CN105085359A - Nitrogen-containing heterocyclic substituted pyrrolidine formyl thiomorpholin DPP-IV inhibitor - Google Patents

Nitrogen-containing heterocyclic substituted pyrrolidine formyl thiomorpholin DPP-IV inhibitor Download PDF

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CN105085359A
CN105085359A CN201410190993.3A CN201410190993A CN105085359A CN 105085359 A CN105085359 A CN 105085359A CN 201410190993 A CN201410190993 A CN 201410190993A CN 105085359 A CN105085359 A CN 105085359A
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formyl radical
alkyl
base
compound
independently selected
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黄海洪
申竹芳
赵红义
环奕
姜茜
林紫云
李鹏
刘泉
刘率男
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Institute of Materia Medica of CAMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses a nitrogen-containing heterocyclic substituted pyrrolidine formyl thiomorpholin DPP-IV inhibitor, a preparation method therefor and use thereof. Specifically, the invention relates to a compound shown in a formula (I), a stereisomer thereof and pharmaceutically acceptable salt thereof mentioned in the description. The invention further relates to a pharmaceutical composition comprising the compound, use of the compound in preparing drugs for treating and/or preventing diseases or illnesses associated with DDP-IV excessive activity or DPP-IV overexpression and a method of treating associated diseases by using the compound. The compound disclosed by the invention has the effect of effectively inhibiting the activity of DDP-IV. The FORMULA is shown in the description.

Description

Nitrogen-containing hetero cyclosubstituted pyrrolidine formyl base thiomorpholine class DPP-IV inhibitor
Technical field
The invention belongs to medical art.Relate to the nitrogen-containing hetero cyclosubstituted pyrrolidine formyl base thiomorpholine class DPP-IV inhibitor shown in general formula (I); and pharmacy acceptable salt and isomer thereof; the preparation of this compounds; diabetes are being prevented and/or treated containing their pharmaceutical composition and this compounds; application in the diabetes of non-insulin-dependent, is especially suppressing the purposes in DPP-IV.
Background technology
Diabetes (DiabetesMellitus, DM) are a kind of multi-pathogenesis chronic metabolic disease.2013, global diabetic subject's number about 3.82 hundred million, expected diabetic subject's number in 2035 and will reach 5.92 hundred million.According to estimates, China's diabetes number in 2013 is 0.984 hundred million, has occupied first of the world, will be increased to 1.42 hundred million (InternationalDiabetesFederation, 2013Update) to diabetes number in 2035.Diabetes have become threatened the 3rd of human health the large killer after cardiovascular disordeies and tumour.
Diabetes are divided into insulin-dependent diabetes mellitus (insulin-dependentdiabetesmellitus, IDDM, i.e. type 1 diabetes) and non insulin dependent diabetes (noninsulin-dependentdiabetesmellitusNIDDM, i.e. diabetes B), wherein diabetes B is the most common, accounts for diabetic subject's more than 90%.Although the antidiabetic medicine such as existing at least Regular Insulin, biguanides, sulfonylurea, glycosidase inhibitor and thiazolidinediones in the market, but above-mentioned traditional antidiabetic drug is general all problem [the KahnSE such as to reduce gradually with the side effects such as body weight increase, hypoglycemia and drug effect, HaffnerSM, etal.Glycemicdurabilityofrosiglitazone, metformin, orglyburidemonotherapy. [J] .NEnglJMed, 2006,355:2477-80], therefore in the urgent need to the medicine of development of new.
Glucagon-like peptide 1 (GLP-1, and glucose-dependent-insulinotropic polypeptide (GIP glucagon-likepeptide-1), glucose-dependentinsulinotropicpolypeptide) can promote that when blood sugar increasing insulin releasing, glucagon suppression are secreted, insulin gene expression can also be stimulated simultaneously, promote the propagation of insulin synthesis and β cell, the two plays an important role in blood glucose regulation process in vivo.And endogenous GLP-1 and GIP can be degraded and inactivation rapidly by DPP IV (dipeptidylpeptidaseIV, DPP-IV) in vivo, the transformation period is very short.DPP-IV inhibitor can increase the concentration of endogenous GIP and GLP-1 in blood; thus effectively can promote insulin secretion; the hypoglycemic effect simultaneously with protection β cell function is being fallen; and the side effect that hypoglycemia and body weight increase can not be caused; because its action target spot is clear and definite, become the research and development focus for the treatment of diabetes B medicine.
DPP-IV belongs to serine peptidases family, jointly belongs to DPP2, DPP8, DPP9, FAP and POP etc. in addition of this family with it.Animal model experiment result shows, suppress DPP8/9 can cause the toxic reaction [LankasGR such as such as anaemia, alopecia, thrombopenia and splenomegaly, LeitingB, etal.DipeptidylpeptidaseIVinhibitionforthetreatmentoftyp e2diabetes:potentialimportanceofselectivityoverdipeptidy lpeptidases8and9.Diabetes, 2005,54:2988-2994].Therefore, for the significant [BhumikaDP of design and development of the selective depressant of the single target spot of DPP-IV, ManJunathDG.Recentapproachestomedicinalchemistryandthera peuticpotentialofdipeptidylpeptidase-4 (DPP-4) inhibitors.EuropeanJournalofMedicinalChemistry, 2014,74:574-605], this is also difficult point and the key point of the research and development of new selective DPP-IV inhibitor.
Therefore, this area selective DPP-IV inhibitors that still Structure of need is novel, activity is strong is to meet the demand of clinical treatment.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind ofly has novel structure and active strong selective DPP-IV inhibitors.The present inventor finds; nitrogen-containing hetero cyclosubstituted pyrrolidine formyl base thiomorpholine class DPP-IV inhibitor has stronger inhibit activities and selectivity to DPP-IV; thus provide novel, the active strong selective DPP-IV inhibitors of a class formation, can be used for the prevention and therapy of diabetes.The present invention is based on above discovery and complete.
summary of the invention
For this reason, first aspect present invention provides the compound shown in formula (I) and steric isomer thereof, its pharmacologically acceptable salts,
Wherein,
N independently selected from 0,1,2;
X is independently selected from C, N;
Y independently selected from singly-bound, C 1-3alkyl ,-NR 1-,-O-,-S-,-CO-,-SO-,-SO 2-,-CONR 2-,-COO-,-SO 2nR 3-,-SO 2o-,-NR 4cO-,-OCO-,-NR 5sO 2-,-OSO 2-,-NR 6cONR 7-,-NR 8cOO-, wherein R 1, R 1, R 2, R 3, R 4, R 5, R 6, R 7and R 8may be the same or different, be selected from hydrogen and C independently of one another 1-3alkyl;
B ring is independently selected from C 3-6cycloalkyl, is selected from the heteroatomic C of nitrogen, oxygen, sulphur containing 1-2 3-6heterocyclylalkyl, aryl, is selected from the heteroatomic heteroaryl of nitrogen, oxygen, sulphur containing 1-9 carbon atom and 1-4;
R is independently selected from hydrogen, halogen, C 1-3alkyl, C 1-3alkoxyl group, trifluoromethyl, cyano group, nitro, ester group, amino, methylamino-, dimethylamino, hydroxyl, carboxyl, C 3-6cycloalkyl, Heterocyclylalkyl, C 6-10aryl, is selected from the heteroatomic heteroaryl of nitrogen, oxygen, sulphur containing 1-9 carbon atom and 1-4;
Wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are optionally selected from following group by 1-4 (such as 1-3,1-2,1,2 or 3) and replace: hydroxyl, halogen, cyano group, amino, substituted-amino, nitro, trifluoromethyl, trifluoromethoxy, C 1-6alkyl, C 3-7cycloalkyl, C 3-7heterocyclylalkyl, aryl, C 3-7heteroaryl, C 1-6alkyl oxy, C 1-6alkyl formyl radical, C 1-6alkyl oxygen formyl radical, C 3-7cycloalkyl oxy, C 3-7cycloalkyl formyl radical, C 3-7cycloalkyloxy group formyl radical, C 3-7heterocyclylalkyl oxygen base, C 3-7heterocyclylalkyl formyl radical, C 3-7heterocyclylalkyl oxygen formyl radical, aryloxy, aryl formyl radical, aryl oxide formyl radical, C 4-9heteroaryl oxygen base, C 4-9heteroaryl formyl radical, C 4-9heteroaryl oxygen formyl radical;
M is selected from 0,1,2 or 3.
The compound of any one according to a first aspect of the present invention, described compound its be the compound shown in formula (IA), its pharmacologically acceptable salts,
Wherein,
N independently selected from 0,1,2;
X is independently selected from C, N;
Y independently selected from singly-bound, C 1-3alkyl ,-NR 1-,-O-,-S-,-CO-,-SO-,-SO 2-,-CONR 2-,-COO-,-SO 2nR 3-,-SO 2o-,-NR 4cO-,-OCO-,-NR 5sO 2-,-OSO 2-,-NR 6cONR 7-,-NR 8cOO-, wherein R 1, R 1, R 2, R 3, R 4, R 5, R 6, R 7and R 8may be the same or different, be selected from hydrogen and C independently of one another 1-3alkyl;
B ring is independently selected from C 3-6cycloalkyl, is selected from the heteroatomic C of nitrogen, oxygen, sulphur containing 1-2 3-6heterocyclylalkyl, aryl, is selected from the heteroatomic heteroaryl of nitrogen, oxygen, sulphur containing 1-9 carbon atom and 1-4;
R is independently selected from hydrogen, halogen, C 1-3alkyl, C 1-3alkoxyl group, trifluoromethyl, cyano group, nitro, ester group, amino, methylamino-, dimethylamino, hydroxyl, carboxyl, C 3-6cycloalkyl, Heterocyclylalkyl, C 6-10aryl, is selected from the heteroatomic heteroaryl of nitrogen, oxygen, sulphur containing 1-9 carbon atom and 1-4;
Wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are optionally selected from following group by 1-4 (such as 1-3,1-2,1,2 or 3) and replace: hydroxyl, halogen, cyano group, amino, substituted-amino, nitro, trifluoromethyl, trifluoromethoxy, C 1-6alkyl, C 3-7cycloalkyl, C 3-7heterocyclylalkyl, aryl, C 3-7heteroaryl, C 1-6alkyl oxy, C 1-6alkyl formyl radical, C 1-6alkyl oxygen formyl radical, C 3-7cycloalkyl oxy, C 3-7cycloalkyl formyl radical, C 3-7cycloalkyloxy group formyl radical, C 3-7heterocyclylalkyl oxygen base, C 3-7heterocyclylalkyl formyl radical, C 3-7heterocyclylalkyl oxygen formyl radical, aryloxy, aryl formyl radical, aryl oxide formyl radical, C 4-9heteroaryl oxygen base, C 4-9heteroaryl formyl radical, C 4-9heteroaryl oxygen formyl radical;
M is selected from 0,1,2 or 3.
The compound of any one and steric isomer thereof according to a first aspect of the present invention, its pharmacologically acceptable salts,
Wherein, preferably
N independently selected from 1,2;
X is independently selected from C, N;
Y independently selected from singly-bound, C 1-3alkyl ,-O-,-CO-,-SO 2-,-COO-,-NR 4cO-, wherein R 4independently selected from hydrogen and C 1-3alkyl;
B ring is independently selected from C 3-6cycloalkyl, aryl, is selected from the heteroatomic heteroaryl of nitrogen, oxygen, sulphur containing 1-9 carbon atom and 1-4;
R is independently selected from hydrogen, halogen, C 1-3alkyl, C 1-3alkoxyl group, trifluoromethyl, cyano group, nitro, C 3-6cycloalkyl, C 6-10aryl, is selected from the heteroatomic heteroaryl of nitrogen, oxygen, sulphur containing 1-9 carbon atom and 1-4;
Wherein said alkyl, cycloalkyl, aryl and heteroaryl are optionally selected from following group by 1-4 (such as 1-3,1-2,1,2 or 3) and replace: hydroxyl, halogen, cyano group, amino, substituted-amino, nitro, trifluoromethyl, trifluoromethoxy, C 1-6alkyl, C 1-6alkyl oxy, C 1-6alkyl formyl radical, C 1-6alkyl oxygen formyl radical;
M is selected from 0,1,2 or 3.
The compound of any one and steric isomer thereof according to a first aspect of the present invention, its pharmacologically acceptable salts,
Wherein, preferred
N independently selected from 1,2;
X is independently selected from C, N;
Y independently selected from singly-bound ,-CH 2-,-O-,-CO-,-SO 2-,-COO-,-NHCO-;
B ring is independently selected from substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazol radical, substituted or unsubstituted tetrazole base, Qu generation or do not replace oxadiazolyl, substituted or unsubstituted pyridyl;
R is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxyl group, trifluoromethyl, cyano group, nitro, substituted or unsubstituted cyclopropyl, substituted or unsubstituted phenyl, substituted or unsubstituted tetrazole base; Wherein said cyclopropyl, phenyl and tetrazole base are optionally selected from following group by 1-4 (such as 1-3,1-2,1,2 or 3) and replace: hydroxyl, fluorine, chlorine, bromine, cyano group, amino, substituted-amino, nitro, trifluoromethyl, trifluoromethoxy, C 1-6alkyl, C 1-6alkyl oxy, C 1-6alkyl formyl radical, C 1-6alkyl oxygen formyl radical;
M is selected from 0,1,2 or 3.
The compound of any one and steric isomer thereof according to a first aspect of the present invention, its pharmacologically acceptable salts,
Wherein, most preferred
N is selected from 1, and 2;
X is selected from C, N;
Y is selected from menu key ,-CH 2-,-O-,-CO-,-SO 2-,-COO-,-NHCO-;
B ring is selected from cyclohexyl, phenyl, naphthyl, quinolyl, pyrazolyl, triazol radical, tetrazole Ji ， oxadiazolyl, pyridyl;
R is selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxyl group, trifluoromethyl, cyano group, nitro, cyclopropyl, phenyl, 1-methyl isophthalic acid H-tetrazole base;
M is selected from 0,1,2 or 3.
Pharmacy acceptable salt described in the present invention is the compounds of this invention and the salt being selected from following acid and being formed: hydrochloric acid, Hydrogen bromide, tosic acid, tartrate, toxilic acid, lactic acid, methylsulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid.Be preferably hydrochloric acid, Hydrogen bromide, tosic acid or trifluoroacetic acid.
The compound of any one according to a first aspect of the present invention, its target compound of the present invention prepared for embodiment (represent with structural formula or describe with systematic naming method) and steric isomer, its pharmacologically acceptable salts.
The compound of any one according to a first aspect of the present invention, it is be selected from following compound:
Second aspect present invention provides the method preparing compound described in any one of first aspect present invention, and it comprises the following steps:
(i)
Step one:
At the temperature of 10 DEG C to 40 DEG C (such as 10 DEG C to 35 DEG C, 15 DEG C to 30 DEG C, 20 DEG C to 30 DEG C or 20 DEG C to 25 DEG C), under the condensing agent (such as EDCI, HOBT or both mixtures) and alkali (such as diisopropyl ethyl amine) existence of 1-2 equivalent, in organic solvent (such as acetonitrile), make compound shown in formula 1a and thiomorpholine react 12-24 hour, obtain the compound shown in formula 2a;
Step 2:
At-80 DEG C to-70 DEG C (such as-80 DEG C to-75 DEG C ,-75 DEG C to-70 DEG C), in solvent (such as methylene dichloride), by the oxidation 2-6 hour under oxygenant (such as dimethyl sulfoxide (DMSO)) effect of the compound shown in formula 2a, obtain the compound shown in formula 3a;
Step 3:
At the temperature of 10 DEG C to 40 DEG C (such as 10 DEG C to 20 DEG C, 20 DEG C to 30 DEG C or 30 DEG C to 40 DEG C), in acid condition (such as acetic acid), make the compound shown in formula 3a and aliphatic heterocycle amine b react about 2-24 hour, obtain the compound shown in formula c;
Step 4:
At the temperature of 10 DEG C to 40 DEG C (such as 10 DEG C to 35 DEG C, 15 DEG C to 30 DEG C, 20 DEG C to 30 DEG C or 20 DEG C to 25 DEG C); in Hydrochloride/ethyl acetate; make compound shown in formula c remove Boc protecting group, obtain the compounds of this invention shown in formula IA.If with the 1a of racemization for raw material, by above-mentioned steps and method, then obtain the compounds of this invention shown in formula I;
Wherein, the definition of B ring, R, X, Y, n and m as described in the first aspect of the invention.
Third aspect present invention provides a kind of pharmaceutical composition, its comprise treat and/or prevent significant quantity any one of first aspect present invention described in compound and steric isomer thereof, its pharmacologically acceptable salts, and one or more optional pharmaceutically acceptable carriers or vehicle.
Fourth aspect present invention provides compound and steric isomer thereof described in any one of first aspect present invention, its pharmacologically acceptable salts, or pharmaceutical composition described in any one of third aspect present invention is for the preparation for the treatment of and/or preventing and the purposes in the medicine of DPP-IV hyperactivity or the disease relevant with DPP-IV overexpression or illness.In one embodiment, described with DPP-IV hyperactivity or the disease relevant with DPP-IV overexpression or illness be selected from following disease or illness: diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus (NIDDM), diabetes B etc.
Fourth aspect present invention additionally provides compound and steric isomer thereof described in any one of first aspect present invention, its pharmacologically acceptable salts, or pharmaceutical composition described in any one of third aspect present invention is for the preparation of the purposes treated and/or prevented in the medicine of diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus (NIDDM), diabetes B etc.
Fourth aspect present invention additionally provides compound and steric isomer thereof described in any one of first aspect present invention, its pharmacologically acceptable salts, or pharmaceutical composition described in any one of third aspect present invention is being prepared as the purposes in the medicine of DPP-IV inhibitor.
Fifth aspect present invention provides a kind of method treated and/or prevented in experimenter in need with DPP-IV hyperactivity or the disease relevant with DPP-IV overexpression or illness, the method comprise to experimenter's administering therapeutic in need and/or prevention significant quantity any one of first aspect present invention described in compound and steric isomer thereof, its pharmacologically acceptable salts, or the pharmaceutical composition described in any one of third aspect present invention.The method of any one according to a fifth aspect of the present invention, wherein said with DPP-IV hyperactivity or the disease relevant with DPP-IV overexpression or illness be selected from diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus (NIDDM), diabetes B etc.
Fifth aspect present invention additionally provides a kind of method treating and/or preventing diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus (NIDDM), diabetes B in experimenter in need, the method comprise to experimenter's administering therapeutic in need and/or prevention significant quantity any one of first aspect present invention described in compound and steric isomer thereof, its pharmacologically acceptable salts, or pharmaceutical composition described in any one of third aspect present invention.
Sixth aspect present invention provide be used for the treatment of and/or prevent the disease relevant with DPP-IV hyperactivity or DPP-IV overexpression or illness any one of first aspect present invention described in compound and steric isomer thereof, its pharmacologically acceptable salts.Compound according to a sixth aspect of the present invention, wherein said with DPP-IV hyperactivity or the disease relevant with DPP-IV overexpression or illness be selected from: diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus (NIDDM), diabetes B etc.
Sixth aspect present invention additionally provide be used for the treatment of and/or prevent diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus (NIDDM), diabetes B etc. any one of first aspect present invention described in compound and steric isomer thereof, its pharmacologically acceptable salts.
The feature that any one of either side of the present invention or this either side has is equally applicable to any one of other either side or this other either side, as long as they can not be conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.In the present invention, such as, when mentioning " any one of first aspect present invention ", be somebody's turn to do the arbitrary sub-aspect that " any one " refers to first aspect present invention, when other side is mentioned in a similar manner, also there is similar meaning.
detailed Description Of The Invention:
Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.Here is the definition of the present invention's multiple term used, and these definition are applicable to term used in the whole specification sheets of the application, unless separately explained in particular case.
Term " alkoxyl group " refers to alkyl-O-, and alkyl wherein as described herein.
As described herein, term " halogen ", " halogen ", " halogen atom ", " halo " etc. represent fluorine, chlorine, bromine or iodine, particularly represent fluorine, chlorine or bromine.
As described herein, term " alkyl " refers to the alkyl having and specify number carbonatoms, and it is the alkyl of straight or branched, and it can comprise its subbase group, such as, mention " C 1-6alkyl " time, it can also comprise C 1-5alkyl, C 1-4alkyl, C 2-6alkyl, C 2-4the group of the subrange that alkyl etc. represent, and concrete group such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group, hexyl.
As described herein, term " aryl " in this article separately or in combination, be defined as monocycle or bicyclic aromatic group.The example of aryl includes but not limited to phenyl, naphthyl etc.Similarly, term " aryloxy-" refers to an aryl, and it is connected with the other parts of compound by oxygen.
As described herein, term " heteroaryl " refers to have 1 to 4 heteroatoms as annular atoms in this article, and remaining annular atoms is the aryl of carbon, and heteroatoms comprises oxygen, sulphur and nitrogen.The example of heteroaryl includes but not limited to pyrazolyl, oxadiazolyl, quinolyl, tetrazole base, triazol radical, pyridyl, pyrimidyl, imidazolyl, furyl, thienyl, pyrazinyl, isoquinolyl, tetrahydro isoquinolyl etc.In one embodiment, described heteroaryl is pyrazolyl, oxadiazolyl, quinolyl, tetrazole base, triazol radical, pyridyl.
As described herein, term " cycloalkyl " refers to the cyclic alkyl having and specify number ring carbon atom number, and it can comprise its subbase group, such as, mention " C 3-6cycloalkyl " time, it can also comprise C 3-5cycloalkyl, C 3-4cycloalkyl, C 4-6the group of the subrange that cycloalkyl etc. represent, and concrete group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
As described herein, term " Heterocyclylalkyl " refers to the cycloheteroalkyl having and specify number annular atoms number, and bag refers to monocycle or condensed ring group, in ring, have 3 to 6 annular atomses, wherein one or two annular atoms is selected from the heteroatoms of nitrogen, oxygen or sulphur, and all the other annular atomses are carbon.These rings can also have one or more double bond, and but, these rings do not have the π-electron system of total conjugated.Heterocyclylalkyl includes but not limited to pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base etc.
As described herein, term " significant quantity " refers to the dosage that can realize treating and/or preventing disease of the present invention or illness in experimenter.
As described herein, term " pharmaceutical composition ", it can also refer to " composition ", and it is used in experimenter and particularly realizes in Mammals treating and/or preventing disease of the present invention or illness.
As described herein, term " experimenter " can refer to patient or other accept formula I or its pharmaceutical composition to treat and/or prevent the animal of disease of the present invention or illness, particularly Mammals, such as people, dog, monkey, ox, horse etc.
As described herein, term " disease and/or illness " refers to a kind of physical state of described experimenter, and this physical state is relevant with disease of the present invention and/or illness.Such as, disease of the present invention and/or illness both can refer to a kind of physical state, such as, in the physical state compared with hyperglycemia, also can refer to a kind of morbid state, such as, show as the morbid state such as hyperglycemia, diabetes.Do not distinguish for physical state and morbid state in this article, or the two can refer to mutually, such as " hyperglycemia " and " hyperglycemia " can exchange use.
As described herein, as do not specialized, " % " refers to the per-cent of w/w, particularly when describing solid matter.Certainly, when describing liquid substance, being somebody's turn to do the per-cent (solid being dissolved in the situation of liquid) that " % " can refer to weight/volume, or volume/volume per-cent (liquid being dissolved in the situation of liquid) can be referred to.
As described herein, term " pharmacy is acceptable " is such as when describing " pharmacologically acceptable salts ", represent this salt its not still subject physiologic learn and can accept, but also the synthetic pharmaceutically having use value can be referred to, such as at the salt as intermediate for being formed when carrying out chiral separation, although the salt of this intermediate directly can not give experimenter, this salt can work for obtaining in end product of the present invention.
Further aspect of the present invention also relates to the pharmaceutical composition using the compounds of this invention as active ingredient.This pharmaceutical composition can be prepared according to method well known in the art.By pharmaceutically acceptable to the compounds of this invention and one or more solid or liquid excipient and/or assistant agent being combined, make any formulation being suitable for human or animal and using.The content of the compounds of this invention in its pharmaceutical composition is generally 0.1-95 % by weight.
The compounds of this invention or the pharmaceutical composition containing it can administrations in a unit, route of administration can be enteron aisle or non-bowel, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be made ordinary preparation, also can be made into is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
In order to the compounds of this invention is made tablet, various vehicle well known in the art can be widely used, comprise thinner, tamanori, wetting agent, disintegrating agent, lubricant, solubility promoter.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, calcium carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and solubility promoter can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet can also be made coating tablet further, such as sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
In order to administration unit is made capsule, effective constituent the compounds of this invention can be mixed with thinner, solubility promoter, mixture is directly placed in hard capsule or soft capsule.Also effective constituent the compounds of this invention first particle or micropill be can be made with thinner, tamanori, disintegrating agent, then hard capsule or soft capsule are placed in.Also the capsule preparing the compounds of this invention is can be used for for the preparation of each thinner of the compounds of this invention tablet, tamanori, wetting agent, disintegrating agent, solubility promoter kind.
For the compounds of this invention is made injection, appropriate this area conventional solubilizing agent, solubility promoter, pH adjusting agent, osmotic pressure regulator can be added with water, ethanol, Virahol, propylene glycol or their mixture as solvent.Solubilizing agent or solubility promoter can be poloxamer, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjusting agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepared lyophilized injectable powder, N.F,USP MANNITOL, glucose etc. also can be added as propping agent.
In addition, as needs, also tinting material, sanitas, spices, correctives or other additive can be added in pharmaceutical preparation.
For reaching medication object, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can with any known medication administrations.
The dosage of the compounds of this invention pharmaceutical composition is according to preventing or the character of disease therapy and severity, and the individual instances of patient or animal, route of administration and formulation etc. can have large-scale change.In general, the Suitable dosage ranges of the every day of the compounds of this invention is 0.001-150mg/Kg body weight, is preferably 0.1-100mg/Kg body weight, is more preferably 1-60mg/Kg body weight, most preferably is 2-30mg/Kg body weight.Above-mentioned dosage can a dose unit or be divided into several dosage unit administration, and this depends on the clinical experience of doctor and comprises the dosage regimen using other treatment means.
Compound of the present invention or composition can be taken separately, or merge with other treatment medicine or symptomatic drugs and use.When compound of the present invention and other medicine exist act synergistically time, its dosage should be adjusted according to practical situation.
advantageous Effects
In the present invention, all compounds all have novel chemical structure; and the external DPP-IV inhibit activities of most of nitrogen-containing hetero cyclosubstituted pyrrolidine formyl base thiomorpholine class DPP-IV inhibitor reaches more than 50% in the present invention, the wherein external DPP-IV inhibit activities IC of 30 compounds 50reach micromolar levels, especially the IC of 18 compounds 50value reaches 10 -7mol/L level, the IC of 12 compounds 50value reaches 10 -8mol/L level, demonstrate good DPP-IV inhibit activities and selectivity, one of them compound has demonstrated hypoglycemic activity in obvious body.This research contents provides novel, the active strong selective DPP-IV inhibitors of a class formation, can be used for the prevention and therapy of diabetes B and associated conditions thereof.
Embodiment
Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible at this.
For following whole embodiment, standard operation well known by persons skilled in the art and purification process can be used.Except as otherwise noted, all temperature represent with DEG C (degree Celsius).The structure of compound is determined by nuclear magnetic resonance spectrum (NMR) and/or mass spectrum (MS).M.p. be with DEG C fusing point provided, the non-correction up of temperature.
preparation embodiment part
The structure of compound be by proton nmr spectra ( 1hNMR), carbon-13 nmr spectra ( 13cNMR) or mass spectrum (MS) determine.Proton nmr spectra and carbon spectral displacement (δ) provide with the unit of 1,000,000/(ppm).Nuclear magnetic resonance spectrum Mercury-300 or Mercury-400 type nmr determination, deuterochloroform (CDCl 3) or heavy water (D 2o) or deuterated dimethyl sulfoxide (DMSO-d6) make solvent, tetramethylsilane (TMS) or 3-(trimethyl silicon based) deuterated Sodium Propionate (TSP) are interior mark.
Fusing point adopts Japanese YanacoM.P-500D type melting point detector to measure, and temperature does not correct.
High resolution mass spectrum adopts Agilent1100seriesLC/MSDtrapmassspectrometer LC-MS instrument to measure.
Electronic balance adopts Japanese YanacoLY-300 type electronic balance.
Polarimeter adopts Perkin-Elmer241MC type polarimeter to measure under (20 DEG C) under sodium vapor lamp.
Column chromatography generally uses 200 ~ 300 orders or 300 ~ 400 order silica gel to be carrier.
Anhydrous solvent is all by standard method process.Other reagent is commercially available analytical pure.
Wherein,
(±)-BINAP is 2,2'-bis (diphenylphosphino)-1,1'-binaphthyl, i.e. the two diphenyl phosphine of 1,1'-dinaphthalene-2,2'-.
Davep is 2-dicyclohexylphosphino-2'-(N, N-dimethylamino) biphenyl, i.e. 2-dicyclohexyl phosphino--2'-(N, N-dimethylamino) xenyl.
DIAD is diisopropylazodicarboxylate, i.e. diisopropyl azodiformate.
DIPEA is N, N-diisopropylethylamine, DIPEA.
DMAP is 4-dimethylaminopyridine, i.e. DMAP.
DMF is N, N-dimethylformamide, i.e. DMF.
EDCI is 1-(3-(dimethylamino) propyl)-3-ethylcarbodiimidehydrochloride, i.e. 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride.
HOBT is 1-hydroxybenzotriazole, i.e. I-hydroxybenzotriazole.
TFA is trifluoroaceticacid, i.e. trifluoroacetic acid.
THF is tetrahydrofuran, i.e. tetrahydrofuran (THF).
Preparation example
The synthetic route of route 1 intermediate 3a
The first step 4-{ [(2S, 4R)-N-tertbutyloxycarbonyl-4-hydroxy-pyrrolidine-2-base]-formyl radical } preparation of thiomorpholine 2a
By (2S, 4R)-N-tertbutyloxycarbonyl-4-hydroxyl pyrrolidine-2-carboxylic acid 1a (5.08g, 22mmol), HOBt (2.70g, 20mmol), DIPEA (5.2mL, 30mmol) with thiomorpholine (2mL, 20mmol) be placed in 100mL single port bottle, add 50mL acetonitrile, system is muddy, add EDCI (4.22g subsequently, 22mmol), stirred overnight at room temperature, system is clarified.Steam except acetonitrile, by 300mL diluted ethyl acetate system, and wash twice by the saturated salt containing 0.5N sodium hydroxide.Divide and get ethyl acetate layer, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, obtains off-white color solid, and with ether making beating, filters to obtain intermediate 2a, white solid 4.79g, yield 75.8%.m.p.163-164℃， (c0.50,CH 3OH)。 1HNMR(400MHz,CDCl 3)δ:4.80(t,J＝7.2Hz,0.4H, CHC＝O),4.71(t,J＝7.6Hz,0.6H,CHC＝O),4.53&4.47(br,1H,CH-OHinpyrrolidine),4.05-3.75(m,4H,CH 2NCH 2inthiomorpholine),3.70-3.48(m,2H,CH 2Ninpyrrolidine),2.89-2.50(m,5H,CH 2SCH 2inthiomorpholine,OH),2.28-1.90(m,2H,CH 2CHC＝Oinpyrrolidine),1.45&1.43(2s,9H,Boc). 13C-NMR(100MHz,CDCl 3)δ:170.9,170.8,154.4,153.9,79.8,79.6,69.7,68.9,55.4,54.9,54.8,48.1,47.8,44.9,44.7,38.7,38.3,28.3,27.7,27.1.MS(ESI-TOF +):m/z[M+H] +calcdforC 14H 25N 2O 4S:317.1530,found:317.1502.
Second step 4-{ [(2S, 4R)-N-tertbutyloxycarbonyl-4-oxo-pyrroli-2-base]-formyl radical } preparation of thiomorpholine 3a
DMSO (0.355mL, 5mmol) is dissolved in 3mL anhydrous methylene chloride, is cooled to-78 DEG C, slowly drip oxalyl chloride (0.35mL, 4mmol) and produce a large amount of bubble, insulated and stirred 15min.By 4-{ [(2S; 4R)-N-tertbutyloxycarbonyl-4-hydroxy-pyrrolidine-2-base]-formyl radical } thiomorpholine 2a (462mg; dichloromethane solution (3mL) 2mmol) is slowly added dropwise in above-mentioned reaction system; system milky turbidity, insulated and stirred 30min.Slowly rise to 0 DEG C, ice bath stirs 30min, adds methylene dichloride 15mL, organic phase uses 10% citric acid solution and salt water washing respectively, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure, gained crude product is through silica gel column chromatography (300-400 order, λ=230nm) be separated, methylene chloride-methanol (V:V=100:1.1) mixed solution is eluent, obtains intermediate 3a, white solid 0.347g, yield 81.5%. 1HNMR(400MHz,CDCl 3)δ:5.21-5.01(m,1H,CHC＝O),4.11-3.61(m,6H,CH 2NCH 2inthiomorpholine,COCH 2Ninpyrrolidine),2.89-2.38(m,6H,CH 2SCH 2inthiomorpholine,CO CH 2 CH),1.47(s,9H,Boc). 13C-NMR(100MHz,CDCl 3)δ:208.5,207.5,170.2,169.9,154.0,153.4,80.9,55.4,53.6,52.9,52.6,52.0,48.5,48.0,44.7,41.4,41.1,28.1,27.9,27.2.
The synthetic route of route 2 intermediate 5b
The preparation of the first step N-tertbutyloxycarbonyl-4-(4-chloro-phenyl-) piperazine 4a
By 4-chloroiodobenzone (0.382g, 1.6mmol) with N-tert-butoxycarbonyl-piperazine (0.229g, 1.23mmol) be placed in tube sealing, add in Isosorbide-5-Nitrae-dioxane (3mL), add cesium carbonate (0.802g, 2.46mmol), palladium (9mg) and Davep (3mg), 100 DEG C of reactions are spent the night, and filter, concentrating under reduced pressure.Gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=100:25) mixed solution is eluent.Obtain intermediate 4a, white solid 159mg, yield 43.7%.
The preparation of second step 1-(4-chloro-phenyl-) piperazine 5b
Be dissolved in 1mL methylene dichloride by N-tertbutyloxycarbonyl-4-(4-chloro-phenyl-) piperazine 4a (0.159g, 0.54mmol), drip trifluoroacetic acid (0.5mL) under ice bath, reaction 1h, adds water, discards dichloromethane layer.Aqueous phase sodium carbonate adjusts pH=8, with dichloromethane extraction, merges organic phase.With saturated salt washing, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure.Obtain intermediate 5b, off-white color solid 74mg, yield 69.8%. 1HNMR(400MHz,DMSO-d 6)δ:7.20(d,J＝8.8Hz,2H),6.92(d,J＝9.6Hz,2H),3.30(brs,1H),3.02(t,J＝4.8Hz,4H),2.82(t,J＝4.4Hz,4H).
The synthetic route of route 3 intermediate 7b
The preparation of the first step N-tertbutyloxycarbonyl-4-(4-trifluoromethyl) piperazine 5a
With 4-methyl bromobenzene trifluoride (0.493g, 2.2mmol) and N-tert-butoxycarbonyl-piperazine (0.373g, 2.0mmol) for raw material, adopt the first step similar operations step in preparation 4a, obtain intermediate 5a, white solid 71mg, yield 10.8%.
The preparation of second step 1-(4-trifluoromethyl) piperazine 7b
With N-tertbutyloxycarbonyl-4-(4-trifluoromethyl) piperazine 5a (0.070g, 0.212mmol) for raw material, adopt second step similar operations step in preparation 5b, obtain intermediate 7b, white solid 30mg, yield 61.2%. 1HNMR(400MHz,DMSO-d 6)δ:7.48(d,J＝8.8Hz,2H),7.03(d,J＝8.4Hz,2H),3.31(brs,1H),3.18(t,J＝4.8Hz,4H),2.82(t,J＝4.8Hz,4H).
The synthetic route of route 4 intermediate 8b
The preparation of the first step N-tertbutyloxycarbonyl-4-(4-cyano-phenyl) piperazine 6a
To be dissolved in 3mLDMSO to fluorobenzonitrile (0.363g, 3mmol) and N-tert-butoxycarbonyl-piperazine (0.837g, 4.5mmol), add salt of wormwood (0.828g, 6mmol), 100 DEG C of tube sealing reaction 6h, add water precipitation solid, filter, washing, ether is washed.Obtain intermediate 6a, white solid 724mg, yield 84.1%.
The preparation of second step 1-(4-cyano-phenyl) piperazine 8b
With N-tertbutyloxycarbonyl-4-(4-cyano-phenyl) piperazine 6a (0.724g, 2.52mmol) for raw material, adopt second step similar operations step in preparation 5b, obtain intermediate 8b, white solid 234mg, yield 49.7%. 1HNMR(400MHz,DMSO-d 6)δ:7.49(d,J＝8.8Hz,2H),6.85(d,J＝9.2Hz,2H),3.31(brs,1H),3.30(m,4H),3.03(m,4H).
The synthetic route of route 5 intermediate 9b
The preparation of the first step N-tertbutyloxycarbonyl-4-(4-nitrophenyl) piperazine 7a
By 4-bromo nitrobenzene (0.222g, 1.1mmol) with N-tert-butoxycarbonyl-piperazine (0.186g, 1.0mmol) be dissolved in 3mL toluene, add cesium carbonate (0.456g, 1.4mmol), palladium (0.22mg) and (±)-BINAP (2mg), 100 DEG C of tube sealing reactions spend the night, and filter, concentrating under reduced pressure.Obtain intermediate 7a, Orange red solid 300mg, yield 97.7%.
The preparation of second step 1-(4-nitrophenyl) piperazine 9b
7a (0.300g, 0.977mmol) is dissolved in 2mL methylene dichloride, adds 7N Hydrochloride/ethyl acetate, stirring at room temperature, separate out solid, filter.Gained solid 1.5N sodium hydroxide solution dissociates, and with dichloromethane extraction, organic phase salt is washed, anhydrous sodium sulfate drying, filtration, concentrating under reduced pressure.Obtain intermediate 9b, yellow solid 188mg, yield 93.1%. 1HNMR(400MHz,CDCl 3)δ:8.13(d,J＝9.3Hz,1H),6.82(d,J＝9.3Hz,1H),3.39(t,J＝4.8Hz,2H),3.03(t,J＝5.2Hz,2H).
The synthetic route of route 6 intermediate 10b
The preparation of the first step N-tertbutyloxycarbonyl-4-(naphthalene-2-base) piperazine 8a
By 2-bromonaphthalene (0.250g, 1.22mmol) with N-tert-butoxycarbonyl-piperazine (0.250g, 1.34mmol) be dissolved in 2mL dioxane, add cesium carbonate (0.517g, 1.59mmol), palladium (0.4mg) and Davep (0.2mg), 100 DEG C of tube sealing reactions spend the night, and filter, concentrating under reduced pressure.Gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=93:7) mixed solution is eluent.Obtain intermediate 8a, yellow solid 380mg, yield 99.7%.
The preparation of second step 1-(naphthalene-2-base) piperazine 10b
8a (0.380g, 1.22mmol) is dissolved in 3mL methylene dichloride, adds trifluoroacetic acid (1mL), stirring at room temperature 3.5h.Add water, once, aqueous phase sodium carbonate regulates pH=8 to washed with dichloromethane aqueous phase, and with dichloromethane extraction four times, organic phase salt is washed, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure.Obtain intermediate 10b, white solid 200mg, yield 52.6%.
The synthetic route of route 7 intermediate 11b
The preparation of the first step N-tertbutyloxycarbonyl-4-(quinoline-2-base) piperazine 9a
By quinoline-2-base triflate (0.277g; 1.0mmol) with N-tert-butoxycarbonyl-piperazine (0.222g; 1.1mmol) be dissolved in 3mL dry toluene, add cesium carbonate (0.456g, 1.4mmol); (±)-BINAP (2mg) and palladium (0.22mg); under argon shield, tube sealing 100 DEG C reaction 12 hours, after being cooled to room temperature; by insolubles filtering in reaction system, concentrating under reduced pressure.Gained crude product is through column chromatography for separation, and petroleum ether-ethyl acetate (V:V=3:1) mixed solution is eluent, obtains intermediate 9a, white solid 270mg, yield 86.3%.
The preparation of second step 1-(quinoline-2-base) piperazine 11b
9a (0.263g, 0.839mmol) is dissolved in 2mL methylene dichloride, adds trifluoroacetic acid (0.65mL), stirring at room temperature 3.5h.Add water, aqueous phase 2N sodium hydroxide solution regulates pH=8, and with dichloromethane extraction three times, organic phase salt is washed, anhydrous sodium sulfate drying, filtration, concentrating under reduced pressure.Obtain intermediate 11b, faint yellow solid 169mg, yield 94.4%. 1HNMR(300MHz,CDCl 3)δ:7.88(d,J＝9.0Hz,1H),7.70(d,J＝8.1Hz,1H),7.59(d,J＝8.1Hz,1H),7.53(t,J＝8.1Hz,1H),7.22(t,J＝7.2Hz,1H),6.97(d,J＝9.0Hz,1H),3.72(t,J＝4.8Hz,4H),3.02(t,J＝4.8Hz,4H),1.98(brs,1H).
The synthetic route of route 8 intermediate 12b
The preparation of the first step N-tertbutyloxycarbonyl-4-(quinoline-3-base) piperazine 10a
By 3-bromoquinoline (0.9mL, 6.6mmol) with N-tert-butoxycarbonyl-piperazine (1.12g, 6mmol) be dissolved in 18mL dry toluene, add cesium carbonate (2.73g, 8.4mmol), (±)-BINAP (12mg) and palladium (1.3mg), tube sealing 100 DEG C reaction 1 hour, add gac (0.1g), 50 DEG C of heating 20min, filter.Filtrate is concentrated into about 5mL, places crystallization, filters, and dries, obtains intermediate 10a, faint yellow tabular crystal 1.57g, yield 83.4%.
The preparation of second step 1-(quinoline-3-base) piperazine trihydrochloride salt 12b
10a (0.40g, 1.28mmol) is dissolved in 2mL methylene dichloride, adds 7N Hydrochloride/ethyl acetate (6mL), stirring at room temperature 1h.Filter, washed with diethylether, dry.Obtain intermediate 12b, faint yellow solid 400mg, yield 97.3%. 1HNMR(400MHz,DMSO-d 6)δ9.71(brs,4H),9.27(d,J＝2.7Hz,1H),8.50(s,1H),8.31(d,J＝8.5Hz,1H),8.10(d,J＝7.8Hz,1H),7.82(m,2H),3.76(t,J＝4.8Hz,4H),3.28(br,4H).
The synthetic route of route 9 intermediate 13b
The preparation of the first step 3-phenyl-5-trichloromethyl-1,2,4-oxadiazole 11a
N`-hydroxybenzene carbonamidine (0.3g, 2.2mmol) is dissolved in toluene (5mL), add Trichloroacetic anhydride (0.51mL, 2.64), reflux under argon atmosphere 5h, is cooled to room temperature.Concentrating under reduced pressure, adds water 20mL, is extracted with ethyl acetate three times, merges organic phase, washes with saturated sodium bicarbonate solution, and saturated salt is washed, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure.Gained crude product is through silica gel (300-400 order) pillar layer separation, and sherwood oil-methylene dichloride (V:V=100:1) mixed solution is eluent.Obtain intermediate 11a, colorless oil 540mg, yield 92.9%.
The preparation of second step 1-(3-phenyl-1,2,4-oxadiazole-5-base) piperazine 13b
11a (0.54g, 2.05mmol) is dissolved in DMF (2mL), slowly instills in the DMF solution (2mL) of Piperazine anhydrous, stirring at room temperature 5h, concentrating under reduced pressure.Gained crude product is through silica gel (300-400 order) pillar layer separation, and methylene chloride-methanol (V:V=100:1) mixed solution is eluent.Obtain intermediate 13b, white foam solid 255mg, yield 54.0%.
The synthetic route of route 10 intermediate 14b
The preparation of the first step N-tertbutyloxycarbonyl-4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine 12a
By 3-oxo dithiobutanoic acid N methyl esters (0.948g, 6.4mmol) with N-tert-butoxycarbonyl-piperazine (1.43g, 7.68mmol) be dissolved in dehydrated alcohol (30mL), reflux 3h, add phenylhydrazine (0.75mL, 7.68mmol), acetic acid (5) and 4A molecular sieve (1.28g) reflux 12h.Remove ethanol under reduced pressure, be dissolved in methylene dichloride (90mL), use 1N hydrochloric acid (6mL), water (10mL), saturated NaHCO successively 3solution (10mL) and saturated aqueous common salt (10mL) are washed, anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure, gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=9:1) mixed solution is eluent.Obtain intermediate 12a, white solid 1.767mg, yield 80.7%.
The preparation of second step 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine 14b
12a (3.1g, 9.06mmol) is dissolved in methylene dichloride (33mL), under ice-water bath, drips TFA (11mL), stir 1.5h, add water (90mL), gets aqueous phase, and wash with methylene dichloride (20mL × 2).Aqueous phase sodium carbonate regulates pH to 8-9, system milky turbidity.Extract by ethyl acetate (40mL × 3), merge organic phase, wash, anhydrous sodium sulfate drying with salt solution (15mL), filter, concentrating under reduced pressure, obtains intermediate 14b, off-white color solid 2.16g, yield 98.6%. 1HNMR(Mercury400MHz,DMSO-d6)δ:7.76(d,J＝8.0Hz,2H),7.45(t,J＝8.0Hz,2H),7.26(t,J＝7.6Hz,1H),5.77(s,1H),2.72(brs,4H),2.70(brs,4H),2.50(s,3H).
The synthetic route of route 11 intermediate 15b
The preparation of the first step 3-cyclopropyl-5-trichloromethyl-1,2,4-oxadiazole 13a
N`-hydroxycyclopropyl carbonamidine (0.6g, 5.99mmol) is dissolved in toluene (5mL), adds Trichloroacetic anhydride (1.34mL, 7.19mmol), reflux under argon atmosphere 5.5h, is cooled to room temperature.Concentrating under reduced pressure, adds water 20mL, is extracted with ethyl acetate three times, merges organic phase, washes with saturated sodium bicarbonate solution, and saturated salt is washed, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure.Gained crude product is through silica gel (300-400 order) pillar layer separation, and sherwood oil-methylene dichloride (V:V=100:3) mixed solution is eluent.Obtain intermediate 13a, colorless oil 1.04g, yield 76.5%.
The preparation of second step 1-(3-cyclopropyl-1,2,4-oxadiazole-5-base) piperazine 15b
13a (1.015g, 4.46mmol) is dissolved in DMF (2mL), slowly instills in the DMF solution (2mL) of Piperazine anhydrous (0.769g, 8.93mmol), stirring at room temperature 5h, concentrating under reduced pressure.Gained crude product is through silica gel (300-400 order) pillar layer separation, and methylene chloride-methanol (V:V=100:1) mixed solution is eluent.Obtain intermediate 15b, faint yellow solid 330mg, yield 38.1%.
The synthetic route of route 12 intermediate 16b
The preparation of the first step N-tertbutyloxycarbonyl-4-(6-(1-methyl isophthalic acid H-tetrazole-5-base) pyridin-3-yl) piperazine 14a
By bromo-for commercially available 5-2-(1-methyl isophthalic acid H-tetrazole-5-base) pyridine (0.72g, 3.0mmol) with N-tert-butoxycarbonyl-piperazine (0.615g, 3.3mmol) be dissolved in 8mL anhydrous dioxane, add cesium carbonate (1.08g), Davep (1mg) and palladium (0.3mg), tube sealing 100 DEG C reaction 3 hours, cooling, filters.Filtrate concentrates, and adds water, and filter, ether is washed, and washing is dried, obtained intermediate 14a, off-white color solid 0.9g, yield 87.0%.
The preparation of second step 1-(6-(1-methyl isophthalic acid H-tetrazole-5-base) pyridin-3-yl) piperazine trihydrochloride salt 16b
14a (0.40g, 1.16mmol) is dissolved in 2mL methylene dichloride, adds 7N Hydrochloride/ethyl acetate (6mL), stirring at room temperature 1h.Filter, washed with diethylether, dry.Obtain intermediate 16b, off-white color solid 400mg, yield 97.8%. 1HNMR(400MHz,DMSO-d 6)δ:9.47(brs,2H),8.56(d,J＝2.7Hz,1H),8.09(d,J＝8.9Hz,1H),7.61(dd,J＝2.9Hz,J＝8.9Hz,1H),6.44-5.76(br,2H),4.38(s,3H),3.65(t,J＝5.2Hz,4H),3.23(m,4H).
The synthetic route of route 13 intermediate 17b
The preparation of the first step N-tertbutyloxycarbonyl-4-(naphthalene-1-base formyl radical) piperazine 15a
By naphthalene-1-formic acid (0.38g, 2.2mmol), HOBt (0.297g, 2.2mmol), triethylamine (0.3mL, 2.2mmol) with N-tert-butoxycarbonyl-piperazine (0.373g, 2.0mmol) be placed in 50mL single port bottle, add 10mL acetonitrile, add EDCI (0.422g subsequently, 2.2mmol), stirring at room temperature 3h.Add methylene dichloride (50mL) and saturated sodium bicarbonate solution (10mL), divide and get dichloromethane layer, wash by saturated salt, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=1:1) mixed solution is eluent.Obtain intermediate 15a, pale yellow oil 0.742g, yield 100%.
The preparation of second step 1-(naphthalene-1-base formyl radical) piperazine hydrochloride 17b
15a (0.58g, 1.71mmol) is dissolved in methylene dichloride (2mL), adds 7N Hydrochloride/ethyl acetate (6mL), stirring at room temperature 1h.Filter, washed with diethylether, dry.Obtain intermediate 17b, white solid 438mg, yield 91.6%.
The synthetic route of route 14 intermediate 18b
The preparation of the first step N-tertbutyloxycarbonyl-4-(quinoline-2-base formyl radical) piperazine 16a
By quinoline-2-formic acid (0.38g, 2.2mmol), HOBt (0.297g, 2.2mmol), triethylamine (0.3mL, 2.2mmol) with N-tert-butoxycarbonyl-piperazine (0.373g, 2.0mmol) be placed in 50mL single port bottle, add 10mL acetonitrile, add EDCI (0.422g subsequently, 2.2mmol), stirring at room temperature 4h.Add methylene dichloride (50mL) and saturated sodium bicarbonate solution (10mL), divide and get dichloromethane layer, wash by saturated salt, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=3:2) mixed solution is eluent.Obtain intermediate 16a, colorless oil 0.612g, yield 89.7%.
The preparation of second step 1-(quinoline-2-base formyl radical) piperazine 18b
16a (0.412g, 1.2mmol) is dissolved in methylene dichloride (2mL), adds 7N Hydrochloride/ethyl acetate (6mL), stirring at room temperature 1h.Filter, obtain white solid, regulate pH=8 with 2N sodium hydroxide solution, and with dichloromethane extraction three times, organic phase salt is washed, anhydrous sodium sulfate drying, filtration, concentrating under reduced pressure.Obtain intermediate 18b, white solid 258mg, yield 89.3%. 1HNMR(300MHz,DMSO-d 6)δ:9.56(brs,2H),8.56(d,J＝8.7Hz,1H),8.06(m,2H),7.86(t,J＝6.9Hz,1H),7.74(m,2H),7.21(br,1H),3.96(m,2H),3.81(m,2H),3.30-3.10(m,4H).
The synthetic route of route 15 intermediate 19b
The preparation of the first step N-tertbutyloxycarbonyl-4-(4-bromobenzenesulfonyl) piperazine 17a
By N-tert-butoxycarbonyl-piperazine (0.373g, 2.0mmol) be placed in 50mL single port bottle with catalytic amount DMAP, add methylene dichloride (4mL) and triethylamine (0.33mL, 2.4mmol), 4-bromobenzene sulfonyl chloride (0.511g is added under ice bath, 2.0mmol), stirring at room temperature 1h.Add methylene dichloride (50mL) and water (20mL), divide and get dichloromethane layer, wash by saturated salt, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=3:1) mixed solution is eluent.Obtain intermediate 17a, white solid 720mg, yield 89.1%.
The preparation of second step 1-(4-bromobenzenesulfonyl) piperazine hydrochloride 19b
17a (0.440g, 1.09mmol) is dissolved in methylene dichloride (2mL), adds 7N Hydrochloride/ethyl acetate (6mL), stirring at room temperature 1h.Filter, obtain intermediate 19b, white solid 373mg, yield 100%. 1HNMR(300MHz,DMSO-d 6)δ:9.21(brs,2H),7.92(d,J＝8.7Hz,2H),7.73(d,J＝8.7Hz,1H),3.16(br,8H).
The synthetic route of route 16 intermediate 20b
The preparation of the first step N-tertbutyloxycarbonyl-4-(phenylcarbamoyl) piperazine 18a
N-tert-butoxycarbonyl-piperazine (0.41g, 2.2mmol) is dissolved in 10mLTHF, drips phenyl isocyanate (0.217mL, 2.0mmol) under ice bath, stirring at room temperature 0.5h.Add methylene dichloride 50mL, organic phase 10% citric acid solution is washed once, and salt is washed, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure.Obtain intermediate 18a, white solid 553mg, yield 90.5%.
The preparation of second step 1-(phenylcarbamoyl) piperazine 20b
18a (0.426g, 1.4mmol) is dissolved in methylene dichloride (2mL), adds 7N Hydrochloride/ethyl acetate (6mL), stirring at room temperature 1h.Filter, obtain white solid 300mg, yield 89.0%.Above-mentioned white solid (161mg, 0.668) is regulated pH=8 with saturated sodium bicarbonate solution, and with dichloromethane extraction three times, organic phase salt is washed, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure.Obtain intermediate 20b, colorless oil 67mg, yield 48.9%. 1HNMR(300MHz,DMSO-d 6)δ:9.13(brs,2H),8.76(s,1H),7.45(d,J＝8.2Hz,2H),7.24(t,J＝7.7Hz,2H),6.95(t,J＝7.1Hz,1H),3.68(t,J＝5.1Hz,2H),3.12(t,J＝4.8Hz,4H).
The synthetic route of route 17 intermediate 21b
The preparation of the first step N-tertbutyloxycarbonyl-4-((5-chloro-3-methyl isophthalic acid phenyl-1H-pyrazoles-4-base) methyl) piperazine 19a
By chloro-for 5-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-formaldehyde (0.44g, 2.0mmol) with N-tert-butoxycarbonyl-piperazine (391mg, 2.1mmol) be dissolved in 10mL methylene dichloride, then 1 Glacial acetic acid is added, and add sodium triacetoxy borohydride (1.27g, 6.0mmol), stirred overnight at room temperature.In reaction solution, add 5mL saturated sodium bicarbonate solution, stir 15 minutes, add methylene dichloride 20mL, divide and get organic phase, use saturated common salt water washing, with anhydrous sodium sulfate drying, filter, concentrating under reduced pressure.Gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=70:30) mixed solution is eluent.Obtain intermediate 19a, pale yellow oil 740mg, yield 94.9%.
The preparation of second step 1-((the chloro-3-methyl isophthalic acid of 5--phenyl-1H-pyrazoles-4-base) methyl) piperazine 21b
19a (0.50g, 1.28mmol) is dissolved in methylene dichloride (2mL), adds 7N Hydrochloride/ethyl acetate (6mL), stirring at room temperature 1h.Ether replacement solvent, steaming desolventizes, and obtains intermediate 21b, white solid 500mg, yield 98.0%.
The synthetic route of route 18 intermediate 22b
The preparation of the first step N-tertbutyloxycarbonyl-4-(quinoline-2-base) homopiperazine 20a
By 2-quinolyl triflate (0.831g, 3mmol) with N-tert-butoxycarbonyl-piperazine (0.66g, 3.3mmol) be dissolved in 3mL anhydrous dioxane, add cesium carbonate (1.4g, 4.5mmol), (±)-BINAP (6mg) and palladium (1mg), tube sealing 100 DEG C reaction 4.5 hours.Filter, concentrating under reduced pressure, gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=3:1) mixed solution is eluent.Obtain intermediate 20a, pale yellow oil 815mg, yield 89.1%.
The preparation of second step 1-(quinoline-2-base) piperazine 22b
Be dissolved in by 20a (0.815g, 2.5mmol) in 6mL methylene dichloride, drip TFA (2mL) under ice-water bath, stir 1.5h, add water (90mL), gets aqueous phase, and wash with methylene dichloride (20mL × 2).Aqueous phase sodium carbonate regulates pH to 8-9.Extract with methylene dichloride (40mL × 3), merge organic phase, wash, anhydrous sodium sulfate drying with salt solution (15mL), filter, concentrating under reduced pressure, obtains intermediate 22b, pale yellow oil 500mg, yield 88.3%. 1HNMR(400MHz,CDCl 3)δ:7.84(d,J＝9.1Hz,1H),7.65(d,J＝8.4Hz,1H),7.57(d,J＝7.9Hz,1H),7.50(t,J＝7.2Hz,1H),7.17(t,J＝7.4Hz,1H),6.86(d,J＝9.1Hz,1H),3.91(t,J＝5.2Hz,2H),3.87(t,J＝6.2Hz,2H),3.10(t,J＝5.6Hz,2H),2.87(t,J＝5.6Hz,2H),2.24(brs,1H),1.96(m,2H).
The synthetic route of route 19 intermediate 23b
The preparation of the first step N-tertbutyloxycarbonyl-4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) homopiperazine 21a
By 3-oxo dithiobutanoic acid N methyl esters (0.074g, 0.5mmol) with N-tertbutyloxycarbonyl homopiperazine (0.11g, 0.55mmol) be dissolved in dehydrated alcohol (3mL), reflux 6h, add phenylhydrazine (0.054mL, 0.55mmol), acetic acid (1) reflux 12h.Remove ethanol under reduced pressure, be dissolved in methylene dichloride (20mL), use 1N hydrochloric acid (2mL), water (5mL), saturated NaHCO successively 3solution (5mL) and saturated aqueous common salt (5mL) are washed, anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure, gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=9:1) mixed solution is eluent.Obtain intermediate 21a, yellow oil 142mg, yield 79.8%.
The preparation of second step 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) homopiperazine 23b
21a (0.142g, 0.4mmol) is dissolved in methylene dichloride (2mL), under ice-water bath, drips TFA (0.65mL), stir 1.5h, add water (20mL), gets aqueous phase, and wash with methylene dichloride (20mL × 2).Aqueous phase sodium carbonate regulates pH to 8-9.Extract with methylene dichloride (15mL × 3), merge organic phase, wash with salt solution (10mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure.Obtain intermediate 23b, yellow oil 80mg, yield 98.6%. 1HNMR(400MHz,CDCl 3)δ:7.62(d,J＝7.7Hz,2H),7.41(t,J＝7.8Hz,2H),7.26(m,1H),5.65(s,1H),3.14(m,4H),2.93(t,J＝6.0Hz,2H),2.85(t,J＝5.6Hz,2H),2.25(s,3H),2.21(brs,1H),1.70(m,2H).
The synthetic route of route 20 intermediate 24b
The preparation of the first step N-tertbutyloxycarbonyl-4-Phenoxypiperidines 22a
By phenol (0.226g, 2.4mmol), N-tertbutyloxycarbonyl-4-piperidine alcohols (0.400g, 2.0mmol) with triphenylphosphine (0.73g, 2.4mmol) be dissolved in anhydrous THF (12mL), DIAD (0.47mL, 2.4mmol) is dripped under ice bath.Stirring is spent the night, concentrating under reduced pressure, and gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=9:1) mixed solution is eluent.Obtain intermediate 22a, colorless oil 432mg, yield 78.0%.
The preparation of second step 4-Phenoxypiperidines 24b
22a (0.432g, 1.56mmol) is dissolved in methylene dichloride (6mL), drip TFA (2mL) under ice-water bath, stirring is spent the night, and adds saturated sodium bicarbonate and regulates pH to 8.Extract with methylene dichloride (20mL × 2), merge organic phase, wash with salt solution (10mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure.Obtain intermediate 24b, faint yellow solid 80mg, yield 85.5%.
The synthetic route of route 21 intermediate 25b
The preparation of the first step N-tertbutyloxycarbonyl-4-(quinoline-2-oxygen base) piperidines 23a
By 2-hydroxyquinoline (0.348g, 2.4mmol), N-tertbutyloxycarbonyl-4-piperidine alcohols (0.400g, 2.0mmol) with triphenylphosphine (0.73g, 2.4mmol) be dissolved in anhydrous THF (12mL), DIAD (0.47mL, 2.4mmol) is dripped under ice bath.Stirring at room temperature 5h, concentrating under reduced pressure, gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=9:1) mixed solution is eluent.Obtain intermediate 23a, colorless oil 467mg, yield 71.2%.
The preparation of second step 4-(quinoline-2-oxygen base) piperidines 25b
23a (0.467g, 1.424mmol) is dissolved in methylene dichloride (4mL), under ice-water bath, drips TFA (2mL), stirring is spent the night, and add water (20mL), adds ether (10mL), divide and take off layer, sodium carbonate regulates pH to 8.Extract with methylene dichloride (20mL × 2), merge organic phase, wash with salt solution (10mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure.Obtain intermediate 25b, white solid 270mg, yield 83.1%. 1HNMR(400MHz,CDCl 3)δ:7.98(d,J＝8.8Hz,1H),7.80(d,J＝8.4Hz,1H),7.70(d,J＝8.0Hz,1H),7.60(t,J＝7.7Hz,1H),7.36(t,J＝7.5Hz,1H),6.87(d,J＝8.8Hz,1H),5.46(m,1H),3.20(m,2H),3.03(brs,1H),2.91(m,2H),2.18(m,2H),1.81(m,2H).
The synthetic route of route 22 intermediate 26b
The preparation of the first step N-tertbutyloxycarbonyl-4-benzoxy phenylpiperidines 24a
By phenylformic acid (0.293g, 2.4mmol), N-tertbutyloxycarbonyl-4-piperidine alcohols (0.400g, 2.0mmol) with triphenylphosphine (0.73g, 2.4mmol) be dissolved in anhydrous THF (12mL), DIAD (0.47mL, 2.4mmol) is dripped under ice bath.Stirred overnight at room temperature, concentrating under reduced pressure, gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=9:1) mixed solution is eluent.Obtain intermediate 24a, pale yellow oil 440mg, yield 72.1%.
The preparation of second step 4-benzoxy phenylpiperidines 26b
24a (0.44g, 1.44mmol) is dissolved in methylene dichloride (6mL), drip TFA (2mL) under ice-water bath, stirring is spent the night, and regulates pH to 8 with saturated sodium bicarbonate solution.Extract with methylene dichloride (20mL × 5), merge organic phase, wash with salt solution (10mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure.Obtain intermediate 26b, faint yellow solid 280mg, yield 94.9%. 1HNMR(400MHz,CDCl 3)δ:8.05(d,J＝7.6Hz,2H),7.58(t,J＝7.4Hz,1H),7.46(t,J＝7.7Hz,2H),5.35(brs,1H),5.22(m,1H),3.25(m,2H),3.02(m,2H),2.14(m,2H),1.93(m,2H).
The synthetic route of route 23 intermediate 27b
The preparation of the first step N-tertbutyloxycarbonyl-4-phenylcarbamoyl piperidines 25a
By N-t-butoxycarbonylpiperidin-4-formic acid (1g, 4.37mmol), HOBt (0.59g, 4.37mmol), triethylamine (0.68mL, 4.81mmol) with aniline (0.44g, 4.37mmol) be placed in 50mL single port bottle, add 10mL acetonitrile, add EDCI (0.843g subsequently, 4.4mmol), stirring at room temperature 5h.Add methylene dichloride (50mL) and saturated sodium bicarbonate solution (10mL), divide and get dichloromethane layer, wash by saturated salt, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=7:3) mixed solution is eluent.Obtain intermediate 25a, off-white color solid 0.83g, yield 62.5%.
The preparation of second step 4-phenylcarbamoyl piperidines 27b
25a (0.23g, 0.756mmol) is dissolved in methylene dichloride (2mL), drip TFA (0.7mL) under ice-water bath, stirring is spent the night, and regulates pH to 8 with saturated sodium bicarbonate solution.Extract with methylene dichloride (20mL × 5), merge organic phase, wash with salt solution (10mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure.Obtain intermediate 27b, white solid 70mg, yield 45.5%.
The synthetic route of route 24 intermediate 28b
The preparation of the first step N-tertbutyloxycarbonyl-4-(4-phenyl-1H-1,2,3-triazole-1-base) piperidines 26a
By N-tertbutyloxycarbonyl-4-azido-piperidines (0.23g, 1.0mmol), diisopropyl ethyl amine (0.65g, 5mmol), cuprous iodide (0.057g, 0.03mmol) be placed in 25mL single port bottle, add 10mL methyl alcohol, add phenylacetylene (0.107g, 1.05mmol) subsequently, stirring at room temperature 2h.Concentrating under reduced pressure, adds ethyl acetate (50mL) and water (10mL), divides and gets ethyl acetate layer, and with 10% lemon pickling, saturated salt is washed, anhydrous sodium sulfate drying, and filter, steaming desolventizes.Obtain intermediate 26a, faint yellow solid 0.285g, yield 80.3%.
The preparation of second step 4-(4-phenyl-1H-1,2,3-triazole-1-base) piperidines 28b
26a (0.275g, 0.838mmol) is dissolved in methylene dichloride (2mL), under ice-water bath, drips TFA (0.7mL), stir 2h, regulate pH to 8 with saturated sodium bicarbonate solution.Extract with methylene dichloride (20mL × 5), merge organic phase, wash with salt solution (10mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure.Obtain intermediate 28b, off-white color solid 170mg, yield 89.0%.
The synthetic route of route 25 intermediate 29b
The preparation of the first step N-tertbutyloxycarbonyl-4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base)-5,6-dihydro-1 (2H)-pyridine 27a
By 1; 2; 3; 6-tetrahydropyridine-4-pinacol borate (0.612g, 1.98mmol), 3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base triflate (0.578g, 1.89mmol), sodium carbonate (0.421g; 3.97mmol) He four triphenyl phosphorus palladiums (2%mmol) drop into 25mL bottle with two necks; add 6mL dioxane and 6mL water under argon shield, 80 DEG C of reaction 6h, are cooled to room temperature.Add water, with dichloromethane extraction, merge organic phase, with salt washing, anhydrous sodium sulfate drying, filters.Concentrating under reduced pressure, gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=100:10) mixed solution is eluent.Obtain intermediate 27a, orange/yellow solid 0.161g, yield 25.1%.
The preparation of second step N-tertbutyloxycarbonyl-4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperidines 28a
27a (0.161g, 0.475mmol) is dissolved in 6mL methyl alcohol, adds 10% palladium carbon (20mg), stirred overnight at room temperature, filter, concentrated.Obtain intermediate 28a, yellow oil 0.132g, yield 81.5%.
The preparation of the 3rd step 4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperidines 29b
By 28a (132mg, 0.387mmol) be dissolved in 2mL methylene dichloride, add trifluoroacetic acid (0.7mL), stirring at room temperature 3h, add saturated sodium bicarbonate solution, regulate pH to 8, with dichloromethane extraction, merge organic phase, wash with salt, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure.Obtain intermediate 29b, pale yellow oil 67mg, yield 66.7%. 1HNMR(400MHz,CDCl 3)δ:7.50–7.33(m,5H),6.06(s,1H),3.26(m,2H),2.82(m,1H),2.70(m,2H),2.31(s,3H),1.84(m,4H).
The synthetic route of route 26 intermediate 30b
The preparation of the first step N-tertbutyloxycarbonyl-4-(quinoline-2-base)-5,6-dihydro-1 (2H)-pyridine 29a
By 1; 2; 3; 6-tetrahydropyridine-4-pinacol borate (0.612g, 1.98mmol), 2-chloroquinoline (0.31g, 1.89mmol), sodium carbonate (0.421g; 3.97mmol) He four triphenyl phosphorus palladiums (2%mmol) drop into 25mL bottle with two necks; add 6mL dioxane and 6mL water under argon shield, 80 DEG C of reaction 6.5h, are cooled to room temperature.Add water, with dichloromethane extraction, merge organic phase, with salt washing, anhydrous sodium sulfate drying, filters.Concentrating under reduced pressure, gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=100:10) mixed solution is eluent.Obtain intermediate 29a, colorless oil 0.40g, yield 68.3%.
The preparation of second step N-tertbutyloxycarbonyl-4-(quinoline-2-base) piperidines 30a
29a (0.20g, 0.645mmol) is dissolved in 6mL methyl alcohol, adds 10% palladium carbon (20mg), stirred overnight at room temperature, filter, concentrated.Obtain intermediate 30a, pale yellow oil 0.16g, yield 79.6%.
The preparation of the 3rd step 4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperidines 30b
By 30a (160mg, 0.513mmol) be dissolved in 2mL methylene dichloride, add trifluoroacetic acid (0.7mL), stirring at room temperature 3h, add saturated sodium bicarbonate solution, regulate pH to 8, with dichloromethane extraction, merge organic phase, wash with salt, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure.Obtain intermediate 30b, pale yellow oil 100mg, yield 91.7%. 1HNMR(400MHz,CDCl 3)δ:8.11(d,J＝8.5Hz,1H),8.04(d,J＝8.5Hz,1H),7.78(d,J＝8.1Hz,1H),7.69(t,J＝7.7Hz,1H),7.49(t,J＝7.5Hz,1H),7.36(d,J＝8.5Hz,1H),3.29(m,2H),3.08(m,1H),2.86(m,2H),2.36(brs,1H),2.03(m,2H),1.89(m,2H).
The synthetic route of route 27 intermediate 31b
The preparation of the first step N-tertbutyloxycarbonyl-4-(4-trifluoromethyl)-5,6-dihydro-1 (2H)-pyridine 31a
By 1; 2; 3; 6-tetrahydropyridine-4-pinacol borate (0.55g, 1.78mmol), to 5 bromine benzotrifluoride (0.24mL, 1.69mmol), sodium carbonate (0.376g; 3.55mmol) He four triphenyl phosphorus palladiums (2%mmol) drop into 50mL bottle with two necks; add 11mL dioxane and 11mL water under argon shield, 80 DEG C of reaction 3h, are cooled to room temperature.Add water, with dichloromethane extraction, merge organic phase, with salt washing, anhydrous sodium sulfate drying, filters.Concentrating under reduced pressure, gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=100:8) mixed solution is eluent.Obtain intermediate 31a, pale yellow oil 0.40g, yield 72.3%.
The preparation of second step N-tertbutyloxycarbonyl-4-(4-trifluoromethyl) piperidines 32a
31a (0.20g, 0.611mmol) is dissolved in 2mL methyl alcohol, adds 10% palladium/carbon (20mg), stirring at room temperature 3h, filter, concentrated.Obtain intermediate 32a, pale yellow oil 0.20g, yield 99.5%.
The preparation of the 3rd step 4-(4-trifluoromethyl) piperidines 31b
By 32a (200mg, 0.608mmol) be dissolved in 3mL methylene dichloride, add trifluoroacetic acid (1mL), stirring at room temperature 2h, add saturated sodium bicarbonate solution, regulate pH to 8, with dichloromethane extraction, merge organic phase, wash with salt, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure.Obtain intermediate 31b, faint yellow solid 129mg, yield 92.8%. 1HNMR(400MHz,CDCl 3)δ7.57(d,J＝8.1Hz,2H),7.34(d,J＝8.1Hz,2H),3.42(brs,1H),3.27(m,2H),2.80(m,2H),2.71(m,1H),1.88(m,2H),1.73(m,2H).
The synthetic route of route 28 intermediate 32b
The preparation of the first step N-tertbutyloxycarbonyl-4-(biphenyl-2-base)-5,6-dihydro-1 (2H)-pyridine 33a
By 1; 2; 3; 6-tetrahydropyridine-4-pinacol borate (0.612g, 1.98mmol), 2-bromo biphenyl (0.33mL, 1.89mmol), sodium carbonate (0.421g; 3.97mmol) He four triphenyl phosphorus palladiums (2%mmol) drop into 50mL bottle with two necks; add 12mL dioxane and 12mL water under argon shield, 80 DEG C of reactions are spent the night, and are cooled to room temperature.Add water, with dichloromethane extraction, merge organic phase, with salt washing, anhydrous sodium sulfate drying, filters.Concentrating under reduced pressure, gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=100:5) mixed solution is eluent.Obtain intermediate 33a, colorless oil 0.443g, yield 69.9%.
The preparation of second step N-tertbutyloxycarbonyl-4-(biphenyl-2-base) piperidines 34a
31a (0.20g, 0.597mmol) is dissolved in 10mL methyl alcohol, adds 10% palladium carbon (20mg), stirring at room temperature 5h, filter, concentrated.Obtain intermediate 34a, white solid 0.181g, yield 90.0%.
The preparation of the 3rd step 4-(biphenyl-2-base) piperidines 32b
By 34a (181mg, 0.54mmol) be dissolved in 3mL methylene dichloride, add trifluoroacetic acid (1mL), stirring at room temperature 2h, add saturated sodium bicarbonate solution, regulate pH to 8, with dichloromethane extraction, merge organic phase, wash with salt, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure.Obtain intermediate 32b, off-white color solid 120mg, yield 93.8%. 1HNMR(400MHz,CDCl 3)δ:7.46–7.33(m,5H),7.31–7.16(m,4H),3.36(m,2H),2.85(m,1H),2.69(m,2H),2.05(m,2H),1.82(m,2H).
The synthetic route of route 29 intermediate 33b
The preparation of 4-(1-phenyl-1H-tetrazole-5-base) piperidines dihydrochloride 33b
By 25a (400mg, 1.316mmol) be dissolved in 10mL anhydrous tetrahydro furan, add triphenylphosphine (800mg, 2.63mmol) with trimethyl silicon based triazonmethane (0.35mL, 2.63mmol), under ice bath, drip DIAD (0.52mL, 2.63mmol) stirring at room temperature 6 days, reflux 1h, cools in backward system and adds 7N Hydrochloride/ethyl acetate, stirring at room temperature 1h.Add ethyl acetate, supernatant discarded, 2 times repeatedly, filter, filter cake ethyl acetate is washed, dry intermediate 33b, white solid 300mg, yield 86.0%. 1HNMR(400MHz,DMSO-d 6)δ:9.29(brs,1H),9.16(brs,1H),8.35(brs,1H),7.68(s,5H),3.29(m,3H),2.96(m,2H),2.02(m,4H).
The synthetic route of route 30 intermediate 34b
The preparation of the first step N-tertbutyloxycarbonyl-4-(4-trifluoromethyl) homopiperazine 35a
Will to 5 bromine benzotrifluoride (0.336g, 1.5mmol) with N-tertbutyloxycarbonyl homopiperazine (0.325g, 1.65mmol) be dissolved in 2mL1, in 4-dioxane, add cesium carbonate (0.684g, 2.1mmol), palladium (1mg) and (±)-BINAP (3mg), 100 DEG C of tube sealing reaction 22h, filter, concentrating under reduced pressure.Gained crude product is through silica gel (300-400 order) pillar layer separation, and petroleum ether-ethyl acetate (V:V=4:1) mixed solution is eluent.Obtain intermediate 35a, dark brown oily matter 0.509g, yield 98.6%.
The preparation of second step 1-(4-trifluoromethyl) homopiperazine 34b
By 35a (0.500g, 1.453mmol) be dissolved in 6mL methylene dichloride, add trifluoroacetic acid (2mL), stirring at room temperature 2h, add saturated sodium bicarbonate solution, regulate pH to 8, with dichloromethane extraction, merge organic phase, wash with salt, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure.Obtain intermediate 34b, brown oil 317mg, yield 89.5%. 1HNMR(400MHz,CDCl 3)δ:7.43(d,J＝8.8Hz,2H),6.70(d,J＝8.8Hz,2H),3.62(m,4H),3.29(brs,1H),3.07(t,J＝5.6Hz,2H),2.89(t,J＝6.0Hz,2H),1.97(m,2H).
The synthetic route of route 31 intermediate 35b
The preparation of the first step N-tertbutyloxycarbonyl-4-(4-cyano-phenyl) piperazine 36a
To be dissolved in 2mLDMSO to fluorobenzonitrile (0.182g, 1.5mmol) and N-tertbutyloxycarbonyl homopiperazine (0.38mL, 1.95mmol), add salt of wormwood (0.414g, 3mmol), 100 DEG C of tube sealing reaction 5h, add water precipitation solid, filters, washing.Obtain intermediate 36a, white solid 215mg, yield 47.6%.
The preparation of second step 1-(4-cyano-phenyl) homopiperazine 35b
36a (0.200g, 0.66mmol) is dissolved in 2mL methylene dichloride, adds trifluoroacetic acid (0.75mL), stirring at room temperature 2h, adds water and ether, point water intaking phase, aqueous phase with washed with diethylether once, regulate pH to 8 with saturated sodium bicarbonate solution, with dichloromethane extraction three times, merge organic phase, wash with salt, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure.Obtain intermediate 35b, off-white color solid 116mg, yield 87.2%. 1HNMR(400MHz,CDCl 3)δ:7.45(d,J＝6.8Hz,2H),6.67(d,J＝7.2Hz,2H),3.61(m,4H),3.05(t,J＝4.0Hz,2H),2.85(t,J＝4.8Hz,2H),2.03(brs,1H),1.92(m,2H).
The synthetic route of route 32 intermediate 36b
The preparation of the first step N-tertbutyloxycarbonyl-4-(4-cyano-phenyl) piperazine 37a
P-fluoronitrobenzene (0.212g, 1.5mmol) and N-tertbutyloxycarbonyl homopiperazine (0.38mL, 1.95mmol) are dissolved in 2mLDMSO, add salt of wormwood (0.414g, 3mmol), 100 DEG C of tube sealing reaction 5h, add water precipitation solid, filters, washing.Obtain intermediate 37a, yellow solid 455mg, yield 94.4%.
The preparation of second step 1-(4-cyano-phenyl) homopiperazine 36b
37a (0.400g, 1.25mmol) is dissolved in 3mL methylene dichloride, adds trifluoroacetic acid (1mL), stirring at room temperature 1h, regulate pH to 8 with saturated sodium bicarbonate solution, separate out solid, filter, washing.Obtain intermediate 36b, yellow solid 222mg, yield 80.4%. 1HNMR(400MHz,CDCl 3)δ:8.11(d,J＝9.5Hz,2H),6.65(d,J＝9.4Hz,2H),3.69(t,J＝6.0Hz,2H),3.64(t,J＝5.6Hz,2H),3.06(t,J＝5.6Hz,2H),2.85(t,J＝5.6Hz,2H),1.92(m,2H).
Embodiment
embodiment 1
Compound 14-{ [(2S, 4S)-4-(4-cyclohexylpiperazin-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-cyclohexylpiperazin-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 1c
By 4-{ [(2S; 4S)-N-tertbutyloxycarbonyl-4-oxo-pyrroli-2-base]-formyl radical } thiomorpholine 3a (0.112g; 0.365mmol) with commercially available 1-cyclohexylpiperazin 1b (57mg; 0.339mmol) be dissolved in 4mL methylene dichloride; then 1 Glacial acetic acid is added; and add sodium triacetoxy borohydride (0.216g, 1.017mmol), stirred overnight at room temperature.In reaction solution, add 5mL saturated sodium bicarbonate solution, stir 15 minutes, add methylene dichloride 20mL, divide and get organic phase, use saturated common salt water washing, with anhydrous sodium sulfate drying, filter, concentrating under reduced pressure.Gained crude product is through silica gel (300-400 order) pillar layer separation, and methylene chloride-methanol (V:V=100:3.5) mixed solution is eluent.Obtain intermediate 1c, white solid 88mg, yield 55.7%.
Second step 4-{ [(2S, 4S)-4-(4-cyclohexylpiperazin-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine tri hydrochloride 1
With 1c (88mg, 0.188mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 1, white solid 78mg, yield 87.6%.m.p.228-230℃， (c0.50,CH 3OH)。 1hNMR (300MHz, D 2o) δ: 4.83 (m, 1H, cHc=O), 3.94-3.83 (m, CH 2nCH 2inthiomorpholine), 3.78 (m, 2H, CH 2nCH 2inthiomorpholine), 3.71 (m, 1H, N cHinpyrrolidine), 3.66-3.49 (m, 2H, NH cH 2 inpyrrolidine), 3.48-2.55 (m, 14H, CH 2nCH 2inpiperazine, cH 2 cHinpyrrolidine, CH 2sCH 2inthiomorpholine, CHincyclohexane), 2.15-1.08 (m, 11H, cH 2 cHinpyrrolidine, (CH 2) 5incyclohexane) .HR-MS (ESI): C 19h 35n 4oS calculated value 367.25261, measured value [M-3HCl+H] +367.25186.
embodiment 2
Compound 24-{ [(2S, 4S)-4-(4-(4-p-methoxy-phenyl)-piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(4-p-methoxy-phenyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 2c
With 3a (82mg, 0.263mmol) and commercially available 1-(4-p-methoxy-phenyl) piperazine 2b (48mg, 0.25mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 2c, white solid 76mg, yield 62.3%.
Second step 4-{ [(2S, 4S)-4-(4-(4-p-methoxy-phenyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine tri hydrochloride 2
With 2c (60mg, 0.12mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 2, white solid 50mg, yield 82.0%.m.p.170-171℃， (c0.50,CH 3OH)。 1hNMR (300MHz, D 2o) δ: 7.43 (d, J=9.0Hz, 2H, aromatic), 7.12 (d, J=9.0Hz, aromatic), 4.90 (t, J=9.0Hz, 1H, cHc=O), 3.94-3.69 (m, 9H, N cHinpyrrolidine, NH cH 2 inpyrrolidine, cH 3 o, CH 2nCH 2inthiomorpholine), 3.63 (m, 4H, ArN (CH 2 ) 2 ) 3.55 (m, 1H, NH cH 2 inpyrrolidine), 3.24 (m, 4H, CH 2nCH 2inpiperazine), 3.00 (m, 1H, m, 1H, cH 2 cHinpyrrolidine), 2.82-2.61 (m, 4H, CH 2sCH 2inthiomorpholine), 2.10 (m, 1H, cH 2 cHinpyrrolidine). 13c-NMR (100MHz, D 2o-TSP) δ: 169.2,161.2,139.5,124.3,118.4,65.3,60.5,58.7,55.4,52.6,51.0,49.6,48.5,34.3,30.0,29.4.HR-MS (ESI): C 20h 31n 4o 2s calculated value 391.21622, measured value [M-3HCl+H] +391.21555.
embodiment 3
Compound 34-{ [(2S, 4S)-4-(4-phenylpiperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-phenylpiperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 3c
With 3a (127mg, 0.404mmol) and commercially available N-phenylpiperazine 3b (94mg, 0.582mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 3c, white solid 125mg, yield 67.2%.
Second step 4-{ [(2S, 4S)-4-(4-phenylpiperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine tri hydrochloride 3
With 3c (78mg, 0.170mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 3, white solid 70mg, yield 88.6%.m.p.218-219℃， (c0.38,CH 3OH)。 13c-NMR (100MHz, D 2o-TSP) δ: 168.8,148.9,133.0,128.2,121.6,112.9,65.5,60.4,53.5,52.5,51.0,48.8,48.5,33.8,30.0,29.4.HR-MS (ESI): C 19h 29n 4oS calculated value 361.20566, measured value [M-3HCl+H] +361.20490.
embodiment 4
Compound 44-{ [(2S, 4S)-4-(4-(4-fluorophenyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(4-fluorophenyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 4c
With 3a (79mg, 0.25mmol) and commercially available 1-(4-fluorophenyl) piperazine 4b (43mg, 0.238mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 4c, white solid 87mg, yield 76.3%.
Second step 4-{ [(2S, 4S)-4-(4-(4-fluorophenyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine tri hydrochloride 4
With 4c (80mg, 0.167mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 4, white solid 70mg, yield 86.4%.m.p.172-174℃， (c0.50,CH 3OH)。 1hNMR (300MHz, D 2o) δ: 7.24 (m, 5H, aromatic), 4.94 (t, J=8.4Hz, 1H, cHc=O), 4.03 (m, 2H, N cHinpyrrolidine, NH cH 2 inpyrrolidine), 3.90 (t, J=4.8Hz, 2H, CH 2nCH 2inthiomorpholine), 3.81 (t, J=5.4Hz, 2H, CH 2nCH 2inthiomorpholine), 3.65 (dd, J=9.3Hz, J=11.4Hz, 1H, NH cH 2 inpyrrolidine), 3.56 (m, 4H, ArN (CH 2 ) 2 ), 3.44 (m, 4H, CH 2nCH 2inpiperazine), 3.12 (m, 1H, cH 2 cHinpyrrolidine), 2.86-2.67 (m, 4H, CH 2sCH 2inthiomorpholine), 2.20 (m, 1H, cH 2 cHinpyrrolidine). 13c-NMR (100MHz, D 2o-TSP) δ: 168.7,162.4 (d, J=240.5Hz), 145.7 (d, J=2.6Hz), 123.5 (d, J=8.4Hz), 119.3 (d, J=22.7Hz), 65.5,60.4,53.7,52.7,51.0,48.7,48.5,33.7,30.0,29.4.HR-MS (ESI): C 19h 28n 4oSF calculated value 379.19624., measured value [M-3HCl+H] +379.19568.
embodiment 5
Compound 54-{ [(2S, 4S)-4-(4-(4-chloro-phenyl-) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(4-chloro-phenyl-) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 5c
With 3a (79mg, 0.25mmol) and 1-(4-chloro-phenyl-) piperazine 5b (45mg, 0.238mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 5c, white solid 79mg, yield 66.9%.
Second step 4-{ [(2S, 4S)-4-(4-(4-chloro-phenyl-) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine tri hydrochloride 5
With 5c (72mg, 0.148mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 5, white solid 70mg, yield 94.6%.m.p.198-200℃， (c0.50,CH 3OH)。 1hNMR (D 2o, 300MHz) δ: 7.42 (d, J=8.7Hz, 2H, aromatic), 7.14 (d, J=9Hz, 2H, aromatic), 4.96 (dd, J=7.5Hz, J=10.2Hz, 1H, cHc=O), 4.21 (m, 1H, N cHinpyrrolidine), 4.06 (dd, J=7.8Hz, J=12.3Hz, 1H, NH cH 2 inpyrrolidine), 3.90 (t, J=4.5Hz, 2H, CH 2nCH 2inthiomorpholine), 3.79 (t, J=5.1Hz, 2H, CH 2nCH 2inthiomorpholine), 3.72 (m, 1H, NH cH 2 inpyrrolidine), 3.60-3.46 (m, 8H, ArN (CH 2 ) 2 , CH 2nCH 2inpiperazine), 3.18 (m, 1H, cH 2 cHinpyrrolidine), 2.86-2.67 (m, 4H, CH 2sCH 2inthiomorpholine), 2.26 (m, 1H, cH 2 cHinpyrrolidine). 13c-NMR (100MHz, D 2o-TSP) δ: 168.5,149.6,132.4,130.6,122.2,104.2,65.6,60.3,54.2,51.0,50.6,48.6,48.2,33.4,30.0,29.4.HR-MS (ESI): C 19h 28n 4oSCl calculated value 395.16669, measured value [M-3HCl+H] +395.16626.
embodiment 6
Compound 64-{ [(2S, 4S)-4-(4-(4-bromophenyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(4-bromophenyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 6c
With 3a (79mg, 0.25mmol) and commercially available 1-(4-bromophenyl) piperazine 6b (57mg, 0.238mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 6c, white solid 105mg, yield 82.0%.
Second step 4-{ [(2S, 4S)-4-(4-(4-bromophenyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine tri hydrochloride 6
With 6c (100mg, 0.186mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 6, white solid 90mg, yield 89.1%.m.p.213-214℃， (c0.50,CH 3OH)。 1hNMR (D 2o, 300MHz) δ: 7.57 (d, J=9.0Hz, 2H, aromatic), 7.08 (d, J=9.0Hz, 2H, aromatic), 4.96 (dd, J=7.8Hz, J=10.2Hz, 1H, cHc=O), 4.23 (m, 1H, N cHinpyrrolidine), 4.06 (dd, J=8.1Hz, J=12.3Hz, 1H, NH cH 2 inpyrrolidine), 3.90 (t, J=4.5Hz, 2H, CH 2nCH 2inthiomorpholine), 3.80 (t, J=5.1Hz, 2H, CH 2nCH 2inthiomorpholine), 3.71 (m, 1H, NH cH 2 inpyrrolidine), 3.59-3.46 (m, 8H, ArN (CH 2 ) 2 , CH 2nCH 2inpiperazine), 3.18 (m, 1H, cH 2 cHinpyrrolidine), 2.88-2.68 (m, 4H, CH 2sCH 2inthiomorpholine), 2.25 (m, 1H, cH 2 cHinpyrrolidine). 13c-NMR (100MHz, D 2o-TSP) δ: 168.5,150.2,135.4,122.4,117.9,65.6,60.3,54.2,51.0,50.3,48.6,48.2,33.4,30.0,29.4.HR-MS (ESI): C 19h 28n 4oSBr calculated value 439.11617, measured value [M-3HCl+H] +439.11542.
embodiment 7
Compound 74-{ [(2S, 4S)-4-(4-(4-trifluoromethyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(4-trifluoromethyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 7c
With 3a (43mg, 0.136mmol) and 1-(4-trifluoromethyl) piperazine 7b (30mg, 0.130mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 7c, white solid 50mg, yield 72.5%.
Second step 4-{ [(2S, 4S)-4-(4-(4-trifluoromethyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine tri hydrochloride 7
With 7c (50mg, 0.095mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 7, white solid 90mg, yield 89.1%.m.p.142-143℃， (c0.30,CH 3OH)。 1hNMR (400MHz, D 2o) δ: 7.70 (d, J=8.8Hz, 2H, aromatic), 7.21 (d, J=8.4Hz, 2H, aromatic), 4.96 (dd, J=7.2Hz, J=10.0Hz, 1H, cHc=O), 4.20 (m, 1H, N cHinpyrrolidine), 4.07 (dd, J=8.0Hz, J=12.4Hz, 1H, NH cH 2 inpyrrolidine), 3.91 (t, J=4.8Hz, 2H, CH 2nCH 2inthiomorpholine), 3.81 (t, J=5.2Hz, 2H, CH 2nCH 2inthiomorpholine), 3.71 (dd, J=9.6Hz, J=12.4Hz, 1H, NH cH 2 inpyrrolidine), 3.64 (m, 4H, ArN (CH 2 ) 2 ), 3.51 (m, 4H, CH 2nCH 2inpiperazine), 3.19 (m, 1H, cH 2 cHinpyrrolidine), 2.86-2.70 (m, 4H, CH 2sCH 2inthiomorpholine), 2.24 (m, 1H, cH 2 cHinpyrrolidine) .HR-MS (ESI): C 20h 28n 4oSF 3calculated value 429.19304, measured value [M-3HCl+H] +429.19235.
embodiment 8
Compound 84-{ [(2S, 4S)-4-(4-(4-cyano-phenyl piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(4-cyano-phenyl piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 8c
With 3a (79mg, 0.25mmol) and 1-(4-cyano-phenyl) piperazine 8b (45mg, 0.238mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 8c, white solid 80mg, yield 69.6%.
4th step 4-{ [(2S, 4S)-4-(4-(4-cyano-phenyl piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine tri hydrochloride 8
With 8c (72mg, 0.148mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 8, white solid 60mg, yield 81.1%.m.p.166-168℃， (c0.50,CH 3OH)。 1hNMR (300MHz, D 2o) δ: 7.71 (d, J=9.0Hz, 2H, aromatic), 7.13 (d, J=8.7Hz, 2H, aromatic), 4.96 (dd, J=7.8Hz, J=10.5Hz, 1H, cHc=O), 4.22 (m, 1H, N cHinpyrrolidine), 4.07 (dd, J=8.1Hz, J=12.0Hz, 1H, NH cH 2 inpyrrolidine), 3.90 (t, J=5.4Hz, 2H, CH 2nCH 2inthiomorpholine), 3.79 (t, J=5.1Hz, 2H, CH 2nCH 2inthiomorpholine), 3.76 (m, 1H, NH cH 2 inpyrrolidine), 3.69 (m, 4H, ArN (CH 2 ) 2 ), 3.52 (m, 4H, CH 2nCH 2inpiperazine), 3.19 (m, 1H, cH 2 cHinpyrrolidine), 2.86-2.67 (m, 4H, CH 2sCH 2inthiomorpholine), 2.24 (m, 1H, cH 2 cHinpyrrolidine). 13c-NMR (100MHz, D 2o-TSP) δ: 168.4,155.0,137.0,123.5,118.6,104.2,65.7,60.3,54.2,51.0,48.6,48.0,47.7,33.3,30.0,29.4.HR-MS (ESI): C 20h 28n 5oS calculated value 386.20091, measured value [M-3HCl+H] +386.20047.
embodiment 9
Compound 94-{ [(2S, 4S)-4-(4-(4-nitrophenyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(4-nitrophenyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 9c
With 3a (94mg, 0.30mmol) and 1-(4-nitrophenyl) piperazine 9b (62mg, 0.30mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 9c, yellow oil 142mg, yield 93.4%.
4th step 4-{ [(2S, 4S)-4-(4-(4-nitrophenyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine tri hydrochloride 9
With 9c (126mg, 0.25mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 9, yellow solid 106mg, yield 82.8%.m.p.185-187℃。 1hNMR (300MHz, D 2o) δ: 8.20 (d, J=9.3Hz, 2H, aromatic), 7.08 (d, J=9.3Hz, 2H, aromatic), 4.95 (dd, J=7.5Hz, J=10.2Hz, 1H, cHc=O), 4.05 (m, 2H, N cHinpyrrolidine, NH cH 2 inpyrrolidine), 3.90 (t, J=5.1Hz, 2H, CH 2nCH 2inthiomorpholine), 3.84-3.65 (m, 7H, CH 2nCH 2inthiomorpholine, NH cH 2 inpyrrolidine, ArN (CH 2 ) 2 ), 3.42 (m, 4H, CH 2nCH 2inpiperazine), 3.15 (m, 1H, cH 2 cHinpyrrolidine), 2.86-2.70 (m, 4H, CH 2sCH 2inthiomorpholine), 2.22 (m, 1H, cH 2 cHinpyrrolidine). 13c-NMR (75MHz, D 2o-TSP) δ: 168.6,156.8,141.7,129.1,116.8,65.7,60.4,54.0,51.0,48.5,48.3,47.5,33.4,30.0,29.4.HR-MS (ESI): C 19h 28n 5o 3s calculated value 406.19074, measured value [M-3HCl+H] +406.19055.
embodiment 10
Compound 104-{ [(2S, 4S)-4-(4-(naphthalene-2-base) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(naphthalene-2-base) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 10c
With 3a (67mg, 0.215mmol) and 1-(naphthalene-2-base) piperazine 10b (67mg, 0.236mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 10c, faint yellow solid 74mg, yield 67.9%.
The first step 4-{ [(2S, 4S)-4-(4-(naphthalene-2-base) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine tri hydrochloride 10
With 10c (70mg, 0.137mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 10, white solid 61mg, yield 87.1%.m.p.170-172℃。 1hNMR (400MHz, D 2o) δ: 7.99 (d, J=9.1Hz, 1H, aromatic), 7.93 (t, J=8.7Hz, 2H, aromatic), 7.63 – 7.56 (m, 2H, aromatic), 7.53 (t, J=7.5Hz, 1H, aromatic), 7.49 (dd, J=9.1, J=2.3Hz, 1H, aromatic), 4.97 (dd, J=7.8, J=10.0Hz, 1H cHc=O), 4.20 (m, 1H, N cHinpyrrolidine), 4.06 (dd, J=7.8, J=12.1Hz, 1H, NH cH 2 inpyrrolidine), 3.92 (t, J=5.3Hz, 2H, CH 2nCH 2inthiomorpholine), 3.82 (t, J=5.1Hz, 2H, CH 2nCH 2inthiomorpholine), 3.75-3.65 (m, 5H, cH 2 cHinpyrrolidine, ArN (CH 2 ) 2 ), 3.54 (m, 4H, CH 2nCH 2inpiperazine), 3.19 (m, 1H, cH 2 cHinpyrrolidine), 2.90 – 2.67 (m, 4H, CH 2sCH 2inthiomorpholine), 2.25 (dt, J=10.1, J=12.8, Hz, 1H, cH 2 cHinpyrrolidine). 13cNMR (100MHz, D 2o-TSP) δ: 168.6,147.9,136.6,132.9,132.7,130.6,130.2,128.5,122.3,65.6,60.4,54.0,51.3,51.1,48.6,48.5,33.6,30.0,29.4.HR-MS (ESI): C 23h 31n 4oS calculated value 411.22131, measured value [M-3HCl+H] +411.22031.
embodiment 11
Compound 114-{ [(2S, 4S)-4-(4-(quinoline-2-base) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine four hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(quinoline-2-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 11c
With 3a (98mg, 0.313mmol) and 1-(quinoline-2-base) piperazine 11b (67mg, 0.313mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 11c, white solid 94mg, yield 58.8%.
4th step 4-{ [(2S, 4S)-4-(4-(quinoline-2-base) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine four hydrochloride 11
With 11c (94mg, 0.184mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 11, white solid 88mg, yield 86.3%.m.p.240-242℃， (c0.50,CH 3OH)。 1hNMR (300MHz, D 2o) δ: 8.47 (d, J=9.6Hz, 1H, aromatic), 7.94 (d, J=8.1Hz, 1H, aromatic), 7.87 (m, 2H, aromatic), 7.61 (t, J=6.6Hz, 1H, aromatic), 7.43 (d, J=9.6Hz, 1H, aromatic), 4.95 (t, J=9.0Hz, 1H cHc=O), 4.11 (t, J=4.5Hz, 4H, ArN (CH 2 ) 2 ), 4.00-3.77 (m, 6H, N cHinpyrrolidine, NH cH 2 inpyrrolidine, CH 2nCH 2inthiomorpholine), 3.57 (t, J=10.8Hz, 1H, NH cH 2 inpyrrolidine), 3.94 (m, 4H, CH 2nCH 2inpiperazine), 3.06 (m, 1H, cH 2 cHinpyrrolidine), 2.86-2.68 (m, 4H, CH 2sCH 2inthiomorpholine), 2.13 (m, 1H, cH 2 cHinpyrrolidine). 13cNMR (75MHz, D 2o-TSP) δ 168.7,154.7,147.5,138.8,136.3,131.6,129.3,124.3,120.5,114.3,65.8,60.4,53.6,51.0,48.7,48.5,47.4,33.8,30.0,29.4.HR-MS (ESI): C 22h 30n 5oS calculated value 412.21656, measured value [M-4HCl+H] +412.21542.
embodiment 12
Compound 124-{ [(2S, 4S)-4-(4-(quinoline-3-base) piperazine-1 base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine four hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(quinoline-3-base) piperazine-1 base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 12c
By 1-(quinoline-3-base) piperazine trihydrochloride salt 12b (128mg; 0.4mmol) be suspended in 6mL methylene dichloride; add triethylamine (0.17mL; 1.2mmol); be stirred to and dissolve completely; add 4-{ [(2S; 4S)-N-tertbutyloxycarbonyl-4-oxo-pyrroli-2-base]-formyl radical } thiomorpholine 3a (94mg; 0.3mmol), three Glacial acetic acid and sodium triacetoxy borohydride (191mg; 0.9mmol), stirring at room temperature 12 hours.In reaction solution, add 5mL saturated sodium bicarbonate solution, stir 15 minutes, add methylene dichloride 20mL, divide and get organic phase, use saturated common salt water washing, with anhydrous sodium sulfate drying, filter, concentrating under reduced pressure.Gained crude product is through silica gel (300-400 order) pillar layer separation, and methylene chloride-methanol (V:V=100:4) mixed solution is eluent.Obtain intermediate 12c, white solid 150mg, yield 98.0%.
Second step 4-{ [(2S, 4S)-4-(4-(quinoline-3-base) piperazine-1 base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine four hydrochloride 12
With 12c (90mg, 0.176mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 12, yellow solid 80mg, yield 81.6%.m.p.191-192℃。 1hNMR (400MHz, D 2o) δ: 9.03 (d, J=2.5Hz, 1H, aromatic), 8.50 (d, J=1.8Hz, 1H, aromatic), 8.11 (t, J=8.4Hz, 2H, aromatic), 7.93 (t, J=7.7Hz, 1H, aromatic), 7.86 (t, J=7.7Hz, 1H, aromatic), 4.95 (t, J=9.6Hz, 1H cHc=O), 4.02 (m, 2H, N cHinpyrrolidine, NH cH 2 inpyrrolidine), 3.92 (t, J=4.5Hz, 2H, CH 2nCH 2inthiomorpholine), 3.82 (m, 2H, CH 2nCH 2inthiomorpholine), 3.73 (t, J=4.6Hz, 4H, ArN (CH 2 ) 2 ), 3.64 (m, 1H, NH cH 2 inpyrrolidine), 3.39 (m, 4H, CH 2nCH 2inpiperazine), 3.14 (m, 1H, cH 2 cHinpyrrolidine), 2.86-2.68 (m, 4H, CH 2sCH 2inthiomorpholine), 2.18 (m, 1H, cH 2 cHinpyrrolidine). 13cNMR (125MHz, DMSO-d 6) δ: 164.8,143.2,138.9,134.5,129.6,129.0,129.0,127.3,123.5,122.0,64.8,62.0,56.3,47.4,44.8,44.7,44.2,29.8,26.8,26.3.HR-MS (ESI): C 23h 31n 4oS calculated value 412.21656, measured value [M-4HCl+H] +412.21558.
embodiment 13
Compound 134-{ [(2S, 4S)-4-(4-(3-phenyl-1,2,4-oxadiazole-5-base) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(3-phenyl-1,2,4-oxadiazole-5-base) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 13c
With 3a (68mg, 0.215mmol) and 1-(3-phenyl-1,2,4-oxadiazole-5-base) piperazine 13b (55mg, 0.236mmol) is raw material, adopts the first step similar operations step in embodiment 1, obtain intermediate 13c, white solid 80mg, yield 70.8%.
Second step 4-{ [(2S, 4S)-4-(4-(3-phenyl-1,2,4-oxadiazole-5-base) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine tri hydrochloride 13
With 13c (80mg, 0.152mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 13, white solid 60mg, yield 74.1%.m.p.161-162℃。 1hNMR (300MHz, D 2o) δ: 7.91 (d, J=6.9Hz, 2H, aromatic), 7.60 (m, 3H, aromatic), 4.94 (dd, J=7.2Hz, J=10.2Hz, 1H, cHc=O), 4.18-3.93 (m, 6H, N cHinpyrrolidine, NH cH 2 inpyrrolidine, ArN (CH 2 ) 2 ), 3.90 (t, J=4.8Hz, 2H, CH 2nCH 2inthiomorpholine), 3.80 (t, J=5.1Hz, 2H, CH 2nCH 2inthiomorpholine), 3.43 (m, 4H, CH 2nCH 2inpiperazine), 3.14 (m, 1H, cH 2 cHinpyrrolidine), 2.88-2.67 (m, 4H, CH 2sCH 2inthiomorpholine), 2.21 (m, 1H, cH 2 cHinpyrrolidine) .HR-MS (ESI): C 21h 29n 6o 2s calculated value 429.20672, measured value [M-3HCl+H] +429.20587.
embodiment 14
Compound 144-{ [(2S, 4S)-4-(4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 14c
With 3a (157mg, 0.5mmol) and 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine 14b (121mg, 0.5mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 14c, white solid 241mg, yield 89.3%.
Second step 4-{ [(2S, 4S)-4-(4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1 base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine tri hydrochloride 14
With 14c (220mg, 0.407mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 14, white solid 170mg, yield 76.2%.m.p.193-195℃， (c0.50,CH 3OH)。 1hNMR (300MHz, D 2o) δ: 7.84-7.45 (m, 5H, aromatic), 6.12 (s, 1H), 4.93 (dd, J=7.8Hz, J=10.3Hz, 1H, cHc=O), 4.29-4.08 (m, 1H, N cHinpyrrolidine), 4.00 (dd, J=8.0Hz, J=12.2Hz, 1H, NH cH 2 inpyrrolidine), 3.88 (m, 2H, CH 2nCH 2inthiomorpholine), 3.77 (t, J=4.9Hz, 2H, CH 2nCH 2inthiomorpholine), 3.65 (dd, J=9.5Hz, J=12.2Hz, 1H, NH cH 2 inpyrrolidine), 3.45-3.32 (m, 4H, ArN (CH 2 ) 2 ), 3.28 (m, 4H, CH 2nCH 2inpiperazine), 3.10 (m, 1H, cH 2 cHinpyrrolidine), 2.88-2.60 (m, 4H, CH 2sCH 2inthiomorpholine), 2.33 (s, 3H), 2.16 (m, 1H, cH 2 cHinpyrrolidine). 13cNMR (75MHz, D 2o-TSP) δ: 168.2,154.4,151.7,138.3,133.2,132.9,127.5,65.6,60.2,54.0,51.0,49.6,48.5,47.9,33.2,29.9,29.3,14.4.HR-MS (ESI): C 21h 29n 6o 2s calculated value 441.24311, measured value [M-3HCl+H] +441.24203.
embodiment 15
Compound 154-{ [(2S, 4S)-4-(4-(3-cyclopropyl-1,2,4-oxadiazole-5-base) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine dihydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(3-cyclopropyl-1,2,4-oxadiazole-5-base) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 15c
With 3a (108mg, 0.344mmol) with 1-(3-cyclopropyl-1,2,4-oxadiazole-5-base) piperazine 15b (60mg, 0.308mmol) be raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 15c, colorless oil 100mg, yield 65.8%.
Second step 4-{ [(2S, 4S)-4-(4-(3-cyclopropyl-1,2,4-oxadiazole-5-base) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine dihydrochloride 15
With 15c (100mg, 0.203mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 15, white solid 96mg, yield 95.0%.m.p.153-155℃， (c0.50,CH 3OH)。 1hNMR (300MHz, D 2o) δ: 4.94 (dd, J=7.5Hz, J=10.2Hz, 1H, cHc=O), 4.17 (m, 1H, N cHinpyrrolidine), 4.04 (dd, J=7.8Hz, J=12.0Hz, 1H, NH cH 2 inpyrrolidine), 3.94-3.74 (m, 6H, CH 2nCH 2inthiomorpholine, ArN (CH 2 ) 2 ), 3.68 (m, 1H, NH cH 2 inpyrrolidine), 3.44 (m, 4H, CH 2nCH 2inpiperazine), 3.15 (m, 1H, cH 2 cHinpyrrolidine), 2.85-2.66 (m, 4H, CH 2sCH 2inthiomorpholine), 2.23 (m, 1H, cH 2 cHinpyrrolidine), 1.91 (m, 1H, CHincyclopropane), 1.04 (m, 2H, CH 2incyclopropane), 0.91 (m, 2H, CH 2incyclopropane) .HR-MS (ESI): C 18h 29n 6o 2s calculated value 393.2072, measured value [M-2HCl+H] +393.20609.
embodiment 16
Compound 164-{ [(2S, 4S)-4-(4-(6-(1-methyl isophthalic acid H-tetrazole-5-base) pyridin-3-yl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine four hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(6-(1-methyl isophthalic acid H-tetrazole-5-base) pyridin-3-yl) piperazine-1 base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 16c
With 3a (98mg, 0.313mmol) with 1-(6-(1-methyl isophthalic acid H-tetrazole-5-base) pyridin-3-yl) piperazine trihydrochloride salt 16b (118mg, 0.33mmol) be raw material, adopt the first step similar operations step in embodiment 12, obtain intermediate 16c, pale yellow oil 95mg, yield 54.9%.
Second step 4-{ [(2S, 4S)-4-(4-(6-(1-methyl isophthalic acid H-tetrazole-5-base) pyridin-3-yl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine four hydrochloride 16
With 16c (95mg, 0.175mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 16, yellow solid 87mg, yield 72.5%.m.p.177-178℃。 1HNMR(300MHz,D 2O)δ:8.48(s,1H,aromatic),7.98(d,J＝8.7Hz,1H,aromatic),7.83(dd,J＝3.0Hz,J＝9.0Hz,1H,aromatic),4.99(dd,J＝7.8Hz,J＝10.2Hz,1H, CHC＝O),4.35(m,1H,N CHinpyrrolidine),4.31(s,1H,CH 3),4.15(m,1H,NH CH 2 inpyrrolidine),3.92-3.74(m,7H,CH 2NCH 2inthiomorpholine,ArN (CH 2 ) 2 ,NH CH 2 inpyrrolidine),3.65(m,4H,CH 2NCH 2inpiperazine),3.24(m,1H, CH 2 CHinpyrrolidine),2.86-2.68(m,4H,CH 2SCH 2inthiomorpholine),2.32(m,1H, CH 2 CHinpyrrolidine).
embodiment 17
Compound 174-{ [(2S, 4S)-4-(4-(naphthalene-1-base formyl radical) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine dihydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(naphthalene-1-base formyl radical) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 17c
With 3a (108mg, 0.344mmol) and 1-(naphthalene-1-base formyl radical) piperazine hydrochloride 17b (85mg, 0.308mmol) for raw material; adopt the first step similar operations step in embodiment 12; obtain intermediate 17c, colorless oil 110mg, yield 66.7%.
Second step 4-{ [(2S, 4S)-4-(4-(naphthalene-1-base formyl radical) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine dihydrochloride 17
With 17c (110mg, 0.204mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 17, white solid 81mg, yield 77.9%.m.p.185-186℃， (c0.50,CH 3OH)。 1hNMR (300MHz, D 2o) δ: 8.07 (m, 2H, aromatic), 7.81 (t, J=3.9Hz, 1H, aromatic), 7.70-7.55 (m, 4H, aromatic), 4.92 (dd, J=8.1Hz, J=10.5Hz, 1H, cHc=O), 4.19 (m, 2H, CON (CH 2) 2inpiperazine), 4.12 (m, 1H, NCHinpyrrolidine), 4.00 (m, 1H, NH cH 2 inpyrrolidine), 3.91-3.73 (m, 4H, CH 2nCH 2inthiomorpholine), 3.63 (m, 1H, NH cH 2 inpyrrolidine), 3.53 (m, 4H, CH 2nCH 2inpiperazine), 3.27-3.04 (m, 3H, cH 2 cHinpyrrolidine, CON (CH 2) 2inpiperazine), 2.84-2.63 (m, 4H, CH 2sCH 2inthiomorpholine), 2.17 (m, 1H, cH 2 cHinpyrrolidine) .HR-MS (ESI): C 24h 31n 4o 2s calculated value 439.21622, measured value [M-2HCl+H] +439.21561.
embodiment 18
Compound 184-{ [(2S, 4S)-4-(4-(quinoline-2-base formyl radical) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(quinoline-2-base formyl radical) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 18c
With 3a (97mg, 0.31mmol) and 1-(quinoline-2-base formyl radical) piperazine 18b (75mg, 0.31mmol) for raw material; adopt the first step similar operations step in embodiment 1; obtain intermediate 18c, colorless oil 131mg, yield 78.4%.
Second step 4-{ [(2S, 4S)-4-(4-(quinoline-2-base formyl radical) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine tri hydrochloride 18
With 18c (131mg, 0.243mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 18, white solid 123mg, yield 92.5%.m.p.166-167℃， (c0.50,CH 3OH)。 1hNMR (300MHz, D 2o) δ: 8.69 (d, J=8.4Hz, 1H, aromatic), 8.13 (m, 2H, aromatic), 7.97 (m, 1H, aromatic), 7.81 (m, 2H, aromatic), 4.95 (dd, J=7.8Hz, J=10.5Hz, 1H cHc=O), 4.24 (m, 1H, N cHinpyrrolidine), 4.15 (m, 2H, CON (CH 2) 2inpiperazine), 4.05 (m, 1H, NH cH 2 inpyrrolidine), 3.95-3.75 (m, 6H, CH 2nCH 2inthiomorpholine, CON (CH 2) 2inpiperazine), 3.70 (m, 1H, NH cH 2 inpyrrolidine), 3.61-3.37 (m, 4H, CH 2nCH 2inpiperazine), 3.17 (m, 1H, cH 2 cHinpyrrolidine), 2.84-2.66 (m, 4H, CH 2sCH 2inthiomorpholine), 2.25 (m, 1H, cH 2 cHinpyrrolidine) .HR-MS (ESI): C 23h 30n 5o 2s calculated value 440.21147, measured value [M-3HCl+H] +440.21051.
embodiment 19
Compound 194-{ [(2S, 4S)-4-(4-(4-bromobenzenesulfonyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine dihydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(4-bromobenzenesulfonyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 19c
With 3a (109mg, 0.344mmol) and 1-(4-bromobenzenesulfonyl) piperazine hydrochloride 19b (71mg, 0.308mmol) for raw material; adopt the first step similar operations step in embodiment 12; obtain intermediate 19c, colorless oil 100mg, yield 54.1%.
Second step 4-{ [(2S, 4S)-4-(4-(4-bromobenzenesulfonyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine dihydrochloride 19
With 19c (131mg, 0.243mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 19, white solid 83mg, yield 87.4%.m.p.162-163℃。 1hNMR (300MHz, D 2o) δ: 7.88 (d, J=8.4Hz, 2H, aromatic), 7.75 (d, J=7.8Hz, 2H, aromatic), 4.88 (dd, J=8.7Hz, J=10.8Hz, 1H, cHc=O), 4.02-3.80 (m, 4H, N cHinpyrrolidine, NH cH 2 inpyrrolidine, CH 2nCH 2inthiomorpholine), 3.77 (t, J=3.9Hz, 2H, CH 2nCH 2inthiomorpholine), 3.52 (m, 1H, NH cH 2 inpyrrolidine), 3.37-3.18 (m, 8H, CH 2nCH 2inpiperazine, SO 2n (CH 2) 2inpiperazine), 3.02 (m, 1H, cH 2 cHinpyrrolidine), 2.84-2.62 (m, 4H, CH 2sCH 2inthiomorpholine), 2.06 (m, 1H, cH 2 cHinpyrrolidine) .HR-MS (ESI): C 19h 28n 4o 3s 2br calculated value 503.07807, measured value [M-2HCl+H] +503.07803.
embodiment 20
Compound 204-{ [(2S, 4S)-4-(4-(phenylcarbamoyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine dihydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(phenylcarbamoyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 20c
With 3a (108mg, 0.344mmol) and 1-(phenylcarbamoyl) piperazine 20b (74mg, 0.308mmol) for raw material; adopt the first step similar operations step in embodiment 1; obtain intermediate 20c, colorless oil 87mg, yield 58.0%.
Second step 4-{ [(2S, 4S)-4-(4-(phenylcarbamoyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine dihydrochloride 20
With 20c (87mg, 0.179mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 20, white solid 74mg, yield 90.2%.m.p.187-189℃， (c0.50,CH 3OH)。 1hNMR (300MHz, D 2o) δ: 7.42 (t, J=7.9Hz, 2H, aromatic), 7.28 (m, 2H, aromatic), 7.24 (m, 1H, aromatic), 4.94 (dd, J=7.7Hz, J=10.3Hz, 1H, cHc=O), 4.06 (m, 2H, NCHinpyrrolidine, NH cH 2 inpyrrolidine), 3.91 (t, J=5.1Hz, 2H, CH 2nCH 2inthiomorpholine), 3.85-3.78 (m, 6H, CON (CH 2) 2inpiperazine, CH 2nCH 2inthiomorpholine), 3.66 (dd, J=8.8Hz, J=11.2Hz, 1H, NH cH 2 inpyrrolidine), 3.32 (m, 4H, CH 2nCH 2inpiperazine), 3.14 (m, 1H, cH 2 cHinpyrrolidine), 2.86-2.68 (m, 4H, CH 2sCH 2inthiomorpholine), 2.19 (m, 1H, cH 2 cHinpyrrolidine) .HR-MS (ESI): C 20h 30n 5o 2s calculated value 404.21147, measured value [M-2HCl+H] +404.21118.
embodiment 21
Compound 214-{ [(2S, 4S)-4-(4-((the chloro-3-methyl isophthalic acid of 5--phenyl-1H-pyrazoles-4-base) methyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-((the chloro-3-methyl isophthalic acid of 5--phenyl-1H-pyrazoles-4-base) methyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 21c
With 3a (108mg, 0.344mmol) with 1-((the chloro-3-methyl isophthalic acid of 5--phenyl-1H-pyrazoles-4-base) methyl) piperazine dihydrochloride (123mg, 0.34mmol) be raw material, adopt the first step similar operations step in embodiment 12, obtain intermediate 21c, colorless oil 90mg, yield 49.7%.
Second step 4-{ [(2S, 4S)-4-(4-((the chloro-3-methyl isophthalic acid of 5--phenyl-1H-pyrazoles-4-base) methyl) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine tri hydrochloride 21
With 21c (90mg, 0.153mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 21, white solid 91mg, yield 100%.m.p.172-173℃。HR-MS (ESI): C 24h 34n 6oSCl calculated value 489.21978, measured value [M-3HCl+H] +489.21860.
embodiment 22
Compound 224-{ [(2S, 4S)-4-(4-(quinoline-2-base) homopiperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine four hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(quinoline-2-base) homopiperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 22c
With 3a (108mg, 0.344mmol) and 1-(quinoline-2-base) homopiperazine 22b (70mg, 0.308mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 22c, faint yellow solid 109mg, yield 67.3%.
Second step 4-{ [(2S, 4S)-4-(4-(quinoline-2-base) homopiperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine four hydrochloride 22
With 22c (109mg, 0.208mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 22, faint yellow solid 87mg, yield 73.7%.m.p.205-207℃， (c0.50,CH 3OH)。 1hNMR (300MHz, D 2o) δ: 8.47 (d, J=9.6Hz, 1H, aromatic), 7.95 (m, 2H, aromatic), 7.86 (m, 1H, aromatic), 7.61 (m, 1H, aromatic), 7.37 (d, J=9.9Hz, 1H, aromatic), 4.93 (dd, J=7.5Hz, J=10.2Hz, 1H cHc=O), 4.29 (m, 3H, N cHinpyrrolidine, ArN (CH 2 ) 2 ), 4.02 (m, 3H, NH cH 2 inpyrrolidine, ArN (CH 2 ) 2 ), 3.89 (m, 2H, CH 2nCH 2inthiomorpholine), 3.79 (t, J=5.1Hz, 2H, CH 2nCH 2inthiomorpholine), 3.75-3.65 (m, 3H, NH cH 2 inpyrrolidine, CH 2nCH 2inhomopiperazine), 3.54 (m, 2H, CH 2nCH 2inhomopiperazine), 3.14 (m, 1H, cH 2 cHinpyrrolidine), 2.86 – 2.65 (m, 4H, CH 2sCH 2inthiomorpholine), 2.47 (m, 2H, CH 2 cH 2 cH 2), 2.26 (m, 1H, cH 2 cHinpyrrolidine) .HR-MS (ESI): C 23h 32n 5oS calculated value 426.23074, measured value [M-4HCl+H] +426.23080.
embodiment 23
Compound 234-{ [(2S, 4S)-4-(4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 23c
With 3a (108mg, 0.344mmol) with 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) homopiperazine 23b (80mg, 0.308mmol) be raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 23c, colorless oil 53mg, yield 30.8%.
Second step 4-{ [(2S, 4S)-4-(4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine tri hydrochloride 23
With 23c (53mg, 0.096mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 23, white solid 44mg, yield 81.5%.m.p.162-163℃， (c0.50,CH 3OH)。 1hNMR (300MHz, D 2o) δ: 7.61 (m, 5H, aromatic), 6.31 (s, 1H, aromatic), 4.91 (dd, J=6.9Hz, J=9.9Hz, 1H, cHc=O), 4.26 (m, 1H, N cHinpyrrolidine), 3.98-3.85 (m, 3H, NH cH 2 inpyrrolidine, CH 2nCH 2inthiomorpholine), 3.78 (t, J=5.1Hz, 2H, CH 2nCH 2inthiomorpholine), 3.64 (m, 1H, NH cH 2 inpyrrolidine), 3.57 (m, 2H, CH 2nCH 2inhomopiperazine), 3.46 (m, 2H, CH 2nCH 2inhomopiperazine), 3.31 (t, J=6.0Hz, 2H, ArN (CH 2 ) 2 ), 3.20 (m, 2H, ArN (CH 2 ) 2 ), 3.04 (m, 1H, cH 2 cHinpyrrolidine), 2.85 – 2.65 (m, 4H, CH 2sCH 2inthiomorpholine), 2.33 (s, 3H, CH 3), 2.20-2.04 (m, 3H, CH 2 cH 2 cH 2, cH 2 cHinpyrrolidine) .HR-MS (ESI): C 24h 35n 6oS calculated value 455.25876, measured value [M-3HCl+H] +455.25781.
embodiment 24
Compound 244-{ [(2S, 4S)-4-(4-Phenoxypiperidines-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine dihydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-Phenoxypiperidines-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 24c
With 3a (110mg, 0.35mmol) and 4-Phenoxypiperidines 24b (62mg, 0.35mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 24c, white foam solid shape thing 118mg, yield 71.1%.
Second step 4-{ [(2S, 4S)-4-(4-Phenoxypiperidines-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine dihydrochloride 24
With 24c (118mg, 0.248mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 24, white solid 110mg, yield 100%.m.p.154-155℃。 1hNMR (400MHz, D 2o) δ: 7.42 (t, J=7.9Hz, 2H, aromatic), 7.12 (m, 3H, aromatic), 4.96 (dd, J=7.7Hz, J=10.3Hz, 1H, cHc=O), 4.78 (m, 1H, OCHinpiperidine), 4.30 (m, 1H, NCHinpyrrolidine), 4.08 (dd, J=8.0Hz, J=12.3Hz, 1H, NH cH 2 inpyrrolidine), 3.91 (t, J=5.2Hz, 2H, CH 2nCH 2inthiomorpholine), 3.81 (t, J=5.1Hz, 2H, CH 2nCH 2inthiomorpholine), 3.72 (dd, J=9.5Hz, J=12.4Hz, 1H, NH cH 2 inpyrrolidine), 3.57 (m, 2H, CH 2nCH 2inpiperidine), 3.44 (m, 2H, CH 2nCH 2inpiperidine), 3.20 (m, 1H, cH 2 cHinpyrrolidine), 2.86-2.68 (m, 4H, CH 2sCH 2inthiomorpholine), 2.33-2.15 (m, 5H, OCH (CH 2 ) 2 inpiperidine, cH 2 cHinpyrrolidine) .HR-MS (ESI): C 20h 30n 3o 2s calculated value 376.20532, measured value [M-2HCl+H] +376.20435.
embodiment 25
Compound 254-{ [(2S, 4S)-4-(4-(quinoline-2-oxygen base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(quinoline-2-oxygen base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 25c
With 3a (110mg, 0.35mmol) and 4-(quinoline-2-oxygen base) piperidines 25b (80mg, 0.35mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 25c, off-white color solid 105mg, yield 57.1%.
Second step 4-{ [(2S, 4S)-4-(4-(quinoline-2-oxygen base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine tri hydrochloride 25
With 25c (105mg, 0.20mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 25, white solid 103mg, yield 96.3%.m.p.163-165℃。 1hNMR (300MHz, D 2o) δ: 4.73 (d, J=9.0Hz, 1H, aromatic), 8.08 (d, J=8.1Hz, 1H, aromatic), 7.94 (m, 2H, aromatic), 7.71 (m, 1H, aromatic), 7.48 (d, J=9.3Hz, 1H, aromatic), 5.52 (m, 1H, O cHinpiperidine), 4.97 (dd, J=7.5Hz, J=10.2Hz, 1H, cHc=O), 4.36 (m, 1H, N cHinpyrrolidine), 4.10 (dd, J=8.4Hz, J=12.6Hz, 1H, NH cH 2 inpyrrolidine), 3.91 (t, J=4.2Hz, 2H, CH 2nCH 2inthiomorpholine), 3.84-3.71 (m, 3H, CH 2nCH 2inthiomorpholine, NH cH 2 inpyrrolidine), 3.70-3.50 (m, 4H, CH 2nCH 2inpiperidine), 3.22 (m, 1H, cH 2 cHinpyrrolidine), 2.87-2.66 (m, 4H, CH 2sCH 2inthiomorpholine), 2.42 (m, 4H, OCH (CH 2 ) 2 inpiperidine), 2.30 (m, 1H, cH 2 cHinpyrrolidine) .HR-MS (ESI): C 23h 31n 4o 2s calculated value 427.21622, measured value [M-3HCl+H] +427.21439.
embodiment 26
Compound 264-{ [(2S, 4S)-4-(4-benzoyloxy piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine dihydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-benzoyloxy piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 26c
With 3a (110mg, 0.35mmol) and 1-benzoxy phenylpiperidines 26b (72mg, 0.35mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 26c, colorless oil 90mg, yield 51.1%.
Second step 4-{ [(2S, 4S)-4-(4-benzoyloxy piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine dihydrochloride 26
With 26c (90mg, 0.179mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 26, white solid 80mg, yield 94.1%.m.p.158-160℃。 1hNMR (300MHz, D 2o) δ: 8.09 (d, J=7.2Hz, 2H, aromatic), 7.72 (t, J=7.5Hz, 1H, aromatic), 7.57 (t, J=7.8Hz, 2H, aromatic), 5.34 (m, 1H, O cHinpiperidine), 4.97 (dd, J=7.8Hz, J=10.5Hz, 1H, cHc=O), 4.31 (m, 1H, N cHinpyrrolidine), 4.09 (dd, J=8.1Hz, J=12.3Hz, 1H, NH cH 2 inpyrrolidine), 3.90 (t, J=4.2Hz, 2H, CH 2nCH 2inthiomorpholine), 3.80 (t, J=5.1Hz, 2H, CH 2nCH 2inthiomorpholine), 3.73 (dd, J=9.6Hz, J=12.3Hz, 1H, NH cH 2 inpyrrolidine), 3.67-3.46 (m, 4H, CH 2nCH 2inpiperidine), 3.21 (m, 1H, cH 2 cHinpyrrolidine), 2.87-2.66 (m, 4H, CH 2sCH 2inthiomorpholine), 2.41-2.19 (m, 5H, cH 2 cHinpyrrolidine, OCH (CH 2 ) 2 inpiperidine) .HR-MS (ESI): C 21h 30n 3o 3s calculated value 404.20024, measured value [M-2HCl+H] +404.19897.
embodiment 27
Compound 274-{ [(2S, 4S)-4-(4-phenylcarbamoyl piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine dihydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-phenylcarbamoyl piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 27c
With 3a (86mg, 0.275mmol) and 4-phenylcarbamoyl piperidines 27b (56mg, 0.275mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 27c, colorless oil 53mg, yield 38.4%.
Second step 4-{ [(2S, 4S)-4-(4-phenylcarbamoyl piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine dihydrochloride 27
With 27c (53mg, 0.106mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 27, white solid 40mg, yield 80.1%.m.p.178-180℃。 1hNMR (300MHz, D 2o) δ: 7.44 (m, 4H, aromatic), 7.28 (m, 1H, aromatic), 4.96 (dd, J=7.5Hz, J=10.5Hz, 1H, cHc=O), 4.28 (m, 1H, N cHinpyrrolidine), 4.09 (dd, J=7.8Hz, J=12.0Hz, 1H, NH cH 2 inpyrrolidine), 3.90 (t, J=4.2Hz, 2H, CH 2nCH 2inthiomorpholine), 3.80 (t, J=5.1Hz, 2H, CH 2nCH 2inthiomorpholine), 3.76-3.64 (m, 3H, NH cH 2 inpyrrolidine, CH 2nCH 2inpiperidine), 3.31 (m, 2H, CH 2nCH 2inpiperidine), 3.19 (m, 1H, cH 2 cHinpyrrolidine), 2.93-2.67 (m, 5H, CH 2sCH 2inthiomorpholine, CO cHinpiperidine), 2.34-2.19 (m, 3H, COCH (CH 2 ) 2 inpiperidine, cH 2 cHinpyrrolidine), 2.15-2.00 (m, 2H, COCH (CH 2 ) 2 inpiperidine) .HR-MS (ESI): C 21h 31n 4o 2s calculated value 403.21622, measured value [M-2HCl+H] +403.21622.
embodiment 28
Compound 284-{ [(2S, 4S)-4-(4-(4-phenyl-1H-1,2,3-triazole-1-base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(4-phenyl-1H-1,2,3-triazole-1-base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 28c
With 3a (83mg, 0.263mmol) with 4-(4-phenyl-1H-1,2,3-triazole-1-base) piperidines 28b (60mg, 0.263mmol) be raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 28c, off-white color solid 84mg, yield 60.9%.
Second step 4-{ [(2S, 4S)-4-(4-(4-phenyl-1H-1,2,3-triazole-1-base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine tri hydrochloride 28
With 28c (84mg, 0.16mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 28, white solid 75mg, yield 93.8%.m.p.179-180℃。 1hNMR (300MHz, D 2o) δ: 8.42 (s, 1H, aromatic), 7.81 (m, 2H, aromatic), 7.56-7.44 (m, 3H, aromatic), 4.98 (m, 2H, cHc=O, N cHinpiperidine), 4.34 (m, 1H, N cHinpyrrolidine), 4.11 (dd, J=7.2Hz, J=11.7Hz, 1H, NH cH 2 inpyrrolidine), 3.95-3.72 (m, 7H, CH 2nCH 2inthiomorpholine, NH cH 2 inpyrrolidine, CH 2nCH 2inpiperidine), 3.52 (m, 2H, CH 2nCH 2inpiperidine), 3.22 (m, 1H, cH 2 cHinpyrrolidine), 2.89-2.41 (m, 8H, CH 2sCH 2inthiomorpholine, CH (CH 2 ) 2 inpiperidine), 2.30 (m, 1H, cH 2 cHinpyrrolidine) .HR-MS (ESI): C 22h 31n 6oS calculated value 427.22601, measured value [M-3HCl+H] +427.22601.
embodiment 29
Compound 294-{ [(2S, 4S)-4-(4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine dihydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 29c
With 3a (85mg, 0.269mmol) with 4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperidines 29b (65mg, 0.269mmol) be raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 29c, colorless oil 78mg, yield 53.8%.
Second step 4-{ [(2S, 4S)-4-(4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine dihydrochloride 29
With 29c (78mg, 0.145mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 29, off-white color solid 64mg, yield 86.5%. 1hNMR (400MHz, D 2o) δ: 7.65 (m, 3H, aromatic), 7.49 (m, 2H, aromatic), 6.44 (s, 1H, aromatic), 4.92 (dd, J=7.6Hz, J=10.4Hz, 1H, cHc=O), 4.20 (m, 1H, N cHinpyrrolidine), 4.02 (dd, J=8.0Hz, J=12.4Hz, 1H, NH cH 2 inpyrrolidine), 3.89 (m, 2H, CH 2nCH 2inthiomorpholine), 3.77 (t, J=5.2Hz, 2H, CH 2nCH 2inthiomorpholine), 3.68 (dd, J=9.6Hz, J=12.4Hz, 1H, NH cH 2 inpyrrolidine), 3.62 (m, 2H, CH 2nCH 2inpiperidine), 3.13 (m, 4H, CH 2nCH 2inpiperidine, cH 2 cHinpyrrolidine, CHinpiperidine), 2.84-2.66 (m, 4H, CH 2sCH 2inthiomorpholine), 2.36 (s, 3H, CH 3), 2.20 (m, 3H, cH 2 cHinpyrrolidine, CH (CH 2 ) 2 inpiperidine), 1.97 (m, 2H, CH (CH 2 ) 2 inpiperidine) .HR-MS (ESI): C 24h 34n 5oS calculated value 440.24786, measured value [M-2HCl+H] +440.24799.
embodiment 30
Compound 304-{ [(2S, 4S)-4-(4-(quinoline-2-base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 30c
With 3a (133mg, 0.42mmol) and 4-(quinoline-2-base) piperidines 30b (90mg, 0.42mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 30c, faint yellow solid 91mg, yield 42.5%.
Second step 4-{ [(2S, 4S)-4-(4-(quinoline-2-base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine tri hydrochloride 30
With 30c (91mg, 0.176mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 30, off-white color solid 91mg, yield 100%. 1hNMR (400MHz, D 2o) δ: 9.12 (d, J=8.8Hz, 1H, aromatic), 8.30 (d, J=8.4Hz, 1H, aromatic), 8.24 (d, J=8.8Hz, 1H, aromatic), 8.17 (t, J=7.2Hz, 1H, aromatic), 8.03 (d, J=8.8Hz, 1H, aromatic), 7.96 (d, J=7.2Hz, 1H, aromatic), 5.00 (dd, J=7.6Hz, J=10.4Hz, 1H cHc=O), 4.38 (m, 1H, N cHinpyrrolidine), 4.13 (dd, J=8.0Hz, J=12.4Hz, 1H, NH cH 2 inpyrrolidine), 3.95-3.67 (m, 8H, CH 2nCH 2inthiomorpholine, NH cH 2 inpyrrolidine, CH 2nCH 2inpiperidine, CHinpiperidine), 3.48 (m, 2H, CH 2nCH 2inpiperidine), 3.25 (m, 1H, cH 2 cHinpyrrolidine), 2.84-2.69 (m, 4H, CH 2sCH 2inthiomorpholine), 2.52 (m, 2H, CH (CH 2 ) 2 inpiperidine), 2.35 (m, 3H, CH (CH 2 ) 2 inpiperidine, cH 2 cHinpyrrolidine) .HR-MS (ESI): C 23h 31n 4oS calculated value 411.22141, measured value [M-3HCl+H] +411.22141.
embodiment 31
Compound 314-{ [(2S, 4S)-4-(4-(4-trifluoromethyl) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine dihydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(4-trifluoromethyl) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 31c
With 3a (110mg, 0.35mmol) and 4-(trifluoromethyl) piperidines 31b (80mg, 0.35mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 31c, white solid 36mg, yield 19.5%.
Second step 4-{ [(2S, 4S)-4-(4-(4-trifluoromethyl) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine dihydrochloride 31
With 31c (36mg, 0.068mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 31, pale pink solid 30mg, yield 93.8%. 1hNMR (400MHz, D 2o) δ: 7.74 (d, J=8.1Hz, 2H, aromatic), 7.51 (d, J=8.1Hz, 2H, aromatic), 4.96 (dd, J=7.6Hz, J=10Hz, 1H, cHc=O), 4.33-4.22 (m, 1H, N cHinpyrrolidine, CH 2nCH 2inpiperidine), 4.09 (dd, J=8.0Hz, J=12.4Hz, 1H, NH cH 2 inpyrrolidine), 3.91 (t, J=4.8Hz, 2H, CH 2nCH 2inthiomorpholine), 3.82 (t, J=5.1Hz, 2H, CH 2nCH 2inthiomorpholine), 3.79-3.67 (m, 3H, NH cH 2 inpyrrolidine, CH 2nCH 2inpiperidine), 3.32 (m, 2H, CH 2nCH 2inpiperidine), 3.20 (m, 1H, cH 2 cHinpyrrolidine), 3.10 (m, 1H, CHinpiperidine), 2.87-2.68 (m, 4H, CH 2sCH 2inthiomorpholine), 2.33-2.21 (m, 3H, cH 2 cHinpyrrolidine, CH (CH 2 ) 2 inpiperidine), 2.06 (m, 2H, CH (CH 2 ) 2 inpiperidine) .HR-MS (ESI): C 21h 29n 3oSF 3calculated value 428.19779, measured value [M-2HCl+H] +428.19891.
embodiment 32
Compound 324-{ [(2S, 4S)-4-(4-(biphenyl-2-base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine dihydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(biphenyl-2-base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 32c
With 3a (110mg, 0.35mmol) and 4-(biphenyl-2-base) piperidines 32b (83mg, 0.35mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 32c, white solid 72mg, yield 38.5%.
Second step 4-{ [(2S, 4S)-4-(4-(biphenyl-2-base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine dihydrochloride 32
With 32c (72mg, 0.135mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 32, off-white color solid 60mg, yield 88.2%. 1hNMR (400MHz, D 2o) δ: 7.60-7.45 (m, 5H, aromatic), 7.44-7.30 (m, 4H, aromatic), 4.91 (m, 1H, cHc=O), 4.15 (m, 1H, N cHinpyrrolidine), 4.01 (m, 1H, NH cH 2 inpyrrolidine), 3.89 (m, 2H, CH 2nCH 2inthiomorpholine), 3.78 (s, 2H, CH 2nCH 2inthiomorpholine), 3.73-3.55 (m, 3H, NH cH 2 inpyrrolidine, CH 2nCH 2inpiperidine), 3.17-2.99 (m, 4H, CH 2nCH 2inpiperidine, CHinpiperidine, cH 2 cHinpyrrolidine), 2.85-2.66 (m, 4H, CH 2sCH 2inthiomorpholine), 2.22 (m, 1H, cH 2 cHinpyrrolidine), 2.06 (s, 4H, CH (CH 2 ) 2 inpiperidine) .HR-MS (ESI): C 26h 34n 3oS calculated value 436.24171, measured value [M-2HCl+H] +436.24271.
embodiment 33
Compound 334-{ [(2S, 4S)-4-(4-(1-phenyl-1H-tetrazole-5-base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(1-phenyl-1H-tetrazole-5-base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 33c
With 3a (110mg, 0.35mmol) with 4-(1-phenyl-1H-tetrazole-5-base) piperidines dihydrochloride 33b (93mg, 0.31mmol) be raw material, adopt the first step similar operations step in embodiment 12, obtain intermediate 33c, colorless oil 119mg, yield 68.4%.
Second step 4-{ [(2S, 4S)-4-(4-(1-phenyl-1H-tetrazole-5-base) piperidin-1-yl)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine tri hydrochloride 33
With 33c (119mg, 0.211mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 33, white solid 100mg, yield 88.5%. 1hNMR (400MHz, D 2o) δ: 7.81-7.68 (m, 3H, aromatic), 7.61 (m, 2H, aromatic), 4.95 (dd, J=7.6Hz, J=10Hz, 1H, cHc=O), 4.25 (m, 1H, N cHinpyrrolidine), 4.05 (dd, J=8.2Hz, J=12.4Hz, 1H, NH cH 2 inpyrrolidine), 3.90 (m, 2H, CH 2nCH 2inthiomorpholine), 3.79 (t, J=5.0Hz, 2H, CH 2nCH 2inthiomorpholine), 3.76-3.64 (m, 3H, NH cH 2 inpyrrolidine, CH 2nCH 2inpiperidine), 3.50 (m, 1H, CHinpiperidine), 3.32-3.12 (m, 3H, CH 2nCH 2inpiperidine, cH 2 cHinpyrrolidine), 2.85-2.67 (m, 4H, CH 2sCH 2inthiomorpholine), 2.36-2.13 (m, 5H, cH 2 cHinpyrrolidine, CH (CH 2 ) 2 inpiperidine) .HR-MS (ESI): C 21h 30n 7oS calculated value 428.22271, measured value [M-3HCl+H] +428.22379.
embodiment 34
Compound 344-{ [(2S, 4S)-4-(4-(4-trifluoromethyl) homopiperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(4-trifluoromethyl) homopiperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 34c
With 3a (110mg, 0.35mmol) and 1-(4-trifluoromethyl) homopiperazine 34b (85mg, 0.31mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 34c, colorless oil 160mg, yield 84.2%.
Second step 4-{ [(2S, 4S)-4-(4-(4-trifluoromethyl) homopiperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine tri hydrochloride 34
With 34c (147mg, 0.295mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 34, white solid 147mg, yield 90.7%. 1hNMR (400MHz, D 2o) δ: 7.63 (d, J=8.7Hz, 2H, aromatic), 6.95 (d, J=8.7Hz, 2H, aromatic), 4.94 (dd, J=7.9Hz, J=9.8Hz, 1H, cHc=O), 4.38 (m, 1H, N cHinpyrrolidine), 4.04 (dd, J=8.1Hz, J=12.5Hz, 1H, NH cH 2 inpyrrolidine), 3.97-3.85 (m, 4H, ArN (CH 2 ) 2 , CH 2nCH 2inthiomorpholine), 3.81-3.70 (m, 3H, CH 2nCH 2inthiomorpholine, NH cH 2 inpyrrolidine), 3.65 (t, J=6.4Hz, 4H, CH 2nCH 2inhomopiperazine), 3.55 (m, 2H, ArN (CH 2 ) 2 ), 3.16 (m, 1H, cH 2 cHinpyrrolidine), 2.85-2.66 (m, 4H, CH 2sCH 2inthiomorpholine), 2.38-2.22 (m, 3H, CH 2 cH 2 cH 2, cH 2 cHinpyrrolidine) .HR-MS (ESI): C 21h 30n 4oSF 3calculated value 443.20869, measured value [M-3HCl+H] +443.20703.
embodiment 35
Compound 354-{ [(2S, 4S)-4-(4-(4-cyano-phenyl) homopiperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(4-cyano-phenyl) homopiperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 35c
With 3a (110mg, 0.35mmol) and 1-(4-cyano-phenyl) homopiperazine 35b (70mg, 0.35mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 35c, white foam solid 90mg, yield 51.4%.
Second step 4-{ [(2S, 4S)-4-(4-(4-cyano-phenyl) homopiperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine tri hydrochloride 35
With 35c (90mg, 0.18mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 35, yellow solid 83mg, yield 97.6%. 1hNMR (400MHz, D 2o) δ: 7.65 (d, J=8.7Hz, 2H, aromatic), 6.91 (d, J=8.8Hz, 2H, aromatic), 4.92 (dd, J=8.0Hz, J=10.4Hz, 1H, cHc=O), 4.32 (m, 1H, N cHinpyrrolidine), 4.01 (dd, J=8.0Hz, J=12.6Hz, 1H, NH cH 2 inpyrrolidine), 3.94 (t, J=5.0Hz, 2H, CH 2nCH 2inthiomorpholine), 3.89 (m, 2H, ArN (CH 2 ) 2 ), 3.79 (t, J=5.1Hz, 2H, CH 2nCH 2inthiomorpholine), 3.74-3.63 (m, 3H, NH cH 2 inpyrrolidine, ArN (CH 2 ) 2 ), 3.63-3.41 (m, 4H, CH 2nCH 2inhomopiperazine), 3.13 (m, 1H, cH 2 cHinpyrrolidine), 2.85-2.66 (m, 4H, CH 2sCH 2inthiomorpholine), 2.36 – 2.20 (m, 3H, CH 2 cH 2 cH 2, cH 2 cHinpyrrolidine) .HR-MS (ESI): C 21h 30n 5oS calculated value 400.21656, measured value [M-3HCl+H] +400.21555.
embodiment 36
Compound 364-{ [(2S, 4S)-4-(4-(4-nitrophenyl) homopiperazine-1-base)-pyrrolidin-2-yl]-formyl radical }-thiomorpholine tri hydrochloride
The first step 4-{ [(2S, 4S)-N-tertbutyloxycarbonyl-4-(4-(4-nitrophenyl) homopiperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of thiomorpholine 36c
With 3a (110mg, 0.35mmol) and 1-(4-nitrophenyl) homopiperazine 36b (77mg, 0.35mmol) for raw material, adopt the first step similar operations step in embodiment 1, obtain intermediate 36c, yellow oil 129mg, yield 70.9%.
Second step 4-{ [(2S, 4S)-4-(4-(4-nitrophenyl) homopiperazine-1-base)-pyrrolidin-2-yl]-formyl radical } preparation of-thiomorpholine tri hydrochloride 35
With 36c (129mg, 0.249mmol) for raw material, adopt second step similar operations step in embodiment 1, obtain compound 36, yellow solid 105mg, yield 80.2%. 1HNMR(400MHz,D 2O)δ:8.19(d,J＝9.3Hz,2H,aromatic),6.89(d,J＝9.4Hz,2H,aromatic),4.91(dd,J＝7.7Hz,J＝10.1Hz,1H, CHC＝O),4.28(m,1H,N CHinpyrrolidine),3.98(m,3H,NH CH 2 inpyrrolidine,ArN (CH 2 ) 2 ),3.88(m,2H,ArN (CH 2 ) 2 ),3.79(t,J＝5.1Hz,2H,CH 2NCH 2inthiomorpholine),3.76-3.65(m,3H,NH CH 2 inpyrrolidine,CH 2NCH 2inthiomorpholine),3.63-3.42(m,4H,CH 2NCH 2inhomopiperazine),3.11(m,1H, CH 2 CHinpyrrolidine),2.85-2.66(m,4H,CH 2SCH 2inthiomorpholine),2.32(m,2H,CH 2 CH 2 CH 2),2.22(m,1H, CH 2 CHinpyrrolidine).
test example part
test example 1, DPP-IV inhibitor in-vitro screening method
reagent:
1. reaction substrate: Gly-Pro-p-nitroanilidehydrochloride (Sigma, G0513), uses ddH 2o is dissolved into 0.026M storage liquid, and-20 DEG C keep in Dark Place.
2.DPP-IV enzyme: recombination human source DPP-IV albumen (Sigma, D4943) ,-20 DEG C of preservations.
3. testing sample: DMSO is dissolved as 10 -2m, 4 DEG C of preservations.
4. positive control drug: Sitagliptin DMSO is dissolved as 10 -2m, 4 DEG C of preservations.
5.2 × Hepesbuffer:1.6gNaCl, 0.074gKCl, 0.027gNa 2hPO 42H 2o, 0.2gGlucose, 1gHepes are dissolved in 90mlddH 2in O, with NaOH adjust pH to 7.05, be settled to 100ml, 0.22 μm of filtration, 4 DEG C of preservations.
In 6.Tis-HClbuffer:6.06gTris to 1L distilled water, with HCl adjust pH to 8.0.
detection method
Sample and positive drug Sitagliptin ddH 2it is 10 that O is diluted to concentration -4the solution of M, DPP-IV Tis/HClbuffer (pH=8.0) preparation, concentration is 2mU/ml.Hepesbuffer (pH=7.05) dilution of substrate Gly-Pro-p-nitroanilide working fluid, concentration is 0.26mM.Experiment sets up negative control group, positive controls and sample sets.Reaction cumulative volume is 100 μ l, and wherein negative control group adds ddH 2o10 μ l, DPP-IV enzyme working fluid 50 μ l and substrate working fluid 40 μ l; Positive controls adds Sitagliptin solution 10 μ l, DPP-IV enzyme working fluid 50 μ l and substrate working fluid 40 μ l; Sample sets adds sample solution 10 μ l, DPP-IV working fluid 50 μ l and substrate working fluid 40 μ l.By monitoring reaction at 37 DEG C, in 60min, absorbancy change under 405nm, carrys out the restraining effect of assess sample to DPP-IV.
The inhibiting rate method of calculation of sample to DPP-IV are as follows:
Inhibiting rate (%)=(Δ OD 60-0negative control group-Δ OD 60-0sample sets)/Δ OD 60-0negative control group × 100%
It is generally acknowledged that positive control Sitagliptin is 10 -5during M, inhibiting rate is that 90-100% can think that this experiment reaction is reliable, and sample inhibiting rate is greater than 40% and thinks effective.
positive compound IC 50 calculating:
1. for first screening, (concentration of testing compound is 10 -5m) activated compound (namely inhibit activities is greater than 50%), arranges different concentration gradient that is 10 -8, 10 -7, 10 -6with 10 -5m carries out DPP-IV Inhibition test.
2. the reaction density of compound and inhibiting rate are drawn concentration-response curve, the fitting formula that statistical procedures obtains, Y is inhibiting rate, X is compound concentration, when Y is 50%, namely reach 50% inhibiting rate active time corresponding compound concentration be the half effective inhibition concentration (IC of this compound 50), test-results is in table 1.
The enzyme level determination of activity result of table 1 embodiment of the present invention compound
Conclusion:
In test-compound, 30 external DPP-IV inhibit activities of embodiment reach more than 50%, and IC 50reach a μM level, 12 example I C 50reach 10 -8mol/L level.Embodiment 14 has the highest external DPP-IV inhibit activities.
test example 2, DPP-IV inhibitor selective evaluation method (DPP8/9 inhibit activities in-vitro evaluation method)
1. reaction substrate: with DPP-IV inhibitor in-vitro screening method.
2.DPP8/9 enzyme: recombination human source DPP8/9 albumen, after purified freeze-drying ,-20 DEG C of preservations.
3. sample: with DPP-IV inhibitor in-vitro screening method.
4. positive control drug: compound (S)-4-(2-amino-(R)-3-methylvaleryl) isoindoline hydrochloride DMSO is dissolved as 10 -2m, 4 DEG C of preservations.
5.2 × Hepesbuffer: with DPP-IV inhibitor in-vitro screening method.
6.Tis/HClbuffer: with DPP-IV inhibitor in-vitro screening method.
evaluation method
Sample and positive drug ddH 2it is 10 that O is diluted to concentration -4the solution of M, Tis/HClbuffer (pH=8.0) preparation of DPP8 enzyme, concentration is 60ng/ml, DPP9 enzyme compound concentration is 40ng/ml.Hepesbuffer (pH=7.05) dilution of substrate Gly-Pro-p-nitroanilide working fluid, concentration is 0.52mM.Experiment sets up negative control group, positive controls and sample sets.Reaction cumulative volume is 100 μ l, and wherein negative control group adds ddH 2o10 μ l, DPP8/9 enzyme working fluid 50 μ l and substrate working fluid 40 μ l; Positive controls adds positive control drug solns 10 μ l, DPP8/9 enzyme working fluid 50 μ l and substrate working fluid 40 μ l; Sample sets adds sample solution 10 μ l, DPP8/9 enzyme working fluid 50 μ l and substrate working fluid 40 μ l.By monitoring reaction at 37 DEG C, in 60min, absorbancy change under 405nm, evaluates the selectivity of DPP-IV inhibitor, i.e. DPP8/9 inhibition.
Selectivity (DPP8/9 inhibition) method of calculation of DPP-IV inhibitor are as follows:
Inhibiting rate (%)=(Δ OD 60-0negative control group-Δ OD 60-0sample sets)/Δ OD 60-0negative control group × 100%
Test-results is in table 2
Inhibiting rate under positive drug same concentrations is 96.7%.
Conclusion:
Tested 6 have DPP-IV inhibit activities compound, there is no obvious inhibit activities to DPP8/9, show that these 6 compounds have high selectivity to DPP-IV.

Claims (9)

1. the compound represented by general formula (I) and a steric isomer thereof, its pharmacologically acceptable salts,
Wherein,
N independently selected from 0,1,2;
X is independently selected from C, N;
Y independently selected from singly-bound, C 1-3alkyl ,-NR 1-,-O-,-S-,-CO-,-SO-,-SO 2-,-CONR 2-,-COO-,-SO 2nR 3-,-SO 2o-,-NR 4cO-,-OCO-,-NR 5sO 2-,-OSO 2-,-NR 6cONR 7-,-NR 8cOO-, wherein R 1, R 1, R 2, R 3, R 4, R 5, R 6, R 7and R 8may be the same or different, be selected from hydrogen and C independently of one another 1-3alkyl;
B ring is independently selected from C 3-6cycloalkyl, is selected from the heteroatomic C of nitrogen, oxygen, sulphur containing 1-2 3-6heterocyclylalkyl, aryl, is selected from the heteroatomic heteroaryl of nitrogen, oxygen, sulphur containing 1-9 carbon atom and 1-4;
R is independently selected from hydrogen, halogen, C 1-3alkyl, C 1-3alkoxyl group, trifluoromethyl, cyano group, nitro, ester group, amino, methylamino-, dimethylamino, hydroxyl, carboxyl, C 3-6cycloalkyl, Heterocyclylalkyl, C 6-10aryl, is selected from the heteroatomic heteroaryl of nitrogen, oxygen, sulphur containing 1-9 carbon atom and 1-4;
Wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are optionally selected from following group by 1-4 (such as 1-3,1-2,1,2 or 3) and replace: hydroxyl, halogen, cyano group, amino, substituted-amino, nitro, trifluoromethyl, trifluoromethoxy, C 1-6alkyl, C 3-7cycloalkyl, C 3-7heterocyclylalkyl, aryl, C 3-7heteroaryl, C 1-6alkyl oxy, C 1-6alkyl formyl radical, C 1-6alkyl oxygen formyl radical, C 3-7cycloalkyl oxy, C 3-7cycloalkyl formyl radical, C 3-7cycloalkyloxy group formyl radical, C 3-7heterocyclylalkyl oxygen base, C 3-7heterocyclylalkyl formyl radical, C 3-7heterocyclylalkyl oxygen formyl radical, aryloxy, aryl formyl radical, aryl oxide formyl radical, C 4-9heteroaryl oxygen base, C 4-9heteroaryl formyl radical, C 4-9heteroaryl oxygen formyl radical;
M is selected from 0,1,2 or 3.
2. compound according to claim 1, its pharmacologically acceptable salts, described compound by shown in general formula (IA),
Wherein,
N independently selected from 0,1,2;
X is independently selected from C, N;
Y independently selected from singly-bound, C 1-3alkyl ,-NR 1-,-O-,-S-,-CO-,-SO-,-SO 2-,-CONR 2-,-COO-,-SO 2nR 3-,-SO 2o-,-NR 4cO-,-OCO-,-NR 5sO 2-,-OSO 2-,-NR 6cONR 7-,-NR 8cOO-, wherein R 1, R 1, R 2, R 3, R 4, R 5, R 6, R 7and R 8may be the same or different, be selected from hydrogen and C independently of one another 1-3alkyl;
B ring is independently selected from C 3-6cycloalkyl, is selected from the heteroatomic C of nitrogen, oxygen, sulphur containing 1-2 3-6heterocyclylalkyl, aryl, is selected from the heteroatomic heteroaryl of nitrogen, oxygen, sulphur containing 1-9 carbon atom and 1-4;
R is independently selected from hydrogen, halogen, C 1-3alkyl, C 1-3alkoxyl group, trifluoromethyl, cyano group, nitro, ester group, amino, methylamino-, dimethylamino, hydroxyl, carboxyl, C 3-6cycloalkyl, Heterocyclylalkyl, C 6-10aryl, is selected from the heteroatomic heteroaryl of nitrogen, oxygen, sulphur containing 1-9 carbon atom and 1-4;
Wherein said alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are optionally selected from following group by 1-4 (such as 1-3,1-2,1,2 or 3) and replace: hydroxyl, halogen, cyano group, amino, substituted-amino, nitro, trifluoromethyl, trifluoromethoxy, C 1-6alkyl, C 3-7cycloalkyl, C 3-7heterocyclylalkyl, aryl, C 3-7heteroaryl, C 1-6alkyl oxy, C 1-6alkyl formyl radical, C 1-6alkyl oxygen formyl radical, C 3-7cycloalkyl oxy, C 3-7cycloalkyl formyl radical, C 3-7cycloalkyloxy group formyl radical, C 3-7heterocyclylalkyl oxygen base, C 3-7heterocyclylalkyl formyl radical, C 3-7heterocyclylalkyl oxygen formyl radical, aryloxy, aryl formyl radical, aryl oxide formyl radical, C 4-9heteroaryl oxygen base, C 4-9heteroaryl formyl radical, C 4-9heteroaryl oxygen formyl radical;
M is selected from 0,1,2 or 3.
3. compound according to any one of claim 1 to 2 and steric isomer thereof, its pharmacologically acceptable salts, in described compound,
N independently selected from 1,2;
X is independently selected from C, N;
Y independently selected from singly-bound, C 1-3alkyl ,-O-,-CO-,-SO 2-,-COO-,-NR 4cO-, wherein R 4independently selected from hydrogen and C 1-3alkyl;
B ring is independently selected from C 3-6cycloalkyl, aryl, is selected from the heteroatomic heteroaryl of nitrogen, oxygen, sulphur containing 1-9 carbon atom and 1-4;
R is independently selected from hydrogen, halogen, C 1-3alkyl, C 1-3alkoxyl group, trifluoromethyl, cyano group, nitro, C 3-6cycloalkyl, C 6-10aryl, is selected from the heteroatomic heteroaryl of nitrogen, oxygen, sulphur containing 1-9 carbon atom and 1-4;
Wherein said alkyl, cycloalkyl, aryl and heteroaryl are optionally selected from following group by 1-4 (such as 1-3,1-2,1,2 or 3) and replace: hydroxyl, halogen, cyano group, amino, substituted-amino, nitro, trifluoromethyl, trifluoromethoxy, C 1-6alkyl, C 1-6alkyl oxy, C 1-6alkyl formyl radical, C 1-6alkyl oxygen formyl radical;
M is selected from 0,1,2 or 3.
4. compound according to claim 3 and steric isomer thereof, its pharmacologically acceptable salts, in described compound,
N independently selected from 1,2;
X is independently selected from C, N;
Y independently selected from singly-bound ,-CH 2-,-O-,-CO-,-SO 2-,-COO-,-NHCO-;
B ring is independently selected from substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted triazol radical, substituted or unsubstituted tetrazole base, Qu generation or do not replace oxadiazolyl, substituted or unsubstituted pyridyl;
R is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxyl group, trifluoromethyl, cyano group, nitro, substituted or unsubstituted cyclopropyl, substituted or unsubstituted phenyl, substituted or unsubstituted tetrazole base; Wherein said cyclopropyl, phenyl and tetrazole base are optionally selected from following group by 1-4 (such as 1-3,1-2,1,2 or 3) and replace: hydroxyl, fluorine, chlorine, bromine, cyano group, amino, substituted-amino, nitro, trifluoromethyl, trifluoromethoxy, C 1-6alkyl, C 1-6alkyl oxy, C 1-6alkyl formyl radical, C 1-6alkyl oxygen formyl radical;
M is selected from 0,1,2 or 3.
5. according to compound and the steric isomer thereof of any one of right 1 to 4, its pharmacologically acceptable salts, it is be selected from following compound:
6. prepare the method for compound described in any one of claim 1 to 5, it comprises the following steps:
Step one:
At the temperature of 10 DEG C to 40 DEG C (such as 10 DEG C to 20 DEG C, 20 DEG C to 30 DEG C or 30 DEG C to 40 DEG C), in acid condition (such as acetic acid), make the compound shown in formula 3a and aliphatic heterocycle amine b react about 2-24 hour, obtain the compound shown in formula c;
Step 2:
At the temperature of 10 DEG C to 40 DEG C (such as 10 DEG C to 35 DEG C, 15 DEG C to 30 DEG C, 20 DEG C to 30 DEG C or 20 DEG C to 25 DEG C); in Hydrochloride/ethyl acetate; make compound shown in formula c remove Boc protecting group, obtain the compounds of this invention shown in formula IA.If with the 3a of racemization for raw material, by above-mentioned steps and method, then obtain the compounds of this invention shown in formula I;
Wherein, the definition of R, X, Y, m and n is as described in any one of claims the 1 to 5.
7. a pharmaceutical composition, its comprise treat and/or prevent significant quantity any one of claim 1 to 5 described in compound and steric isomer thereof, its pharmacologically acceptable salts, and one or more optional pharmaceutically acceptable carriers or vehicle.
8. compound and steric isomer thereof described in any one of claim 1 to 5, its pharmacologically acceptable salts, or pharmaceutical composition described in claim 7 is for the preparation for the treatment of and/or preventing and the purposes in the medicine of the method for DPP-IV hyperactivity or the disease relevant with DPP-IV overexpression or illness.
9. purposes according to claim 8, wherein said with DPP-IV hyperactivity or the disease relevant with DPP-IV overexpression or illness be selected from following disease or illness: diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus (NIDDM), diabetes B.
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