydro -2H- pyrans -3- amine two trifluoroacetate preparation
Step 1: (5,6- dihydro-[1,2,4] triazole is simultaneously [4,3-a] by (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5-
Pyrazine -7 (8H)-yl) tetrahydro -2H- pyrans -3- t-butyl carbamate
At room temperature, to 7- ((3R, 5S, 6R) -5- (tertbutyloxycarbonylamino) -6- (2,5- difluorophenyl) tetrahydro -2H-
Pyrans -3- base) -5,6,7,8- tetrahydro-[1,2,4] triazole simultaneously [4,3-a] pyrazine -3- carboxylic acid, ethyl ester (80 mg, 0.14
Mmol the 1 mL aqueous solution of lithium hydroxide (15 mg, 0.28 mmol), stirring 16 are added in tetrahydrofuran (1 mL) solution)
After hour, pH=6 of reaction are adjusted with 1 N dilute hydrochloric acid, are then concentrated to dryness, crude product (2R, 3S, 5R) -2- (2,5- difluorobenzenes
Base) -5- (5,6- dihydro-[1,2,4] triazole simultaneously [4,3-a] pyrazine -7 (8H)-yl) tetrahydro -2H- pyrans -3- carbamic acid uncle
Butyl ester is directly used in react in next step.
Step 2: (5,6- dihydro-[1,2,4] triazole is simultaneously [4,3-a] by (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5-
Pyrazine -7 (8H)-yl) two trifluoroacetate of tetrahydro -2H- pyrans -3- amine
At room temperature, by (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (5,6- dihydros-[1,2,4] triazole simultaneously [4,3-
A] pyrazine -7 (8H)-yl) tetrahydro -2H- pyrans -3- t-butyl carbamate crude product is dissolved in methylene chloride (2 mL), it is added three
Fluoroacetic acid (0.5 mL) is simultaneously stirred overnight, and concentration of reaction solution obtains crude product, and recrystallization purifying obtains (2R, 3S, 5R) -2- (2,5- difluoros
Phenyl) -5- (5,6- dihydro-[1,2,4] triazole simultaneously [4,3-a] pyrazine -7 (8H)-yl) tetrahydro -2H- pyrans -3- amine two or three
Fluoroacetate (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] pyrrole
Pyridine -6 (7H)-yl) tetrahydro -2H- pyrans -3- amine three trifluoroacetate preparation
At room temperature, to (2R, 3S, 5R) -2- (2,5- difluorophenyl) -5- (4,5- dihydro -2H- pyrazolo [3,4-c] pyrroles
Pyridine -6 (7H)-yl) tetrahydro -2H- pyrans -3- t-butyl carbamate (60 mg, 0.14 nnol) methylene chloride (3 mL) it is molten
In liquid be added trifluoroacetic acid (1 mL), stirring 16 hours after, by reaction solution concentration, wash sterling (2R, 3S, 5R) -2- (2,
5- difluorophenyl) -5- (4,5- dihydro -2H- pyrazolo [3,4-c] pyridine -6 (7H)-yl) tetrahydro -2H- pyrans -3- amine three or three
Fluoroacetate (50 mg, faint yellow solid), yield: 54 %.
Embodiment 18:6- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -4,5,
The preparation of 6,7- tetrahydro -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl esters dihydrochloride
Step 1: 4,5,6,7- tetrahydro -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl esters
At 0 DEG C, by compound 6-BOC-4,5,6,7- tetrahydro -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acids (500
Mg, 1.87 mmol) it is dissolved in methanol (12 ml), it is added thionyl chloride (1 g, 9.3 mmol), reaction solution temperature rising reflux reaction 6
After hour, reaction solution concentration is dissolved with methanol (50 ml), and triethylamine adjusts PH=7-8, concentration, then is washed with methylene chloride, mistake
Filter, dry compound as white solid 4,5,6,7- tetrahydro -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl esters (280 mg,
1.54 mmol), yield 82%.
Step 2: 6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl) tetrahydro -2H-
Pyrans -3- base) -4,5,6,7- tetrahydro -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl esters
At room temperature, by compound 4,5,6,7- tetrahydro -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl esters (1.5 g, 8
Mmol), compound (3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- oxinane -3- ketone (2.7 g, 8
Mmol), isopropyl titanate (7 g, 24mmol) is dissolved in the in the mixed solvent of methylene chloride (30 ml) and methanol (3 ml), stirring
Overnight, sodium cyanoborohydride (1.5 g, 24 mmol) are added, after room temperature reaction 6 hours, water (2 ml) and diatomite is added
(10 g) is filtered afterwards, and filtrate concentration, column chromatography for separation obtains faint yellow compound 6- ((3R, 5S, 6R) -5- ((tert-butoxy carbonyl
Base) amido) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -4,5,6,7- tetrahydro -2H- pyrazolo [3,4-c] pyrrole
Pyridine -3- carboxylate methyl ester (0.9 g, 1.8 mmol), yield 22%.
Step 3: 6- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -4,5,6,
7- tetrahydro -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl esters dihydrochloride
At room temperature, by compound 6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl)
Tetrahydro -2H- pyrans -3- base) and -4,5,6,7- tetrahydro -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl esters (0.05 g, 0.1
Mmol it) is added into 4mol/L HCl/ dioxane (1 ml), reacts 1 hour.LCMS monitors fully reacting, and reaction solution is used
Ether (2 ml) dilution, removes supernatant, and solid is dry, obtain compound as white solid 6- ((3R, 5S, 6R) -5- amino -6- (2,
5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -4,5,6,7- tetrahydro -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl esters two
Hydrochloride (40 mg, 0.086mmol), yield 86%.
Embodiment 19:6- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -4,5,
The preparation of 6,7- tetrahydro -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid dihydrochloride
Step 1: 6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl) tetrahydro -2H-
Pyrans -3- base) -4,5,6,7- tetrahydro -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid synthesis
At room temperature by compound 6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl) four
Hydrogen -2H- pyrans -3- base) and -4,5,6,7- tetrahydro -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl esters (0.3 g, 0.6
Mmol), lithium hydroxide (51 mg, 1.2m mol), be dissolved in the mixed solution of tetrahydrofuran (3 ml) and water (3 ml), room temperature
Reaction is overnight.Reaction solution 1N hydrochloric acid is adjusted into PH=5-6, is concentrated to give crude Compound 6- ((3R, 5S, 6R) -5- ((tertiary fourth oxygen
Base carbonyl) amido) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -4,5,6,7- tetrahydro -2H- pyrazolo [3,4-c]
Pyridine-3-carboxylic acid (faint yellow solid, 0.4 g, 0.8mmol).
Step 2: 6- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -4,5,6,
The synthesis of 7- tetrahydro -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid dihydrochloride
At room temperature by compound 6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl) four
Hydrogen -2H- pyrans -3- base) addition of -4,5,6,7- tetrahydro -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acids (0.4 g, 0.6 mmol)
In 4mol/L HCl/ dioxane (4 ml) solvent, reacts 1 hour, reaction solution is concentrated, HPLC preparative separation is used after concentration
Dilute hydrochloric acid processing, obtains 6- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -4,5,6,7-
Tetrahydro -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) tetrahydro -2H- pyrans -3- base) -4,5,
The preparation of 6,7- tetrahydro -2H- pyrazolo [3,4-c] Niacinamide dihydrochloride
Step 1: 6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl) tetrahydro -2H-
Pyrans -3- base) -4,5,6,7- tetrahydro -2H- pyrazolo [3,4-c] Niacinamide synthesis
At room temperature, by compound 6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl)
Tetrahydro -2H- pyrans -3- base) and -4,5,6,7- tetrahydro -2H- pyrazolo [3,4-c] pyridine-3-carboxylic acid methyl esters (0.1 g, 0.2
Mmol it) being added into dioxane (2 ml), ammonium hydroxide (2 ml), 100 DEG C of vexed tanks are reacted 5 hours, reaction solution saturated sodium-chloride,
Ethyl acetate (5 ml) extraction, organic phase concentration, HPLC preparation purifying obtain compound as white solid 6- ((3R, 5S, 6R) -5-
((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -4,5,6,7- tetrahydro -2H- pyrazoles
And [3,4-c] Niacinamide (38 mg, 0.079 mmol), yield 40%.
Step 2: 6- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -4,5,6,
The synthesis of 7- tetrahydro -2H- pyrazolo [3,4-c] Niacinamide dihydrochloride
At room temperature, by compound 6- ((3R, 5S, 6R) -5- ((tert-butoxycarbonyl) amido) -6- (2,5- difluorophenyl)
Tetrahydro -2H- pyrans -3- base) and -4,5,6,7- tetrahydro -2H- pyrazolo [3,4-c] Niacinamides (38 mg, 0.079
Mmol it) is added into 4M HCl/ dioxane (1 ml), reacts at room temperature 3 hours, concentration, dry compound as white solid/6-
((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -4,5,6,7- tetrahydro -2H- pyrazolo
[3,4-c] Niacinamide dihydrochloride (20 mg, 0.044 mmol), HPLC:95%, yield 56%, MS (ESI)
M/z:378(M+1).
Embodiment 21:7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -5,
The preparation of 6,7,8- imidazolidine simultaneously two trifluoroacetate of [1,2-a] pyrazine -3- Ethyl formate
Step 1: the synthesis of 5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester
20mL tetrahydro will be dissolved under imidazo [1,2-a] pyrazine -3- carboxylic acid, ethyl ester (780 mg, 4.08 mmol) stirring
In furans, 10% palladium carbon 400mg is then added and removes the reaction solution of catalyst after hydrogen shield lower 35 DEG C of stirrings 12 hours, subtracts
Pressure concentration, column chromatographic purifying obtain 5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine -3- carboxylic acid, ethyl ester (600 mg, yield:
75.3%, off-white powder).
Step 2: 7- ((3R, 5S, 6R) -5-(Boc- amino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -
The synthesis of 5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- Ethyl formate
At room temperature, to (3R, 5S, 6R) -5-Boc- amino -6- (2,5- difluorophenyl) 2H- oxinane -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 tetraisopropyl titanate (800mg, 2.82 mmol) are added in methylene chloride (20 mL) solution), it is small to be stirred at room temperature 12
When.After reaction solution is cooled to 0 DEG C, NaBH is added3CN (258 mg, 4.09 mmol) and 8mL ethyl alcohol, heating are stirred at room temperature anti-
After answering 8 hours, reaction solution is quenched with water, and is concentrated under reduced pressure, and column chromatographic purifying obtains 7- ((3R, 5S, 6R) -5-(Boc- amino) -
6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- Ethyl formate
(60 mg, yield: 5.8%, off-white powder).
Third step 7- ((3R, 5S, 6R) -5- amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -5,6,7,
The synthesis of 8- imidazolidine simultaneously two trifluoroacetate of [1,2-a] pyrazine -3- Ethyl formate
At room temperature, to 7- ((3R, 5S, 6R) -5-(Boc- amino) -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3-
Base) -5,3 mL dichloromethanes of 6,7,8- imidazolidines simultaneously [1,2-a] pyrazine -3- Ethyl formate (35 mg, 0.069 mmol)
Trifluoroacetic acid 1ml is added in alkane solution, is stirred at room temperature 2 hours, concentration of reaction solution, obtains target product 7- ((3R, 5S, 6R) -5-
Amino -6- (2,5- difluorophenyl) tetrahydro -2H- pyrans -3- base) -5,6,7,8- imidazolidine simultaneously [1,2-a] pyrazine -3- formic acid
Two trifluoroacetate of ethyl ester (24 mg, yield: 58.5%, pale solid).
By preferred compounds of the invention1The measurement result of H-NMR, MS are 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-AMCHBr；Manufacturer: Bachem；Article No.: I-1225.
2.DPP-4 inhibition of enzyme activity detection method:
By untested compound by various concentration be dissolved in detection buffer (25 mM Tris-HCl, 140 mM NaC1,10
MM KC1,0.1% BSA, pH 7.4) in.DPP-4 and untested compound are added in 384 orifice plates, is incubated for 15 points for 37 DEG C after mixing
Clock.Substrate (H-Gly-Pro-AMCHBr) starting reaction is added.Orifice plate is put into microplate reader, under enzyme kinetics mode,
A length of 380 nm of selective exitation light wave, wavelength of transmitted light are that 460 nm read fluorescent value.It reads 1 time within every 15 seconds, continuously reads 40
A circulation.Each experimental group fluorescent value variation slope is calculated within the linear response phase, calculate inhibiting rate or using SigmaPlot or
The half-inhibitory concentration IC of 5 software of GraphPad Prism fitting compound50Value.
[table 2]
Table 2: inhibiting effect of the test compound to DPP-IV
| 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 |
By the test data in table 2 it is found that above compound has good inhibiting effect to DPP-4.
3.DPP-9 inhibition of enzyme activity detection method
By untested compound by various concentration be dissolved in detection buffer (25 mM Tris-HCl, 140 mM NaC1,10
MM KC1,0.1% BSA, pH 7.4) in.DPP-9 and untested compound are added in 384 orifice plates, is incubated for 15 points for 37 DEG C after mixing
Clock.Substrate (H-Gly-Pro-AMCHBr) starting reaction is added.Orifice plate is put into microplate reader, under enzyme kinetics mode,
A length of 380 nm of selective exitation light wave, wavelength of transmitted light are that 460 nm read fluorescent value.It reads 1 time within every 15 seconds, continuously reads 40
A circulation.Each experimental group fluorescent value variation slope is calculated within the linear response phase, uses SigmaPlot or GraphPad
5 software of Prism is fitted compound IC50Value.
[table 3]
Table 3: inhibiting effect of the test compound to DPP-9
| Compound | DPP-9 IC50 (μM) |
| 1’ | >100 |
| 2’ | 100 |
| 5’ | >30 |
| 13’ | >30 |
4.DPP-8 enzyme activity inhibits detection method
By untested compound by various concentration be dissolved in detection buffer (25 mM Tris-HCl, 140 mM NaC1,10
MM KC1,0.1% BSA, pH 7.4) in.DPP-8 and untested compound are added in 384 orifice plates, is incubated for 15 points for 37 DEG C after mixing
Clock.Substrate (H-Gly-Pro-AMCHBr) starting reaction is added.Orifice plate is put into microplate reader, under enzyme kinetics mode,
A length of 380 nm of selective exitation light wave, wavelength of transmitted light are that 460 nm read fluorescent value.It reads 1 time within every 15 seconds, continuously reads 40
A circulation.Each experimental group fluorescent value variation slope is calculated within the linear response phase, uses SigmaPlot or GraphPad Prism
5 softwares are fitted compound IC50Value.
[table 4]
Table 4: inhibiting effect of the test compound to DPP-8
| Compound | DPP-8 IC50(μM) |
| 1’ | >300 |
| 2’ | >30 |
| 3’ | 300 |
| 12’ | >30 |
| 13’ | >30 |
By table 2-4 as it can be seen that the compound of the present invention is different for the inhibiting effect of different DPP, relative to DPP-8 and DPP-
For 9, above compound of the present invention has significant selection inhibiting effect to DPP-4.
Test example 2: safety testing
In cardiac muscle cell, the potassium channel of human Ether-a-go-go Related Gene (hERG) coding is mediated
A kind of Delayed Rectifier Potassium Current (IKr).IKr inhibition is that drug leads to the most important mechanism of QT interval prolongation.In hERG test,
Manual patch-clamp method criterion is if compound IC50> 30 μM, then determine that compound acts on hERG unrestraint.
Effect using manual patch-clamp detection test compound and comparison medicine (Ao Malieting) to hERG potassium-channel,
Test concentrations are 0.1,0.3,1,3,10,30 μM.In cardiac muscle cell, human Ether-a-go-go Related Gene
(hERG) potassium channel encoded mediates a kind of Delayed Rectifier Potassium Current (IKr), and IKr inhibition is that drug causes QT interval prolongation most heavy
The mechanism wanted.
Test cell is that transfection has hERG cDNA and stablizes the CHO cell line in the expression channel hERG.Cell is placed on down
It sets in the electrophysiological recording slot under microscope.Continuous perfusion is made with extracellular fluid in track.Experimentation is using conventional complete thin
Born of the same parents' patch-clamp electric current recording technique.Test result 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 |
By the test data in table 5 it is found that in this test, 50% inhibition concentration (IC of the above compound for hERG50)
Value is all larger than 30 μM, and nothing causes heart QT intervals to extend safety risks.
3. CYP enzyme Inhibition test of test example
Metabolic enzyme needed for clinical commonly used drug passes through liver metabolism is many kinds of.FDA drug interaction guideline
It is recommended that preclinical need to investigate compound to this 7 Main Subtype CYP enzymes of CYP1A2,2B6,2C8,2C9,2C19,2D6,3A4
Inhibiting effect, current study show that, in 7 main metabolic enzymes, CYP3A4 is maximum for the effect in metabolic process in medicine.Such as
Untested compound has inhibiting effect to CYP3A4, then illustrate the compound clinically with the drug combination that is metabolized by CYP3A4
When, the activity of CYP3A4 enzyme can be inhibited, and then weaken the metabolism for being combined drug, exposure increases in prototype body, causes safety
Risk, therefore CYP Inhibition test becomes the important indicator of preclinical druggability evaluation.
178 μ L hepatomicrosome solution are added into 1.1mL centrifuge tube, and (hepatomicrosome is in the final concentration of of reaction system
0.2mg/mL).Positive inhibitor and untested compound are added without in blank sample, it is corresponding that 2 μ LDMSO are added, add 200 μ
Target methanol solution in L, 1 min(of vortex mixed, that is, minute), it is eventually adding 20 μ L NADPH solution.Non-blank-white sample, to
The stock solution (10 μM) of 2 μ L inhibitor or untested compound is added in 1.1mL centrifuge tube, after vortex mixed under the conditions of 37 °C
Preincubate 5min is added 20 μ L NADPH solution and starts to react (final concentration of 1 mM of the NADPH in reaction system), at 37 °C
20min is incubated under conditions of shaking.Target methanol solution terminates reaction in being added after incubation, is centrifuged under 4000 rpm of sample
5 min take supernatant to be analyzed to LC/MS/MS.
LC-MS/MS analysis: mass spectrum API4000Q-TRAP, liquid phase are Shimadzu LC-20AD system.Chromatographic column is
kinetex C18Column (3.0 mm * 50 mm, 2.6 μm)；+ 0.1% formic acid of mobile phase A Xiang Weishui, B phase are+0.1% first of acetonitrile
Acid, flow velocity are 0.8 mL/min, and column temperature is room temperature.Use ion source for the source ESI, scanning mode is that multiple reaction monitors (MRM).
[table 6]
Table 6: suppression result of the test compound to different CYP hypotypes
From the test data in table 6, the compound of aforementioned present invention is respectively for above-mentioned different CYP hypotype
IC5010 μM are all larger than, the overwhelming majority is greater than 50 μM, shows that the compounds of this invention has excellent safety, drug interaction
Risk it is low.
Preparation example 1
As the specific embodiment of combination of oral medication, the tablet of the 100mg potency consisted of the following compositions is manufactured.
The compound 100mg of composition embodiment 1
Microcrystalline cellulose 268mg
Croscarmellose sodium 20mg
Magnesium stearate 4mg
Amount to 392mg
Firstly, active material, microcrystalline cellulose and cross-linked carboxymethyl cellulose are mixed, then will be mixed with magnesium stearate
Object is lubricated and is pressed for tablet.
Preparation example 2
Manufacture the capsule filling granule containing following component.
The compound 15mg of composition embodiment 2
Lactose 90mg
Corn flour 42mg
HPC-L 3mg
Amount to 150mg
Formula (1) compound represented, lactose pass through the sieve of 60 sieve meshes.Corn flour is set to pass through the sieve of 120 sieve meshes.By they
Mixing adds HPC-L solution in mixed-powder, is mediated, be granulated, dried.After resulting dry particle whole grain, by it
150mg is filled into 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
Corn flour 274mg
HPC-L 16mg
Amount to 1000mg
Formula (1) compound represented and lactose are passed through to the sieve of 60 meshes.Corn flour is passed through to the sieve of 120 meshes.By it
Using V-Mixer mix.HPC-L(low-viscosity hydroxypropylcelluloand is added in mixed-powder) aqueous solution, mediated,
It is granulated (0.5~1mm of extrusion granulation aperture), dry step.By resulting dry particle shaking screen (12/60 sieve mesh) mistake
Sieve, obtains granule.
Industrial availability
According to the present invention it is possible to the compound as dipeptidyl peptidase-IV inhibitor be provided, to dipeptidyl peptidase-IV
With high inhibitory activity and with excellent pharmacokinetic properties, can be used for treating and preventing including treatment diabetes, especially
It is the DPP-4 related disease of II patients with type Ⅰ DM.
Claims (27)
1. compound or its pharmaceutically acceptable salt that the following general formula (1) indicates,
In formula,
(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；
Under the either case of above-mentioned (1)~(5), A2With A3Between and A4With A5Between be double bond,
In the case where above-mentioned (6) or (7), A2With A3Between and A1With A5Between be double bond；
R1、R2Each independently with A3、A4Or A5In conjunction with, and be separately hydrogen atom ,-S (=O)2-C1-6Alkyl, C1-6Alkane
Base ,-COO-C1-6Alkyl, the C being substituted with halogen atoms1-6Alkyl ,-(C=O)-NH-C1-6Alkyl ,-(C=O)-N (C1-6Alkane
Base)2,-COOH or-(C=O)-NH2；
On condition that working as A1、A2、A3And A4In 2 be nitrogen when, if R1And R2In a side be hydrogen atom, then R1And R2In it is another
One Fang Buwei hydrogen atom and the alkyl being substituted with halogen atoms；
Ar is the phenyl optionally replaced by 1~5 halogen atom.
2. compound according to claim 1 or its pharmaceutically acceptable salt, wherein
R1、R2It is separately hydrogen atom ,-S (=O)2-CH3,-S (=O)2-CH2CH3,-S (=O)2-CH(CH3)2、-
COOH、-COOCH3、-COOCH2CH3、-CF3Or-(C=O)-NH2。
3. compound according to claim 1 or its pharmaceutically acceptable salt, wherein the compound is selected from following
Formula (a), (b), (c), (d), (e), (f) and any one compound in (h),
Wherein, Ar is the phenyl optionally replaced by 1~5 halogen atom,
R9、R10And R11It is each independently selected from hydrogen atom ,-S (=O)2-C1-6Alkyl, C1-6Alkyl ,-COO-C1-6Alkyl, by halogen
The C that plain atom replaces1-6Alkyl ,-(C=O)-NH-C1-6Alkyl ,-(C=O)-N (C1-6Alkyl)2,-COOH or-(C=O)-NH2。
4. compound according to claim 3 or its pharmaceutically acceptable salt, wherein the compound is selected from following
Formula (a), (b), (c), (d), (e), (f) and any one compound in (h),
Wherein, Ar is the phenyl optionally replaced by 1~5 halogen atom,
R9、R10And R11It is each independently selected from hydrogen atom ,-S (=O)2-CH3,-S (=O)2-CH2CH3,-S (=O)2-CH
(CH3)2、-COOH、-COOCH3、-COOCH2CH3、-CF3Or-(C=O)-NH2。
5. compound or its pharmaceutically acceptable salt, wherein the compound is to be selected from following compounds,
6. the manufacturing method of compound according to claim 1 comprising synthetic method shown in scheme 1,
In formula, A1~A5、Ar、R1And R2With definition having the same in claim 1,
Amine shown in ketone shown in formula (2) and formula (3) 0-50 DEG C at a temperature of carry out 0.5-30 hours reduction aminations, obtain
To reduced aminate shown in formula (4), the product is further sloughed into amido protecting in the case where pH is 2~6 acid condition
Base obtains formula (1) compound.
7. the manufacturing method of compound according to claim 6, wherein amine shown in ketone shown in formula (2) and formula (3)
10-40 DEG C at a temperature of carry out reduction amination, obtain reduced aminate shown in formula (4).
8. the manufacturing method of compound according to claim 6, wherein amine shown in ketone shown in formula (2) and formula (3)
The reduction amination for carrying out 1-24 hours, obtains reduced aminate shown in formula (4).
9. the manufacturing method of compound according to claim 6, wherein amine compounds shown in the formula (3) in above scheme 1
Object is formula (8) compound represented, and synthetic method shown in formula (8) the compound represented Utilization plan 2 manufactures,
In formula, R1And R2With claim 1 definition having the same,
Formula (5) carries out bromo in solvent carbon tetrachloride, with bromine, then the temperature with 2- Aminopyrazine at 0-40 DEG C
It is lower to carry out 0.5-20 hour ring closure reactions, obtain Formula (7), by the Formula (7) 0-40 DEG C at a temperature of lead to
Palladium carbon catalytic hydrogenation is crossed, formula (8) compound represented is obtained.
10. the manufacturing method of compound according to claim 9, wherein Formula (5) in a solvent, with bromine into
Row bromo, then with 2- Aminopyrazine 10-30 DEG C at a temperature of carry out ring closure reaction, obtain Formula (7).
11. the manufacturing method of compound according to claim 9, wherein Formula (5) in a solvent, with bromine into
Then row bromo carries out 1-12 hours ring closure reactions with 2- Aminopyrazine, obtains Formula (7).
12. the manufacturing method of compound according to claim 9, wherein by the temperature of the Formula (7) at 20-30 DEG C
Degree is lower by palladium carbon catalytic hydrogenation, obtains formula (8) compound represented.
13. the manufacturing method of compound according to claim 6, wherein amination shown in the formula (3) in above scheme 1
Closing object isThe manufacture of synthetic method shown in compound 1g Utilization plan 3,
2- Aminomethylpyrazine is stirred at room temperature overnight with trifluoroacetic anhydride, obtains compound 1b, by compound 1b three
Under the action of chlorethoxyfos and phosphorus pentoxide, cyclization product 1c is obtained, is then restored in presence of hydrogen with Pd/C, and use Boc
Amino is protected, carries out bromo with NBS, bromo-derivative 1e is carried out in organic solvent to insert carbonyl reaction, product 1f with cobalt octacarbonyl
After taking off Boc-, target compound is obtained.
14. the manufacturing method of compound according to claim 13, wherein by bromo-derivative 1e cobalt octacarbonyl in methanol
In carry out insert carbonyl reaction, after product 1f takes off Boc-, obtain target compound.
15. pharmaceutical composition, containing compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt,
And pharmaceutically acceptable carrier or excipient.
16. pharmaceutical composition according to claim 15, wherein further include and any one of Claims 1 to 5 institute
Other active materials associated with the compound stated or its pharmaceutically acceptable salt.
17. pharmaceutical composition according to claim 16, wherein other active materials be melbine or its salt,
Or pioglitazone.
18. pharmaceutical composition according to claim 15 or 16, wherein the composition contains in Claims 1 to 5
The unit dose 0.01-1000mg of described in any item compounds.
19. pharmaceutical composition according to claim 18, wherein the composition contains any in Claims 1 to 5
The unit dose of compound described in is 0.5-800mg.
20. pharmaceutical composition according to claim 18, wherein the composition contains any in Claims 1 to 5
The unit dose of compound described in is 1-400mg.
21. pharmaceutical composition according to claim 18, wherein the composition contains any in Claims 1 to 5
The unit dose of compound described in is 5-200mg.
22. pharmaceutical composition according to claim 18, wherein the composition contains any in Claims 1 to 5
The unit dose of compound described in is 10-100mg.
23. pharmaceutical composition according to claim 18, wherein the composition contains any in Claims 1 to 5
The unit dose of compound described in is 15-50mg.
24. a kind of pharmaceutical preparation for being used to treat disease relevant to dipeptidyl peptidase-IV for being suitable for administration to mammal,
In, comprising compound according to any one of claims 1 to 5 or its pharmaceutically acceptable salt as effective component, the medicine
Any one of object preparation in solid pharmaceutical preparation, semisolid preparation, liquid preparation and gaseous state preparation.
25. the treatment or prevention agent of disease relevant to dipeptidyl peptidase-IV, containing described in any one of Claims 1 to 5
Compound or its pharmaceutically acceptable salt as effective component.
26. compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt or the compound or its
Pharmaceutically acceptable salt and composition associated with other active materials are to be used to prepare treatment relevant with dipeptidyl peptidase-IV
Application in the drug of disease.
27. application according to claim 26, wherein disease relevant to dipeptidyl peptidase-IV is selected from diabetes, obesity
Disease, insulin resistance or hyperlipidemia.
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| CN113620957B (en) * | 2020-05-08 | 2022-04-19 | 盛世泰科生物医药技术(苏州)有限公司 | Preparation method of aminomethyl pyrazine compound |
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