CN102639500B - Tricyclic compound, preparation method and pharmaceutical use thereof - Google Patents

Tricyclic compound, preparation method and pharmaceutical use thereof Download PDF

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Publication number
CN102639500B
CN102639500B CN201180004613.7A CN201180004613A CN102639500B CN 102639500 B CN102639500 B CN 102639500B CN 201180004613 A CN201180004613 A CN 201180004613A CN 102639500 B CN102639500 B CN 102639500B
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base
general formula
azabicyclo
ethyl
methyl
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CN102639500A (en
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杨方龙
董庆
张学军
梁金栋
范江
刘柏年
康思顺
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Abstract

Disclosed is a tricyclic compound represented by a general formula (I), preparation method thereof, pharmaceutical composition comprising the compound and use thereof as an GPR119 agonist and as a medicament for treating diabetes and diseases with metabolic syndrome, wherein the substituent groups in the general formula (I) are as defined in the description.

Description

Tricyclic compound, its preparation method and in application pharmaceutically
Technical field
The present invention relates to a kind of new tricyclic antidepressants derivative, its preparation method and containing the pharmaceutical composition of this derivative and its as therapeutical agent particularly as the purposes of GPR119 agonist and the medicine in the disease of preparation treatment anti-diabetic and metabolic syndrome.
Background technology
A classical symptom of type ii diabetes is the Regular Insulin that the while of going out insulin resistant with patients, pancreatic beta cell cannot secrete q.s.The medicine of clinical treatment type ii diabetes can be divided into two classes based on this point, a kind of medicine being used to the insulin-resistant conditions improving the organ-tissue such as liver, muscle; The second acts on the medicine that pancreatic beta cell promotes its excreting insulin.At present, have developed multiple medicine to be used for realizing this purpose, as glucagon kind polypeptide-1 analogue (GLP-1mimetics), simultaneously because its mechanism of action is glucose dependency, may can not make the symptom of patient from becoming hypoglycemic in clinical treatment use procedure, thus become desirable medicine.To on GLP-1 Research foundation, have developed again DPP IV (DPPIV) inhibitor, also successfully become the medicine for treatment of novel I type i diabetes.Along with research further deeply, especially to the research of pancreatic beta cell excreting insulin process, make a kind of g protein coupled receptor GPR119 become the novel targets of a potential type ii diabetes treatment.
G protein coupled receptor 119 (GPR119) is a kind of orphan receptor found through Human genome sequencing analysis, and its assignment of genes gene mapping, in X chromosome, is mainly expressed in the beta Cell of islet in pancreatic tissue and intestinal cell.After further research, find that Oleoyl monoethanolamide (OEA) and derivative of fatty acid oleoyl lysolecithin are the endogenic ligands of GPR119.By to be combined with GPR119 and exciting GPR119 can improve the intracellular cyclic monophosphate of β (cAMP) concentration, the stimulus-secretion coupling in activated cell, promote flow of calcium ions, thus promote that Regular Insulin vesica is secreted into outside born of the same parents.
The histocyte expression characteristic of GPR119 and function are all pointed out, and activate this receptor and can promote GLP-1 and insulin secretion, contribute to glycemic control.This concept has been used in the pharmaceutical research relevant to diabetes.In testing the isolated perfusion being separated rat Langerhans islet, GPR119 agonist can stimulate first phase and the secretion of the second phase of Regular Insulin, and this promoting insulin secretion has glucose dependency.In addition, GPR119 agonist also can promote mouse intestinal L cell line secretes GLP-1.The therapeutic action of GPR119 agonist to diabetes obtains demonstration in experimentation on animals.The Regular Insulin in blood circulation, GLP-1 and GIP level can be significantly improved to Oral Administration in Rats GPR119 agonist, reduce the blood sugar concentration of rat after accepting carbohydrate tolerance test simultaneously.Give diabetes rat oral GPR119 agonist continued treatment (ZDF rat) every day 4 weeks, its fasting blood glucose level obviously reduces, the tolerance of carbohydrate tolerance test significantly improves, glycated hemoglobin levels significantly improves, significantly increase with insulin content, prompting islet function makes moderate progress simultaneously.Above-mentioned test-results all shows, application GPR119 agonist can improve the diabetic symptom of experimental animal.
As the new formulation for the treatment of type ii diabetes, the main advantage of GPR119 agonist have multiple secretomotor effect to secretin's (comprising GLP-1 and GIP) and pancreas islet.This feature be resistance to DPP-4 degrade GLP-1 analogue and DPP-4 inhibitor not available for.In addition, animal experiment is pointed out, and GPR119 agonist also has the potential controlling body weight.This novel mechanism of action may bring renewal, stronger hypoglycemic effect for treating diabetes, thus contributes to the diversity increasing diabetes drug treatment, with the demand of satisfied different patient.
Disclose the patent application of a series of GPR119 agonist at present, comprising WO2009055331, WO2008070692 and WO2009126535.
Although disclosed the GPR119 agonist of the disease of a series for the treatment of diabetes and metabolic syndrome at present, but still need to develop the new compound with better drug effect, through continuous effort, the present invention's design has the compound of the structure shown in general formula (I), and finds that the compounds exhibit with this class formation goes out excellent effect and effect.
Summary of the invention
The object of the present invention is to provide the compound shown in a kind of general formula (I), and their tautomer, enantiomorph, diastereomer, raceme and pharmaceutically useful salt, and meta-bolites and metabolic precursor thereof or prodrug.
Wherein:
Ring A is selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl, and wherein said cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally selected from halogen, cyano group, nitro, alkyl, thiazolinyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR by one or more independently of one another further 2,-NR 3r 4,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4,-NR 3c (O) R 4,-NR 3s (O) mr 4,-S (O) mr 2or-S (O) mnR 3r 4substituting group replaced;
Ring B is selected from heterocyclic radical, aryl or heteroaryl, and wherein said aryl or heteroaryl are optionally selected from halogen, cyano group, nitro, alkyl, thiazolinyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,=O ,-OR by one or more independently of one another further 2,-(CH 2) mnR 3r 4,-NR 3r 4,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4,-NR 3c (O) R 4,-NR 3s (O) mr 4,-S (O) mr 2or-S (O) mnR 3r 4substituting group replaced;
Ring C is selected from:
L 1be selected from a key or-(CH 2) 1-4-;
L 2be selected from a key or-(CH 2) 1-4-, a wherein arbitrary-CH 2-optional further by one or more O, N (R 7) or S replaced, an or arbitrary-CH 2-optional further by one or more be selected from the substituting group of alkyl or halogen replace;
Work as L 1when being selected from a key, then ring A is aryl or heteroaryl;
R 1be selected from alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) R 2or-C (O) OR 2, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally selected from halogen, cyano group, nitro, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR by one or more independently of one another further 2,-NR 3r 4,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4,-NR 3c (O) R 4,-NR 3s (O) mr 4,-S (O) mr 2or-S (O) mnR 3r 4substituting group replaced;
R 2be selected from hydrogen atom, halogen, cyano group, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, hydroxyalkyl, alkoxyl group, cycloalkyl or heterocyclic radical independently of one another optional further by one or more be selected from the substituting group of halogen, cyano group, nitro, hydroxyl, alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl replace;
R 3and R 4be selected from hydrogen atom, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl independently of one another, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are independent separately is optionally selected from alkyl, halogen, oxo, thiazolinyl, alkynyl, nitro, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR by one or more further 7,-NR 8r 9,-C (O) R 7,-C (O) OR 7,-C (O) NR 8r 9,-NR 8c (O) R 9,-NR 8s (O) mr 9,-S (O) mr 7or-S (O) mnR 8r 9substituting group replaced;
Or, R 3and R 4heterocyclic radical is formed, containing one or more N, O or S (O) in wherein said heterocyclic radical with the nitrogen-atoms be connected mheteroatoms, and described heterocyclyl is selected from alkyl, halogen, oxo, thiazolinyl, alkynyl, nitro, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR by one or more further 7,-NR 8r 9,-C (O) R 7,-C (O) OR 7,-C (O) NR 8r 9,-NR 8c (O) R 9,-NR 8s (O) mr 9,-S (O) mr 7or-S (O) mnR 8r 9substituting group replaced;
R 5be selected from hydrogen atom or alkyl;
R 6be selected from hydrogen atom, alkyl, halogen, haloalkyl, thiazolinyl, alkynyl, nitro, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 2,-NR 3r 4,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4,-NR 3c (O) R 4,-NR 3s (O) mr 4,-S (O) mr 2or-S (O) mnR 3r 4; Or two R 6form oxo together;
R 7, R 8and R 9independently be selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately;
Z be selected from singly-bound, double bond ,-C (O)-,-C=C (R 7) ,-O-,-N (R 7)-or-C (O)-N (R 7)-, is when q is 0, and Z can not be double bond;
M is 0,1 or 2;
P is 0,1 or 2;
Q is 0,1 or 2;
R is 0,1 or 2;
S is 0,1 or 2; And
U is 0,1 or 2.
The present invention relates to the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, comprising the compound shown in general formula (II) or its pharmaceutically useful salt:
Wherein:
Ring A is selected from:
Ring B is selected from:
R 10be selected from halogen, cyano group, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or-OR identical or differently 2;
R 11be selected from hydrogen atom, halogen, cyano group, nitro, alkyl, thiazolinyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 2,-NR 3r 4,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4,-NR 3c (O) R 4,-NR 3s (O) mr 4,-S (O) mr 2or-S (O) mnR 3r 4;
L 1, L 2, R 1~ R 5definition as described in general formula (I) compound;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is 0,1 or 2; And
Q is 0,1 or 2.
The present invention relates to the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, comprising the compound shown in general formula (III) or its pharmaceutically useful salt:
Wherein:
Ring A is selected from:
Ring B is selected from:
R 10be selected from halogen, cyano group, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or-OR identical or differently 2;
R 11be selected from hydrogen atom, halogen, cyano group, nitro, alkyl, thiazolinyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 2,-NR 3r 4,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4,-NR 3c (O) R 4,-NR 3s (O) mr 4,-S (O) mr 2or-S (O) mnR 3r 4;
Z be selected from singly-bound, double bond ,-C (O)-,-C=C (R 7) ,-O-,-N (R 7)-or-C (O)-N (R 7)-, is when q is 0, and Z can not be double bond;
L 1, L 2, R 1~ R 4, R 7definition as described in general formula (I) compound;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is 0,1 or 2; And
U is 0,1 or 2.
The present invention relates to the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, comprising the compound shown in general formula (IV) or its pharmaceutically useful salt:
Wherein:
Ring A is selected from:
Ring B is selected from:
R 10be selected from halogen, cyano group, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or-OR identical or differently 2;
R 11be selected from hydrogen atom, halogen, cyano group, nitro, alkyl, thiazolinyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 2,-NR 3r 4,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4,-NR 3c (O) R 4,-NR 3s (O) mR 4,-S (O) mR 2or-S (O) mNR 3r 4;
L 1, L 2, R 1~ R 5definition as described in general formula (I) compound;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is that 0,1 or 2, p and q additions are at least 1;
Q is 0,1 or 2;
R is that 0,1 or 2, r and s additions are at least 1; And
S is 0,1 or 2.
The present invention relates to the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, comprising the compound shown in logical formula V or its pharmaceutically useful salt:
Wherein:
Ring A is selected from:
Ring B is selected from:
R 1for heteroaryl, wherein said heteroaryl optional further by one or more be selected from the substituting group of halogen, alkyl or haloalkyl replace;
R 10for halogen;
R 11be selected from hydrogen atom, halogen, cyano group, alkyl ,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4,-NR 3c (O) R 4,-NR 3s (O) mR 4,-S (O) mR 2or-S (O) mNR 3r 4;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
R 2~ R 4definition as described in general formula (II) compound.
The present invention relates to the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, comprising the compound shown in general formula (VI) or its pharmaceutically useful salt:
Wherein: ring B, R 1, R 10or the definition of n is as described in logical formula V compound.
The present invention relates to the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, comprising the compound shown in general formula (VII) or its pharmaceutically useful salt:
Wherein: ring B, R 1, R 10or the definition of n is as described in logical formula V.
The present invention relates to the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, comprising the compound shown in general formula (VIII) or its pharmaceutically useful salt:
Wherein: ring B, R 1, R 10or the definition of n is as described in logical formula V.
Preferred version of the present invention, the compound shown in a kind of general formula (VII) or its pharmaceutically useful salt, wherein ring B is phenyl.
Preferred version of the present invention, the compound shown in a kind of general formula (VIII) or its pharmaceutically useful salt, wherein ring B is
r 10for halogen, n is 0,1,2,3 or 4.
Preferred version of the present invention, a kind of general formula (VII) or the compound described in general formula (VIII) or its pharmaceutically useful salt, wherein:
R 11be selected from hydrogen atom, halogen, cyano group, alkyl ,-C (O) R 2,-C (O) NR 3r 4,-C (O) OR 2,-S (O) mR 2;
M is 0,1 or 2.
Preferred version of the present invention, a kind of general formula (VII) or the compound described in general formula (VIII) or its pharmaceutically useful salt, wherein R 11for-S (O) mR 2, m is 1 or 2.
Preferred version of the present invention, the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein ring A is heterocyclic radical, aryl or heteroaryl.
Preferred version of the present invention, the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein ring A is heterocyclic radical, aryl or heteroaryl, and ring A is optionally selected from halogen, cyano group ,-C (O) R by one or more 2,-C (O) NR 3r 4,-C (O) OR 2or-S (O) mr 2substituting group replaced.
Preferred version of the present invention, the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein ring A is heterocyclic radical or heteroaryl, and ring A is optionally by-a S (O) mr 2replace, m is 1 or 2.
Preferred version of the present invention, the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein ring A optionally by one or more cyano group or halogen replace.
Preferred version of the present invention, a kind of general formula (I), (II), (III) or the compound shown in (IV) or its pharmaceutically useful salt, wherein L 1be key or-a CH 2-.
Preferred version of the present invention, a kind of general formula (I), (II), (III) or the compound shown in (IV) or its pharmaceutically useful salt, wherein L 2for-O-,-CH 2-,-N (R 7)-CH 2-or-O-CH 2-.
Preferred version of the present invention, a kind of general formula (I), (II), (III) or the compound shown in (IV) or its pharmaceutically useful salt, wherein R 1for-C (O) OR 2.
Preferred version of the present invention, a kind of general formula (I), (II), (III) or the compound shown in (IV) or its pharmaceutically useful salt, wherein R 1for:
Preferred version of the present invention, a kind of general formula (I), (II), (III) or the compound shown in (IV) or its pharmaceutically useful salt, wherein R 1for alkyl or heteroaryl, wherein said alkyl or heteroaryl optional further by one or more be selected from the substituting group of halogen, hydroxyl, alkyl or haloalkyl replace.
Preferred version of the present invention, a kind of general formula (I), (II), (III) or the compound shown in (IV) or its pharmaceutically useful salt, wherein R 1for
R 10the substituting group being selected from halogen, alkyl, cycloalkyl or haloalkyl replaced identical or differently; And
N is 0,1,2,3 or 4.
Preferred version of the present invention, the compound shown in a kind of general formula (II) or its pharmaceutically useful salt, wherein p and q is 0 or 1.
Preferred version of the present invention, the compound shown in a kind of general formula (III) or its pharmaceutically useful salt, wherein Z is selected from singly-bound or-an O-.
Typical compound of the present invention includes, but are not limited to:
Or its pharmaceutically useful salt.
The present invention relates to the method that one prepares the compound or pharmaceutically acceptable salt thereof shown in general formula (I), the method comprises:
General formula (IA) compound and general formula (IB) compound are reacted, obtains general formula (I) compound;
Wherein: PG is leavings group, halogen or alkylsulfonyl is preferably;
Ring A, ring B, ring C, R 1, L 1and L 2definition consistent with general formula (I) compound.
The present invention relates to the method that one prepares the compound or pharmaceutically acceptable salt thereof shown in general formula (I), the method comprises:
General formula (IC) compound and general formula (ID) compound are reacted under the condition of palladium class catalyzer, obtains general formula (I) compound;
Wherein: L 1it is a key; X is halogen; Ring A, ring B, ring C, R 1and L 2definition consistent with general formula (I) compound.
The present invention relates to the preparation method that one prepares the compound or its salt described in general formula (I), comprise the following steps:
Be there is nucleophilic substitution reaction in the basic conditions in general formula (IE) compound and general formula (IF) compound, obtain general formula (I) compound.
Wherein: PG is leavings group, halogen or alkylsulfonyl is preferably;
Ring A, ring B, ring C, R 1, L 1and L 2definition consistent with general formula (I) compound.
The present invention relates to the preparation method that one prepares the compound or its salt described in general formula (I), comprise the following steps:
General formula compound (IH) and compound (IJ) carry out Suzuki reaction, obtain general formula (I) compound.
Wherein: L 1it is a key; X is halogen; Ring A, ring B, ring C, R 1and L 2definition consistent with general formula (I) compound.
Another aspect of the present invention relates to the compound shown in general formula (I) or the purposes of its pharmaceutically useful salt in preparation GPR119 agonist.
Another aspect of the present invention relates to the compound shown in general formula (I) or its pharmaceutically useful salt, as the medicine of GPR119 agonist.
The invention still further relates to the compounds of this invention or the purposes of its pharmaceutically useful salt in the medicine of disease preparing treatment diabetes and metabolic syndrome.
The invention still further relates to the compounds of this invention or its pharmaceutically useful salt medicine as the disease for the treatment of diabetes and metabolic syndrome.
Further, another aspect of the present invention relates to a kind of pharmaceutical composition, and it contains the compound shown in general formula (I) or its pharmaceutically useful salt and pharmaceutically useful carrier thereof or vehicle for the treatment of effective dose.This pharmaceutical composition is used as the medicine of GPR119 agonist.The purposes of this pharmaceutical composition in preparation treatment GPR119 agonist.This pharmaceutical composition preparation treatment diabetes and metabolic syndrome disease medicine in purposes.Said composition is as the medicine of disease for the treatment of diabetes and metabolic syndrome.
Another aspect of the present invention relates to a kind of method for the treatment of the disease of diabetes and metabolic syndrome, the method comprises the compound shown in general formula (I) or its pharmaceutically useful salt of the effective therapeutic dose of patient giving needs treatment, or contains the pharmaceutical composition of the compound shown in general formula (I) or its pharmaceutically useful salt.
Another aspect of the present invention relates to as the compound shown in the general formula (I) of the medicine of the disease for the treatment of diabetes and metabolic syndrome or its pharmaceutically useful salt, or contains the pharmaceutical composition of the compound shown in general formula (I) or its pharmaceutically useful salt.
Another aspect of the present invention relates to a kind of method regulating Regular Insulin, the method comprises the compound shown in general formula (I) or its pharmaceutically useful salt of the effective therapeutic dose of patient giving needs treatment, or contains the pharmaceutical composition of the compound shown in general formula (I) or its pharmaceutically useful salt.
Another aspect of the present invention relates to as the compound shown in the general formula (I) of the medicine regulating Regular Insulin or its pharmaceutically useful salt, or contains the pharmaceutical composition of the compound shown in general formula (I) or its pharmaceutically useful salt.
detailed description of the invention
Unless stated to the contrary, otherwise following use term in the specification and in the claims has following implication.
" alkyl " refers to saturated aliphatic hydrocarbon group, comprises straight chain and the branched group of 1 to 20 carbon atom.Alkyl preferably containing 1 to 12 carbon atom, non-limiting example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1,1,2-thmethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethyl amyl group, 2,4-dimethyl amyl group, 2,2-dimethyl amyl group, 3,3-dimethyl amyl group, 2-ethyl pentyl group, 3-ethyl pentyl group, n-octyl, 2,3-dimethylhexanyl, 2,4-dimethylhexanyl, 2,5-dimethylhexanyl, 2,2-dimethylhexanyl, 3,3-dimethylhexanyl, 4,4-dimethylhexanyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethyl amyl group, positive decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers etc.Low alkyl group more preferably containing 1 to 6 carbon atom, non-limiting example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1, 1-dimethyl propyl, 1, 2-dimethyl propyl, 2, 2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1, 1, 2-thmethylpropyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2, 3-dimethylbutyl etc.Alkyl can be replacement or unsubstituted, when substituted, substituting group can be substituted on any spendable tie point, be preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio, oxo ,-OR 2,-NR 3r 4,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4,-NR 3c (O) R 4,-NR 3s (O) mr 4,-S (O) mr 2or-S (O) mnR 3r 4.
" cycloalkyl " refers to the unsaturated monocycle of saturated or part or many rings cyclic hydrocarbon substituent, and it comprises 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, and more preferably cycloalkyl ring comprises 3 to 10 carbon atoms.The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc.Polycyclic naphthene base comprises the cycloalkyl of volution, condensed ring and bridged ring.
" spiro cycloalkyl group " refers to 5 to 20 yuan, and share the polycyclic moiety of a carbon atom (title spiro atom) between monocycle, these can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, be more preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, two spiro cycloalkyl group base or many spiro cycloalkyl group by the number according to sharing spiro atom between ring and ring, is preferably single spiro cycloalkyl group and two spiro cycloalkyl group.Be more preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises
" cycloalkyl " refers to 5 to 20 yuan, each ring in system and other rings in system share the full carbon polycyclic moiety of a pair carbon atom adjoined, wherein one or more rings can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, be more preferably 7 to 10 yuan.Dicyclo, three rings, Fourth Ring or polycyclic fused ring alkyl can be divided into according to the number of makeup ring, be preferably dicyclo or three rings, be more preferably 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic alkyls.The non-limiting example of cycloalkyl comprises
" bridge ring alkyl " refers to 5 to 20 yuan, and any two rings share the full carbon polycyclic moiety of two carbon atoms directly do not connected, and these can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, be more preferably 7 to 10 yuan.Dicyclo, three rings, Fourth Ring or many rings bridge ring alkyl can be divided into according to the number of makeup ring, be preferably dicyclo, three rings or Fourth Ring, more elect dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises
Described cycloalkyl ring can condense on aryl, heteroaryl or heterocycloalkyl ring, and the ring wherein linked together with precursor structure is cycloalkyl, and non-limiting example comprises indanyl, tetralyl, benzocyclohepta alkyl etc.Cycloalkyl can be optional replacement or unsubstituted, when substituted, substituting group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio, oxo ,-OR 2,-NR 3r 4,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4,-NR 3c (O) R 4,-NR 3s (O) mr 4,-S (O) mr 2or-S (O) mnR 3r 4.
" thiazolinyl " refers to the alkyl as defined above be made up of at least two carbon atoms and at least one carbon-to-carbon double bond.Such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl etc.Thiazolinyl can be replacement or unsubstituted, when substituted, substituting group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio ,-OR 2,-NR 3r 4,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4,-NR 3c (O) R 4,-NR 3s (O) mr 4,-S (O) mr 2or-S (O) mnR 3r 4.
" alkynyl " refers to the alkyl as defined above of at least two carbon atoms and at least one carbon-to-carbon triple bond composition.Such as ethynyl, 1-proyl, 2-propynyl, 1-, 2-or 3-butynyl etc.Alkynyl can be replacement or unsubstituted, when substituted, substituting group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio ,-OR 2,-NR 3r 4,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4,-NR 3c (O) R 4,-NR 3s (O) mr 4,-S (O) mr 2or-S (O) mnR 3r 4.
" heterocyclic radical " refers to the unsaturated monocycle of saturated or part or many rings cyclic hydrocarbon substituent, and it comprises 3 to 20 annular atomses, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) mthe heteroatoms of (wherein m is integer 0 to 2), but do not comprise the loop section of-O-O-,-O-S-or-S-S-, all the other annular atomses are carbon.Preferably include 3 to 12 annular atomses, wherein 1 ~ 4 is heteroatoms, and more preferably cycloalkyl ring comprises 3 to 10 annular atomses.The non-limiting example of monocyclic cycloalkyl comprises pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base, 1,2,3,6-tetrahydro pyridyl etc.Polycyclic naphthene base comprises the heterocyclic radical of volution, condensed ring and bridged ring." spiro heterocyclic radical " refers to 5 to 20 yuan, and share the polycyclic heterocyclic group of an atom (title spiro atom) between monocycle, wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) pthe heteroatoms of (wherein p is integer 0 to 2), all the other annular atomses are carbon.These can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, be more preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiro heterocyclic radical, two spiro heterocyclic radical or many spiro heterocyclic radicals by the number according to sharing spiro atom between ring and ring, is preferably single spiro cycloalkyl group and two spiro cycloalkyl group.Be more preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises
" fused heterocycle base " refers to 5 to 20 yuan, each ring in system and other rings in system share the polycyclic heterocyclic group of a pair atom adjoined, one or more ring can contain one or more double bond, but neither one ring has the π-electron system of total conjugated, wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) pthe heteroatoms of (wherein p is integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, be more preferably 7 to 10 yuan.Dicyclo, three rings, Fourth Ring or many rings fused heterocycloalkyl can be divided into according to the number of makeup ring, be preferably dicyclo or three rings, be more preferably 5 yuan/5 yuan or 5 yuan/6 yuan fused bicyclic heterocycle bases.The non-limiting example of fused heterocycle base comprises
" bridge heterocyclic radical " refers to 5 to 14 yuan, any two rings share the polycyclic heterocyclic group of the atom that two directly do not connect, these can contain one or more double bond, but neither one ring has the π-electron system of total conjugated, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) mthe heteroatoms of (wherein m is integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, be more preferably 7 to 10 yuan.7 to 10 yuan.Dicyclo, three rings, Fourth Ring or many rings bridge ring alkyl can be divided into according to the number of makeup ring, be preferably dicyclo, three rings or Fourth Ring, more elect dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises:
Described heterocyclic ring can condense on aryl, heteroaryl or cycloalkyl ring, and the ring wherein linked together with precursor structure is heterocyclic radical, and non-limiting example comprises:
Deng.Heterocyclic radical can be optional replacement or unsubstituted, when substituted, substituting group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio, oxo ,-OR 2,-NR 3r 4,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4,-NR 3c (O) R 4,-NR 3s (O) mr 4,-S (O) mr 2or-S (O) mnR 3r 4.
" aryl " refers to 6 to 14 yuan of full carbon monocycles or fused polycycle (namely sharing the right ring of adjacent carbon atoms) group, there is many rings (namely it is with the ring of the phase adjacency pair carbon atom) group of the π-electron system of conjugation, be preferably 6 to 10 yuan, such as phenyl and naphthyl.Described aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is aryl rings, and non-limiting example comprises:
Aryl can be replacement or unsubstituted, when substituted, substituting group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio ,-OR 2,-NR 3r 4,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4,-NR 3c (O) R 4,-NR 3s (O) mr 4,-S (O) mr 2or-S (O) mnR 3r 4.
" heteroaryl " refers to comprise 1 to 4 heteroatoms, the heteroaromatic system of 5 to 14 annular atomses, and wherein heteroatoms comprises oxygen, sulphur and nitrogen.Be preferably 5 to 10 yuan.Heteroaryl is preferably 5 yuan or 6 yuan, such as furyl, thienyl, pyridyl, pyrryl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, tetrazyl etc.Described heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is heteroaryl ring, and non-limiting example comprises:
Heteroaryl can be optional replacement or unsubstituted, when substituted, substituting group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio ,-OR 2,-NR 3r 4,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4,-NR 3c (O) R 4,-NR 3s (O) mr 4,-S (O) mr 2or-S (O) mnR 3r 4.
" alkoxyl group " refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), and wherein the definition of alkyl is described above.Non-limiting example comprises methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.Alkoxyl group can be optional replacement or unsubstituted, when substituted, substituting group is preferably one or more following group, independently selected from being alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio ,-OR 2,-NR 3r 4,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4,-NR 3c (O) R 4,-NR 3s (O) mr 4,-S (O) mr 2or-S (O) mnR 3r 4.
" haloalkyl " refers to that alkyl is by one or more halogen substiuted.
" hydroxyl " refers to-OH group.
" hydroxyalkyl " refers to that alkyl is optionally substituted by a hydroxyl group.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" amino " refers to-NH 2.
" cyano group " refers to-CN.
" nitro " refers to-NO 2.
" benzyl " refers to-CH 2-phenyl.
" oxo " refers to=O.
" carboxylic acid " refers to-C (O) OH.
" carboxylicesters " refers to-C (O) O (alkyl) or (cycloalkyl).
" optionally " or " optionally " mean subsequently described ground event or environment can but need not occur, this explanation comprises this event or environment occurs or not spot occasion.Such as, " optionally by heterocyclic group that alkyl replaces " mean alkyl can but must not exist, this explanation comprises situation that heterocyclic group replaced by alkyl and heterocyclic group not by situation that alkyl replaces.
" replacement " refers to the one or more hydrogen atoms in group, is preferably maximum 5, is more preferably 1 ~ 3 hydrogen atom and is replaced by the substituting group of respective number independently of one another.Self-evident, substituting group is only in their possible chemical position, those skilled in the art can determine when not paying and too much making great efforts (by experiment or theoretical) may or impossible replacement.Such as, have the amino of free hydrogen or hydroxyl and the carbon atom with unsaturated (as olefinic) key in conjunction with time may be unstable.
" pharmaceutical composition " represent containing on one or more compounds described herein or its physiology/mixture of pharmaceutically useful salt or prodrug and other chemical compositions, and other components such as physiology/pharmaceutically useful carrier and vehicle.The object of pharmaceutical composition promotes the administration to organism, is beneficial to the absorption of activeconstituents and then plays biological activity.
M and R 2~ R 4definition as described in general formula (I) compound.
the synthetic method of the compounds of this invention
In order to complete object of the present invention, the present invention adopts following technical scheme:
The preparation method of the compound or its salt described in general formula of the present invention (I), comprises the following steps:
General formula (IG) compound and SULPHURYL CHLORIDE are reacted, obtains general formula (IB) compound of alkylsulfonyl protection; Sulphonate is formed see R.K.Crossland and K.L.Servis, J.Org.Chem., 1970,35,3195-3196 about by its corresponding alcohol; Or by general formula (IG) halogenations, obtain general formula (IB) compound;
Be there is nucleophilic substitution reaction in the basic conditions in general formula (IA) compound and general formula (IB) compound, obtain general formula (I) compound; There is provided the reagent of alkaline condition to include but not limited to carbonate, be preferably salt of wormwood or cesium carbonate.About the reaction conditions of sulphonate displacement, see P.J.Gilligan etc., J.Med.Chem., 1992,35,4344-4361.
When PG is hydroxyl ,-L 2when H group is also containing hydroxyl, there is Mitsunobu and react in general formula (IA) compound and general formula (IB) compound, obtain formula (I) compound under the existence of triphenylphosphine and diisopropyl azodiformate; About Mitsunobu reaction summary see D.L.Hughes Organic Reactions, 42,335.
There is nucleophilic substitution reaction in compound a and compound b, obtain general formula (IA) compound, compound a is nucleophilic reagent, containing nucleophilic group.
When L1 is a chemical bond, the preparation method of general formula (IA) compound obtains optionally through following two kinds of flow processs preparation: compound c and compound d, under palladium class catalyst, is preferably Pd (PPh 3) 4or PdCl 2(PPh 3) 2, there is Suzuki coupled reaction in the basic conditions, obtain general formula (IA) compound; Adjacent similar, also there is Suzuki coupled reaction in Verbindung and compound f, obtains general formula (IA) compound; Above-mentioned Suzuki coupled reaction occurs between the aryl boric acid of replacement or the aryl bromide of heteroaryl-boronic acids and replacement or hetaryl halogenides (bromide or muriate), obtains general formula (IA) compound; About Suzuki reaction conditions, see N.Miyaura and A.Suzuki, Chem.Rev., 1995,95,2457-2483; A.Suzuki, J.Organometallic Chem.1999,576,147-168.
Wherein: PG is leavings group, halogen or alkylsulfonyl is preferably;
Ring A, ring B, ring C, R 1, L 1and L 2definition consistent with general formula (I) compound.
The preparation method of the compound or its salt described in general formula of the present invention (I), comprises the following steps:
General formula (IC) compound and general formula (ID) compound are reacted in the basic conditions, obtains general formula (I) compound; About Suzuki reaction conditions, see N.Miyaura and A.Suzuki, Chem.Rev., 1995,95,2457-2483; A.Suzuki, J.Organometallic Chem.1999,576,147-168.General formula (IC) compound by compound g and compound h, nucleophilic substitution reaction can occur in the basic conditions to be prepared and obtains.
Wherein: L 1it is a key; X is halogen; Ring A, ring B, ring C, R 1and L 2definition consistent with general formula (I) compound.
The preparation method of the compound or its salt described in general formula of the present invention (I), comprises the following steps:
Be there is nucleophilic substitution reaction in the basic conditions in general formula (IE) compound and general formula (IF) compound, obtain general formula (I) compound; There is provided the reagent of alkaline condition to include but not limited to carbonate, be preferably salt of wormwood or cesium carbonate.About the reaction conditions of sulphonate displacement, see P.J.Gilligan etc., J.Med.Chem., 1992,35,4344-4361.General formula (IE) compound by compound j and compound k, nucleophilic substitution reaction can occur in the basic conditions to be prepared and obtains.
Wherein: PG is identical or different, be leavings group, be preferably halogen or alkylsulfonyl;
Ring A, ring B, ring C, R 1, L 1and L 2definition consistent with general formula (I) compound.
The preparation method of the compound or its salt described in general formula of the present invention (I), comprises the following steps:
Compound (IC) and connection boric acid pinacol ester, under the catalysis of two (diphenyl phosphine) ferrocene palladium chloride, obtain compound (IH); Compound (IH) and compound (IJ) carry out Suzuki reaction, obtain general formula (I) compound.
Wherein: L 1it is a key; X is halogen; Ring A, ring B, ring C, R 1and L 2definition consistent with general formula (I) compound.
The preparation method of the compound or its salt described in general formula of the present invention (I), comprises the following steps:
Compound m sloughs tert-butoxycarbonyl under the acidic conditions of trifluoracetic acid or hydrochloric acid, obtains compound n; Compound n is optional to react with various electrophilic reagent, and electrophilic reagent includes but not limited to: 1) alpha-halogen heteroaryl, reacting by heating under alkaline condition; 2) methyl-chloroformate; 3) benzylic halides or substituting group halogenide; 4) acyl chlorides and SULPHURYL CHLORIDE; 5) isocyanic ester and lsothiocyanates.Can carry out under condition well known to a person skilled in the art in the solvent be applicable to is as methylene dichloride, chloroform, tetrahydrofuran (THF), acetonitrile or dimethyl sulfoxide (DMSO) with the reaction of electrophilic reagent.
Compound n also can with cyanogen bromide reaction, obtain corresponding cyano group sulfonamide derivatives, this cyano group sulfonamide derivatives can be further converted to heterocycle, and Bao draws together but Bu Xian Yu oxadiazole.
Wherein: ring A, ring B, ring C, R 1, L 1and L 2definition consistent with general formula (I) compound.
Embodiment
Be used for further describing the present invention below in conjunction with embodiment, but these embodiments not limit scope of the present invention.
Embodiment
The structure of compound by nucleus magnetic resonance (NMR) or/and mass spectrum (MS) is determined.NMR displacement (δ) is with 10 -6(ppm) unit provides.The mensuration of NMR is that measuring solvent is deuterated dimethyl sulfoxide (DMSO-d with Bruker AVANCE-400 nuclear magnetic resonance spectrometer 6), deuterochloroform (CDCl 3), deuterated methanol (CD 3oD), tetramethylsilane (TMS) is inside designated as.
The mensuration of MS is with FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
The mensuration of HPLC uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 × 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 × 4.6mm chromatographic column).
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, and the specification that the silica-gel plate that tlc (TLC) uses adopts is 0.15mm ~ 0.2mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm ~ 0.5mm.
Column chromatography generally uses Yantai Huanghai Sea silica gel 200 ~ 300 order silica gel to be carrier.
Known starting raw material of the present invention can adopt or synthesize according to methods known in the art, maybe can buy from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, splendid far away chemistry science and technology (Accela ChemBio Inc), reach the companies such as auspicious chemical.
Argon atmospher or nitrogen atmosphere refer to that reaction flask connects argon gas or the nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.
Pressure hydration reaction uses Parr 3916EKX type hydrogenation instrument and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument.
Hydrogenation vacuumizes usually, is filled with hydrogen, repeatable operation 3 times.
Microwave reaction uses CEM Discover-S 908860 type microwave reactor.
Without specified otherwise in embodiment, react and carry out under nitrogen atmosphere or argon atmospher.
Without specified otherwise in embodiment, solution refers to the aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature.
Room temperature is optimum temperature of reaction, is 20 DEG C ~ 30 DEG C.
The monitoring of the reaction process in embodiment adopts tlc (TLC), the system of reacting the developping agent used has: methylene dichloride and methanol system, normal hexane and ethyl acetate system, the volume ratio of solvent regulates according to the polarity difference of compound.
The system of eluent of the column chromatography that purifying compounds adopts and the developping agent system of tlc comprise: A: methylene dichloride and methanol system, B: normal hexane and ethyl acetate system, the volume ratio of solvent is different and regulate according to the polarity of compound, also can add the alkalescence such as a small amount of triethylamine and acetic acid or acid reagent regulates.
Embodiment 1,2
Trans-(3aR, 6aS)-5-[the bromo-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
Cis-(3aR, 6aS)-5-[the bromo-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
The first step
(3aR, 6aS)-1,2,3,3a, 4,5,6,6a-octahydro cyclopentano [c] pyrroles-5-alcohol
Under ice bath, by cis-(3aR, 6aS)-5-hydroxyl-3,3a, 4,5,6,6a-, six hydrogen-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 1a (2.20g, 0.01mol, known method " Bioorganic & Medicinal Chemistry Letters (2010); 20 (5), 1674-1676 " is adopted to prepare and obtain) be dissolved in 20mL methylene dichloride, be added dropwise to the 4M methanol hydrochloride solution of 30mL, rise to room temperature, stirring reaction 12 hours.Concentrating under reduced pressure reaction solution, obtains crude title product (3aR, 6aS)-1,2,3,3a, 4,5,6,6a-octahydro cyclopentano [c] pyrroles-5-alcohol 1b (1.50g, yellow solid), and product is not purified directly carries out next step reaction.
Second step
(3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-5-alcohol
By crude product (3aR, 6aS)-1,2,3,3a, 4,5,6,6a-octahydro cyclopentano [c] pyrroles-5-alcohol 1b (1.50g, 9.20mmol) be dissolved in 20mL N, in N-N,N-DIMETHYLACETAMIDE, add the chloro-5-ethyl-pyrimidin (1.30g, 9.20mmol) of 2-and salt of wormwood (2.50g successively, 18.40mmol), 150 DEG C of stirring reactions 12 hours are risen to.Filter, add 50mL water, be extracted with ethyl acetate (50mL × 3), merge organic phase, use water (20mL × 3) successively, saturated ammonia chloride solution (40mL × 3) washing, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtains crude title product (3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-5-alcohol 1c (2.20g, yellow liquid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：234.1[M+1]
3rd step
[(3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-5-base] methylsulfonic acid acid anhydride
Under ice bath, by crude product (3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-5-alcohol 1c (1.80g, 7.70mmol) is dissolved in 20mL anhydrous methylene chloride, add triethylamine (2mL, 14.50mmol), methylsulfonyl chloride (0.65mL, 8.50mmol) is added dropwise to, rise to room temperature, stirring reaction 12 hours.Add saturated sodium bicarbonate solution 30mL, dichloromethane extraction (10mL × 3), merge organic phase, use water (20mL × 3) successively, saturated nacl aqueous solution (20mL × 3) washs, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, obtain crude title product cis-[(3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-5-base] methylsulfonic acid acid anhydride 1d (1.60g, yellow solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：312.1[M+1]
4th step
4-Nmethanesulphonylpiperazine-1-carboxylic acid tert-butyl ester
Under ice bath, by piperazine-1-carboxylic acid tert-butyl ester (40g, 22mmol) be dissolved in 300mL anhydrous methylene chloride, add triethylamine (61mL, 44mmol), be added dropwise to containing methylsulfonyl chloride (29.60g, 25.80mmol) dichloromethane solution, rise to room temperature after dropwising, stirring reaction 12 hours, separates out a large amount of solid.Filter; filtrate is washed with saturated ammonium chloride solution (100mL × 3); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; obtain crude title product 4-Nmethanesulphonylpiperazine-1-carboxylic acid tert-butyl ester 1e (52g, white solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：165.1[M+1-100]
5th step
1-Nmethanesulphonylpiperazine
Under ice bath, be dissolved in 40mL methylene dichloride by 4-Nmethanesulphonylpiperazine-1-carboxylic acid tert-butyl ester 1e (4g, 1.50mmol), be added dropwise to 40mL 4M methanol hydrochloride solution, rise to room temperature, stirring reaction 12 hours, separates out a large amount of solid.Filter, obtain crude title product 1-Nmethanesulphonylpiperazine 1f (2.90g, white solid), product is not purified directly carries out next step reaction.
6th step
The bromo-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenol
By crude product 1-Nmethanesulphonylpiperazine 1f (400mg; 2mmol) be dissolved in 10mL ethylene dichloride, add the bromo-4-hydroxy-benzaldehyde (402mg, 2mmol) of 3-and sodium triacetoxy borohydride (848mg successively; 4mmol), 80 DEG C of stirring reactions 5 hours are risen to.Add 10mL saturated sodium bicarbonate solution adjust ph to 9; dichloromethane extraction (20mL × 3); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system A, obtains the bromo-4-of title product 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenol 1g (300mg; white solid), productive rate: 43.0%.
MS m/z(ESI)：348.6[M+1]
7th step
Trans-(3aR, 6aS)-5-[the bromo-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
Cis-(3aR, 6aS)-5-[the bromo-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
By bromo-for 2-4-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenol 1g (500mg; 1.44mmol) with crude product cis-[(3aR; 6aS)-2-(5-ethyl-pyrimidine-2-base)-3; 3a; 4; 5; 6; 6a-six hydrogen-1H-cyclopentano [c] pyrroles-5-base] methylsulfonic acid acid anhydride 1d (536mg; 1.72mmol) be dissolved in 10mL acetonitrile, then add cesium carbonate (936mg, 2.88mmol); rise to 80 DEG C of stirring reactions 4 hours, then 50 DEG C are reacted 12 hours.Filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain a pair diastereomer product, trans-(3aR respectively, 6aS)-5-[the bromo-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3, 3a, 4, 5, 6, 6a-six hydrogen-1H-cyclopentano [c] pyrroles 1 (300mg, white solid), cis-(3aR, 6aS)-5-[the bromo-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3, 3a, 4, 5, 6, 6a-six hydrogen-1H-cyclopentano [c] pyrroles 2 (8mg, white solid).
MS m/z(ESI)：564.1[M+1]
1 1H NMR(400MHz，CDCl 3)δ8.18(d，2H)，7.51(d，1H)，7.15(d，1H)，6.82(d，1H)，4.96-4.95(m，1H)，3.75-3.70(m，2H)，3.54-3.50(m，2H)，3.46(s，2H)，3.25(s，4H)，3.10-3.09(m，2H)，2.78(s，3H)，2.54(s，4H)，2.46(q，2H)，2.29-2.20(m，2H)，1.90-1.86(m，2H)，1.19(t，3H).
2 1H NMR(400MHz，CDCl 3)δ8.19(d，2H)，7.51(d，1H)，7.14(d，1H)，6.82(d，1H)，4.90-4.86(m，1H)，3.90-3.84(m，2H)，3.65-3.60(m，2H)，3.43(s，2H)，3.25(s，4H)，2.93-2.90(m，2H)，2.78(s，3H)，2.54(s，4H)，2.46(q，2H)，2.44-2.30(m，2H)，2.20-1.95(m，2H)，1.19(t，3H).
Embodiment 3
(3aR, 6aS)-5-[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
The first step
The bromo-2-of (3aR, 6aS)-5-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
By (3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-5-alcohol 1c (800mg, 3.43mmol) be dissolved in 10mL ethylene dichloride, add carbon tetrabromide (1.70g, 5.10mmol), ice bath is down to 0 DEG C, drip the dichloromethane solution of 5mL triphenylphosphine (1.35g, 5.10mmol), rise to stirring at room temperature and react 12 hours.Add 10mL water washing, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product (3aR, 6aS) the bromo-2-of-5-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles 3a (200mg, white solid), productive rate: 20.0%.
MS m/z(ESI)：298.0[M+1]
Second step
The chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenol
By 1-Nmethanesulphonylpiperazine 1f (2g; 10mmol) with 3-chloro-4-hydroxyl-phenyl aldehyde (1.56g; 10mmol) add in 20mL ethylene dichloride; rise to 80 DEG C of stirring reactions 2 hours; be cooled to room temperature; add sodium triacetoxy borohydride (4.23g, 20mmol) again, 80 DEG C of stirring reactions 5 hours.Add 100mL saturated sodium bicarbonate solution; dichloromethane extraction (50mL × 3); organic phase saturated nacl aqueous solution washing (50mL × 3); anhydrous magnesium sulfate drying, filters, filtrate reduced in volume; gained resistates is purified with eluent system A with silica gel column chromatography; obtain the chloro-4-of title product 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenol 3b (2g, white solid), productive rate: 66.7%.
MS m/z(ESI)：305.0[M+1]
3rd step
(3aR, 6aS)-5-[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
By bromo-for (3aR, 6aS)-5-2-(5-ethyl-pyrimidine-2-base)-3,3a; 4; 5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles 3a (100mg; 0.33mmol) with the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenol 3b (102mg; 0.33mmol) be dissolved in 5mL DMF, then add cesium carbonate (214mg; 0.66mmol), be warming up to return stirring and react 5 hours.Filter, add 30mL water, extraction into ethyl acetate (10mL × 4), merge organic phase, use water (5mL × 3) successively, saturated nacl aqueous solution washing (10mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A by thin-layer chromatography chromatography, obtain title product (3aR, 6aS)-5-[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3, 3a, 4, 5, 6, 6a-six hydrogen-1H-cyclopentano [c] pyrroles 3 (50mg, white solid), productive rate: 29.0%.
MS m/z(ESI)：519.7[M+1]
1H NMR(400MHz，CDCl 3)δ8.18(s，2H)，7.27(d，1H)，7.09(d，1H)，6.84(d，1H)，4.90-4.87(m，1H)，3.90-3.85(m，2H)，3.65-3.61(m，2H)，3.44(s，2H)，3.25(s，4H)，2.93-2.91(m，2H)，2.78(s，3H)，2.55(s，4H)，2.47(q，2H)，2.44-2.32(m，2H)，2.20-1.97(m，2H)，1.19(t，3H).
Embodiment 4
(3aR, 6aS)-5-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
The first step
(3aR, 6aS)-5-(bromo-2, the 6-dilquoro-phenogy of 4-)-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
By bromo-for (3aR, 6aS)-5-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles 3a (60mg, 0.20mmol) be dissolved in 5mL N with bromo-2, the 6-difluoro-phenol (42mg, 0.20mmol) of 4-, in dinethylformamide, add salt of wormwood (130mg, 0.40mmol) again, be warming up to 150 DEG C of stirring reactions 5 hours.Add 30mL water, extraction into ethyl acetate (10mL × 4), merge organic phase, use water (10mL × 2) successively, saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtains crude title product (3aR, 6aS)-5-(4-bromo-2,6-dilquoro-phenogy)-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles 4a (80mg, faint yellow solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：426.1[M+1]
Second step
(3aR, 6aS)-5-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
By crude product (3aR; 6aS)-5-(4-bromo-2; 6-dilquoro-phenogy)-2-(5-ethyl-pyrimidine-2-base)-3; 3a; 4,5,6; 6a-six hydrogen-1H-cyclopentano [c] pyrroles 4a (85mg; 0.20mmol), (4-methanesulfonylphenYl) boric acid (48mg, 0.24mmol) and 1; 1 '-two (diphenyl phosphine) ferrocene palladium chloride (15mg; 0.20mmol) be dissolved in 10mL Isosorbide-5-Nitrae-dioxane, then add cesium carbonate (195mg; 0.60mmol), intensification 110 DEG C of stirring reactions 3 hours.Filter, filtrate reduced in volume, purify gained resistates by thin-layer chromatography chromatography with eluent system A; obtain title product (3aR; 6aS)-5-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3,3a; 4; 5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles 4 (60mg; white solid), productive rate: 60.0%.
MS m/z(ESI)：500.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.22(s，2H)，8.01(d，2H)，7.69(t，2H)，7.14(d，2H)，4.97-4.93(m，1H)，3.87-3.82(m，2H)，3.73-3.69(m，2H)，3.10(s，3H)，2.85-2.82(m，2H)，2.48(q，2H)，2.37-2.33(m，2H)，2.02-1.99(m，2H)，1.20(t，3H).
Embodiment 5
(3aR, 6aS)-5-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
The first step
(3aR, 6aS)-5-methylene radical-1,3,3a, 4,6,6a-six hydrogen-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester
By methyltriphenylphospbromide bromide phosphorus (3.93g, 11mmol) be dissolved in 15mL tetrahydrofuran (THF), be cooled to 0 DEG C, by 5mL containing potassium tert.-butoxide (1.12g, tetrahydrofuran solution 10mmol) joins in reaction solution, keeps 0 DEG C of stirring reaction 0.5 hour.Rise to stirring at room temperature again and react 0.5 hour, be then heated to back flow reaction 1 hour.Reaction solution is cooled to 0 DEG C, adds 5mL 5-ketone-1,3,3a, 4,6,6a-, six hydrogen-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 5a (1.12g, 5mmol, adopt known method " Bioorganic & Medicinal Chemistry Letters (2010), 20 (5), 1674-1676 " prepare and obtain) tetrahydrofuran solution, removing ice bath, is warming up to back flow reaction 4 hours.Add 30mL water, be extracted with ethyl acetate (50mL × 3), merge organic phase, saturated nacl aqueous solution washing (50mL × 3), anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product (3aR, 6aS)-5-methylene radical-1,3,3a, 4,6,6a-, six hydrogen-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 5b (0.70g, yellow liquid), productive rate: 62.5%.
MS m/z(ESI)：168.1[M-55]
Second step
(3aR, 6aS)-5-(hydroxymethyl)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester
The tetrahydrofuran solution of 21mL1M borine is dissolved in 20mL tetrahydrofuran (THF), is cooled to 0 DEG C, 2,3-divinyl (2mL, 20.20mmol) is joined in above-mentioned system in batches, keep 0 DEG C of stirring reaction 3 hours.Will containing (3aR, 6aS)-5-methylene radical-1,3,3a, 4,6, the tetrahydrofuran solution 15mL of 6a-six hydrogen-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 5b (1g, 4.50mmol) is slowly added drop-wise in reaction solution, rises to stirring at room temperature and reacts 12 hours.Reaction solution is cooled to 0 DEG C, slowly adds 10mL10% sodium hydroxide solution, adds 75mL30% superoxol subsequently, rises to room temperature.Reaction solution concentrating under reduced pressure, aqueous phase is extracted with ethyl acetate (50mL × 3), merges organic phase, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, obtain crude title product (3aR, 6aS)-5-(hydroxymethyl)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 5c (0.90g, yellow liquid), productive rate: 83.3%.
MS m/z(ESI)：186.1[M-55]
3rd step
(3aR, 6aS)-5-(Methanesulfonvloxvmethvl)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester
Under ice bath, by (3aR, 6aS)-5-(hydroxymethyl)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 5c (0.90g, 3.73mmol) is dissolved in 50mL anhydrous methylene chloride, add triethylamine (0.75g, 7.46mmol), methylsulfonyl chloride (0.45mL, 5.60mmol) is added dropwise to, stirring reaction 2 hours, then rise to room temperature reaction 12 hours.Add methylene dichloride 50mL, use water (50mL × 2) successively, saturated nacl aqueous solution (50mL × 2) washs, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, obtain crude title product (3aR, 6aS)-5-(Methanesulfonvloxvmethvl)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 5d (1g, yellow liquid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：264.1[M-55]
4th step
(3aR, 6aS)-5-[(bromo-2, the 6-dilquoro-phenogy of 4-) methyl]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl esters
By crude product (3aR, 6aS)-5-(Methanesulfonvloxvmethvl)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 5d (320mg, 1mmol) be dissolved in 10mLN with bromo-2, the 6-difluoro-phenol (230mg, 1.10mmol) of 4-, in dinethylformamide, add cesium carbonate (650mg, 2mmol) again, be warming up to 90 DEG C of stirring reactions 2 hours.Add 15mL water, extraction into ethyl acetate (30mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, obtain crude title product (3aR, 6aS)-5-[(bromo-2, the 6-dilquoro-phenogy of 4-) methyl]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 5e (400mg, yellow liquid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：378[M-55]
5th step
(3aR, 6aS)-5-[[the fluoro-4-of 2,6-bis-(methanesulfonylphenYl) phenoxy group] methyl]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester
By crude product (3aR; 6aS)-5-[(4-bromo-2; 6-dilquoro-phenogy) methyl]-3; 3a; 4,5,6; 6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 5e (400mg; 0.93mmol), (4-methanesulfonylphenYl) boric acid (310mg, 1.57mmol) and 1; 1 '-two (diphenyl phosphine) ferrocene palladium chloride (68mg; 0.09mmol) be dissolved in 30mL Isosorbide-5-Nitrae-dioxane, then add cesium carbonate (910mg; 2.78mmol), intensification 120 DEG C of stirring reactions 3 hours.Filter, add 20mL water, extraction into ethyl acetate (30mL × 2); merge organic phase, anhydrous magnesium sulfate drying, filter; filtrate reduced in volume, obtains crude title product (3aR, 6aS)-5-[[2; the fluoro-4-of 6-bis-(methanesulfonylphenYl) phenoxy group] methyl]-3,3a, 4; 5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 5f (400mg; brown oil), productive rate: 85.1%.
MS m/z(ESI)：452.1[M-55]
6th step
(3aR, 6aS)-5-[[the fluoro-4-of 2,6-bis-(methanesulfonylphenYl) phenoxy group] methyl]-1,2,3,3a, 4,5,6,6a-octahydro cyclopentano [c] pyrroles
By (3aR; 6aS)-5-[[2; the fluoro-4-of 6-bis-(methanesulfonylphenYl) phenoxy group] methyl]-3,3a, 4; 5; 6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 5f (400mg, 0.80mmol) is dissolved in 10mL methyl alcohol; be added dropwise to 5mL 2M methanol hydrochloride solution, stirring reaction 48 hours.Dripping saturated sodium hydroxide solution to reaction solution pH is 10; dichloromethane extraction (30mL × 3); merge organic phase; anhydrous magnesium sulfate drying, filters, filtrate reduced in volume; obtain crude title product (3aR; 6aS)-5-[[the fluoro-4-of 2,6-bis-(methanesulfonylphenYl) phenoxy group] methyl]-1,2; 3; 3a, 4,5; 6; 6a-octahydro cyclopentano [c] pyrroles 5g (300mg, brown oil), product is not purified directly carries out next step reaction.
MS m/z(ESI)：408.1[M+1]
7th step
(3aR, 6aS)-5-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
By crude product 5-[[the fluoro-4-of 2,6-bis-(methanesulfonylphenYl) phenoxy group] methyl]-1,2; 3,3a, 4; 5,6,6a-octahydro cyclopentano [c] pyrroles 5g (250mg; 0.60mmol) be dissolved in 10mL N; in N-N,N-DIMETHYLACETAMIDE, add the chloro-5-ethyl-pyrimidin (87mg, 0.60mmol) of 2-and salt of wormwood (210mg successively; 1.50mmol), 150 DEG C of stirring reactions 6 hours are risen to.Be cooled to room temperature; add 20mL water; be extracted with ethyl acetate (30mL × 3); merge organic phase, anhydrous magnesium sulfate drying, filter; filtrate reduced in volume; purify gained resistates with silica gel column chromatography with eluent system B, obtain title product (3aR, 6aS)-5-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-2-(5-ethyl-pyrimidine-2-base)-3; 3a, 4,5; 6; 6a-six hydrogen-1H-cyclopentano [c] pyrroles 5 (80mg, white solid), productive rate: 25%.
MS m/z(ESI)：514.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.20(s，2H)，8.01(d，2H)，7.69(d，2H)，7.20-7.10(m，2H)，4.14(d，2H)，3.85-3.70(m，2H)，3.57-3.46(m，2H)，3.10(s，3H)，2.93-2.82(m，2H)，2.48(t，2H)，2.27-2.23(m，2H)，1.88-1.82(m，1H)，1.45-1.40(m，2H)，1.19(t，3H).
Embodiment 6
(3aR, 6aS)-5-[the bromo-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl esters
The first step
(3aR, 6aS)-5-mesyloxy-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester
Under ice bath, by (3aR, 6aS)-5-hydroxyl-3,3a, 4,5,6,6a-, six hydrogen-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 1a (25g, 120mmol) is dissolved in 50mL anhydrous methylene chloride, add triethylamine (35g, 440mmol), methylsulfonyl chloride (20mL, 230mmol) is added dropwise to, stirring reaction 2 hours, then rise to room temperature reaction 12 hours.Reaction solution saturated sodium bicarbonate solution (200mL × 3) washing, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, obtain crude title product (3aR, 6aS)-5-mesyloxy-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 6a (30g, light yellow solid), product is not purified directly carries out next step reaction.
Second step
(3aR, 6aS)-5-[the bromo-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl esters
By bromo-for 2-4-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenol 1k (230mg; 0.70mmol) with crude product (3aR, 6aS)-5-mesyloxy-3,3a; 4; 5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 6a (240mg; 0.80mmol) be dissolved in 10mL acetonitrile; add cesium carbonate (445mg, 1.40mmol) again, rise to 85 DEG C of stirring reactions 6 hours.Filter; filtrate reduced in volume, purifies gained resistates by thin-layer chromatography chromatography with developping agent system B, obtains title product (3aR; 6aS)-5-[the bromo-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-3; 3a, 4,5; 6; 6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 6 (300mg, white solid), productive rate: 93.0%.
MS m/z(ESI)：558.2[M+1]
1H NMR(400MHz，CDCl 3)δ7.48(s，1H)，7.21-7.23(m，1H)，7.03(d，1H)，4.97-5.02(m，1H)，3.40-3.43(m，4H)3.08-3.12(m，6H)，2.86(s，3H)，2.80(m，2H)，2.42-2.43(m，4H)，1.97-2.02(m，2H)，1.77-1.82(m，2H)，1.39(s，9H).
Embodiment 7
(1R, 5S)-6-[[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
The first step
5-benzyl-4,6-dicarbapentaborane-3a, 6a-dihydro-1H-pyrrolo-[3,4-c] pyrazoles-3-ethyl formate
1-benzyl-pyrrole-2,5-diketone 7a (5g, 26.70mmol) is dissolved in 30mL toluene, adds ethyl diazoacetate (2.9mL, 28mmol), be warming up to 100 DEG C, stirring reaction 5 hours.Concentrating under reduced pressure reaction solution, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product 5-benzyl-4,6-dicarbapentaborane-3a, 6a-dihydro-1H-pyrrolo-[3,4-c] pyrazoles-3-ethyl formate 7b (6.70g, white solid), productive rate: 91.9%.
MS m/z(ESI)：302.1[M+1]
1H NMR(400MHz，CDCl 3)δ7.36-7.28(m，5H)，7.14(s，1H)，4.90-4.87(m，1H)，4.64(s，2H)，4.57-4.54(m，1H)，4.33(q，2H)，1.36(t，3H).
Second step
(1R, 5S)-3-benzyl 2,4-dicarbapentaborane-3-azabicyclo also [3.1.0] hexane-6-ethyl formate
By 5-benzyl-4,6-dicarbapentaborane-3a, 6a-dihydro-1H-pyrrolo-[3,4-c] pyrazoles-3-ethyl formate 7b (2.10g, 7mmol) is placed in reaction flask, is heated to 190 DEG C, reacts 1 hour at 190 DEG C.Be chilled to room temperature, add 200mL ethyl acetate, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product (1R, 5S)-3-benzyl 2,4-dicarbapentaborane-3-azabicyclo is [3.1.0] hexane-6-ethyl formate 7c (11g, white solid) also, productive rate: 57.9%.
MS m/z(ESI)：274.1[M+1]
1H NMR(400MHz，CDCl 3)δ7.33-7.28(m，5H)，4.52(s，2H)，4.19(q，2H)，2.88-2.87(m，2H)，2.29-2.27(m，1H)，1.28(t，3H).
3rd step
[(1R, 5S)-3-benzyl-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol
By Lithium Aluminium Hydride (3g, 81mmol) be dissolved in 200mL tetrahydrofuran (THF), slowly add 50mL (1R, 5S) the tetrahydrofuran solution of-3-benzyl 2,4-dicarbapentaborane-3-azabicyclo also [3.1.0] hexane-6-ethyl formate 7c (5.40g, 20mmol), finish, back flow reaction 5 hours, is cooled to 50 DEG C, stirring reaction 16 hours.Be chilled to room temperature, slowly 6mL saturated ammonium chloride solution is instilled under ice-water bath, filter, collect filtrate, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, obtains title product [(1R, 5S)-3-benzyl-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 7d (3.70g, brown oil), productive rate: 91.1%.
MS m/z(ESI)：204.1[M+1]
4th step
[(1R, 5S)-3-azabicyclo is [3.1.0] hexane-6-base also] methyl alcohol
By [(1R, 5S)-3-benzyl-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 7d (3.70g, 18.30mmol) be dissolved in 150mL methyl alcohol, add palladium/carbon (200mg successively, 10%) and ammonium formiate (6.90g, 109.80mmol), back flow reaction 1 hour.Be chilled to room temperature, filter, concentrating under reduced pressure filtrate, obtain crude title product [(1R, 5S)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 7e (2.3g, colorless oil), product is not purified directly carries out next step reaction.
MS m/z(ESI)：114.1[M+1]
5th step
[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol
By crude product [(1R, 5S)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 7e (500mg, 4.42mmol) be dissolved in 5mL N, in N-N,N-DIMETHYLACETAMIDE, add the chloro-5-ethyl-pyrimidin of 2-(630mg successively, 4.42mmol) with salt of wormwood (916mg, 6.63mmol), rise to 150 DEG C of stirring reactions 6 hours.Add 50mL water, be extracted with ethyl acetate (30mL × 3), merge organic phase, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, obtain crude title product [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 7f (1g, brown oil), product is not purified directly carries out next step reaction.
MS m/z(ESI)：220.1[M+1]
6th step
[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate
By crude product [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 7f (1g, 4.40mmol) be dissolved in 10mL anhydrous methylene chloride, add triethylamine (893mg, 8.83mmol), be added dropwise to methylsulfonyl chloride (759mg, 6.62mmol), stirring reaction 12 hours.Add saturated sodium bicarbonate solution 30mL, dichloromethane extraction (10mL × 3), merge organic phase, use water (20mL × 3) successively, saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtain crude title product [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (700mg, brown oil), product is not purified directly carries out next step reaction.
MS m/z(ESI)：298.1[M+1]
7th step
(1R, 5S)-6-[[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By crude product [(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (100mg; 0.34mmol) with the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenol 3b (102mg; 0.34mmol) be dissolved in 5mL N; in N-N,N-DIMETHYLACETAMIDE; add cesium carbonate (221mg again; 0.68mmol), 150 DEG C of stirring reactions 8 hours are warming up to.Add 25mL water, extraction into ethyl acetate (20mL × 3), merge organic phase, use saturated ammonium chloride solution (10mL × 3) successively, saturated nacl aqueous solution washing (10mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by thin-layer chromatography chromatography, obtain title product (1R, 5S)-6-[[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 7 (70mg, white solid), productive rate: 42.0%.
MS m/z(ESI)：492[M+1]
1H NMR(400MHz，CDCl 3)δ8.19(s，2H)，7.35(s，1H)，7.12-1.07(m，1H)，6.87(d，1H)，4.02(d，2H)，3.94(d，2H)，3.55(d，2H)，3.47(s，2H)，3.28-3.25(m，4H)，2.79(s，3H)，2.56-2.55(m，4H)，2.46(q，2H)，1.78-1.77(m，2H)，1.20(q，3H)，0.89-0.86(m，1H).
Embodiment 8
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
The first step
[(1R, 5S)-6-[(bromo-2, the 6-dilquoro-phenogy of 4-) methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (150mg, 0.51mmol) with 4-bromo-2,6-difluoro-phenol (105mg, 0.51mmol) be dissolved in 5mLN, in dinethylformamide, then add cesium carbonate (329mg, 1.02mmol), 90 DEG C of stirring reactions 4 hours are warming up to.Add 20mL water, extraction into ethyl acetate (20mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product [(1R, 5S)-6-[(4-bromo-2,6-dilquoro-phenogy) methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 8a (58mg, colorless oil), productive rate: 42.0%.。
MS m/z(ESI)：412.0[M+1]
Second step
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By [(1R; 5S)-6-[(4-bromo-2; 6-dilquoro-phenogy) methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 8a (85mg; 0.15mol); (4-methanesulfonylphenYl) boric acid (35mg; 0.18mmol) He 1; 1 '-two (diphenyl phosphine) ferrocene palladium chloride (11mg; 0.02mmol) be dissolved in 5mL 1; in 4-dioxane; add cesium carbonate (143mg, 0.42mmol) again, heat up 120 DEG C of stirring reactions 6 hours.Add 20mL water; extraction into ethyl acetate (20mL × 2); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system B by thin-layer chromatography chromatography; obtain title product (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 8 (20mg, white solid), productive rate: 28.0%.
MS m/z(ESI)：486.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.18(s，2H)，8.02(d，2H)，7.70-7.73(m，2H)，7.18(d，2H)，4.14-4.16(m，2H)，3.88-3.91(m，2H)，3.55-3.58(m，2H)，3.10(s，3H)，2.46-2.48(m，2H)，1.73(d，2H)，1.25-1.29(m，1H)，1.16-1.20(m，3H).
Embodiment 9
3-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester
The first step
3-hydroxyl-8-azabicyclo is [3.2.1] octane-8-carboxylic acid tert-butyl ester also
By 8-azabicyclo also [3.2.1] octane-3-alcohol 9a (5g, 39.40mmol) be dissolved in 50mL methyl alcohol, under ice bath, add triethylamine (7.90g successively, 78.70mmol) with tert-Butyl dicarbonate (10.30g, 47.28mmol), rise to stirring at room temperature and react 2 hours.Filter, add 100mL saturated sodium bicarbonate solution, be extracted with ethyl acetate (100mL × 3), merge organic phase, with saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtains crude title product 3-hydroxyl-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 9b (8.10g, white solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：172.1[M-55]
Second step
3-mesyloxy-8-azabicyclo is [3.2.1] octane-8-carboxylic acid tert-butyl ester also
Under ice bath, by crude product 3-hydroxyl-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 9b (50.60g, 0.22mol) be dissolved in 200mL anhydrous methylene chloride, add triethylamine (48.50g, 0.48mol), be added dropwise to methylsulfonyl chloride (20mL, 0.24mol), rise to stirring at room temperature and react 12 hours.Add 10mL water, organic phase uses 1M hydrochloric acid (20mL × 3) successively, saturated nacl aqueous solution (20mL × 3) washs, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtains crude title product 3-mesyloxy-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 9c (62.70g, white solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：250.1[M-55]
3rd step
3-(bromo-2, the 6-dilquoro-phenogy of 4-)-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester
By 3-mesyloxy-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 9c (600mg, 1.96mmol) with 4-bromo-2,6-difluoro-phenol (450mg, 2.16mmol) be dissolved in 5mL N, in dinethylformamide, then add cesium carbonate (1.92g, 5.89mmol), be warming up to 80 DEG C of stirring reactions 1 hour, then 50 DEG C of stirring reactions 12 hours.Filter, filtrate adds 50mL water, is extracted with ethyl acetate (30mL × 3), merges organic phase, with anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purify gained resistates by thin-layer chromatography chromatography with developping agent system B, obtain title product 3-(4-bromo-2,6-dilquoro-phenogy)-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 9d (470mg, white solid), productive rate: 57.3%.
4th step
3-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester
By 3-(4-bromo-2; 6-dilquoro-phenogy)-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 9d (720mg; 1.70mol); (4-methanesulfonylphenYl) boric acid (413mg; 2.05mmol) He 1; 1 '-two (diphenyl phosphine) ferrocene palladium chloride (124mg; 0.17mmol) be dissolved in 7mL 1; in the mixed solvent (V/V=5: 2) of 4-dioxane and water; add cesium carbonate (1.60g; 5.10mmol), 120 DEG C of stirring reactions 4 hours are risen to.Filter; filtrate adds 20mL water; be extracted with ethyl acetate (15mL × 3); merge organic phase; use water (5mL × 3) successively; saturated nacl aqueous solution washing (5mL × 3); anhydrous magnesium sulfate drying; filter, filtrate reduced in volume, purify gained resistates by thin-layer chromatography chromatography with developping agent system B; obtain title product 3-[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 9 (260mg, white solid), productive rate: 29.0%.
MS m/z(ESI)：438.2[M-55]
1H NMR(400MHz，DMSO)δ8.02(s，4H)，7.67(d，2H)，4.61-4.58(m，1H)，4.13(s，2H)，2.08(s，2H)，1.86(s，2H)，1.68-1.64(m，4H)，1.39(s，9H)，1.24(s，3H).
Embodiment 10
3-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-8-(5-ethyl-pyrimidine-2-base)-8-azabicyclo also [3.2.1] octane
The first step
3-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-8-azabicyclo also [3.2.1] octane
By 3-[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 9 (130mg; 0.26mmol) be dissolved in 5mL methyl alcohol, be added dropwise to the methanol solution of 3mL 2M hydrogenchloride, stirring reaction 4 hours.Reaction solution concentrating under reduced pressure; obtain crude title product 3-[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group]-8-azabicyclo also [3.2.1] octane 10a (98mg, white solid), product is not purified directly carries out next step reaction.
Second step
3-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-8-(5-ethyl-pyrimidine-2-base)-8-azabicyclo also [3.2.1] octane
By crude product 3-[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group]-8-azabicyclo also [3.2.1] octane 10a (103mg; 0.25mmol) be dissolved in 2mL N; in N-N,N-DIMETHYLACETAMIDE; add the chloro-5-ethyl-pyrimidin of 2-(35mg successively; 0.25mmol) with salt of wormwood (162mg, 0.49mmol), rise to 150 DEG C of stirring reactions 4 hours.Add 50mL water; be extracted with ethyl acetate (20mL × 3); merge organic phase; use water (20mL × 3) successively; saturated nacl aqueous solution washing (20mL × 3); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; purify gained resistates by thin-layer chromatography chromatography with developping agent system A, obtain title product 3-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-8-(5-ethyl-pyrimidine-2-base)-8-azabicyclo also [3.2.1] octane 10 (60mg; white solid), productive rate: 48.0%.
MS m/z(ESI)：500.2[M+1]
1H NMR(400MHz，DMSO)δ8.26(s，2H)，7.99(s，4H)，7.67(d，2H)，4.62(s，2H)，4.52(s，1H)，3.26(s，3H)，2.34(q，2H)，2.13(t，2H)，1.99-1.94(m，6H)，1.12(t，3H).
Embodiment 11
3-[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-8-(5-ethyl-pyrimidine-2-base)-8-azabicyclo also [3.2.1] octane
The first step
3-[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester
By 3-mesyloxy-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 9c (600mg; 1.96mmol) with the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenol 3b (660mg; 2.16mmol) be dissolved in 10mLN; in dinethylformamide; add cesium carbonate (1.92g; 5.89mmol), 150 DEG C of stirring reactions 5 hours are warming up to.Filter; filtrate adds 50mL water; be extracted with ethyl acetate (30mL × 3); merge organic phase; use water (10mL × 3) successively; saturated nacl aqueous solution washing (10mL × 3); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product 3-[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 11a (750mg; white solid), productive rate: 75.0%.
MS m/z(ESI)：414.2[M+1-100]
Second step
3-[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-8-azabicyclo also [3.2.1] octane
By 3-[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 11a (700mg; 1.36mmol) be dissolved in 5mL methyl alcohol; drip 3mL 2M hydrogen chloride methanol solution, stirring reaction 4 hours.Reaction solution concentrating under reduced pressure; gained resistates is purified with eluent system A with silica gel column chromatography; obtain title product 3-[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-8-azabicyclo also [3.2.1] octane 11b (120mg; white solid), productive rate: 21.0%.
MS m/z(ESI)：414.2[M+1]
3rd step
3-[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-8-(5-ethyl-pyrimidine-2-base)-8-azabicyclo also [3.2.1] octane
By 3-[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-8-azabicyclo also [3.2.1] octane 11b (120mg; 0.29mmol) be dissolved in 3mL N; in N-N,N-DIMETHYLACETAMIDE; add the chloro-5-ethyl-pyrimidin of 2-(41mg successively; 0.29mmol) with cesium carbonate (188mg; 0.57mmol), 150 DEG C of stirring reactions 5 hours are risen to.Add 20mL water; be extracted with ethyl acetate (10mL × 3); merge organic phase; use water (5mL × 3) successively; saturated nacl aqueous solution washing (5mL × 3); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with eluent system A with silica gel column chromatography; obtain title product 3-[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-8-(5-ethyl-pyrimidine-2-base)-8-azabicyclo also [3.2.1] octane 11 (110mg, white solid), productive rate: 73%.
MS m/z(ESI)：520.2[M+1]
1H NMR(400MHz，DMSO)δ8.30(s，2H)，7.30(s，1H)，7.27(d，1H)，7.18(d，1H)，4.94-4.89(m，1H)，4.67(s，2H)，3.44(s，2H)，3.09-3.08(m，4H)，2.86(s，3H)，2.47-2.43(m，6H)，2.10-2.09(m，2H)，1.99-1.93(m，4H)，1.64-1.62(m，2H)，1.23-1.18(m，3H).
Embodiment 12
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[5-(4-methanesulfonylphenYl) pyrazine-2-base] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
The first step
(1R, 5S)-6-[(5-bromo-pyrazine-2-base) oxygen methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 7f (660mg, 3mmol) be dissolved in 20mL anhydrous tetrahydro furan, add sodium hydride (120mg, 3mmol), stirring at room temperature 0.5 hour.Under ice bath, add 2,5-bis-bromo-pyrazine (713mg, 3mmol), rise to stirring at room temperature and react 12 hours.Reaction solution concentrating under reduced pressure, add water 10mL, be extracted with ethyl acetate (20mL × 3), merge organic phase, use water (20mL × 3) successively, saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product (1R, 5S)-6-[(5-bromo-pyrazine-2-base) oxygen methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 12a (170mg, white solid), productive rate: 15.0%.
Second step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[5-(4-methanesulfonylphenYl) pyrazine-2-base] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By (1R; 5S)-6-[(5-bromo-pyrazine-2-base) oxygen methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 12a (170mg; 0.45mmol); (4-methanesulfonylphenYl) boric acid (117mg; 0.58mmol); two (triphen phosphino-) palladium chloride (100mg; 0.14mmol) be dissolved in 20mL N with 1.50mL 2M sodium carbonate solution; in dinethylformamide, rise to 85 DEG C of stirring reactions 5 hours.Add water 100mL, be extracted with ethyl acetate (20mL × 3), merge organic phase, use water (20mL × 3) successively, saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product (1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[5-(4-methanesulfonylphenYl) pyrazine-2-base] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 12 (100mg, white solid), productive rate: 50.0%.
MS m/z(ESI)：452.2[M+1]
1H NMR(400MHz，CDCl3)δ8.55(d，1H)，8.33(d，1H)，8.19(s，2H)，8.13(d，2H)，8.07-8.00(m，2H)，4.33(d，2H)，3.98(d，2H)，3.60(d，2H)，3.09(s，3H)，2.47(q，2H)，1.79(s，2H)，1.25(s，1H)，1.18(t，3H).
Embodiment 13
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(4-methanesulfonylphenYl)-3-pyridine] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
The first step
(1R, 5S)-6-[(6-chloro-3-pyridyl) oxygen methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 7f (436mg, 2mmol) is dissolved in 15mL toluene, adds 6-chloropyridine-3-alcohol (200mg, 1.55mmol), add triphenylphosphine (609mg, 2.33mmol) and N, N again, N ', N '-tetramethyl-Cellmic C 121 (401mg, 2.33mmol), is heated to 60 DEG C and stirs 3 hours.Reaction solution concentrating under reduced pressure, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product (1R, 5S)-6-[(6-chloro-3-pyridyl) oxygen methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 13a (300mg, white solid), productive rate: 61.0%.
MS m/z(ESI)：331.1[M+1]
Second step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(4-methanesulfonylphenYl)-3-pyridine] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By (1R; 5S)-6-[(6-chloro-3-pyridyl) oxygen methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 13a (150mg; 0.45mmol); (4-methanesulfonylphenYl) boric acid (117mg; 0.58mmol); two (triphen phosphino-) palladium chloride (100mg; 0.14mmol) be dissolved in 20mL N with 1.50mL 2M sodium carbonate solution; in dinethylformamide, rise to 85 DEG C of stirring reactions 5 hours.Add 100mL water, be extracted with ethyl acetate (80mL × 3), merge organic phase, use water (20mL × 3) successively, saturated nacl aqueous solution washing (30mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product (1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(4-methanesulfonylphenYl)-3-pyridine] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 13 (110mg, white solid), productive rate: 55.0%.
MS m/z(ESI)：451.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.43(d，1H)，8.20(s，2H)，8.16-8.12(m，2H)，8.03-8.00(m，2H)，7.74(d，1H)，7.30(dd，1H)，4.04(d，2H)，4.00(d，2H)，3.63-3.58(m，2H)，3.09(s，3H)，2.48(q，2H)，1.81-1.78(m，2H)，1.27-1.25(m，1H)，1.19(t，3H).
Embodiment 14
(3aR, 6aS)-5-[the bromo-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl esters
The first step
(3aR, 6aS)-5-benzoyloxy-3,3a, 4,5,6,6a-six hydrogen-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester
By (3aR, 6aS)-5-hydroxyl-3,3a, 4,5,6,6a-six hydrogen-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 1a (5g, 22mmol) is dissolved in 100mL tetrahydrofuran (THF), adds phenylformic acid (2.96g successively, 24.20mmol), triphenylphosphine (8.65g, 33mmol) and diethyl azodiformate (4.2mL, 26.40mmol), be warming up to 50 DEG C, stirring reaction 3 hours.Concentrating under reduced pressure reaction solution, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product (3aR, 6aS)-5-benzoyloxy-3,3a, 4,5,6,6a-, six hydrogen-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 14a (5.70g, colourless viscous liquid), productive rate: 78.5%.
Second step
(3aR, 6aS)-5-hydroxyl-3,3a, 4,5,6,6a-six hydrogen-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester
By (3aR, 6aS)-5-benzoyloxy-3,3a, 4,5,6,6a-six hydrogen-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 14a (5.70g, 17.20mmol) is dissolved in 150mL first alcohol and water (V/V=2: 1) mixed solvent, adds sodium hydride (3.40g, 86mmol), stirring reaction 2 hours.Concentrating under reduced pressure reaction solution, add 50mL water, drip 1M hydrochloric acid and be about 3 to reaction solution pH, be extracted with ethyl acetate (100mL × 2), merge organic phase, with anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product (3aR, 6aS)-5-hydroxyl-3,3a, 4,5,6,6a-six hydrogen-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 14b (3.60g, white solid), productive rate: 92.1%.
3rd step
(3aR, 6aS)-5-mesyloxy-3,3a, 4,5,6,6a-six hydrogen-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester
Under ice bath, by (3aR, 5S, 6aS)-5-hydroxyl-3,3a, 4,5,6,6a-, six hydrogen-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 14b (200mg, 0.88mmol) be dissolved in 10mL anhydrous methylene chloride, add triethylamine (178mg, 1.76mmol), drip methylsulfonyl chloride (120mg, 1mmol), room temperature reaction is risen to 12 hours.Reaction solution saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, obtain crude title product (3aR, 6aS)-5-mesyloxy-3,3a, 4,5,6,6a-, six hydrogen-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 14c (270mg, colorless oil), product is not purified directly carries out next step reaction.
4th step
(3aR, 6aS)-5-[the bromo-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl esters
By bromo-for 2-4-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenol 1k (254mg; 0.73mmol) with crude product (3aR, 6aS)-5-mesyloxy-3,3a; 4; 5,6,6a-, six hydrogen-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 14c (270mg; 0.88mmol) be dissolved in 10mL acetonitrile; add cesium carbonate (475mg, 1.46mmol), rise to 80 DEG C of stirring reactions 4 hours.Filter; filtrate reduced in volume, purifies gained resistates by thin-layer chromatography chromatography with developping agent system B, obtains title product (3aR; 6aS)-5-[the bromo-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-3; 3a, 4,5; 6; 6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 14 (280mg, white solid), productive rate: 50.0%.
MS m/z(ESI)：560.2[M+1]
1H NMR(400MHz，d-DMSO)δ7.49(d，1H)，7.22-7.24(m，1H)，7.04(d，1H)，4.96(br.s，1H)，3.50(t，2H)，3.44(s，2H)，3.10-3.25(m，2H)，3.08-3.11(m，4H)，2.86(s，3H)，2.73(br.s，2H)，2.43(br.s，4H)，2.20(br.s，2H)，1.69(br.s，2H)，1.37(s，9H).
Embodiment 15
(3aR, 6aS)-5-[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl esters
The first step
Bromo-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl esters of (3aR, 6aS)-5-
By (3aR, 6aS)-5-hydroxyl-3,3a, 4,5,6,6a-six hydrogen-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 1a (2.30g, 10mmol) be dissolved in 40mL ethylene dichloride, add carbon tetrabromide (6.60g, 20mmol), ice bath is down to 0 DEG C, drip the dichloromethane solution of 25mL triphenylphosphine (5.20g, 20mmol), rise to stirring at room temperature and react 12 hours.Wash with water (20mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product (3aR, 6aS)-5-bromo-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 15a (1.30g, weak yellow liquid), productive rate: 44.5%.
MS m/z(ESI)：236.0[M-55]
Second step
(3aR, 6aS)-5-[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl esters
By bromo-for (3aR, 6aS)-5-3,3a; 4; 5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 15a (1g; 3.40mmol) with the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenol 3b (1.05g; 3.40mmol) be dissolved in 10mL DMF, then add cesium carbonate (2.20g; 6.80mmol), 150 DEG C of stirring reactions 6 hours are warming up to.Add 50mL water; extraction into ethyl acetate (30mL × 3); merge organic phase; saturated ammonia chloride solution washing (30mL × 5); anhydrous magnesium sulfate drying, filters, filtrate reduced in volume; gained resistates is purified with eluent system A with silica gel column chromatography; obtain title product (3aR, 6aS)-5-[the chloro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-3,3a; 4; 5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 15 (1.20g; white solid), productive rate: 68.0%.
MS m/z(ESI)：514.2[M+1]
1H NMR(400MHz，CDCl 3)δ7.33(d，1H)，7.08(d，1H)，6.82(d，1H)，4.87-4.84(m，1H)，3.62-3.57(m，2H)，3.46(s，2H)3.39-3.37(m，2H)，3.25-3.28(m，4H)，2.79(s，3H)，2.78-2.75(m，2H)，2.57-2.55(m，4H)，2.25-2.22(m，2H)，1.92-1.89(m，2H)，1.46(s，9H).
Embodiment 16
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
The first step
(1R, 5S)-6-(hydroxymethyl)-3-azabicyclo is [3.1.0] hexane-3-carboxylic acid tert-butyl ester also
By [(1R, 5S)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 7e (1.44g, 12.70mmol) be dissolved in 36mL methyl alcohol, add triethylamine (2.50g successively, 25.40mmol), palladium hydroxide (260mg, cat.) and tert-Butyl dicarbonate (3.30g, 15.20mmol), stirring reaction 12 hours.Filter, filtrate reduced in volume, obtains crude title product (1R, 5S)-6-(hydroxymethyl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 16a (2.70g, yellow liquid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：158.1[M-55]
Second step
(1R, 5S)-6-(Methanesulfonvloxvmethvl)-3-azabicyclo is [3.1.0] hexane-3-carboxylic acid tert-butyl ester also
Under ice bath, by crude product (1R, 5S)-6-(hydroxymethyl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 16a (2.70g, 12.70mmol) be dissolved in 30mL anhydrous methylene chloride, add triethylamine (2.57g, 25.40mmol), be added dropwise to 5mL methylsulfonyl chloride (1.74g, dichloromethane solution 15.20mmol), rises to room temperature reaction 12 hours.Add saturated ammonium chloride solution 20mL, extraction separatory, aqueous phase methylene dichloride (20mL × 1) extracts, merge organic phase, use saturated ammonium chloride solution (20mL × 2) successively, saturated nacl aqueous solution (10mL × 2) washs, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtains crude title product (1R, 5S)-6-(Methanesulfonvloxvmethvl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 16b (3g, yellow oily), product is not purified directly carries out next step reaction.
MS m/z(ESI)：236.1[M-55]
3rd step
(1R, 5S)-6-[(bromo-2, the 6-dilquoro-phenogy of 4-) methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
By crude product (1R, 5S)-6-(Methanesulfonvloxvmethvl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 16b (2g, 6.90mmol) with 4-bromo-2,6-difluoro-phenol (1.44g, 6.90mmol) be dissolved in 40mL DMF, then add cesium carbonate (4.50g, 13.80mmol), 150 DEG C of stirring reactions 5 hours are warming up to.Add 100mL water, extraction into ethyl acetate (30mL × 4), merge organic phase, saturated ammonium chloride solution washing (40mL × 5), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtain crude title product (1R, 5S)-6-[(4-bromo-2,6-dilquoro-phenogy) methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 16c (2.20g, yellow liquid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：350[M-55]
4th step
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
By crude product (1R; 5S)-6-[(4-bromo-2; 6-dilquoro-phenogy) methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 16c (2g; 5mmol); (4-methanesulfonylphenYl) boric acid (1.20g; 6mmol) He 1; 1 '-two (diphenyl phosphine) ferrocene palladium chloride (365mg; 0.50mmol) be dissolved in 40mL 1; in 4-dioxane; add cesium carbonate (3.20g, 10mmol) again, be warming up to return stirring and react 3 hours.Filter; filtrate reduced in volume; gained resistates is purified with eluent system B with silica gel column chromatography; obtain title product (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 16 (2g, white solid), productive rate: 84.3%.
MS m/z(ESI)：424.1[M-55]
1H NMR(400MHz，d-DMSO)δ7.98(d，4H)，7.65(d，1H)，4.06(d，2H)，3.39(d，2H)，3.25-3.20(m，5H)，1.56(s，2H)，1.36(s，9H)，0.90-0.89(m，1H)
Embodiment 17
(1R, 5S)-6-[[4-(4-cyano-phenyl)-2,6-dilquoro-phenogy] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
By (1R, 5S)-6-[(4-bromo-2,6-dilquoro-phenogy) methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 16c (300mg, 0.74mmol), (4-cyano-phenyl) boric acid (131mg, 0.89mmol) He 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (54mg, 0.07mmol) be dissolved in 3mL 1, in the mixed solvent of 4-dioxane and 2mL water, add three hypophosphite monohydrate potassium (591mg, 2.22mmol) again, be warming up to 120 DEG C of stirring reactions 7 hours.Filter, add 20mL water, extraction into ethyl acetate (20mL × 3), merge organic phase, saturated nacl aqueous solution washing (15mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates by thin-layer chromatography chromatography with developping agent system B, obtains title product (1R, 5S)-6-[[4-(4-cyano-phenyl)-2,6-dilquoro-phenogy] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 17 (70mg, white solid), productive rate: 22%.
MS m/z(ESI)：371.1[M-55]
1H NMR(400MHz，d-DMSO)δ8.21(d，4H)，7.65(d，2H)，4.06(d，2H)，3.40(d，2H)，3.25(s，2H)，1.56(t，2H)，1.35(s，9H)，0.93-0.89(m，1H).
Embodiment 18
3-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester
The first step
The bromo-8-azabicyclo of 3-is [3.2.1] octane-8-carboxylic acid tert-butyl ester also
By crude product 3-hydroxyl-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 9b (2.20g, 9.70mmol) be dissolved in 20mL methylene dichloride, add carbon tetrabromide (4.80g, 14.50mmol), under ice bath, be added dropwise to the dichloromethane solution of 20mL triphenylphosphine (3.81g, 14.50mmol), rise to stirring at room temperature and react 12 hours.Reaction solution concentrating under reduced pressure, purifies gained resistates with silica gel column chromatography with eluent system B, obtains the bromo-8-azabicyclo of title product 3-also [3.2.1] octane-8-carboxylic acid tert-butyl ester 18a (1.96g, yellow liquid), productive rate: 70.0%.
Second step
3-(bromo-2, the 6-dilquoro-phenogy of 4-)-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester
By bromo-for 3-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 18a (500mg, 1.73mmol) with 4-bromo-2,6-difluoro-phenol (361mg, 1.73mmol) be dissolved in 5mLN, in dinethylformamide, add salt of wormwood (716mg, 5.19mmol) again, be warming up to 120 DEG C of stirring reactions 4 hours.Add 50mL water, be extracted with ethyl acetate (20mL × 3), merge organic phase, use water (10mL × 3) successively, saturated nacl aqueous solution washing (10mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with developping agent system B, obtain title product 3-(bromo-2, the 6-dilquoro-phenogy of 4-)-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 18b (330mg, yellow liquid), productive rate: 46.3%.
3rd step
3-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester
By 3-(4-bromo-2; 6-dilquoro-phenogy)-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 18b (390mg; 0.93mmol); (4-methanesulfonylphenYl) boric acid (224mg; 1.12mmol) He 1; 1 '-two (diphenyl phosphine) ferrocene palladium chloride (68mg; 0.09mmol) be dissolved in 6mL 1; in 4-dioxane and water (V/V=5: 1) mixed solvent; add three hypophosphite monohydrate potassium (743mg again; 2.29mmol), 120 DEG C of stirring reactions 4 hours are warming up to.Filter; add 20mL water; be extracted with ethyl acetate (20mL × 3); merge organic phase; saturated nacl aqueous solution washing (10mL × 3); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 3-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 18 (170mg; white solid), productive rate: 37.0%.
MS m/z(ESI)：438.2[M-55]
1H NMR(400MHz，d-DMSO)δ8.01-7.97(m，4H)，7.66(d，2H)，4.59(s，1H)，4.11(s，2H)，3.32(s，3H)，2.19(d，2H)，2.10-2.06(m，2H)，1.99-1.93(s，4H)，1.40(s，9H).
Embodiment 19
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid-1-methylcyclopropyl groups ester
The first step
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
Under ice bath; by (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 16 (1.10g; 2.30mmol) be dissolved in 5mL methylene dichloride; be added dropwise to 20mL 4M methanol hydrochloride solution, rise to room temperature, stirring reaction 12 hours.Concentrating under reduced pressure reaction solution; obtain crude title product (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 19a (800mg; white solid), product is not purified directly carries out next step reaction.
Second step
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid-1-methylcyclopropyl groups ester
By crude product (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 19a (150mg; 0.36mmol); triethylamine (73mg; 0.72mmol) be added in 8mL methylene dichloride; under ice bath; add 1mL (1-methylcyclopropyl groups) (4-nitrophenyl) carbonic ether 19b (102mg; 0.43mmol; adopt known method " patent WO2010009195 " prepare and obtain) dichloromethane solution, rise to stirring at room temperature and react 12 hours.Filter, add 100mL methylene dichloride, use 1M sodium hydroxide solution (10mL) successively, 1M hydrochloric acid (10mL), saturated nacl aqueous solution washing (10mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product (1R, 5S)-6-[[2, the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid-1-methylcyclopropyl groups ester 19 (100mg, white solid), productive rate: 58.8%.
MS m/z(ESI)：424.2[M-53]
1H NMR(400MHz，d-DMSO)δ7.98(d，4H)，7.65(d，2H)，4.05(d，2H)，3.41(d，2H)，3.35-3.28(m，5H)，1.56(s，2H)，1.42(s，3H)，0.91-0.90(m，1H)，0.74-0.72(m，2H)，0.57-0.56(m，2H).
Embodiment 20
9-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-7-oxa--3-azabicyclic also [3.3.1] nonane-3-carboxylic acid tert-butyl ester
The first step
9-hydroxyl-7-oxa--3-azabicyclic also [3.3.1]-3-in ninth of the ten Heavenly Stems carboxylic acid tert-butyl ester
By 3-benzyl-7-oxa--3-azabicyclic also [3.3.1]-9-in ninth of the ten Heavenly Stems alcohol 20a (2g, 8.57mmol, known method " patent WO2010009195 " is adopted to prepare and obtain) be dissolved in 50mL methyl alcohol, add triethylamine (1.73g, 17.14mmol) and tert-Butyl dicarbonate (2.25g, 10.29mmol) successively, add palladium hydroxide (1.81g again, 2.57mmol), replacing hydrogen 3 times, stirring reaction 12 hours.Filter, filtrate reduced in volume, obtains crude title product 9-hydroxyl-7-oxa--3-azabicyclic also [3.3.1]-3-in ninth of the ten Heavenly Stems carboxylic acid tert-butyl ester 20b (2.31g, yellow liquid), and product is not purified directly carries out next step reaction.
MS m/z(ESI)：242.2[M+1]
Second step
9-mesyloxy-7-oxa--3-azabicyclic also [3.3.1]-3-in ninth of the ten Heavenly Stems carboxylic acid tert-butyl ester
Under ice bath, by crude product 9-hydroxyl-7-oxa--3-azabicyclic also [3.3.1]-3-in ninth of the ten Heavenly Stems carboxylic acid tert-butyl ester 20b (2.09g, 8.57mmol) be dissolved in 50mL anhydrous methylene chloride, add triethylamine (1.73g, 17.14mmol), drip methylsulfonyl chloride (1.47g, 12.86mmol), rise to room temperature reaction 12 hours.Add water 50mL, extraction separatory, aqueous phase methylene dichloride (50mL × 2) extracts, merge organic phase, use saturated sodium bicarbonate solution (30mL) successively, saturated nacl aqueous solution washing (30mL), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtain crude title product 9-mesyloxy-7-oxa--3-azabicyclic also [3.3.1]-3-in ninth of the ten Heavenly Stems carboxylic acid tert-butyl ester 20c (2.16g, yellow oily), product is not purified directly carries out next step reaction.
3rd step
9-(bromo-2, the 6-dilquoro-phenogy of 4-)-7-oxa--3-azabicyclic also [3.3.1]-3-in ninth of the ten Heavenly Stems carboxylic acid tert-butyl ester
By crude product 9-mesyloxy-7-oxa--3-azabicyclic also [3.3.1]-3-in ninth of the ten Heavenly Stems carboxylic acid tert-butyl ester 20c (1g, 3.11mmol) with 4-bromo-2,6-difluoro-phenol (0.71g, 3.41mmol) be dissolved in 40mLN, in dinethylformamide, then add cesium carbonate (2.03g, 6.22mmol), be warming up to 90 DEG C of stirring reactions 2 hours, then be warming up to 150 DEG C of stirring reactions 5 hours.Add 60mL water, extraction into ethyl acetate (50mL × 3), merges organic phase, saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 9-(4-bromo-2,6-dilquoro-phenogy)-7-oxa--3-azabicyclic also [3.3.1]-3-in ninth of the ten Heavenly Stems carboxylic acid tert-butyl ester 20d (0.32g, yellow solid), productive rate: 23%.
MS m/z(ESI)：379.1[M-55]
4th step
9-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-7-oxa--3-azabicyclic also [3.3.1] nonane-3-carboxylic acid tert-butyl ester
By 9-(4-bromo-2; 6-dilquoro-phenogy)-7-oxa--3-azabicyclic also [3.3.1]-3-in ninth of the ten Heavenly Stems carboxylic acid tert-butyl ester 20d (0.32g; 0.74mmol); (4-methanesulfonylphenYl) boric acid (178mg; 0.89mmol) He 1; 1 '-two (diphenyl phosphine) ferrocene palladium chloride (54mg; 0.07mmol) be dissolved in 20mL 1; in 4-dioxane; add cesium carbonate (0.72g again; 2.22mmol), 120 DEG C of stirring reactions 3 hours are warming up to.Add 20mL water; extraction into ethyl acetate (30mL × 3); merge organic phase; saturated nacl aqueous solution washing (30mL); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with eluent system B with silica gel column chromatography; obtain title product 9-[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group]-7-oxa--3-azabicyclic also [3.3.1] nonane-3-carboxylic acid tert-butyl ester 20 (0.18g, white solid), productive rate: 48.7%.
MS m/z(ESI)：454.1[M-55]
1H NMR(400MHz，CDCl 3)δ8.01-8.04(m，2H)，7.70-7.72(m，2H)，7.19-7.21(m，2H)，4.27-4.63(m，7H)，3.85-3.94(m，2H)，3.16-3.19(m，1H)，3.11(s，3H)，3.03-3.07(m，1H)，1.49(s，9H).
Embodiment 21
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid-1-methyl-cyclobutyl ester
The first step
(1-methyl-cyclobutyl) (4-nitrophenyl) carbonic ether
By chlorine carbonic acid-(4-nitrophenyl) ester (1.68g, 8.36mmol) be dissolved in 20mL methylene dichloride, add crude product 1-methyl-cyclobutyl alcohol 21a (600mg successively, 6.97mmol, known method " patent WO2010009195 " is adopted to prepare and obtain), DMAP (60mg, cat.) and 5mL trimethylpyridine, stirring reaction 12 hours.Drip the reaction of 1M hydrochloric acid, separatory, merge organic phase, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product (1-methyl-cyclobutyl) (4-nitrophenyl) carbonic ether 21b (0.40g, colourless liquid), productive rate: 24%.
Second step
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid-1-methyl-cyclobutyl ester
Under ice bath; by (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 19a (166mg; 0.40mmol); triethylamine (81mg; 0.80mmol) be dissolved in 10mL methylene dichloride; add 2mL (1-methyl-cyclobutyl) (4-nitrophenyl) carbonic ether 21b (100mg; dichloromethane solution 0.40mmol), rises to stirring at room temperature and reacts 15 hours.Add 40mL methylene dichloride, use 1M sodium hydroxide solution (10mL × 2) successively, 1M hydrochloric acid (10mL), saturated nacl aqueous solution washing (10mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product (1R, 5S)-6-[[2, the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid-1-methyl-cyclobutyl ester 21 (82mg, white solid), productive rate: 58.8%.
MS m/z(ESI)：492.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.01-8.04(m，2H)，7.70-7.73(m，2H)，7.17-7.27(m，2H)，4.08-4.10(m，2H)，3.60-3.62(m，2H)，3.37-3.41(m，2H)，3.10(s，3H)，2.28-2.31(m，2H)，2.08-2.13(m，2H)，1.76-1.78(m，1H)，1.64-1.66(m，1H)，1.57(s，3H)，1.25-1.27(m，2H)，1.13-1.15(m，1H).
Embodiment 22
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(3-pyridine)-3-pyridine] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By (1R, 5S)-6-[(6-chloro-3-pyridyl) oxygen methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 13a (100mg, 0.30mmol), 3-pyridine boronic acid (48.30mg, 0.39mmol), two (triphen phosphino-) palladium chloride (100mg, 0.14mmol) be dissolved in 20mLN with 1.5mL 2M sodium carbonate solution, in dinethylformamide, rise to 85 DEG C of stirring reactions 12 hours.Add water 100mL, be extracted with ethyl acetate (50mL × 3), merge organic phase, use water (20mL × 3) successively, saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purify gained resistates by thin-layer chromatography chromatography with developping agent system B, obtain title product (1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(3-pyridine)-3-pyridine] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 22 (50mg, white solid), productive rate: 44.6%.
MS m/z(ESI)：374.2[M+1]
1H NMR(400MHz，CDCl 3)δ9.13(d，1H)，8.60(dd，1H)，8.41(d，1H)，8.32-8.23(m，1H)，8.17(s，2H)，7.68(d，1H)，7.38(dd，1H)，7.29(dd，1H)，4.00(dd，4H)，3.58(dd，2H)，2.46(q，2H)，1.98(s，1H)，1.77(dd，2H)，1.18(t，3H).
Embodiment 23
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[5-(the fluoro-4-pyridine of 3-) pyrazine-2-base] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By (1R, 5S)-6-[(5-bromo-pyrazine-2-base) oxygen methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 12a (100mg, 0.27mmol), (the fluoro-4-pyridine of 3-) boric acid (75mg, 0.53mmol), two (triphen phosphino-) palladium chloride (50mg, 0.07mmol) be dissolved in 10mL N with 1mL 2M sodium carbonate solution, in dinethylformamide, rise to 85 DEG C of stirring reactions 3 hours.Add 30mL water, be extracted with ethyl acetate (30mL × 3), merge organic phase, use water (20mL × 2) successively, saturated nacl aqueous solution washing (20mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product (1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[5-(the fluoro-4-pyridine of 3-) pyrazine-2-base] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 23 (70mg, white solid), productive rate: 67.3%.
MS m/z(ESI)：393.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.73-8.72(m，1H)，8.58-8.51(m，2H)，8.37(d，1H)，8.18(s，2H)，8.00(dd，1H)，4.35(d，2H)，3.97(d，2H)，3.61-3.56(m，2H)，2.48(q，2H)，1.80-1.76(m，2H)，1.31-1.26(m，1H)，1.19(t，3H).
Embodiment 24
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[(5-pyrimidine-5-base-pyridine-2-base) oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By (1R, 5S)-6-[(5-bromo-pyrazine-2-base) oxygen methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 12a (170mg, 0.45mmol), pyrimidine-5-base-boric acid (73mg, 0.59mmol), two (triphen phosphino-) palladium chloride (35mg, 0.05mmol) be dissolved in 6mL N with 1.5mL 2M sodium carbonate solution, in dinethylformamide, rise to 85 DEG C of stirring reactions 5 hours.Add 30mL water, be extracted with ethyl acetate (30mL × 3), merge organic phase, use water (20mL × 2) successively, saturated nacl aqueous solution washing (20mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A, obtain title product (1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[(5-pyrimidine-5-base-pyridine-2-base) oxygen methyl]-3-azabicyclo also [3.1.0] hexane 24 (110mg, faint yellow solid), productive rate: 65.0%.
MS m/z(ESI)：376.2[M+1]
1H NMR(400MHz，CDCl 3)δ9.27(s，2H)，9.25(s，1H)，8.53(d，1H)，8.36(d，1H)，8.17(d，2H)，4.34(d，2H)，3.95(d，2H)，3.57(d，2H)，2.46(q，2H)，1.78-1.77(m，2H)，1.30-1.26(m，1H)，1.18(t，3H).
Embodiment 25
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[the fluoro-4-of 2-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
The first step
The fluoro-4-of 2-(4-methylsulfonyl phenyl) phenol
By the fluoro-phenol 25a of bromo-for 4-2-(478mg, 2.50mmol) be dissolved in (V/V=4: 1) in the mixed solvent of 15mL first alcohol and water, add (4-methylsulfonyl phenyl) boric acid (1g, 5mmol) with sodium carbonate (269mg, 2.50mmol), add tetra-triphenylphosphine palladium (200mg, 0.14mmol), 120 DEG C, microwave reaction 10 minutes.Add 50mL water and 30mL ethyl acetate successively, dripping 1M hydrochloric acid is 3 to reaction solution pH.Filter, filtrate is extracted with ethyl acetate (30mL × 3), merge organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains the fluoro-4-of title product 2-(4-methylsulfonyl phenyl) phenol 25b (82mg, white solid), productive rate: 56.1%.
MS m/z(ESI)：284.1[M+18]
Second step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[the fluoro-4-of 2-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
By [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (110mg, 1mmol) with the fluoro-4-of 2-(4-methylsulfonyl phenyl) phenol 25b (133mg, 0.50mmol) be dissolved in 10mLN, in dinethylformamide, add salt of wormwood (138mg, 1mmol), be warming up to 100 DEG C of stirring reactions 5 hours.Add 15mL water; be extracted with ethyl acetate (30mL × 3); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; with the tertiary ether of first and methyl alcohol (V/V=50: 1) mixed solvent washing purifying gained resistates; obtain title product (1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[the fluoro-4-of 2-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 25 (135mg; white solid), productive rate: 57.5%.
MS m/z(ESI)：468.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.18(s，2H)，7.99(d，2H)，7.71(d，2H)，7.35-7.39(m，2H)，7.07(t，1H)，4.07(d，2H)，3.98(d，2H)，3.59(d，2H)，3.10(s，3H)，2.47(q，2H)，1.79(s，2H)，1.25-1.28(m，1H)，1.19(t，3H).
Embodiment 26,27
Trans-(3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-5-[the fluoro-4-of 2-(4-methylsulfonyl phenyl) phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
Cis-(3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-5-[the fluoro-4-of 2-(4-methylsulfonyl phenyl) phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
Trans-(3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-5-[the fluoro-4-of 2-(4-methylsulfonyl phenyl) phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
Cis-(3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-5-[the fluoro-4-of 2-(4-methylsulfonyl phenyl) phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
By (3aR, 6aS) the bromo-2-of-5-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles 3a (340mg, 1.15mmol) be dissolved in 30mL DMF with the fluoro-4-of 2-(4-methylsulfonyl phenyl) phenol 25b (300mg, 1.13mmol), add salt of wormwood (172mg again, 1.24mmol), be warming up to 60 DEG C of stirring reactions 1 hour, then be warming up to 120 DEG C of stirring reactions 1 hour.Add 50mL water, extraction into ethyl acetate (30mL × 3), merge organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain a pair diastereomer, trans-(3aR respectively, 6aS)-2-(5-ethyl-pyrimidine-2-base)-5-[the fluoro-4-of 2-(4-methylsulfonyl phenyl) phenoxy group]-3, 3a, 4, 5, 6, 6a-six hydrogen-1H-cyclopentano [c] pyrroles 26 (54mg, white solid), productive rate: 29.5%.Cis-(3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-5-[the fluoro-4-of 2-(4-methylsulfonyl phenyl) phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles 27 (160mg, white solid), productive rate: 10.0%.
MS m/z(ESI)：482.2[M+1]
26 1H NMR(400MHz，CDCl 3)δ8.20(s，2H)，8.07-7.90(m，2H)，7.77-7.65(m，2H)，7.41-7.27(m，2H)，7.03(t，1H)，5.10-4.93(m，1H)，3.75(dd，2H)，3.53(dd，2H)，3.09(s，5H)，2.48(q，2H)，2.32(dd，2H)，2.04-1.85(m，2H)，1.19(t，3H).
27 1H NMR(400MHz，CDCl 3)δ8.19(s，2H)，8.02-7.92(m，2H)，7.73-7.64(m，2H)，7.34-7.27(m，2H)，7.06-6.94(m，1H)，4.94(s，1H)，3.84(dd，2H)，3.67(dd，2H)，3.08(s，3H)，2.89(d，2H)，2.53-2.33(m，4H)，2.03-1.90(m，2H)，1.20(t，3H).
Embodiment 28
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(the fluoro-4-pyridine of 3-) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By [(1R, 5S)-6-[(4-bromo-2,6-dilquoro-phenogy) methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 8a (100mg, 0.24mol), (the fluoro-4-pyridine of 3-) boric acid (34mg, 0.24mmol) He 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (3.50mg, 0.01mmol) be dissolved in 10mL 1, in 4-dioxane, add three hypophosphite monohydrate potassium (191.50mg, 0.72mmol) again, be warming up to return stirring and react 5 hours.Filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product (1R, 5S)-6-[[2, the fluoro-4-of 6-bis-(the fluoro-4-pyridine of 3-) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 28 (60mg, white solid), productive rate: 57.6%.
MS m/z(ESI)：427.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.56(s，1H)，8.49(s，1H)，8.19(s，2H)，7.36-7.34(m，1H)，7.22(d，2H)，4.16(d，2H)，3.92(d，2H)，3.57(d，2H)，2.47(q，2H)，1.74(s，2H)，1.20-1.17(m，4H).
Embodiment 29
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-(5-propyl group pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 19a (150mg; 0.36mmol); the chloro-5-propyl-pyrimidin (56mg, 0.36mmol) of 2-and salt of wormwood (149mg, 1.10mmol) are dissolved in 5mL N; in dinethylformamide, be warming up to 150 DEG C of stirring reactions 8 hours.Cooling; add 20mL water; be extracted with ethyl acetate (10mL × 3); merge organic phase; with saturated ammonium chloride solution washing (10mL × 5); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume, purifies gained resistates by thin-layer chromatography chromatography with developping agent system B, obtains title product (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-(5-propyl group pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 29 (100mg, white solid), productive rate: 55.5%.
MS m/z(ESI)：500.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.16(s，2H)，8.02(q，2H)，7.71(q，2H)，7.17(d，2H)，4.14(d，2H)，3.90(d，2H)，3.56(d，2H)，3.10(s，3H)，2.39(t，2H)，1.72(s，2H)，1.59-1.53(m，2H)，1.24-1.21(m，1H)，0.93(t，3H).
Embodiment 30
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-[the fluoro-5-of 3-(trifluoromethyl)-2-pyridine]-3-azabicyclo also [3.1.0] hexane
By (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 19a (20mg; 0.05mmol); triethylamine (12mg; 0.12mmol) be dissolved in 5mL methylene dichloride; under ice bath; be added dropwise to the fluoro-5-of 2,3-bis-(trifluoromethyl) pyridine (9mg, 0.05mmol); rise to stirring at room temperature and react 2 hours; add salt of wormwood (13mg, 0.10mmol) again, stirring at room temperature 12 hours.Filter; filtrate reduced in volume; gained resistates is purified with developping agent system B by thin-layer chromatography chromatography; obtain title product (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-[the fluoro-5-of 3-(trifluoromethyl)-2-pyridine]-3-azabicyclo also [3.1.0] hexane 30 (20mg, white solid), productive rate: 76.0%.
MS m/z(ESI)：543.1[M+1]
1H NMR(400MHz，CDCl 3)δ8.17(s，1H)，8.03-8.01(m，2H)，7.71(q，2H)，7.33-7.30(m，1H)，7.19(d，2H)，4.14(d，2H)，4.07-4.04(m，2H)，3.71(d，2H)，3.10(s，3H)，1.76(d，2H)，1.25-1.22(m，1H).
Embodiment 31
4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-3,5-difluorophenyl] benzonitrile
By [(1R, 5S)-6-[(4-bromo-2,6-dilquoro-phenogy) methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 8a (100mg, 0.24mol), (4-cyano-phenyl) boric acid (43mg, 0.29mmol) He 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (17mg, 0.02mmol) be dissolved in 10mL 1, in 4-dioxane, add cesium carbonate (238mg, 0.70mmol) again, be warming up to 120 DEG C of stirring reactions 2 hours.Cooling, add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (10mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates by thin-layer chromatography chromatography with developping agent system B, obtains title product 4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-3,5-difluorophenyl] benzonitrile 31 (59mg, white solid), productive rate: 56.0%.
MS m/z(ESI)：433.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.18(s，2H)，7.73-7.75(m，2H)，7.67-7.63(m，2H)，7.14-7.16(m，2H)，4.13-4.15(m，2H)，3.88-3.91(m，2H)，3.55-3.57(m，2H)，2.44-2.49(m，2H)，1.72(d，2H)，1.17-1.20(m，4H).
Embodiment 32
4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-3,5-difluorophenyl] the fluoro-benzonitrile of-2-
The first step
(the fluoro-phenyl of 4-cyano group-3-) boric acid
2-(2-Dimethylaminoethoxy)-N, N-dimethyl-ethylamine (0.5mL, 2.53mmol) is dissolved in 20mL tetrahydrofuran (THF), under ice bath, adds 2.53mL 2M isopropylmagnesium chloride, stir 20 minutes.Add the iodo-benzonitrile 32a (500mg, 2.02mol) of the fluoro-4-of 2-again, be warming up to 15 DEG C of reactions 2 hours.Reaction solution is cooled to 0 DEG C, then adds three isopropoxy borines (0.9mL, 4.05mmol), rise to room temperature reaction 2 hours.Add 5mL 1M hydrochloric acid, be extracted with ethyl acetate (30mL × 2), merge organic phase, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains title crude product (the fluoro-phenyl of 4-cyano group-3-) boric acid 32b (310mg, yellow oily), product is not purified directly carries out next step reaction.
Second step
4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-3,5-difluorophenyl] the fluoro-benzonitrile of-2-
By [(1R, 5S)-6-[(4-bromo-2,6-dilquoro-phenogy) methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 8a (100mg, 0.24mol), crude product (the fluoro-phenyl of 4-cyano group-3-) boric acid 32b (48mg, 0.30mmol) He 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (18mg, 0.02mmol) be dissolved in 10mL 1, in 4-dioxane, add cesium carbonate (238mg, 0.70mmol) again, be warming up to 120 DEG C of stirring reactions 2 hours.Cooling, add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (10mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates by thin-layer chromatography chromatography with developping agent system B, obtains title product 4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-3,5-difluorophenyl] the fluoro-benzonitrile 32 (10mg, white solid) of-2-, productive rate: 9.1%.
MS m/z(ESI)：451.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.21(s，2H)，7.69-7.72(m，1H)，7.38-7.43(m，2H)，7.14-7.16(m，2H)，4.13-4.16(m，2H)，3.96(d，2H)，3.63(d，2H)，2.48-2.52(m，2H)，1.76(d，2H)，1.26(d，1H)，1.18-1.21(m，3H).
Embodiment 33
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(4-methylsulfonyl phenyl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
The first step
4-(4-methanesulfonylphenYl) phenol
By 4-bromophenol 33a (100mg; 0.58mmol); (4-methanesulfonylphenYl) boric acid (127mg; 0.64mmol) be dissolved in 10m L1 with 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (42mg, 0.05mmol); in 4-dioxane; add three hypophosphite monohydrate potassium (462mg, 1.73mmol) again, be warming up to 120 DEG C of stirring reactions 2 hours.Add 25mL water, extraction into ethyl acetate (50mL × 2), merge organic phase.Aqueous phase 5% sodium hydroxide solution washs (10mL); dripping 3M hydrochloric acid is 6 ~ 7 to reacting liquid pH value; extraction into ethyl acetate (50mL × 2); merge organic phase, anhydrous magnesium sulfate drying, filter; filtrate reduced in volume; obtain title crude product 4-(4-methanesulfonylphenYl) phenol 33b (135mg, gray solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：266.1[M+18]
Second step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(4-methylsulfonyl phenyl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
By [(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (100mg; 0.40mmol) with crude product 4-(4-methanesulfonylphenYl) phenol 33b (120mg; 0.40mmol) be dissolved in 10mL N; in N-N,N-DIMETHYLACETAMIDE; add cesium carbonate (262mg, 0.80mmol) again, be warming up to 120 DEG C of stirring reactions 10 hours.Add 25mL water, extraction into ethyl acetate (20mL × 3), merge organic phase, with saturated nacl aqueous solution washing (10mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product (1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(4-methylsulfonyl phenyl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 33 (70mg, white solid), productive rate: 38.7%.
MS m/z(ESI)：450.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.21(s，2H)，7.97-7.99(m，2H)，7.73-7.74(m，2H)，7.55-7.57(m，2H)，7.00-7.02(m，2H)，4.00-4.03(m，4H)，3.62-3.65(m，2H)，3.09(s，3H)，2.46-2.52(m，2H)，1.79(s，2H)，1.24-1.26(m，1H)，1.18-1.23(m，3H).
Embodiment 34
5-[(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole
The first step
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-formonitrile HCN
By (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 19a (250mg; 0.70mmol) with cyanogen bromide (114mg; 1mmol) be dissolved in 10mL chloroform; add salt of wormwood (398mg, 2.50mmol) again, be warming up to return stirring and react 48 hours.Filter; filtrate reduced in volume; obtain title crude product (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-formonitrile HCN 34a (230mg; white solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：422.1[M+18]
Second step
5-[(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole
By (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-formonitrile HCN 34a (200mg; 0.50mol) and N '-hydroxy-2-methyl-the third amidine (36mg; 0.54mmol) be dissolved in 10mL tetrahydrofuran (THF); add the tetrahydrofuran solution of 0.54mL 1M zinc chloride, sedimentation 15 minutes.Said mixture is dissolved in the mixed solvent of the second alcohol and water of 15mL 4M hydrogenchloride (V/V=1: 1), is warming up to return stirring and reacts 1 hour.Add excessive sodium carbonate neutralization reaction, filter, add ethyl acetate 20mL, with saturated nacl aqueous solution washing (20mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product 5-[(1R, 5S)-6-[[2, the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1, 2, 4-oxadiazole 34 (102mg, white solid), productive rate: 42.0%.
MS m/z(ESI)：490.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.02-8.04(m，2H)，7.70-7.72(m，2H)，7.18-7.20(m，2H)，4.13-4.15(m，2H)，3.83-3.85(m，2H)，3.66-3.69(m，2H)，3.10(s，3H)，2.90-2.94(m，1H)，1.79(s，2H)，1.29-1.31(m，6H)，1.21(s，1H).
Embodiment 35
4-[5-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-2-pyridine] benzonitrile
By (1R, 5S)-6-[(6-chloro-3-pyridyl) oxygen methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 13a (130mg, 0.39mmol), (4-cyano-phenyl) boric acid (75mg, 0.51mmol), two (triphen phosphino-) palladium chloride (100mg, 0.14mmol) be dissolved in 20mL N with 1.5mL 2M sodium carbonate solution, in dinethylformamide, rise to 85 DEG C of stirring reactions 20 hours.Add 100mL water, be extracted with ethyl acetate (50mL × 3), merge organic phase, with saturated nacl aqueous solution washing (15mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product 4-[5-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-2-pyridine] benzonitrile 35 (109mg, white solid), productive rate: 70.0%.
MS m/z(ESI)：398.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.40(d，1H)，8.17(s，2H)，8.05(d，2H)，7.71(dd，3H)，7.28(dd，1H)，4.00(dd，4H)，3.58(d，2H)，2.46(q，2H)，1.78(s，2H)，1.64(s，1H)，1.18(t，3H).
Embodiment 36
(1R, 5S)-6-[(the fluoro-4-pyrimidine of 2,6-bis--5-base-phenoxy group) methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By [(1R, 5S)-6-[(4-bromo-2,6-dilquoro-phenogy) methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 8a (100mg, 0.24mol), pyrimidine-5-base-boric acid (36mg, 0.29mmol) He 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (18mg, 0.02mmol) be dissolved in 5mL 1, in the mixed solvent of 4-dioxane and 1mL water, be warming up to 120 DEG C of stirring reactions 8 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 3), merge organic phase, with saturated nacl aqueous solution washing (5mL × 3), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product (1R, 5S)-6-[(the fluoro-4-pyrimidine of 2,6-bis--5-base-phenoxy group) methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 36 (65mg, white solid), productive rate: 66.0%.
MS m/z(ESI)：410.2[M+1]
1H NMR(400MHz，CDCl 3)δ9.20(s，3H)，8.20(s，2H)，7.77(d，2H)，4.12(d，2H)，3.73(d，2H)，3.44(d，2H)，2.40(q，2H)，1.71(s，2H)，1.11(t，3H)，0.90-0.89(m，1H).
Embodiment 37
3-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-8-(5-ethyl-pyrimidine-2-base)-8-azabicyclo also [3.2.1] octane
The first step
3-[4-(4-methanesulfonylphenYl)-2,6-dilquoro-phenogy]-8-azabicyclo also [3.2.1] octane
By 3-[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 18 (100mg; 0.20mmol) be dissolved in 2mL 2M hydrogen chloride methanol solution, stirring reaction 5 hours.Reaction solution concentrating under reduced pressure; obtain title crude product 3-[4-(4-methanesulfonylphenYl)-2; 6-dilquoro-phenogy]-8-azabicyclo also [3.2.1] octane 37a (85mg, white solid), product is not purified directly carries out next step reaction.
Second step
3-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-8-(5-ethyl-pyrimidine-2-base)-8-azabicyclo also [3.2.1] octane
By crude product 3-[4-(4-methanesulfonylphenYl)-2; 6-dilquoro-phenogy]-8-azabicyclo also [3.2.1] octane 37a (85mg; 0.20mol); the chloro-5-ethyl-pyrimidin of 2-(42mg; 0.30mmol) with salt of wormwood (82mg; 0.60mol) be dissolved in 3mLN, in dinethylformamide, be warming up to 100 DEG C of stirring reactions 12 hours.Add 20mL water; be extracted with ethyl acetate (20mL × 3); merge organic phase; with saturated nacl aqueous solution washing (5mL × 3); anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system B by thin-layer chromatography chromatography; obtain title product 3-[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group]-8-(5-ethyl-pyrimidine-2-base)-8-azabicyclo also [3.2.1] octane 37 (35mg, white solid), productive rate: 34.0%.
MS m/z(ESI)：500.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.26(s，2H)，7.99(t，4H)，7.67(d，2H)，4.63(s，2H)，4.58(t，1H)，3.26(s，3H)，2.43(q，2H)，2.33(d，2H)，2.02-1.99(m，2H)，1.97-1.94(m，4H)，1.30-1.23(m，3H).
Embodiment 38,39
Cis-(3aR, 6aS)-5-[the fluoro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl esters
Trans-(3aR, 6aS)-5-[the fluoro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl esters
The first step
The fluoro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenol
Crude product 1-Nmethanesulphonylpiperazine 1f (4.30g, 0.02mol) is dissolved in 40mL ethylene dichloride, adds the fluoro-4-hydroxy-benzaldehyde (3g, 0.02mol) of 3-, rise to 80 DEG C of stirring reactions 2 hours.Be cooled to room temperature, under ice bath, add ethanoyl sodium borohydride (8.50g, 0.04mol), rise to 80 DEG C of stirring reactions 3 hours, then be down to 50 DEG C of reactions 12 hours.Be down to room temperature; under ice bath, drip 100mL10% sodium hydroxide solution, dripping 10% hydrogen chloride solution to reaction solution pH is 7; dichloromethane extraction (100mL × 3); merge organic phase, anhydrous magnesium sulfate drying, filter; filtrate reduced in volume; obtain the fluoro-4-of crude title product 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenol 38a (3.80g, white solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：289.1[M+1]
Second step
Cis-(3aR, 6aS)-5-[the fluoro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl esters
Trans-(3aR, 6aS)-5-[the fluoro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl esters
By fluoro-for crude product 2-4-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenol 38a (200mg, 0.69mmol) and (3aR, 6aS)-5-bromo-3; 3a; 4,5,6; 6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 15a (200mg; 0.69mmol) be dissolved in 5mL DMF, then add salt of wormwood (192mg; 1.39mmol), 150 DEG C of stirring reactions 4 hours are warming up to.Add 10mL water; extraction into ethyl acetate (10mL × 3); merge organic phase; anhydrous magnesium sulfate drying; filter, filtrate reduced in volume, purify gained resistates by preparative separation method; obtain the isomer that two kinds are configuration reversal; cis-(3aR, 6aS)-5-[the fluoro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-3,3a respectively; 4; 5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 38 (60mg; white solid), productive rate: 21.0%.Trans-(3aR, 6aS)-5-[the fluoro-4-of 2-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-3,3a; 4,5,6; 6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 39 (10mg, white solid), productive rate: 3.0%.
MS m/z(ESI)：498.3[M+1]
38 1H NMR(400MHz，CDCl 3)δ7.07-7.04(m，1H)，6.94(d，1H)，6.85(t，1H)，4.84-4.78(m，1H)，3.57(s，2H)，3.46(s，2H)，3.38-3.36(m，2H)，3.26-3.23(m，3H)，2.78(s，3H)，2.70(s，2H)，2.55-2.53(m，4H)，2.27(s，2H)，1.85(s，3H)，1.46(s，9H).
39 1H NMR(400MHz，CDCl 3)δ7.09-7.05(m，1H)，6.95(d，1H)，6.86(t，1H)，4.91-4.89(m，1H)，3.52-3.47(m，4H)，3.26-3.23(m，6H)，2.91(s，2H)，2.78(s，3H)，2.56-2.53(m，4H)，2.24-2.19(m，2H)，1.82-1.78(m，2H)，1.46(s，9H).
Embodiment 40
4-[4-[[(3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-5-base] oxygen base]-3,5-difluorophenyl] cyanophenyl
By crude product (3aR, 6aS)-5-(4-bromo-2,6-dilquoro-phenogy)-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles 4a (210mg, 0.50mol), (4-cyano-phenyl) boric acid (110mg, 0.75mmol) be dissolved in 20mL 1 with 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (36mg, 0.05mmol), in 4-dioxane, be warming up to 120 DEG C of stirring reactions 3 hours.Filter, add 20mL water, be extracted with ethyl acetate (50mL × 3), merge organic phase, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 4-[4-[[(3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-5-base] oxygen base]-3,5-difluorophenyl] cyanophenyl 40 (80mg, white solid), productive rate: 36.4%.
MS m/z(ESI)：447.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.22(s，2H)，7.72(d，2H)，7.59(d，2H)，7.09-7.14(m，2H)，4.93-4.96(m，1H)，3.82-3.87(m，2H)，3.69-3.73(m，2H)，2.84-2.87(m，2H)，2.49(q，2H)，2.33-2.36(m，2H)，1.97-2.02(m，2H)，1.21(t，3H).
Embodiment 41
9-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-3-(5-ethyl-pyrimidine-2-base) 7-oxa--3-azabicyclic also [3.3.1] nonane
The first step
7-oxa--3-azabicyclic is [3.3.1]-9-in ninth of the ten Heavenly Stems alcohol also
By 3-benzyl-7-oxa--3-azabicyclic also [3.3.1]-9-in ninth of the ten Heavenly Stems alcohol 20a (2g, 8.57mmol, known method " patent WO2010009195 " is adopted to prepare and obtain) be dissolved in 30mL methyl alcohol, add palladium hydroxide (1.81g, 2.57mmol), replacing hydrogen 3 times, stirring reaction 12 hours.Filter, filtrate reduced in volume, obtains crude title product 7-oxa--3-azabicyclic also [3.3.1]-9-in ninth of the ten Heavenly Stems alcohol 41a (1.38g, brown liquid), and product is not purified directly carries out next step reaction.
MS m/z(ESI)：144.1[M+1]
Second step
3-(5-ethyl-pyrimidine-2-base)-7-oxa--3-azabicyclic also [3.3.1]-9-in ninth of the ten Heavenly Stems alcohol
By crude product 7-oxa--3-azabicyclic also [3.3.1]-9-in ninth of the ten Heavenly Stems alcohol 41a (1.23g, 8.57mmol) be dissolved in 20mL ethylene dimethyl, add the chloro-5-ethyl-pyrimidine of 2-(1.23g, 8.57mmol) with salt of wormwood (1.78g, 12.86mmol), 150 DEG C of stirring reactions 7 hours.Add water 30mL, be extracted with ethyl acetate (50mL × 3), merge organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtain crude title product 3-(5-ethyl-pyrimidine-2-base)-7-oxa--3-azabicyclic also [3.3.1]-9-in ninth of the ten Heavenly Stems alcohol 41b (1.26g, yellow oily), product is not purified directly carries out next step reaction.
MS m/z(ESI)：250.2[M+1]
3rd step
[3-(5-ethyl-pyrimidine-2-base)-7-oxa--3-azabicyclic also [3.3.1]-9-in ninth of the ten Heavenly Stems base] methanesulfonate ester
Under ice bath, by crude product 3-(5-ethyl-pyrimidine-2-base)-7-oxa--3-azabicyclic also [3.3.1]-9-in ninth of the ten Heavenly Stems alcohol 41b (1.26g, 5.05mmol) be dissolved in 50mL methylene dichloride, add triethylamine (1.02g, 10.10mmol), methylsulfonyl chloride (0.87g, 7.58mmol) is dripped, rise to room temperature, react 2 hours.Add water 10mL, with dichloromethane extraction (20mL × 3), merge organic phase, with saturated nacl aqueous solution (30mL) washing, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, obtain crude title product [3-(5-ethyl-pyrimidine-2-base)-7-oxa--3-azabicyclic also [3.3.1]-9-in ninth of the ten Heavenly Stems base] methanesulfonate ester 41c (0.71g, yellow oily), product is not purified directly carries out next step reaction.
MS m/z(ESI)：328.1[M+1]
4th step
9-(bromo-2, the 6-dilquoro-phenogy of 4-)-3-(5-ethyl-pyrimidine-2-base)-7-oxa--3-azabicyclic also [3.3.1] nonane
By crude product [3-(5-ethyl-pyrimidine-2-base)-7-oxa--3-azabicyclic also [3.3.1]-9-in ninth of the ten Heavenly Stems base] methanesulfonate ester 41c (500mg, 1.53mmol), 4-bromo-2,6-difluoro-phenol (350mg, 1.68mmol) with salt of wormwood (420mg, 3.05mmol) be dissolved in 20mL DMF, be warming up to 150 DEG C of stirring reactions 7 hours.Add 50mL water, be extracted with ethyl acetate (50mL × 3), merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product 9-(4-bromo-2,6-dilquoro-phenogy)-3-(5-ethyl-pyrimidine-2-base)-7-oxa--3-azabicyclic also [3.3.1] nonane 41d (200mg, faint yellow solid), productive rate: 29.9%.
MS m/z(ESI)：440.1[M+1]
5th step
9-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-3-(5-ethyl-pyrimidine-2-base) 7-oxa--3-azabicyclic also [3.3.1] nonane
By 9-(4-bromo-2; 6-dilquoro-phenogy)-3-(5-ethyl-pyrimidine-2-base)-7-oxa--3-azabicyclic also [3.3.1] nonane 41d (50mg; 0.11mmol); (4-methanesulfonylphenYl) boric acid (28mg; 0.14mmol) He 1; 1 '-two (diphenyl phosphine) ferrocene palladium chloride (5mg; 0.01mmol) be dissolved in 5mL 1; in 4-dioxane; add potassiumphosphate (47mg again; 0.22mmol), 120 DEG C of stirring reactions 5 hours are warming up to.Add 10mL water; extraction into ethyl acetate (20mL × 3); merge organic phase; saturated nacl aqueous solution washing (20mL); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; prepare purifying gained resistates; obtain title product 9-[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group]-3-(5-ethyl-pyrimidine-2-base) 7-oxa--3-azabicyclic also [3.3.1] nonane 41 (22mg, white solid), productive rate: 39.3%.
MS m/z(ESI)：454.1[M-55]
1H NMR(400MHz，CDCl 3)δ8.13-8.22(m，2H)，8.02-8.04(m，2H)，7.70-7.73(m，2H)，7.18-7.23(m，2H)，5.07-5.11(m，1H)，4.77-4.80(m，1H)，4.63-4.66(m，1H)，4.31-4.34(m，1H)，4.17-4.20(m，1H)，3.87-3.90(m，1H)，3.71-3.78(m，2H)，3.28-3.32(m，1H)，3.11(s，3H)，2.44-2.50(m，2H)，2.20(s，1H)，0.96(s，1H)，1.17-1.20(m，3H).
Embodiment 42
3-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester
The first step
3-oxygen-8-azabicyclo is [3.2.1] octane-8-carboxylic acid tert-butyl ester also
By 3-hydroxyl-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 9b (5g, 21.90mmol) be dissolved in 50mL methylene dichloride, add pyridinium chlorochromate (7.10g, 32.90mmol), stirring at room temperature reacts 12 hours.Filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product 3-oxygen-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 42a (4.50g, light green solid), productive rate: 91.0%.
MS m/z(ESI)：170.1[M-55]
Second step
3-methylene radical-8-azabicyclo is [3.2.1] octane-8-carboxylic acid tert-butyl ester also
Under ice bath, the tetrahydrofuran solution 19.8mL of 1M potassium tert.-butoxide is added to 100mL containing methyltriphenylphosphonium bromide (7.14g, in tetrahydrofuran solution 19.80mol), stir 1 hour, add 3-oxygen-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 42a (3g again, 13.30mol), slowly rise to stirring at room temperature and react 12 hours.Add 50mL water, be extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase washed with water (10mL × 3), saturated nacl aqueous solution washing (10mL × 3), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains crude title product 3-methylene radical-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 42b (2.30g, colourless liquid), product is not purified directly carries out next step reaction.
3rd step
3-(hydroxymethyl)-8-azabicyclo is [3.2.1] octane-8-carboxylic acid tert-butyl ester also
Under ice bath, the tetrahydrofuran solution 6.2mL of 1M borine is added to 10mL crude product 3-methylene radical-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 42b (1g, tetrahydrofuran solution 4.76mol), slowly rises to stirring at room temperature and reacts 12 hours.Slowly add 5mL water, then add 14mL 2M sodium hydroxide solution and 7mL 30% superoxol, reaction solution is heated to 50 DEG C, stirs 1 hour.Be extracted with ethyl acetate (30mL × 3), merge organic phase, organic phase washed with water (10mL × 3), saturated nacl aqueous solution (10mL × 3) washs, anhydrous sodium sulfate drying, filters, filtrate reduced in volume, obtain crude title product 3-(hydroxymethyl)-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 42c (0.81g, colourless liquid), product is not purified directly carries out next step reaction.
4th step
3-(Methanesulfonvloxvmethvl)-8-azabicyclo is [3.2.1] octane-8-carboxylic acid tert-butyl ester also
Under ice bath, by crude product 3-(hydroxymethyl)-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 42c (500mg, 2.19mmol) be dissolved in 5mL anhydrous methylene chloride, add triethylamine (663mg, 6.57mmol), be added dropwise to methylsulfonyl chloride (300mg, 2.63mmol), rise to stirring at room temperature and react 12 hours.Add 10mL water, organic phase uses 1M hydrochloric acid (5mL × 3) successively, saturated nacl aqueous solution washing (5mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtains crude title product 3-(Methanesulfonvloxvmethvl)-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 42d (620mg, colourless liquid), product is not purified directly carries out next step reaction.
5th step
3-[(bromo-2, the 6-dilquoro-phenogy of 4-) methyl]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester
By crude product 3-(Methanesulfonvloxvmethvl)-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 42d (600mg, 1.88mmol) with 4-bromo-2,6-difluoro-phenol (469mg, 2.25mmol) be dissolved in 5mL ethylene dimethyl, add salt of wormwood (778mg again, 5.64mmol), 150 DEG C of stirring reactions 4 hours are warming up to.Add 20mL water, be extracted with ethyl acetate (20mL × 3), merge organic phase, organic phase washed with water (10mL × 3), saturated nacl aqueous solution washing (10mL × 3), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 3-[(bromo-2, the 6-dilquoro-phenogy of 4-) methyl]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 42e (150mg, white solid), productive rate: 18.0%.
MS m/z(ESI)：376.0[M-55]
6th step
3-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester
By 3-[(4-bromo-2; 6-dilquoro-phenogy) methyl]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 42e (150mg; 0.35mol); (4-methanesulfonylphenYl) boric acid (83mg; 0.42mmol) He 1; 1 '-two (diphenyl phosphine) ferrocene palladium chloride (26mg; 0.04mmol) be dissolved in 6mL 1; in the mixed solvent (V/V=5: 1) of 4-dioxane and water; add three hypophosphite monohydrate potassium (279mg; 1.05mmol), 120 DEG C of stirring reactions 7 hours are risen to.Filter; filtrate adds 20mL water; be extracted with ethyl acetate (20mL × 3); merge organic phase; use water (5mL × 3) successively; saturated nacl aqueous solution washing (5mL × 3); anhydrous sodium sulfate drying; filter, filtrate reduced in volume, purify gained resistates by thin-layer chromatography chromatography with developping agent system B; obtain title product 3-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 42 (130mg, white solid), productive rate: 73.0%.
MS m/z(ESI)：452.1[M-55]
1H NMR(400MHz，d-DMSO)δ7.99(s，4H)，7.65(d，2H)，4.18-4.17(m，2H)，4.11-4.06(m，2H)，3.22(s，3H)，2.08-2.07(m，2H)，2.05-2.01(m，1H)，1.99-1.92(m，2H)，1.62-1.60(m，2H)，1.56-1.52(m，2H)，1.43(s，9H).
Embodiment 43
3-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-8-(5-ethyl-pyrimidine-2-base)-8-azabicyclo also [3.2.1] octane
The first step
3-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-8-azabicyclo also [3.2.1] octane
By 3-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-8-azabicyclo also [3.2.1] octane-8-carboxylic acid tert-butyl ester 42 (70mg; 0.14mmol) be dissolved in 2mL 2M hydrogen chloride methanol solution, stirring reaction 12 hours.Reaction solution concentrating under reduced pressure; obtain title crude product 3-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-8-azabicyclo also [3.2.1] octane 43a (55mg, white solid), product is not purified directly carries out next step reaction.
Second step
3-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-8-(5-ethyl-pyrimidine-2-base)-8-azabicyclo also [3.2.1] octane
By crude product 3-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-8-azabicyclo also [3.2.1] octane 43a (55mg; 0.12mol); the chloro-5-ethyl-pyrimidin of 2-(26mg; 0.19mmol) with cesium carbonate (117mg; 0.36mol) be dissolved in 5mL DMF, be warming up to 120 DEG C of stirring reactions 4 hours.Add 20mL water; be extracted with ethyl acetate (20mL × 3); merge organic phase; use water (5mL × 3) successively; saturated nacl aqueous solution washing (5mL × 3); anhydrous sodium sulfate drying; filter; filtrate reduced in volume; purify gained resistates by thin-layer chromatography chromatography with developping agent system B, obtain title product 3-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-8-(5-ethyl-pyrimidine-2-base)-8-azabicyclo also [3.2.1] octane 43 (31mg; white solid), productive rate: 48.0%.
MS m/z(ESI)：514.2[M+1]
1H NMR(400MHz，d-DMSO)δ8.25(s，2H)，7.99(s，4H)，7.65(d，2H)，4.59(s，2H)，4.21(t，2H)，3.27(s，3H)，2.45-2.42(m，2H)，2.14-2.11(m，2H)，2.03-2.01(m，1H)，1.76-1.74(m，2H)，1.62-1.58(m，2H)，1.30-1.26(m，2H)，1.15-1.12(m，3H).
Embodiment 44
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[5-(4-methanesulfonylphenYl)-2-pyridine] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
The first step
(1R, 5S)-6-[(5-bromo-2-pyridyl) oxygen methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 7f (590mg, 2.69mmol) be dissolved in 10mL N, in dinethylformamide, be added dropwise to the N of 5mL containing 60% sodium hydride (129mg, 5.38mmol), dinethylformamide solution, stir 1 hour, reaction solution becomes faint yellow, is warming up to 50 DEG C of stirring reactions 0.5 hour.Be cooled to room temperature, then be added dropwise to the DMF solution of 5mL 2,5-dibromo pyridine (637mg, 2.69mmol), stir 12 hours.Add 100mL water, be extracted with ethyl acetate (50mL × 5), merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product (1R, 5S)-6-[(5-bromo-2-pyridyl) oxygen methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 44a (219mg, white solid), productive rate: 21.9%.
MS m/z(ESI)：377.2[M+1]
Second step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[5-(4-methanesulfonylphenYl)-2-pyridine] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By (1R; 5S)-6-[(5-bromo-2-pyridyl) oxygen methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 44a (200mg; 0.53mmol); (4-methanesulfonylphenYl) boric acid (139mg; 0.69mmol); two (triphen phosphino-) palladium chloride (100mg; 0.14mmol) be dissolved in 10mL glycol dimethyl ether with 2mL 2M sodium carbonate solution, rise to 80 DEG C of stirring reactions 12 hours.Add 100mL water; be extracted with ethyl acetate (30mL × 5); merge organic phase; with saturated nacl aqueous solution washing (50mL); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system B by thin-layer chromatography chromatography; obtain title product (1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[5-(4-methanesulfonylphenYl)-2-pyridine] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 44 (110mg, white solid), productive rate: 46.0%.
MS m/z(ESI)：451.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.38(d，1H)，8.17(s，2H)，8.01(d，2H)，7.82(dd，1H)，7.73-7.69(m，2H)，6.87(d，1H)，4.30(d，2H)，3.96(d，2H)，3.57(d，2H)，3.09(s，3H)，2.46(q，2H)，1.77-1.74(m，2H)，1.31-1.23(m，1H)，1.18(t，3H).
Embodiment 45
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[(5-pyridazine-4-base-2-pyridine) oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By (1R, 5S)-6-[(6-chloro-3-pyridyl base) oxygen methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 13a (200mg, 0.60mmol), tri-tert (pyridazine-4-base) tin (557mg, 1.50mmol) He two (triphen phosphino-) palladium chloride (50mg, 0.06mmol) be dissolved in 10mL 1, in 4-dioxane, rise to 110 DEG C of stirring reactions 20 hours.100mL ethyl acetate is added after reaction solution cooling, use water (30mL × 2) successively, saturated nacl aqueous solution washing (30mL), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product (1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[(5-pyridazine-4-base-2-pyridine) oxygen methyl]-3-azabicyclo also [3.1.0] hexane 45 (80mg, yellow solid), productive rate: 35.7%.
MS m/z(ESI)：375.2[M+1]
1H NMR(400MHz，CDCl 3)δ9.76(s，1H)，9.24(d，1H)，8.46(d，1H)，8.18(s，2H)，8.01(d，1H)，7.81(d，1H)，7.32(dd，1H)，4.05(d，2H)，3.99(d，2H)，3.60(d，2H)，2.47(q，2H)，1.82-1.76(m，2H)，1.69-1.59(m，1H)，1.18(t，3H).
Embodiment 46
(3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-5-[4-(tetrazole-1-base) phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
The first step
4-(tetrazole-1-base) phenol
PAP 46a (5g, 45.80mmol) is dissolved in 42mL acetic acid, adds triethyl orthoformate (24.40mL successively, 146.50mmol) with sodiumazide (3.73g, 57.30mmol), stir 10 minutes, rise to 80 DEG C of stirring reactions 1.5 hours.Add 30mL water and 17mL 6M hydrochloric acid, under ice bath, slowly add the sodium nitrite solution of 6mL 25%, separate out white solid, suction filtration, washes with water (60mL × 2), obtains furnish crude title compound 4-(tetrazole-1-base) phenol 46b (6.30g, pale solid), productive rate: 85.0%.
MS m/z(ESI)：163.0[M+1]
Second step
(3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-5-[4-(tetrazole-1-base) phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
By crude product cis-[(3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-5-base] methylsulfonic acid acid anhydride 1d (160mg, 0.51mmol) be dissolved in 15mL DMF, stir, add crude product 4-(tetrazole-1-base) phenol 46b (75mg, 0.46mmol) with salt of wormwood (141mg, 1.02mmol), be warming up to 100 DEG C of stirring reactions 2 hours.Reaction solution concentrating under reduced pressure, add 50mL water, extraction into ethyl acetate (20mL × 4), merge organic phase, wash with water (20mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates by thin-layer chromatography chromatography with developping agent system B, obtains title product (3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-5-[4-(tetrazole-1-base) phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles 46 (17mg, white solid), productive rate: 10.0%.
MS m/z(ESI)：378.2[M+1]
1H NMR(400MHz，CDCl 3)δ9.93(s，1H)，8.21(s，2H)，7.77(d，2H)，7.14(d，2H)，5.07-4.98(m，1H)，3.78-3.70(m，2H)，3.41-3.36(m，2H)，2.94-2.89(m，2H)，2.43-2.38(m，2H)，1.94-1.90(m，2H)，1.22(s，3H)，1.15-1.10(m，2H).
Embodiment 47
(3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-5-[4-(tetrazole-1-base) phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
By bromo-for crude product (3aR, 6aS)-5-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles 3a (237mg, 0.80mmol) be dissolved in 15mL DMF, stir, add crude product 4-(tetrazole-1-base) phenol 46b (117mg, 0.72mmol) with salt of wormwood (221mg, 1.60mmol), be warming up to 120 DEG C of stirring reactions 2.5 hours.Reaction solution concentrating under reduced pressure, add 50mL water, extraction into ethyl acetate (20mL × 3), merge organic phase, wash with water (20mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates by thin-layer chromatography chromatography with developping agent system A, obtains title product (3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-5-[4-(tetrazole-1-base) phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles 47 (40mg, white solid), productive rate: 15.0%.
MS m/z(ESI)：378.2[M+1]
1H NMR(400MHz，CDCl 3)δ9.61(s，1H)，8.19(s，2H)，7.68(d，2H)，7.00(d，2H)，5.04-4.94(m，1H)，3.77-3.69(m，2H)，3.67-3.60(m，2H)，2.97-2.90(m，2H)，2.48-2.45(m，2H)，1.93-1.88(m，2H)，1.29(s，3H)，1.23-1.18(m，2H).
Embodiment 48
3-sec.-propyl-5-[(1R, 5S)-6-[[5-(4-methanesulfonylphenYl)-2-pyridine] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-1,2,4-oxadiazoles
The first step
(1R, 5S)-(6-methylol)-3-azabicyclo also [3.1.0] hexane-3-formonitrile HCN
By sodium bicarbonate (2.52g, 30mmol) be dissolved in 5mL water, stir, under ice-water bath, be added dropwise to 15mL crude product [(1R, 5S)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 7e (1.13g, dichloromethane solution 10mmol), then the dichloromethane solution being added dropwise to 1.50mL cyanogen bromide (1.27g, 12mmol), 0 DEG C is reacted 40 minutes, then is warming up to 20 DEG C of stirrings 2 hours.Add 10mL water, separatory, aqueous phase, with dichloromethane extraction (30mL × 3), merges organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtains crude title product (1R, 5S)-(6-methylol)-3-azabicyclo also [3.1.0] hexane-3-formonitrile HCN 48a (1.10g, orange oil), product is not purified directly carries out next step reaction.
MS m/z(ESI)：139.1[M+1]
Second step
[(1R, 5S)-3-(3-sec.-propyl-1,2,4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol
By crude product (1R, 5S)-(6-methylol)-3-azabicyclo also [3.1.0] hexane-3-formonitrile HCN 48a (415mg, 3mmol) and N '-hydroxy-2-methyl-propylamine (368mg, 3.60mmol) be dissolved in 15mL tetrahydrofuran (THF), stir, be added dropwise to the tetrahydrofuran solution of 3.60mL 1M protochloride zinc, have a large amount of white solid to generate.Reaction solution concentrating under reduced pressure, adds the ethanolic soln of 4.50mL 4M hydrogenchloride, is warming up to 80 DEG C of reactions 2 hours.Cooling, adding sodium carbonate solid to reaction solution pH is 6, filter, be extracted with ethyl acetate (50mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product [(1R, 5S)-3-(3-sec.-propyl-1,2,4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 48b (270mg, colorless oil), productive rate: 40.0%.
MS m/z(ESI)：224.1[M+1]
3rd step
[(1R, 5S)-3-(3-sec.-propyl-1,2,4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl methylsulfonate
Under ice bath, by [(1R, 5S)-3-(3-sec.-propyl-1,2,4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 48b (250mg, 1.10mmol) be dissolved in 30mL anhydrous methylene chloride, add triethylamine (6.4mL, 3.30mmol), be added dropwise to methylsulfonyl chloride (0.2mL, 2.20mmol), rise to room temperature, stirring reaction 3 hours.Reaction solution concentrating under reduced pressure, adds water 30mL, is extracted with ethyl acetate (30mL × 3), merge organic phase, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, obtain crude title product [(1R, 5S)-3-(3-sec.-propyl-1,2,4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl methylsulfonate 48c (330mg, yellow oily), product is not purified directly carries out next step reaction.
MS m/z(ESI)：302.1[M+1]
4th step
6-(4-methanesulfonylphenYl) pyridine-3-alcohol
By (4-methanesulfonylphenYl) boric acid 48d (1g; 5mmol) with 6-chloropyridine-3-alcohol (650mg; 5mmol) be dissolved in 30mL glycol dimethyl ether; add tetra-triphenylphosphine palladium (288mg; 0.25mmol) and 2M sodium carbonate solution 7.5mL, 100 DEG C of microwave reactions 30 minutes.Reaction solution concentrating under reduced pressure; add water 150mL, dripping 1M hydrochloric acid is 5 ~ 6 to reacting liquid pH value, is extracted with ethyl acetate (50mL × 3); merge organic phase; anhydrous magnesium sulfate drying, filters, filtrate reduced in volume; gained resistates is purified with eluent system B with silica gel column chromatography; obtain title product 6-(4-methanesulfonylphenYl) pyridine-3-alcohol 48e (420mg, white solid), productive rate: 37.5%.
MS m/z(ESI)：249.6[M+1]
5th step
3-sec.-propyl-5-[(1R, 5S)-6-[[5-(4-methanesulfonylphenYl)-2-pyridine] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-1,2,4-oxadiazoles
By crude product [(1R; 5S)-3-(3-sec.-propyl-1; 2; 4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl methylsulfonate 48c (330mg; 1.10mmol) be dissolved in 15mL N; in dinethylformamide; stir; add 6-(4-methanesulfonylphenYl) pyridine-3-alcohol 48e (275mg; 1.10mmol) with salt of wormwood (456mg; 3.30mmol), 90 DEG C of stirring reactions 16 hours are warming up to.Add 100mL water; extraction into ethyl acetate (80mL × 2); merge organic phase; wash with water (50mL × 2); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 3-sec.-propyl-5-[(1R, 5S)-6-[[5-(4-methanesulfonylphenYl)-2-pyridine] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-1; 2; 4-oxadiazole 48 (120mg, white solid), productive rate: 24.0%.
MS m/z(ESI)：455.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.42(d，1H)，8.15(d，2H)，8.03(d，2H)，7.76(d，1H)，7.32(dd，1H)，4.05(d，2H)，3.88(d，2H)，3.67-3.71(m，2H)，3.09(s，3H)，2.90-2.92(m，1H)，1.80-1.84(m，2H)，1.29(d，6H)，1.24-1.28(m，1H).
Embodiment 49
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(4-pyridyl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By (1R, 5S)-6-[(6-chloro-3-pyridyl base) oxygen methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 13a (99mg, 0.30mmol), (4-pyridine) boric acid (44.30mg, 0.36mmol) be dissolved in the mixed solvent of 6mL glycol dimethyl ether and water (V/V=1: 1), add salt of wormwood (83mg successively again, 0.60mmol) He four triphenyl phosphine palladium (35mg, 0.03mmol), 125 DEG C of microwave reactions 30 minutes.Add 10mL water, be extracted with ethyl acetate (25mL × 3), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by thin-layer chromatography chromatography, obtain title product (1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(4-pyridyl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 49 (50mg, white solid), productive rate: 44.6%.
MS m/z(ESI)：373.7[M+1]
1H NMR(400MHz，CDCl 3)δ8.58(d，2H)，8.40(d，2H)，8.18(s，2H)，7.99(m，3H)，4.09(d，2H)，3.88(d，2H)，3.64(d，2H)，2.49(m，2H)，1.85(d，2H)，1.19(m，4H).
Embodiment 50
(1R, 5S)-6-[[the chloro-4-of 2-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
The first step
The chloro-4-of 2-(4-methanesulfonylphenYl) phenol
By the chloro-phenol 50a of bromo-for 4-2-(500mg; 2.40mol); (4-methanesulfonylphenYl) boric acid (531mg; 2.60mmol), 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (35mg; 0.05mmol) He three hypophosphite monohydrate potassium (1.30g; 4.80mmol) be dissolved in 50mL Isosorbide-5-Nitrae-dioxane, be warming up to return stirring and react 5 hours.Filter, filtrate reduced in volume, purify gained resistates by thin-layer chromatography chromatography with developping agent system B, obtain the chloro-4-of title product 2-(4-methanesulfonylphenYl) phenol 50b (400mg, white solid), productive rate: 58.7%.
MS m/z(ESI)：300.1[M+18]
Second step
(1R, 5S)-6-[[the chloro-4-of 2-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By crude product [(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (105mg; 0.35mmol) with the chloro-4-of 2-(4-methanesulfonylphenYl) phenol 50b (100mg; 0.35mmol) be dissolved in 5mL N; in N-N,N-DIMETHYLACETAMIDE; add cesium carbonate (230mg, 0.70mmol) again, be warming up to 150 DEG C of stirring reactions 8 hours.Cooling; add 25mL water; be extracted with ethyl acetate (10mL × 4); merge organic phase; with saturated ammonium chloride solution washing (10mL × 5); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; purify gained resistates by thin-layer chromatography chromatography with developping agent system B, obtain title product (1R, 5S)-6-[[the chloro-4-of 2-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 50 (100mg; white solid), productive rate: 58.4%.
MS m/z(ESI)：484.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.19(s，2H)，8.00(q，2H)，7.72(q，2H)，7.64(d，1H)，7.47-7.44(m，1H)，7.02(d，1H)，4.11(d，2H)，3.99(d，2H)，3.60(d，2H)，3.09(s，3H)，2.47(q，2H)，1.83-1.82(m，2H)，1.28-1.25(m，1H)，1.19(t，3H).
Embodiment 51
2-[(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-1,3-benzoxazole
By crude product (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 19a (20mg; 0.05mmol); triethylamine (15mg; 0.15mmol) be added in 5mL methylene dichloride; under ice bath; add the dichloromethane solution of chloro-1, the 3-benzoxazole (8mg, 0.05mmol) of 1mL 2-; rise to stirring at room temperature and react 2 hours; add salt of wormwood (13mg, 0.10mmol) again, stirring reaction 12 hours.Filter; filtrate reduced in volume; gained resistates is purified with developping agent system A by thin-layer chromatography chromatography; obtain title product 2-[(1R; 5S)-6-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-1,3-benzoxazole 51 (20mg; white solid), productive rate: 41.6%.
MS m/z(ESI)：497.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.02(q，2H)，7.71(q，2H)，7.39(d，1H)，7.26(d，1H)，7.20-7.16(m，3H)，7.04-7.02(m，1H)，4.15(d，2H)，3.96(d，2H)，3.75(d，2H)，3.10(s，3H)，1.82-1.81(m，2H)，1.26-1.25(m，1H).
Embodiment 52
(1R, 5S)-3-(5-bromo pyrimi piperidine-2-base)-6-[[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
By crude product (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 19a (20mg; 0.05mmol); the chloro-pyrimidine (12mg, 0.06mmol) of the bromo-2-of 5-and cesium carbonate (41mg, 0.13mmol) are added to 5mL N; in N-N,N-DIMETHYLACETAMIDE, rise to 150 DEG C of stirring reactions 8 hours.Cooling; add 25mL water; be extracted with ethyl acetate (10mL × 4); merge organic phase; with saturated ammonium chloride solution washing (10mL × 5); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume, purifies gained resistates by thin-layer chromatography chromatography with developping agent system A, obtains title product (1R; 5S)-3-(5-bromo pyrimi piperidine-2-base)-6-[[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 52 (20mg, white solid), productive rate: 80.0%.
MS m/z(ESI)：536.5[M+1]
1H NMR(400MHz，CDCl 3)δ8.32(s，2H)，8.02(d，2H)，7.70(d，2H)，7.18(d，2H)，4.14(d，2H)，3.90(d，2H)，3.58(d，2H)，3.10(s，3H)，1.77-1.75(m，2H)，1.18-1.16(m，1H).
Embodiment 53
(3aR, 6aS)-5-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester
The first step
(3aR, 6aS)-5-(bromo-2, the 6-dilquoro-phenogy of 4-)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester
By bromo-for (3aR, 6aS)-5-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 15a (1g, 3.50mmol), bromo-2, the 6-difluoro-phenol (0.72g of 4-, 3.50mmol) with salt of wormwood (966mg, 7.0mmol) be added in 10mL N,N-dimethylacetamide, rise to 100 DEG C of stirring reactions 12 hours.Cooling, adds 20mL water, is extracted with ethyl acetate (20mL × 3), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product (3aR, 6aS)-5-(bromo-2, the 6-dilquoro-phenogy of 4-)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 53a (1g, white solid), productive rate: 68.5%.
MS m/z(ESI)：364.0[M-55]
Second step
(3aR, 6aS)-5-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester
By (3aR; 6aS)-5-(4-bromo-2; 6-dilquoro-phenogy)-3; 3a; 4,5,6; 6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 53a (500mg; 1.20mol), (4-methanesulfonylphenYl) boric acid (311mg, 1.56mmol); 1; 1 '-two (diphenyl phosphine) ferrocene palladium chloride (88mg, 0.12mmol) and three hypophosphite monohydrate potassium (958mg, 3.60mmol) are dissolved in 10mL 1; in 4-dioxane, be warming up to return stirring and react 12 hours.Filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B; obtain title product (3aR; 6aS)-5-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-3,3a; 4; 5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carboxylic acid tert-butyl ester 53 (380mg; white solid), productive rate: 64.0%.
MS m/z(ESI)：438.1[M-55]
1H NMR(400MHz，CDCl 3)δ8.01(d，2H)，7.75(d，2H)，7.17-7.15(m，2H)，4.92-4.89(m，1H)，3.62-3.57(m，2H)，3.45-3.42(m，2H)，3.10(s，3H)，2.69(s，2H)，2.26-2.25(m，2H)，1.92-1.89(m，2H)，1.48(s，9H).
Embodiment 54,55
Cis-(3aR, 6aS)-5-[the fluoro-4-of 2,6-bis-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
Trans-(3aR, 6aS)-5-[the fluoro-4-of 2,6-bis-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
The first step
The fluoro-4-of 2,6-bis-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenol
By crude product 1-Nmethanesulphonylpiperazine 1f (636mg; 3.20mmol) He 3; the fluoro-4-hydroxy-benzaldehyde of 5-bis-(500mg; 3.20mmol) be dissolved in 10mL ethylene dichloride; be warming up to 80 DEG C of stirring reactions 2 hours, be cooled to room temperature, add sodium triacetoxy borohydride (1.40g; 6.40mmol), 80 DEG C of stirring reactions 12 hours are warming up to.Adding 10mL saturated sodium bicarbonate solution to reacting liquid pH value is 9; dichloromethane extraction (20mL × 3); anhydrous magnesium sulfate drying; filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A; obtain title product 2; the fluoro-4-of 6-bis-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenol 54a (500mg, white solid), productive rate: 51%.
Second step
Cis-(3aR, 6aS)-5-[the fluoro-4-of 2,6-bis-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
Trans-(3aR, 6aS)-5-[the fluoro-4-of 2,6-bis-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
By fluoro-for 2,6-bis-4-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenol 54a (100mg, 0.33mmol); the bromo-2-of (3aR, 6aS)-5-(5-ethyl-pyrimidine-2-base)-3,3a; 4,5,6; 6a-six hydrogen-1H-cyclopentano [c] pyrroles 3a (97mg; 0.33mmol) be dissolved in 5mL DMF with salt of wormwood (91mg, 0.66mmol);, rise to 100 DEG C of stirring reactions 12 hours.Cooling, add 20mL water, be extracted with ethyl acetate (20mL × 3), merge organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain a pair diastereomer product, cis-(3aR respectively, 6aS)-5-[2, the fluoro-4-of 6-bis-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3, 3a, 4, 5, 6, 6a-six hydrogen-1H-cyclopentano [c] pyrroles 54 (30mg, white solid), trans-(3aR, 6aS)-5-[2, the fluoro-4-of 6-bis-[(4-Nmethanesulphonylpiperazine-1-base) methyl] phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3, 3a, 4, 5, 6, 6a-six hydrogen-1H-cyclopentano [c] pyrroles 55 (10mg, white solid).
MS m/z(ESI)：522.3[M+1]
54 1H NMR(400MHz，CDCl 3)δ8.20(s，2H)，6.85(d，2H)，4.84-4.78(m，1H)，3.83-3.78(m，2H)，3.70-3.66(m，2H)，3.45(s，2H)，3.27-3.25(m，4H)，2.79(s，5H)，2.56-2.54(m，4H)，2.48-2.46(m，2H)，2.32-2.29(m，2H)，1.95-1.92(m，2H)，1.20(t，3H).
55 1H NMR(400MHz，CDCl 3)δ8.18(s，2H)，6.91-6.86(m，2H)，4.92(s，1H)，3.70-3.67(m，2H)，3.52-3.47(m，4H)，3.28-3.25(m，4H)，3.13-3.11(m，2H)，2.79(s，3H)，2.57-2.55(m，4H)，2.47-2.45(m，2H)，2.32-2.29(m，2H)，1.78-1.13(m，2H)，1.20-1.17(t，3H).
Embodiment 56
4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-3,5-difluorophenyl] benzylamine
By 4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-3,5-difluorophenyl] benzonitrile 31 (20mg, 46 μm of ol) and potassium hydroxide (3.89mg, 69 μm of ol) be dissolved in 20mL methyl alcohol, add 1mL 30% hydrogen peroxide again, stirring reaction 2 hours.Cooling, add 50mL water, be extracted with ethyl acetate (30mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtains title product 4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-3,5-difluorophenyl] benzylamine 56 (15mg, white solid), productive rate: 75.0%.
MS m/z(ESI)：451.5[M+1]
1H NMR(400MHz，CDCl 3)δ8.21(s，2H)，7.89(d，2H)，7.60-7.62(m，2H)，7.17-7.19(m，2H)，4.12-4.14(m，2H)，3.94-3.97(m，2H)，3.60-3.62(m，2H)，2.46-2.52(m，2H)，1.75(s，2H)，1.26(s，1H)，1.17-1.22(m，3H).
Embodiment 57
4-[the chloro-4-of 5-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-2-oxygen-1-pyridine] the fluoro-benzonitrile of-2-
The first step
4-(5-chloro-4-hydroxyl-2-oxygen-1-pyridine) the fluoro-Bian nitrile of-2-
By 5-chloro-4-hydroxyl-1H-pyridin-2-ones 57a (177mg, 1.21mmol), the iodo-Bian nitrile (300mg, 1.21mmol) of the fluoro-4-of 2-, 1,10-phenanthroline (44mg, 0.24mmol), salt of wormwood (334mg, 2.40mmol) and cuprous iodide (46mg, 0.24mmol) be added in 20mL dimethyl sulfoxide (DMSO), rise to 140 DEG C of stirring reactions 3 hours.Cooling, add 50mL water, dripping 1M hydrogen chloride solution is 2 to reacting liquid pH value, is extracted with ethyl acetate (100mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product 4-(5-chloro-4-hydroxyl-2-oxygen-1-pyridine)-2-fluoro-Bian nitrile 57b (71mg, yellow solid), productive rate: 22.0%.
MS m/z(ESI)：265.1[M+1]
Second step
4-[the chloro-4-of 5-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-2-oxygen-1-pyridine] the fluoro-benzonitrile of-2-
By 4-(5-chloro-4-hydroxyl-2-oxygen-1-pyridine)-2-fluoro-Bian nitrile 57b (71mg, 0.30mmol), crude product [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (80mg, 0.30mmol) with cesium carbonate (175mg, 0.62mmol) be added in 10mL DMF, rise to 90 DEG C of stirring reactions 6 hours.Cooling, add 50mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product 4-[the chloro-4-[[(1R of 5-, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-2-oxygen-1-pyridine] the fluoro-benzonitrile 57 (10mg, light yellow solid) of-2-, productive rate: 8.0%.
MS m/z(ESI)：466.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.20(s，2H)，8.05(s，1H)，7.60-7.64(m，1H)，7.02-7.06(m，2H)，6.51(s，1H)，4.10-4.12(m，2H)，3.99-4.02(m，2H)，3.59-3.62(m，2H)，2.45-2.51(m，2H)，1.83(s，2H)，1.27(s，1H)，1.17-1.21(m，3H).
Embodiment 58
(1R, 5S)-6-[[the fluoro-4-of 2,5-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
The first step
The fluoro-4-of 2,5-bis-(4-methanesulfonylphenYl) phenol
By bromo-for 4-2; 5-difluoro-phenol 58a (500mg; 2.34mmol), (4-methanesulfonylphenYl) boric acid (479mg, 2.34mmol); 1; 1 '-two (diphenyl phosphine) ferrocene palladium chloride (175mg, 0.20mmol) and cesium carbonate (2.34g, 7mmol) are dissolved in 20mL 1; in 4-dioxane, be warming up to 120 DEG C of stirring reactions 2 hours.Cooling; add 60mL water; be extracted with ethyl acetate (20mL × 2); merge organic phase; dripping 4M sodium hydroxide solution is 3 to reacting liquid pH value; extracting and separating, it is 6 to reacting liquid pH value that aqueous phase drips 1M hydrogen chloride solution, is extracted with ethyl acetate (50mL × 2); merge organic phase; anhydrous magnesium sulfate drying, filters, filtrate reduced in volume; obtain crude title product 2; the fluoro-4-of 5-bis-(4-methanesulfonylphenYl) phenol 58b (900mg, gray solid), productive rate: 66.0%.
MS m/z(ESI)：302.1[M+18]
Second step
(1R, 5S)-6-[[the fluoro-4-of 2,5-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By crude product 2; the fluoro-4-of 5-bis-(4-methanesulfonylphenYl) phenol 58b (100mg; 0.35mmol); crude product [(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (105mg, 0.35mmol) and cesium carbonate (339mg, 0.70mmol) be added to 10mL N; in dinethylformamide, rise to 90 DEG C of stirring reactions 3 hours.Cooling; add 40mL water; be extracted with ethyl acetate (40mL × 2); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system B by thin-layer chromatography chromatography; obtain title product (1R, 5S)-6-[[the fluoro-4-of 2,5-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 58 (30mg; white solid), productive rate: 17.7%.
MS m/z(ESI)：486.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.21(s，2H)，8.00(d，2H)，7.70(d，2H)，7.18-7.23(m，1H)，6.79-6.83(m，1H)，4.02-4.06(m，4H)，3.62-3.64(m，2H)，3.09(s，3H)，2.46-2.52(m，2H)，1.82(s，2H)，1.24-1.27(m，1H)，1.18-1.22(m，3H).
Embodiment 59
(3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-5-[4-(4-methanesulfonylphenYl) phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
The first step
(3aR, 6aS)-5-(4-bromine phenoxy group)-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
By bromo-for (3aR, 6aS)-5-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles 3a (300mg, 1mmol), 4-bromophenol (175mg, 1mmol) and salt of wormwood (280mg, 2mmol) are added to 10mL N, in dinethylformamide, rise to 120 DEG C of stirring reactions 5 hours.Cooling, adds 15mL water, is extracted with ethyl acetate (30mL × 3), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtains crude title product (3aR, 6aS)-5-(4-bromine phenoxy group)-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles 59a (350mg, brown oil), product is not purified directly carries out next step reaction.
MS m/z(ESI)：388.1[M+1]
Second step
(3aR, 6aS)-2-(5-ethyl-pyrimidine-2-base)-5-[4-(4-methanesulfonylphenYl) phenoxy group]-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
By crude product (3aR; 6aS)-5-(4-bromine phenoxy group)-2-(5-ethyl-pyrimidine-2-base)-3; 3a; 4; 5; 6,6a-six hydrogen-1H-cyclopentano [c] pyrroles 59a (350mg, 0.90mmol); (4-methanesulfonylphenYl) boric acid (216mg; 1.10mmol), 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (66mg; 0.09mmol) with cesium carbonate (880mg; 2.70mmol) be dissolved in 15mL Isosorbide-5-Nitrae-dioxane, be warming up to 120 DEG C of stirring reactions 5 hours.Cooling; add 20mL water; be extracted with ethyl acetate (30mL × 3); merge organic phase, saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate drying; filter; filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product (3aR; 6aS)-2-(5-ethyl-pyrimidine-2-base)-5-[4-(4-methanesulfonylphenYl) phenoxy group]-3; 3a, 4,5; 6; 6a-six hydrogen-1H-cyclopentano [c] pyrroles 59 (30mg, white solid), productive rate: 7.2%.
MS m/z(ESI)：464.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.19(s，2H)，7.97(d，2H)，7.71(d，2H)，7.51(d，2H)，6.90(d，2H)，4.89-4.94(m，1H)，3.79-3.84(m，2H)，3.65-3.68(m，2H)，3.09(s，3H)，2.88-2.92(m，2H)，2.48(q，2H)，2.38-2.45(m，2H)，1.92-1.97(m，2H)，1.20(t，3H).
Embodiment 60
(1R, 5S)-6-[(the fluoro-4-pyridazine of 2,6-bis--4-base-phenoxy group) methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
The first step
The fluoro-4-pyridazine of 2,6-bis--4-base-phenol
By bromo-for 4-2,6-difluoro-phenol 60a (100mg, 0.48mmol), tri-tert (pyridazine-4-base) tin (196mg, 0.53mmol) be dissolved in 5mL1 with 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (10mg, 0.01mmol), in 4-dioxane, be warming up to 110 DEG C of stirring reactions 10 hours.Cooling, adds 10mL water, is extracted with ethyl acetate (20mL × 3), merge organic phase, saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 2,6-bis-fluoro-4-pyridazine-4-base-phenol 60b (72mg, light yellow solid), productive rate: 72.7%.
MS m/z(ESI)：208.8[M+1]
Second step
(1R, 5S)-6-[(the fluoro-4-pyridazine of 2,6-bis--4-base-phenoxy group) methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By 2, the fluoro-4-pyridazine of 6-bis--4-base-phenol 60b (45mg, 0.22mmol), crude product [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (64mg, 0.22mmol) and cesium carbonate (141mg, 0.43mmol) be added to 10mL N, in dinethylformamide, rise to 90 DEG C of stirring reactions 3 hours.Cooling, add 20mL water, be extracted with ethyl acetate (30mL × 3), merge organic phase, saturated nacl aqueous solution washing (30mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product (1R, 5S)-6-[(2, the fluoro-4-pyridazine of 6-bis--4-base-phenoxy group) methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 60 (15mg, white solid), productive rate: 16.9%.
MS m/z(ESI)：410.2[M+1]
1H NMR(400MHz，CDCl 3)δ9.41-9.43(m，1H)，9.26-9.28(m，1H)，8.17-8.19(m，2H)，7.58-7.60(m，1H)，7.24-7.26(m，2H)，4.17-4.19(m，2H)，3.90-3.93(m，2H)，3.56-3.59(m，2H)，2.44-2.50(m，2H)，1.63-1.65(m，2H)，1.23-1.26(m，1H)，1.16-1.20(m，3H).
Embodiment 61
(3aR, 6aS)-5-[the fluoro-4-of 2,6-bis-(4-cyano-phenyl) phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles
By crude product (3aR, 6aS)-5-(4-bromo-2,6-dilquoro-phenogy)-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles 4a (210mg, 0.50mmol), (4-cyano-phenyl) boric acid (110mg, 0.75mmol), 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (36mg, 0.05mmol) and potassiumphosphate (400mg, 1.50mmol) are dissolved in 20mL 1, in 4-dioxane, heat up 120 DEG C of stirring reactions 3 hours.Filter, filtrate adds 20mL water, extraction into ethyl acetate (50mL × 3), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product (3aR, 6aS)-5-[2, the fluoro-4-of 6-bis-(4-cyano-phenyl) phenoxy group]-2-(5-ethyl-pyrimidine-2-base)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles 61 (80mg, white solid), productive rate: 36.4%.
MS m/z(ESI)：447.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.22(s，2H)，7.74-7.72(m，2H)，7.61-7.59(m，2H)，7.14-7.09(m，2H)，4.96-4.93(m，1H)，3.87-3.69(m，4H)，2.85(s，2H)，2.52-2.46(m，2H)，2.36-2.33(m，2H)，2.02-1.97(m，2H)，1.21-1.19(m，3H)
Embodiment 62
2-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
The first step
4-methene piperidines-1-carboxylic acid tert-butyl ester
By triphenylmethylphosphonium bromide phosphine (1.80g, 0.05mol) be added in 100mL tetrahydrofuran (THF), under ice bath, add potassium tert.-butoxide (5.60g, 0.05mol), stir 30 minutes, reflux 1 hour, then ice bath is cooled to 0 DEG C, drips 20mL 4-oxygen phenylpiperidines-1-carboxylic acid tert-butyl ester 62a (5g, tetrahydrofuran solution 0.03mol), is warming up to return stirring and reacts 4 hours.Add 100mL water, extraction into ethyl acetate (100mL × 3), merge organic phase, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product 4-methene piperidines-1-carboxylic acid tert-butyl ester 62b (4.20g, colorless oil), productive rate: 86.0%.
Second step
2-oxygen base-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
4-methene piperidines-1-carboxylic acid tert-butyl ester 62b (1g, 5.10mmol) and zinc-copper (4.30g, 66mmol) are added in 20mL ether, drip 10mL trichoroacetic chloride (4.70g, DMF 26mmol), stirring reaction 12 hours.Under ice bath, add 100mL saturated sodium bicarbonate solution, filter, extraction into ethyl acetate (50mL × 3), merge organic phase, anhydrous magnesium sulfate drying, filtrate reduced in volume.Add the methanol solution of 50mL 2M ammonium chloride, add activated zinc powder (16g, 0.25mol) in batches, room temperature reaction 12 hours.Filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 2-oxygen base-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 62c (600mg, white solid), productive rate: 50.0%.
3rd step
2-hydroxyl-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
2-oxygen base-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 62c (600mg, 2.53mmol) is dissolved in 10mL methyl alcohol, under ice bath, add sodium borohydride (187mg, 5.06mmol), rise to room temperature, stirring reaction 12 hours.Add 20mL 1M hydrochloric acid, extraction into ethyl acetate (50mL × 3), merge organic phase, saturated nacl aqueous solution washing (100mL × 3), anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, obtain crude title product 2-hydroxyl-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 62d (410mg, colorless solid), productive rate: 68%.
MS m/z(ESI)：186.1[M-55]
4th step
2-methylsulfonyl oxygen base-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
Under ice bath, by crude product 2-hydroxyl-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 62d (200mg, 0.82mmol) be dissolved in 5mL anhydrous methylene chloride, add triethylamine (248mg, 2.46mmol), methylsulfonyl chloride (141mg, 1.24mmol) is dripped, rise to room temperature, stirring reaction 1.5 hours.Add 10mL water; extraction into ethyl acetate (20mL × 3); merge organic phase, use water (5mL × 3) successively, saturated nacl aqueous solution washing (5mL × 3); anhydrous sodium sulfate drying; filter, filtrate reduced in volume, obtains crude title product 2-methylsulfonyl oxygen base-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 62e (215mg; colorless oil), product is not purified directly carries out next step reaction.
5th step
The fluoro-4-of 2,6-bis-(methanesulfonylphenYl) phenol
By bromo-for 4-2; 6-difluoro-phenol 62f (500mg; 2.83mmol), (4-methanesulfonylphenYl) boric acid (690mg, 3.40mmol); 1; 1 '-two (diphenyl phosphine) ferrocene palladium chloride (204mg, 0.28mmol) and three hypophosphite monohydrate potassium (1.90g, 7.20mmol) are dissolved in 12mL 1; in 4-dioxane and water (V/V=5: 1) mixed solvent, be warming up to 120 DEG C of stirring reactions 5 hours.Add 20mL water; extraction into ethyl acetate (20mL × 3); merge organic phase, with saturated nacl aqueous solution washing (10mL × 3), anhydrous sodium sulfate drying; filter; filtrate reduced in volume, obtains crude title product 2,6-bis-fluoro-4-(methanesulfonylphenYl) phenol 62g (570mg; brown solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：302.1[M+18]
6th step
2-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
By crude product 2-methylsulfonyl oxygen base-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 62e (215mg; 0.67mmol); crude product 2; the fluoro-4-of 6-bis-(methanesulfonylphenYl) phenol 62g (191mg; 0.67mmol) be dissolved in 20mL DMF with salt of wormwood (277mg, 2mmol); be warming up to 100 DEG C, stirring reaction 12 hours.Add 20mL water; be extracted with ethyl acetate (50mL × 2); merge organic phase; use water (10mL × 3) successively; saturated nacl aqueous solution washing (10mL × 3); anhydrous sodium sulfate drying; filter; filtrate reduced in volume; purify gained resistates by thin-layer chromatography chromatography with developping agent system B, obtain title product 2-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 62 (250mg; white solid), productive rate: 73.0%.
MS m/z(ESI)：408.2[M+1-100]
1H NMR(400MHz，d-DMSO)δ7.99(s，4H)，7.64(d，2H)，4.83-4.80(m，1H)，3.32(s，3H)，3.25-3.14(m，2H)，2.33-2.28(m，2H)，1.96-1.91(m，2H)，1.53-1.50(m，2H)，1.47-1.35(m，9H)，1.30-1.26(m，2H)，1.15-1.12(m，2H).
Embodiment 63
2-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-7-(5-ethyl-pyrimidine-2-base)-7-azaspiro [3.5] nonane
The first step
2-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-7-azaspiro [3.5] nonane
2-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 62 (150mg, 0.29mmol) is dissolved in 2mL 4M methanol hydrochloride solution, stirring reaction 12 hours.Reaction solution concentrating under reduced pressure; obtain crude title product 2-[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group]-7-azaspiro [3.5] nonane 63a (120mg, white solid), product is not purified directly carries out next step reaction.
Second step
2-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group]-7-(5-ethyl-pyrimidine-2-base)-7-azaspiro [3.5] nonane
By crude product 2-[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group]-7-azaspiro [3.5] nonane 63a (120mg; 0.27mmol) be dissolved in 5mL N; in dinethylformamide; add the chloro-5-ethyl-pyrimidin of 2-(42mg successively; 0.29mmol) with cesium carbonate (263mg, 0.81mmol), rise to 150 DEG C of stirring reactions 5 hours.Be chilled to room temperature; add 10mL water; be extracted with ethyl acetate (10mL × 3); merge organic phase; use water (5mL × 3) successively; saturated nacl aqueous solution washing (5mL × 3); anhydrous magnesium sulfate drying; filter, filtrate reduced in volume, purify gained resistates by thin-layer chromatography chromatography with developping agent system B; obtain title product 2-[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group]-7-(5-ethyl-pyrimidine-2-base)-7-azaspiro [3.5] nonane 63 (75mg, yellow solid), productive rate: 69.0%.
MS m/z(ESI)：234.1[M+1]
1H NMR(400MHz，d-DMSO)δ8.25(s，2H)，7.99(s，4H)，7.64(d，2H)，4.86-4.84(m，1H)，3.32(s，3H)，3.25-3.14(m，2H)，2.33-2.28(m，2H)，2.08-2.06(m，2H)，1.96-1.91(m，2H)，1.53-1.50(m，2H)，1.30-1.26(m，2H)，1.21-1.19(m，2H)，1.13-1.12(m，3H).
Embodiment 64
2-[[4-(tetrazole-1-base) phenoxy group] methyl]-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
The first step
2-(hydroxymethyl)-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
4-methene piperidines-1-carboxylic acid tert-butyl ester 62b (500mg, 2.10mmol) is dissolved in 20mL tetrahydrofuran (THF), under ice bath, add 9-borabi cyclo-[3.3.1] nonane (12.7mL, 6.30mmol), rise to room temperature, stirring reaction 12 hours.Under ice bath, add 1mL water, 2mL 3M sodium hydroxide and 2mL hydrogen peroxide, continue reaction 1 hour.Add 30mL water, be extracted with ethyl acetate (20mL × 3), merge organic phase, saturated nacl aqueous solution washing (30mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product 2-(hydroxymethyl)-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 64a (550mg, colorless viscous), productive rate: 100.0%.
MS m/z(ESI)：200.1[M-55]
Second step
2-[[4-(tetrazole-1-base) phenoxy group] methyl]-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
By 2-(hydroxymethyl)-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 64a (200mg, 0.78mmol) be dissolved in 15mL toluene, stir, add crude product 4-(tetrazole-1-base) phenol 46b (127mg, 0.78mmol), more successively triphenylphosphine (411mg, 1.57mmol) and diisopropyl azodiformate (238mg is added, 1.18mmol), stirring reaction 16 hours.Reaction solution concentrating under reduced pressure, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product 2-[[4-(tetrazole-1-base) phenoxy group] methyl]-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 64 (110mg, white solid), productive rate: 34.0%.
MS m/z(ESI)：400.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.90(s，1H)，7.60-7.58(m，2H)，7.07-7.05(m，2H)，4.00(d，2H)，3.85-3.81(m，2H)，3.32-3.30(m，2H)，2.79-2.76(m，1H)，2.04-2.01(m，2H)，1.73-1.70(m，2H)，1.65-1.61(m，2H)，1.55-1.51(m，2H)，1.46(s，9H).
Embodiment 65
2-[4-(tetrazole-1-base) phenoxy group]-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
By crude product 2-hydroxyl-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 62d (150mg, 0.62mmol) be dissolved in 15mL toluene, stir, add crude product 4-(tetrazole-1-base) phenol 46b (101mg, 0.62mmol), then add triphenylphosphine (328mg successively, 1.25mmol) with diisopropyl azodiformate (189mg, 0.93mmol), be heated to 65 DEG C, stirring reaction 3 hours.Reaction solution concentrating under reduced pressure, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product 2-[4-(tetrazole-1-base) phenoxy group]-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 65 (100mg, white solid), productive rate: 96.0%.
MS m/z(ESI)：286.1[M+1-100]
1H NMR(400MHz，CDCl 3)δ8.89(s，1H)，7.60-7.56(m，2H)，6.98-6.95(m，2H)，4.78-4.75(m，1H)，3.42-3.38(m，2H)，3.36-3.33(m，2H)，2.49-2.45(m，2H)，2.02-1.98(m，2H)，1.60-1.56(m，4H)，1.47(s，9H).
Embodiment 66
(1R, 5S)-6-[[4-(6-chloro-3-pyridyl base)-2,6-dilquoro-phenogy] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By [(1R, 5S)-6-[(4-bromo-2,6-dilquoro-phenogy) methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 8a (70mg, 0.17mmol), (6-chloro-3-pyridyl base) boric acid (27mg, 0.17mmol), 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (12.40mg, 0.02mmol) be dissolved in 10mL Isosorbide-5-Nitrae-dioxane with cesium carbonate (167mg, 0.51mmol), be warming up to 120 DEG C, stirring reaction 2 hours.Add 50mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product (1R, 5S)-6-[[4-(6-chloro-3-pyridyl base)-2,6-dilquoro-phenogy] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 66 (20mg, brown solid), productive rate: 26.7%.
MS m/z(ESI)：443.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.54(s，2H)，8.16(s，2H)，7.76-7.78(m，1H)，7.40-7.42(m，1H)，7.10-7.12(m，1H)，4.12-4.14(m，2H)，3.87-3.90(m，2H)，3.53-3.56(m，2H)，2.43-2.49(m，2H)，1.72(s，2H)，1.26(s，1H)，1.16-1.20(m，3H).
Embodiment 67
2-[2-[4-(tetrazole-1-base) phenoxy group] ethyl]-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
The first step
2-(2-oxyethyl group-2-oxygen-ethylidene)-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
By 60% sodium hydride (92mg; 2.30mmol) be added in 10mL benzene; slowly be added dropwise to phosphine acyl acetic acid three ethyl (414 μ L; 2.10mmol); stir 1 hour, slowly add 2-oxygen base-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 62c (500mg, 2.10mmol); be warming up to 65 DEG C, stirring reaction 30 minutes.Be cooled to room temperature, add 20mL water, be extracted with ethyl acetate (100mL × 2), merge organic phase, use water (50mL × 2) successively, saturated nacl aqueous solution washing (50mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtain crude title product 2-(2-oxyethyl group-2-oxygen-ethylidene)-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 67a (700mg, yellow oily), product is not purified directly carries out next step reaction.
Second step
2-(2-oxyethyl group-2-oxygen-ethyl)-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
By crude product 2-(2-oxyethyl group-2-oxygen-ethylidene)-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 67a (700mg, 2.30mmol) be dissolved in 50mL methyl alcohol, add palladium/carbon (70mg, 10%), pressure hydration, reacts 12 hours.Be chilled to room temperature, filter, filtrate reduced in volume, obtains crude title product 2-(2-oxyethyl group-2-oxygen-ethyl)-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 67b (598mg, pale yellow oil), product is not purified directly carries out next step reaction.
MS m/z(ESI)：212.2[M+1-100]
3rd step
2-(2-hydroxyl)-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
By Lithium Aluminium Hydride (146mg, 3.84mmol) be dissolved in 20mL tetrahydrofuran (THF), under ice bath, slowly add 10mL 2-(2-oxyethyl group-2-oxygen-ethyl)-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 67b (598mg, tetrahydrofuran solution 1.92mmol), finish, react 12 hours.Slow instillation 0.5mL saturated ammonium chloride solution, filter, collect filtrate, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtains crude title product 2-(2-hydroxyl)-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 67c (500mg, colorless oil), product is not purified directly carries out next step reaction.
MS m/z(ESI)：214.1[M-55]
4th step
2-[2-[4-(tetrazole-1-base) phenoxy group] ethyl]-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester
By crude product 2-(2-hydroxyl)-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 67c (200mg, 0.74mmol) be dissolved in 15mL toluene, stir, add crude product 4-(tetrazole-1-base) phenol 46b (108mg, 0.67mmol), add triphenylphosphine (387mg successively again, 1.48mmol) with diisopropyl azodiformate (0.2mL, 1.11mmol), stirring at room temperature 12 hours, reheat to 65 DEG C, stirring reaction 2 hours.Reaction solution concentrating under reduced pressure, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product 2-[2-[4-(tetrazole-1-base) phenoxy group] ethyl]-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 67 (40mg, yellow solid), productive rate: 13.0%.
MS m/z(ESI)：414.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.89(s，1H)，7.59-7.56(m，2H)，7.05-7.01(m，2H)，3.96(t，2H)，3.38-3.23(m，4H)，2.45(dt，1H)，2.08-1.99(m，2H)，1.93(dd，2H)，1.62-1.56(m，2H)，1.52-1.47(m，2H)，1.45(s，9H)，1.40(d，2H).
Embodiment 68
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[2-methyl-4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
The first step
2-methyl-4-(4-methanesulfonylphenYl) phenol
By bromo-for 4-2-methyl-phenol 68a (300mg; 1.60mmol); (4-methanesulfonylphenYl) boric acid (321mg, 1.60mmol), 1; 1 '-two (diphenyl phosphine) ferrocene palladium chloride (117mg; 0.16mmol) be dissolved in 10mL Isosorbide-5-Nitrae-dioxane with cesium carbonate (1.57g, 4.81mmol); be warming up to 120 DEG C, stirring reaction 2 hours.Add 50mL water; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous sodium sulfate drying; filter, filtrate reduced in volume, obtains crude title product 2-methyl-4-(4-methanesulfonylphenYl) phenol 68b (350mg; yellow solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：280.1[M+18]
Second step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[2-methyl-4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
By crude product 2-methyl-4-(4-methanesulfonylphenYl) phenol 68b (100mg; 0.38mmol) be dissolved in 5mLN; in dinethylformamide; add crude product [(1R successively; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (113mg, 0.38mmol) and cesium carbonate (248mg, 0.76mmol); be warming up to 90 DEG C, stirring reaction 4 hours.Add 50mL water; be extracted with ethyl acetate (40mL × 2); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system B by thin-layer chromatography chromatography; obtain title product (1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[2-methyl-4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 68 (130mg; white solid), productive rate: 73.8%.
MS m/z(ESI)：464.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.23(s，2H)，7.96-7.99(m，2H)，7.72-7.74(m，2H)，7.40-7.42(m，2H)，6.88-6.90(m，1H)，4.01-4.03(m，4H)3.60-3.62(m，2H)，3.09(s，3H)，2.49-2.51(m，2H)，2.31(s，3H)，1.82(s，2H)，1.26(s，1H)，1.19-1.24(m，3H).
Embodiment 69
(1R, 5S)-3-(5-chloropyrimide-2-base)-6-[(1R)-1-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] ethyl]-3-azabicyclo also [3.1.0] hexane
The first step
(1R, 5S)-6-formyl radical-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
Under the dry ice bath, by oxalyl chloride (143mg, 0.13mmol) be dissolved in 6mL methylene dichloride, slow dropping dimethyl sulfoxide (DMSO) (190mg, 2.44mmol), stirring reaction 10 minutes, drip 4mL crude product (1R subsequently, 5S) the dichloromethane solution of-6-(hydroxymethyl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 16a (200mg, 0.94mmol), stirring reaction 30 minutes.Drip triethylamine (470mg, 4.69mmol) again, rise to room temperature gradually, stirring reaction 2 hours.Add 10mL shrend to go out reaction; dichloromethane extraction (20mL × 3); merge organic phase, saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying; filter; filtrate reduced in volume, obtains crude title product (1R, 5S)-6-formyl radical-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 69a (210mg; thick pale yellow thing), product is not purified directly carries out next step reaction.
Second step
(1R, 5S)-6-(1-hydroxyethyl)-3-azabicyclo is [3.1.0] hexane-3-carboxylic acid tert-butyl ester also
Under ice bath, by crude product (1R, 5S)-6-formyl radical-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 69a (200mg; 0.94mmol) be dissolved in 5mL tetrahydrofuran (THF); slow dropping 0.6mL 3M methyl-magnesium-bromide, rises to room temperature, stirring reaction 2 hours.Add 5mL saturated ammonium chloride solution cancellation reaction, extraction into ethyl acetate (20mL × 4), merge organic phase, saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains crude title product (1R, 5S)-6-(1-hydroxyethyl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 69b (180mg, light yellow liquid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：172.1[M-55]
3rd step
(1R, 5S)-6-(1-methylsulfonylethyl)-3-azabicyclo is [3.1.0] hexane-3-carboxylic acid tert-butyl ester also
Under ice bath, by crude product (1R, 5S)-6-(1-hydroxyethyl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 69b (180mg, 0.79mmol) be dissolved in 5mL anhydrous methylene chloride, add triethylamine (160mg, 1.58mmol) with DMAP (5mg, cat.), methylsulfonyl chloride (140mg, 1.19mmol) is added dropwise to, be warming up to room temperature, stirring reaction 12 hours.Add 10mL water; with dichloromethane extraction (20mL × 3); with saturated nacl aqueous solution washing (20mL × 2); anhydrous sodium sulfate drying, filters, filtrate reduced in volume; obtain crude title product (1R; 5S)-6-(1-methylsulfonylethyl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 69c (190mg, yellow liquid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：250.1[M-55]
4th step
(1R, 5S)-6-[1-(bromo-2, the 6-dilquoro-phenogy of 4-) ethyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
By bromo-for 4-2; 6-difluoro-phenol (180mg; 0.87mmol) be dissolved in 5mL N; in dinethylformamide; add crude product (1R, 5S)-6-(1-methylsulfonylethyl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 69c (190mg, 0.79mmol) and cesium carbonate (510mg successively; 1.58mmol), 100 DEG C of stirring reactions 2 hours are risen to.Add 20mL water, be extracted with ethyl acetate (20mL × 3), merge organic phase, with saturated nacl aqueous solution washing (20mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product (1R, 5S)-6-[1-(bromo-2, the 6-dilquoro-phenogy of 4-) ethyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 69d (190mg, white solid), productive rate: 57.6%.
MS m/z(ESI)：364.0[M-55]
5th step
(1R, 5S)-6-[(1R)-1-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] ethyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
By (1R; 5S)-6-[1-(4-bromo-2; 6-dilquoro-phenogy) ethyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 69d (190mg; 0.45mmol); (4-methanesulfonylphenYl) boric acid (109mg; 0.55mmol); 1; 1 '-two (diphenyl phosphine) ferrocene palladium chloride (33mg; 0.05mmol) be dissolved in 6mL Isosorbide-5-Nitrae-dioxane with cesium carbonate (440mg, 1.35mmol); be warming up to 120 DEG C, stirring reaction 5 hours.Add 10mL water; be extracted with ethyl acetate (20mL × 3); merge organic phase; with saturated nacl aqueous solution washing (20mL); anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with eluent system B with silica gel column chromatography; obtain title product (1R, 5S)-6-[(1R)-1-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] ethyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 69e (120mg; white solid), productive rate: 59.1%.
MS m/z(ESI)：438.1[M-55]
6th step
(1R, 5S)-6-[(1R)-1-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] ethyl]-3-azabicyclo also [3.1.0] hexane
Under ice bath; by (1R; 5S)-6-[(1R)-1-[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] ethyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 69 (120mg; 0.24mmol) be dissolved in 2mL methylene dichloride; be added dropwise to 5mL 4M methanol hydrochloride solution, be warming up to room temperature, stirring reaction 2 hours.Concentrating under reduced pressure reaction solution; obtain crude title product (1R; 5S)-6-[(1R)-1-[2; the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] ethyl]-3-azabicyclo also [3.1.0] hexane 69f (100mg; white solid), product is not purified directly carries out next step reaction.
7th step
(1R, 5S)-3-(5-chloropyrimide-2-base)-6-[(1R)-1-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] ethyl]-3-azabicyclo also [3.1.0] hexane
By crude product (1R; 5S)-6-[(1R)-1-[the fluoro-4-of 2,6-bis-(4-methanesulfonylphenYl) phenoxy group] ethyl]-3-azabicyclo also [3.1.0] hexane 69f (100mg, 0.23mmol) be dissolved in 5mL N; in N-N,N-DIMETHYLACETAMIDE; add 2,5-dichloro pyrimidine (42mg, 0.28mmol) and N successively; N-diisopropylethylamine (90mg; 0.70mmol), be warming up to 140 DEG C, stirring reaction 7 hours.Add 25mL water, be extracted with ethyl acetate (30mL × 3), merge organic phase, use 1M hydrogen chloride solution (15mL) successively, saturated sodium bicarbonate solution (15mL), saturated nacl aqueous solution washing (15mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product (1R, 5S)-3-(5-chloropyrimide-2-base)-6-[(1R)-1-[2, the fluoro-4-of 6-bis-(4-methanesulfonylphenYl) phenoxy group] ethyl]-3-azabicyclo also [3.1.0] hexane 69 (52mg, white solid), productive rate: 44.4%.
MS m/z(ESI)：506.1[M+1]
1H NMR(400MHz，CDCl 3)δ8.29(s，2H)，8.06-8.08(m，2H)，7.75-7.77(m，2H)，7.22-7.24(m，2H)，3.93-3.96(m，2H)，3.85-3.88(m，1H)，3.61-3.64(m，1H)，3.51-3.54(m，1H)，3.14(s，3H)，1.65-1.70(m，2H)，1.52-1.53(m，3H)，1.08-1.10(m，1H).
Embodiment 70
(1R, 5S)-6-[[the fluoro-4-of 3,5-bis-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
The first step
The fluoro-4-of 3,5-bis-(4-methanesulfonylphenYl) phenol
By bromo-for 4-3; 5-difluoro-phenol 70a (500mg, 2.40mmol), (4-methanesulfonylphenYl) boric acid (478mg; 2.40mmol); 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (174mg, 0.24mmol) and cesium carbonate (2.34g; 7.20mmol) be dissolved in 10mL 1; in 4-dioxane, be warming up to 120 DEG C, stirring reaction 2 hours.Add 50mL water; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous sodium sulfate drying, filters, filtrate reduced in volume; obtain crude title product 3; the fluoro-4-of 5-bis-(4-methanesulfonylphenYl) phenol 70b (519mg, yellow solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：283.0[M-1]
Second step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[2-methyl-4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
By crude product 3; the fluoro-4-of 5-bis-(4-methanesulfonylphenYl) phenol 70b (100mg; 0.35mmol) be dissolved in 5mLN; in dinethylformamide, add crude product [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (105mg successively; 0.35mmol) with cesium carbonate (230mg; 0.70mmol), be warming up to 90 DEG C, stirring reaction 4 hours.Add 50mL water; be extracted with ethyl acetate (40mL × 2); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system B by thin-layer chromatography chromatography; obtain title product (1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[2-methyl-4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 70 (68mg; white solid), productive rate: 40.0%.
MS m/z(ESI)：486.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.20(s，2H)，8.00(d，2H)，7.65(d，2H)，6.57-6.59(m，2H)，4.00-4.02(m，2H)，3.93-3.96(m，2H)，3.60-3.63(m，2H)，3.10(s，3H)，2.46-2.52(m，2H)，1.77(s，2H)，1.24-1.27(m，1H)，1.18-1.22(m，3H).
Embodiment 71
(1R, 5S)-6-[[the fluoro-4-of 3,5-bis-(4-pyridyl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By [(1R, 5S)-6-[(4-bromo-2,6-dilquoro-phenogy) methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 8a (90mg, 2.19mmol), 4-pyridinylboronic acid (27mg, 2.19mmol), 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (16mg, 0.22mmol) with cesium carbonate (214mg, 6.58mmol) be dissolved in 10mL Isosorbide-5-Nitrae-dioxane, heat up 120 DEG C of stirring reactions 2 hours.Add 50mL water, be extracted with ethyl acetate (40mL × 2), merge organic phase, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product (1R, 5S)-6-[[3, the fluoro-4-of 5-bis-(4-pyridyl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 71 (70mg, white solid), productive rate: 22.0%.
MS m/z(ESI)：409.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.70(s，2H)，8.20(s，2H)，7.47(s，2H)，7.21-7.23(m，2H)，4.15-4.17(m，2H)，3.91-3.94(m，2H)，3.57-3.60(m，2H)，2.45-2.51(m，2H)，1.74(s，2H)，1.26(s，1H)，1.17-1.21(m，3H).
Embodiment 72
7-(5-ethyl-pyrimidine-2-base)-2-[2-[4-(tetrazole-1-base) phenoxy group] ethyl]-7-azaspiro [3.5] nonane
The first step
2-(7-azaspiro [3.5] nonane-2-base) ethanol
By crude product 2-(2-hydroxyl)-7-azaspiro [3.5] nonane-7-carboxylic acid tert-butyl ester 67c (200mg, 0.74mmol) be dissolved in 10mL methylene dichloride, be added dropwise to trifluoroacetic acid (114 μ L, 1.48mmol), stirring reaction 2 hours.Reaction solution concentrating under reduced pressure, obtains crude title product 2-(7-azaspiro [3.5] nonane-2-base) ethanol 72a (200mg, yellow oil), and product is not purified directly carries out next step reaction.
Second step
2-[7-(5-ethyl-pyrimidine-2-base)-7-azaspiro [3.5] nonane-2-base] ethanol
By crude product 2-(7-azaspiro [3.5] nonane-2-base) ethanol 72a (200mg, 1.18mmol) be dissolved in 10mLN, in dinethylformamide, add the chloro-5-ethyl-pyrimidin of 2-(168mg successively, 1.18mmol) with salt of wormwood (408mg, 2.90mmol), be warming up to 130 DEG C, stirring reaction 3 hours.Add 50mL water, be extracted with ethyl acetate (50mL × 3), merge organic phase, with saturated nacl aqueous solution washing (50mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product 2-[7-(5-ethyl-pyrimidine-2-base)-7-azaspiro [3.5] nonane-2-base] ethanol 72b (136mg, white solid), productive rate: 42.0%
MS m/z(ESI)：276.2[M+1]
3rd step
7-(5-ethyl-pyrimidine-2-base)-2-[2-[4-(tetrazole-1-base) phenoxy group] ethyl]-7-azaspiro [3.5] nonane
By 2-[7-(5-ethyl-pyrimidine-2-base)-7-azaspiro [3.5] nonane-2-base] ethanol 72b (136mg, 0.49mmol) be dissolved in 15mL toluene, stir, add crude product 4-(tetrazole-1-base) phenol 46b (72mg, 0.44mmol), add triphenylphosphine (256mg successively again, 0.98mmol) with diisopropyl azodiformate (145 μ L, 0.74mmol), stirring at room temperature 12 hours, reheat to 65 DEG C, stirring reaction 2 hours.Reaction solution concentrating under reduced pressure, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product 7-(5-ethyl-pyrimidine-2-base)-2-[2-[4-(tetrazole-1-base) phenoxy group] ethyl]-7-azaspiro [3.5] nonane 72 (17mg, white solid), productive rate: 8%.
MS m/z(ESI)：420.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.89(s，1H)，8.15(s，2H)，7.61-7.53(m，2H)，7.07-7.01(m，2H)，3.97(t，2H)，3.77-3.70(m，2H)，3.69-3.62(m，2H)，2.46(td，3H)，2.13-2.04(m，2H)，1.95(dd，2H)，1.71-1.64(m，2H)，1.59-1.49(m，4H)，1.17(t，3H).
Embodiment 73
4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group] phenyl] cyanobenzene
The first step
4-(4-hydroxy phenyl) cyanobenzene
By (4-cyano-phenyl) boric acid 73a (1g, 6.80mmol), 4-bromophenol (911mg, 5.30mmol), 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (387mg, 0.53mmol) He three hypophosphite monohydrate potassium (4.23g, 4.23mmol) be dissolved in 15mL Isosorbide-5-Nitrae-dioxane, be warming up to return stirring and react 12 hours.Filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 4-(4-hydroxy phenyl) cyanobenzene 73b (840mg, white solid), productive rate: 83.0%.
MS m/z(ESI)：193.8[M-1]
Second step
4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group] phenyl] cyanobenzene
By 4-(4-hydroxy phenyl) cyanobenzene 73b (100mg, 0.50mmol) be dissolved in 5mL N, in dinethylformamide, add crude product [(1R successively, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (137mg, 0.46mmol) and cesium carbonate (325mg, 1mmol), be warming up to 80 DEG C, stirring reaction 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 3), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group] phenyl] cyanobenzene 73 (35mg, white solid), productive rate: 19.0%.
MS m/z(ESI)：397.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.20(s，2H)，7.71-7.63(m，4H)，7.53(d，2H)，7.00(d，2H)，4.02-3.97(m，4H)，3.63-3.60(m，2H)，2.51-2.45(m，2H)，1.78(s，2H)，1.26-1.18(m，4H)
Embodiment 74
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(4-ethanesulfonylphenyl)-2,6-dilquoro-phenogy] methyl]-3-azabicyclo also [3.1.0] hexane
The first step
4-(4-ethanesulfonylphenyl)-2,6-difluoro-phenol
By bromo-for 4-2; 6-difluoro-phenol 74a (500mg, 2.39mmol), (4-ethanesulfonylphenyl) boric acid (512mg; 2.39mmol); 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (175mg, 0.20mmol) and cesium carbonate (2.34g; 7.18mmol) be dissolved in 10mL 1; in 4-dioxane, be warming up to 120 DEG C, stirring reaction 2 hours.Add 50mL water; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous sodium sulfate drying, filters, filtrate reduced in volume; obtain crude title product 4-(4-ethanesulfonylphenyl)-2; 6-difluoro-phenol 74b (200mg, gray solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：297.0[M-1]
Second step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(4-ethanesulfonylphenyl)-2,6-dilquoro-phenogy] methyl]-3-azabicyclo also [3.1.0] hexane
By crude product 4-(4-ethanesulfonylphenyl)-2; 6-difluoro-phenol 74b (100mg; 0.30mmol) be dissolved in 10mL N; in dinethylformamide; add crude product [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (100mg, 0.30mmol) and cesium carbonate (328mg successively; 1mmol), 90 DEG C of stirring reactions 2 hours are risen to.Add 50mL water; be extracted with ethyl acetate (40mL × 2); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system B by thin-layer chromatography chromatography; obtain title product (1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(4-ethanesulfonylphenyl)-2; 6-dilquoro-phenogy] methyl]-3-azabicyclo also [3.1.0] hexane 74 (20mg, white solid), productive rate: 12.5%.
MS m/z(ESI)：500.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.18(s，2H)，7.97-7.99(m，2H)，7.69-7.72(m，2H)，7.17-7.19(m，2H)，4.14-4.16(m，2H)，3.88-3.91(m，2H)，3.55-3.57(m，2H)，3.14-3.19(m，2H)，2.43-2.50(m，2H)，1.72(s，2H)，1.30-1.34(m，3H)，1.26-1.23(m，1H)，1.17-1.20(m，3H).
Embodiment 75
N-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl]-5-(4-methanesulfonylphenYl) piperazine-2-amine
The first step
(1R, 5S)-6-(brooethyl)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By crude product [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (219mg, 1mmol) with carbon tetrabromide (500mg, 1.50mmol) be dissolved in 5mL methylene dichloride, add triphenylphosphine (393mg, 1.50mmol), stirring reaction 3 hours.Add 50mL water, with dichloromethane extraction (10mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product (1R, 5S)-6-(brooethyl)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 75a (260mg, clear crystal), productive rate: 92.2%.
MS m/z(ESI)：284.0[M+1]
Second step
5-bromine piperazine-2-amine
Under ice bath, piperazine-2-amine 75b (11.87g, 12.50mmol) is dissolved in 300mL methylene dichloride, adds N-bromo-succinimide (22.20g, 125mmol) in batches, stirring reaction 2 hours.Add 100mL saturated sodium carbonate solution cancellation reaction, separatory, organic phase washs (50mL × 1) with saturated sodium carbonate solution successively, water washing (50mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product 5-bromine piperazine-2-amine 75c (13g, yellow solid), productive rate: 60.0%.
MS m/z(ESI)：173.9[M+1]
3rd step
5-(4-methanesulfonylphenYl) piperazine-2-amine
By 5-bromine piperazine-2-amine 75c (1g; 5.60mmol); (4-methanesulfonylphenYl) boric acid (1.14g; 5.60mmol); two (triphen phosphino-) palladium chloride (130mg; 0.12mmol) be dissolved in the mixed solvent (V/V=5: 2) of 28mL Isosorbide-5-Nitrae-dioxane and methyl alcohol with 8mL 2M sodium carbonate solution, rise to 100 DEG C of stirring reactions 3 hours.Add 15mL water; suction filtration; filter cake washes with water (40mL × 2); filter cake 120mL ethyl acetate is pulled an oar; stir 20 minutes, suction filtration, obtain crude title product 5-(4-methanesulfonylphenYl) piperazine-2-amine 75d (1.40g; yellow solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：250.1[M+1]
4th step
N-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl]-5-(4-methanesulfonylphenYl) piperazine-2-amine
By crude product 5-(4-methanesulfonylphenYl) piperazine-2-amine 75d (100mg; 0.40mmol) be dissolved in 2mL DMF, add 60% sodium hydride (40mg; 1mmol), 40 DEG C of stirring reactions 0.5 hour is risen to.Be cooled to room temperature, add (1R, 5S)-6-(brooethyl)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 75a (80mg, 0.28mmol), stirring reaction 40 minutes.Add 30mL water; be extracted with ethyl acetate (50mL × 2); merge organic phase; with saturated nacl aqueous solution washing (20mL × 1); anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system A by thin-layer chromatography chromatography; obtain title product N-[[(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl]-5-(4-methanesulfonylphenYl) piperazine-2-amine 75 (30mg, faint yellow solid), productive rate: 23.8%.
MS m/z(ESI)：451.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.56(s，1H)，8.22(s，2H)，8.11(d，2H)，8.03(d，3H)，3.99(d，2H)，3.61(d，2H)，3.51-3.38(m，2H)，3.12(s，3H)，2.50(q，2H)，1.74(s，3H)，1.22(t，3H)，1.13(m，1H).
Embodiment 76
N-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl]-N-methyl-5-(4-methanesulfonylphenYl) piperazine-2-amine
By N-[[(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl]-5-(4-methanesulfonylphenYl) piperazine-2-amine 75 (36mg; 0.08mmol) be dissolved in 1mL N; in dinethylformamide, add 60% sodium hydride (10mg, 0.25mmol); stirring reaction 0.5 hour; add methyl iodide (14mg, 0.10mmol) again, stirring reaction 20 minutes.Add 30mL water; be extracted with ethyl acetate (50mL × 2); merge organic phase; with saturated nacl aqueous solution washing (20mL × 1); anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system A by thin-layer chromatography chromatography; obtain title product N-[[(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl]-N-methyl-5-(4-methanesulfonylphenYl) piperazine-2-amine 76 (17mg, faint yellow solid), productive rate: 45.9%.
MS m/z(ESI)：465.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.60(s，1H)，8.18(d，3H)，8.12(d，2H)，8.03(d，2H)，3.94(d，2H)，3.68(d，2H)，3.56(d，2H)，3.25(s，3H)，3.12(s，3H)，2.48(q，2H)，1.73(s，2H)，1.20(t，3H)，1.14-1.02(m，1H).
Embodiment 77
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(4-methanesulfonylphenYl) triazol-1-yl] methyl]-3-azabicyclo also [3.1.0] hexane
The first step
(1R, 5S)-6-(azido-methyl)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane by crude product [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (2.20g, 7.40mmol) with sodiumazide (1.20g, 18mmol) be dissolved in 10mL N, in dinethylformamide, rise to 80 DEG C of stirring reactions 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 3), merge organic phase, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, obtain crude title product (1R, 5S)-6-(azido-methyl)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 77a (380mg, brown oil), productive rate: 23.0%.
MS m/z(ESI)：245.1[M+1]
Second step
Trimethylammonium-[2-(4-methylsulfonyl) ethynyl] silane
By bromo-for 1-4-methylsulfonyl-benzene 77b (1g; 4.20mmol), triethylamine (1.20g, 12.60mmol); cuprous iodide (71mg; 0.40mmol) He two (triphen phosphino-) palladium chloride (118mg, 0.20mmol) is dissolved in 10mL methylene dichloride, under ice bath cooling; drip ethynyl (trimethylammonium) silane (458mg; 4.70mmol), rise to room temperature, stirring reaction 12 hours.Add 10mL water; be extracted with ethyl acetate (10mL × 2); merge organic phase; use 1M ammonium chloride solution (10mL × 2) successively; saturated nacl aqueous solution washing (10mL × 2); anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with eluent system B with silica gel column chromatography; obtain title product trimethylammonium-[2-(4-methylsulfonyl) ethynyl] silane 77c (1g, faint yellow solid), productive rate: 93.4%.
MS m/z(ESI)：270.1[M+18]
3rd step
1-ethynyl-4-methylsulfonyl-benzene
By trimethylammonium-[2-(4-methylsulfonyl) ethynyl] silane 77c (1g, 4mmol) salt of wormwood (2.20g, 16mmol) is dissolved in 20mL methyl alcohol, stirring reaction 12 hours.Filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 1-ethynyl-4-methylsulfonyl-benzene 77d (400mg, yellow solid), productive rate: 56.3%.
MS m/z(ESI)：198.1[M+18]
4th step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(4-methanesulfonylphenYl) triazol-1-yl] methyl]-3-azabicyclo also [3.1.0] hexane
By crude product (1R; 5S)-6-(azido-methyl)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 77a (100mg; 0.40mmol); 1-ethynyl-4-methylsulfonyl-benzene 77d (74mg, 0.40mmol), cuprous bromide (12mg; 0.08mmol) with triethylamine (81mg; 0.80mmol) be dissolved in 5mL acetonitrile, drip 1mL water, stirring reaction 12 hours.Add 20mL water; be extracted with ethyl acetate (20mL × 3); merge organic phase; anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with eluent system B with silica gel column chromatography; obtain title product (1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(4-methanesulfonylphenYl) triazol-1-yl] methyl]-3-azabicyclo also [3.1.0] hexane 77 (85mg; white solid), productive rate: 55.0%.
MS m/z(ESI)：424.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.18(s，2H)，8.07-8.00(m，4H)，7.97(s，1H)，4.42(d，2H)，3.98(d，2H)，3.59(d，2H)，3.10(s，3H)，2.50-2.45(m，2H)，1.87(s，2H)，1.34-1.31(m，1H)，1.19(t，3H).
Embodiment 78
(1R, 5S)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
By crude product 4-(4-methanesulfonylphenYl) phenol 33b (250mg; 0.80mmol) be dissolved in 5mL N; in dinethylformamide; add crude product (1R successively; 5S)-6-(Methanesulfonvloxvmethvl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 16b (293mg; 0.80mmol) with cesium carbonate (656mg, 1.60mmol), rise to 90 DEG C of stirring reactions 4 hours.Add 50mL water; be extracted with ethyl acetate (40mL × 2); merge organic phase; anhydrous magnesium sulfate drying, filters, filtrate reduced in volume; obtain title product (1R; 5S)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 78 (200mg, white solid), productive rate: 56.0%.
MS m/z(ESI)：388.1[M-55]
1H NMR(400MHz，CDCl 3)δ7.97-7.99(m，2H)，7.72-7.75(m，2H)，7.55-7.57(m，2H)，6.98-7.00(m，2H)，3.86-4.00(m，2H)，3.62-3.72(m，2H)，3.39-3.40(m，2H)，3.09(s，3H)，1.59(s，2H)，1.40(s，9H)，1.17(s，1H).
Embodiment 79
4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group] phenyl] benzamide
By 4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group] phenyl] cyanobenzene 73 (5mg, 12.60 μm of ol) and potassium hydroxide (1mg, 18.90 μm of ol) be dissolved in 5mL ethanol, add hydrogen peroxidase 10 .50mL, stirring reaction 12 hours.Reaction solution concentrating under reduced pressure, add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product 4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group] phenyl] benzamide 79 (3mg, white solid), productive rate: 57.7%.
MS m/z(ESI)：415.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.20(s，2H)，7.99(s，1H)，7.91-7.94(m，2H)，7.65-7.70(m，4H)，7.32(s，1H)，7.03-7.05(m，2H)，3.97-3.99(m，2H)，3.78-3.81(m，2H)，3.45-3.48(m，2H)，2.38-2.40(m，2H)，1.77(s，2H)，1.13(s，1H)，1.09-1.11(m，3H).
Embodiment 80
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[(1R)-1-[4-(4-methanesulfonylphenYl) phenoxy group] ethyl]-3-azabicyclo also [3.1.0] hexane
The first step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-phenyl aldehyde
Under the dry ice bath, by oxalyl chloride (174mg, 1.37mmol) be dissolved in 10mL methylene dichloride, slow dropping dimethyl sulfoxide (DMSO) (232mg, 2.97mmol), reacted after 10 minutes, drip 5mL crude product [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] dichloromethane solution of methyl alcohol 7f (250mg, 1.14mmol), stirring reaction 30 minutes.Drip triethylamine (576mg, 5.71mmol) again, rise to room temperature gradually, stirring reaction 2 hours.Add 10mL shrend to go out reaction, dichloromethane extraction (20mL × 3), merge organic phase, saturated nacl aqueous solution washing (20mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product (1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-phenyl aldehyde 80a (100mg, white solid), productive rate: 40.3%.
MS m/z(ESI)：218.2[M+1]
Second step
1-[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] ethanol
Under ice bath, by (1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-phenyl aldehyde 80a (100mg, 0.46mmol) be added in 5mL tetrahydrofuran (THF), slow dropping 0.3mL 3M methyl-magnesium-bromide, rise to room temperature gradually, stirring reaction 2 hours.Add 15mL saturated ammonium chloride solution cancellation reaction, extraction into ethyl acetate (30mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, obtain crude title product 1-[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] ethanol 80b (100mg, white solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：234.2[M+1]
3rd step
(1R, 5S)-6-(1-chloroethyl)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
Under ice bath, by 1-[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] ethanol 80b (100mg, 0.43mmol) be dissolved in 10mL anhydrous methylene chloride, add triethylamine (0.1mL, 0.86mmol), be added dropwise to methylsulfonyl chloride (0.1mL, 0.64mmol), rise to room temperature, stirring reaction 2 hours.Add methylene dichloride 10mL, with saturated nacl aqueous solution washing (20mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtains crude title product (1R, 5S)-6-(1-chloroethyl)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 80c (100mg, yellow liquid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：252.1[M+1]
4th step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[(1R)-1-[4-(4-methanesulfonylphenYl) phenoxy group] ethyl]-3-azabicyclo also [3.1.0] hexane
By crude product 4-(4-methanesulfonylphenYl) phenol 33b (109mg; 0.44mmol) be dissolved in 10mL N; in dinethylformamide; add crude product (1R successively; 5S)-6-(1-chloroethyl)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 80c (100mg; 0.40mmol) with cesium carbonate (325mg, 1mmol), rise to 110 DEG C of stirring reactions 4 hours.Add 50mL water; be extracted with ethyl acetate (30mL × 2); merge organic phase; with saturated nacl aqueous solution washing (20mL × 2); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; obtain title product (1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[(1R)-1-[4-(4-methanesulfonylphenYl) phenoxy group] ethyl]-3-azabicyclo also [3.1.0] hexane 80 (70mg; white solid), productive rate: 38.0%.
MS m/z(ESI)：464.2[M+1]
1H NMR(400MHz，d-DMSO)8.20(s，2H)，7.95(dd，4H)，7.69(d，2H)，7.07(d，2H)，4.25-4.32(m，1H)，3.73-3.78(m，2H)，3.39-3.45(m，2H)，3.24(s，3H)，2.40(q，2H)，1.73-1.77(m，2H)，1.32(d，3H)，1.11(t，3H)，0.92-0.95(m，1H).
Embodiment 81
3-sec.-propyl-5-[(1R, 5S)-6-[[5-(4-methanesulfonylphenYl) pyrazine-2-base] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-1,2,4-oxadiazoles
The first step
5-(4-methanesulfonylphenYl) pyrazine-2-alcohol
The 3.8mL vitriol oil is cooled to 0 DEG C; add Sodium Nitrite (520mg in batches; 7.60mmol), be warming up to 50 DEG C of stirrings, solid is all dissolved; be cooled to 0 DEG C again; drip the concentrated sulfuric acid solution of 11.2mL crude product 5-(4-methanesulfonylphenYl) piperazine-2-amine 75d (1.40g, 5.60mmol), in keeping, temperature is at 0 DEG C-5 DEG C; stirring at room temperature 15 minutes, then be warming up to 45 DEG C of stirrings 30 minutes.Reaction solution is slowly poured in 300mL frozen water; stir; dripping 12.5M sodium hydroxide solution is 4 to reaction solution pH; suction filtration; filter cake washes with water (50mL × 2); obtain crude title product 5-(4-methanesulfonylphenYl) pyrazine-2-alcohol 81b (1.20g, yellow solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：251.0[M+1]
Second step
3-sec.-propyl-5-[(1R, 5S)-6-[[5-(4-methanesulfonylphenYl) pyrazine-2-base] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-1,2,4-oxadiazoles
By crude product [(1R; 5S)-3-(3-sec.-propyl-1; 2; 4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl methylsulfonate 48c (200mg; 0.66mmol) be dissolved in 5mL N; in dinethylformamide; stir; add 5-(4-methanesulfonylphenYl) pyrazine-2-alcohol 81b (166mg; 0.66mmol) with salt of wormwood (275mg; 1.98mmol), 80 DEG C of stirring reactions 1 hour is warming up to.Add 20mL water; extraction into ethyl acetate (20mL × 2); merge organic phase; with saturated nacl aqueous solution washing (20mL); anhydrous sodium sulfate drying; filter; filtrate reduced in volume; purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 3-sec.-propyl-5-[(1R, 5S)-6-[[5-(4-methanesulfonylphenYl) pyrazine-2-base] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-1; 2; 4-oxadiazole 81 (48mg, white solid), productive rate: 16.0%.
MS m/z(ESI)：456.1[M+1]
1H NMR(400MHz，CDCl 3)δ8.60(s，1H)，8.37(s，1H)，8.17(d，2H)，8.08(d，2H)，4.37(d，2H)，3.90(d，2H)，3.72(d，2H)，3.13(s，3H)，2.97-2.87(m，1H)，1.84(s，2H)，1.33(d，6H)，0.92(s，1H).
Embodiment 82
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
The first step
4-(5-methylsulfonyl-2-pyridine) phenol
By bromo-for 2-5-methanesulfonyl-pyridine 82a (100mg; 425 μm of ol); (4-hydroxy phenyl) boric acid (58mg; 425 μm of ol), 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (30mg; 42.5 μm of ol) and cesium carbonate (414mg; 1.28mmol) be dissolved in 5mL Isosorbide-5-Nitrae-dioxane, heat up 60 DEG C of stirring reactions 2 hours.Add 10mL water; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous sodium sulfate drying, filters, filtrate reduced in volume; gained resistates is purified with developping agent system B by thin-layer chromatography chromatography; obtain title product 4-(5-methylsulfonyl-2-pyridine) phenol 82b (20mg, yellow solid), productive rate: 18.0%.
MS m/z(ESI)：250.1[M+1]
Second step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
By 4-(5-methylsulfonyl-2-pyridine) phenol 82b (20mg; 92.30 μm of ol) be dissolved in 5mL N; in dinethylformamide; add crude product [(1R successively; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (27.40mg; 92.30 μm of ol) and cesium carbonate (60mg, 184.50 μm of ol), rise to 100 DEG C of stirring reactions 4 hours.Add 10mL water; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system A by thin-layer chromatography chromatography; obtain title product (1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 82 (20mg; white solid), productive rate: 48.7%.
MS m/z(ESI)：451.2[M+1]
1H NMR(400MHz，CDCl 3)δ9.14(s，1H)，8.20-8.23(m，3H)，8.04-8.06(m，2H)，7.84-7.86(m，1H)，7.02-7.04(m，2H)，4.00-4.02(m，4H)，3.61-3.63(m，2H)，3.13(s，3H)，2.46-2.50(m，2H)，1.79(s，2H)，1.24(s，1H)，1.18-1.24(m，3H).
Embodiment 83
9-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen base]-7-oxa--3-azabicyclic also [3.3.1] nonane-3-carboxylic acid tert-butyl ester
The first step
9-[[6-(4-methylsulfanylphenyl)-3-pyridyl] oxygen base]-7-oxa--3-azabicyclic also [3.3.1] nonane-3-carboxylic acid tert-butyl ester
By 9-(4-bromo-2,6-dilquoro-phenogy)-7-oxa--3-azabicyclic also [3.3.1]-3-in ninth of the ten Heavenly Stems carboxylic acid tert-butyl ester 20d (300mg, 0.75mmol), (4-methylsulfanylphenyl) boric acid (151mg, 0.90mmol) He 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (55mg, 0.08mmol) be dissolved in 15mL 1, in 4-dioxane, add cesium carbonate (0.73g again, 2.25mmol), 120 DEG C of stirring reactions 2 hours are warming up to.Add 20mL water, extraction into ethyl acetate (30mL × 3), merge organic phase, saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product 9-[[6-(4-methylsulfanylphenyl)-3-pyridyl] oxygen base]-7-oxa--3-azabicyclic also [3.3.1] nonane-3-carboxylic acid tert-butyl ester 83a (152mg, gray solid), productive rate: 42.6%.
MS m/z(ESI)：443.2[M+1]
Second step
9-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen base]-7-oxa--3-azabicyclic also [3.3.1] nonane-3-carboxylic acid tert-butyl ester
Under ice bath, by 9-[[6-(4-methylsulfanylphenyl)-3-pyridyl] oxygen base]-7-oxa--3-azabicyclic also [3.3.1] nonane-3-carboxylic acid tert-butyl ester 83a (150mg, 0.34mmol) be dissolved in 5mL methylene dichloride, add metachloroperbenzoic acid (182mg, 0.75mmol), rise to stirring at room temperature and react 2 hours.Reaction solution saturated sodium bisulfite solution washing (10mL); anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system B by thin-layer chromatography chromatography; obtain title product 9-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen base]-7-oxa--3-azabicyclic also [3.3.1] nonane-3-carboxylic acid tert-butyl ester 83 (5mg, white solid), productive rate: 3.1%.
MS m/z(ESI)：475.6[M+1]
1H NMR(400MHz，d-DMSO)δ8.53-8.54(m，1H)，8.27-8.29(m，2H)，7.98-8.07(m，3H)，7.65-7.68(m，1H)，4.86-4.88(m，1H)，4.24-4.38(m，2H)，3.94-4.01(m，2H)，3.68-3.73(m，2H)，3.33(s，3H)，3.14-3.29(m，2H)，1.89-1.91(m，2H)，1.40(s，9H).
Embodiment 84
(1R, 5S)-6-[(1R)-1-[4-(4-methanesulfonylphenYl) phenoxy group] ethyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
The first step
(1R, 5S)-6-formyl radical-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
Under the dry ice bath, by oxalyl chloride (2.14g, 16.90mmol) be added in 20mL methylene dichloride, slow dropping dimethyl sulfoxide (DMSO) (2.86g, 35.60mmol), reacts 1 hour, drip 40mL (1R subsequently, 5S) the methylene dichloride of-6-(hydroxymethyl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 16a (3g, 14mmol), stirring reaction 2 hours.Drip triethylamine (7.12g, 70.30mmol) again, rise to room temperature gradually, stirring reaction 2 hours.Add 20mL saturated ammonium chloride solution cancellation reaction; organic phase anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; obtain crude title product (1R; 5S)-6-formyl radical-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 84a (3g, yellow oily), product is not purified directly carries out next step reaction.
MS m/z(ESI)：156.1[M-55]
Second step
(1R, 5S)-6-(1-hydroxyethyl)-3-azabicyclo is [3.1.0] hexane-3-carboxylic acid tert-butyl ester also
Under ice bath; by crude product (1R; 5S)-6-formyl radical-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 84a (3g; 14.20mmol) be added in 20mL tetrahydrofuran (THF); slow dropping 3M methyl-magnesium-bromide (3.39g; 28.40mmol), rise to room temperature gradually, stirring reaction 2 hours.Add 20mL water, extraction into ethyl acetate (40mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, obtain crude title product (1R, 5S)-6-(1-hydroxyethyl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 84b (2.80g, yellow oily), product is not purified directly carries out next step reaction.
MS m/z(ESI)：172.1[M-55]
3rd step
(1R, 5S)-6-(1-chloroethyl)-3-azabicyclo is [3.1.0] hexane-3-carboxylic acid tert-butyl ester also
By crude product (1R, 5S)-6-(1-hydroxyethyl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 84b (2.80g, 13mmol) be dissolved in 60mL anhydrous methylene chloride, add triethylamine (2.67g, 26.40mmol), be added dropwise to methylsulfonyl chloride (2.27g, 19.80mmol), stirring reaction 12 hours.Add 60mL water, dichloromethane extraction (50mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, obtain crude title product (1R, 5S)-6-(1-chloroethyl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 84c (3.30g, yellow liquid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：190.0[M-55]
4th step
(1R, 5S)-6-[(1R)-1-[4-(4-methanesulfonylphenYl) phenoxy group] ethyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
By crude product 4-(4-methanesulfonylphenYl) phenol 33b (346mg; 1.39mmol) be dissolved in 5mL N; in dinethylformamide; add crude product (1R successively; 5S)-6-(1-chloroethyl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 84c (342mg; 1.39mmol) with cesium carbonate (908mg, 2.79mmol), rise to 100 DEG C of stirring reactions 2 hours.Add 10mL water; be extracted with ethyl acetate (10mL × 2); merge organic phase; with saturated nacl aqueous solution washing (20mL × 2); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; obtain title product (1R; 5S)-6-[(1R)-1-[4-(4-methanesulfonylphenYl) phenoxy group] ethyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 84 (217mg; yellow solid), productive rate: 34.0%.
MS m/z(ESI)：402.1[M-55]
1H NMR(400MHz，CDCl 3)δ7.97-7.99(m，2H)，7.72-7.74(m，2H)，7.54-7.56(m，2H)，6.97-6.99(m，2H)，4.05-4.18(m，1H)，3.61-3.67(m，2H)，3.35-3.37(m，2H)，3.10(s，3H)，1.60(s，3H)，1.42(s，9H)，1.39(s，2H)，1.26(s，1H).
Embodiment 85
9-[4-(4-methanesulfonylphenYl) phenoxy group]-7-oxa--3-azabicyclic also [3.3.1] nonane-3-carboxylic acid tert-butyl ester
By crude product 9-mesyloxy-7-oxa--3-azabicyclic also [3.3.1]-3-in ninth of the ten Heavenly Stems carboxylic acid tert-butyl ester 20c (142mg; 0.44mmol) with 4-(4-methanesulfonylphenYl) phenol (100mg; 0.40mmol) be dissolved in 5mL N; in N-N,N-DIMETHYLACETAMIDE; add cesium carbonate (262mg again; 0.80mmol), be warming up to 180 DEG C, stirring reaction 7 hours.Add 15mL water; extraction into ethyl acetate (20mL × 3); merge organic phase; saturated nacl aqueous solution washing (20mL × 2); anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system B by thin-layer chromatography chromatography; obtain title product 9-[4-(4-methanesulfonylphenYl) phenoxy group]-7-oxa--3-azabicyclic also [3.3.1] nonane-3-carboxylic acid tert-butyl ester 85 (20mg; white solid), productive rate: 10.5%.
MS m/z(ESI)：418.1[M-55]
1H NMR(400MHz，CDCl 3)δ7.98-8.00(m，2H)，7.72-7.74(m，2H)，7.57-7.59(m，2H)，7.05-7.07(m，2H)，4.60-4.64(m，2H)，4.59-4.60(m，1H)，4.13-4.22(m，2H)，3.82-3.90(m，2H)，3.25-3.28(m，1H)，3.18-3.20(m，1H)，3.17(s，3H)，1.96-1.98(m，2H)，1.50(s，9H).
Embodiment 86
3-sec.-propyl-5-[(1R, 5S)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-1,2,4-oxadiazoles
The first step
(1R, 5S)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
By (1R; 5S)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 78 (200mg; 0.45mmol) be dissolved in the ethyl acetate solution of 20mL 5M hydrogenchloride, stirring reaction 12 hours.Reaction solution concentrating under reduced pressure; obtain crude title product (1R; 5S)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 86a (200mg; white solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：344.1[M+1]
Second step
(1R, 5S)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-formonitrile HCN
By crude product (1R; 5S)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 86a (88mg; 25.60 μm of ol) be dissolved in 10mL chloroform; add cuprous bromide (37mg successively; 38 μm of ol) and salt of wormwood (128mg; 1mmol), at rising to 60 DEG C, stirring reaction 48 hours.Reaction solution concentrating under reduced pressure; obtain crude title product (1R; 5S)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-formonitrile HCN 86b (90mg; yellow solid), product is not purified directly carries out next step reaction.
3rd step
3-sec.-propyl-5-[(1R, 5S)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-1,2,4-oxadiazoles
By crude product (1R; 5S)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-formonitrile HCN 86b (100mg; 0.02mmol) be dissolved in 10mL tetrahydrofuran (THF); add N '-hydroxy-2-methyl-propylamine (30mg successively; 0.03mmol) with zinc chloride (40mg; 0.03mmol), stirring reaction 12 hours.Reaction solution concentrating under reduced pressure, adds the mixing solutions (V/V=1: 1) of the second alcohol and water of 10mL4M hydrogenchloride, refluxes 1 hour.Adding sodium bicarbonate to reaction solution pH is 7; filter; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; purify gained resistates by thin-layer chromatography chromatography with developping agent system B, obtain title product 3-sec.-propyl-5-[(1R, 5S)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-1; 2; 4-oxadiazole 86 (3mg, white solid), productive rate: 2.0%.
MS m/z(ESI)：454.2[M+1]
1H NMR(400MHz，CDCl 3)δ7.97-7.99(m，2H)，7.72-7.74(m，2H)，7.55-7.57(m，2H)，6.98-7.00(m，2H)，3.97-3.99(m，2H)，3.86-3.88(m，2H)，3.67-3.69(m，2H)，3.09(s，3H)，2.89-2.92(m，1H)，1.79(s，2H)，1.37(s，1H)，1.28-1.34(m，6H).
Embodiment 87
[2-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-5-(4-methanesulfonylphenYl) phenyl] methyl alcohol
The first step
The bromo-2-of 5-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group] phenyl aldehyde
By bromo-for 5-2-hydroxy-benzaldehyde 87a (500mg, 2.50mmol) be dissolved in 20mL N, in dinethylformamide, add crude product [(1R successively, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (740mg, 2.50mmol) with salt of wormwood (690mg, 5mmol), rise to 110 DEG C of stirring reactions 4 hours.Add 100mL water, be extracted with ethyl acetate (50mL × 2), merge organic phase, with saturated nacl aqueous solution washing (50mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains the bromo-2-of crude title product 5-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group] phenyl aldehyde 87b (550mg, orange/yellow solid), productive rate: 55.0%.
Second step
2-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-5-(4-methanesulfonylphenYl) phenyl aldehyde
By bromo-for crude product 5-2-[[(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group] phenyl aldehyde 87b (550mg; 1.37mmol); (4-methylacyl phenyl) boric acid (330mg; 1.64mmol) He 1; 1 '-two (diphenyl phosphine) ferrocene palladium chloride (100mg; 0.14mmol) be dissolved in 20mL 1; in 4-dioxane; add cesium carbonate (1.33g again; 4.10mmol), 120 DEG C of stirring reactions 5 hours are warming up to.Add 50mL water; extraction into ethyl acetate (50mL × 3); merge organic phase; anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with eluent system A with silica gel column chromatography; obtain title product 2-[[(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-5-(4-methanesulfonylphenYl) phenyl aldehyde 87c (500mg; white solid), productive rate: 76.9%.
MS m/z(ESI)：478.2[M+1]
3rd step
[2-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-5-(4-methanesulfonylphenYl) phenyl] methyl alcohol
By 2-[[(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-5-(4-methanesulfonylphenYl) phenyl aldehyde 87c (120mg; 0.25mmol) be dissolved in 15mL methyl alcohol; add sodium borohydride (19mg; 0.50mmol), rise to return stirring and react 2.5 hours.Add 20mL water; with dichloromethane extraction (30mL × 2); merge organic phase; anhydrous sodium sulfate drying, filters, filtrate reduced in volume; obtain title product [2-[[(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-5-(4-methanesulfonylphenYl) phenyl] methyl alcohol 87 (110mg, white solid), productive rate: 91.7%.
MS m/z(ESI)：480.2[M+1]
1H NMR(400MHz，d-DMSO)δ8.21(s，2H)，7.93(dd，4H)，7.78(d，1H)，7.61(dd，1H)，7.08(d，1H)，5.13(t，1H)，4.60(d，2H)，4.04(d，2H)，3.80(d，2H)，3.46(d，2H)，3.24(s，3H)，2.42(q，2H)，1.79(s，2H)，1.12(t，3H)，1.08-1.12(m，1H).
Embodiment 88
1-[2-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-5-(4-methanesulfonylphenYl) phenyl]-N-methyl-methylamine
By 2-[[(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-5-(4-methanesulfonylphenYl) phenyl aldehyde 87c (95mg; 0.20mmol) with methylamine hydrochloride (16mg; 0.24mmol) be dissolved in 10mL methyl alcohol; rise to return stirring and react 20 minutes; add sodium borohydride (11mg, 0.30mmol), continue return stirring and react 2.5 hours.Add 20mL water; with dichloromethane extraction (30mL × 2); merge organic phase; anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with eluent system A by thin-layer chromatography chromatography; obtain title product 1-[2-[[(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-5-(4-methanesulfonylphenYl) phenyl]-N-methyl-methylamine 88 (15mg; white solid), productive rate: 15.3%.
MS m/z(ESI)：493.2[M+1]
1H NMR(400MHz，d-DMSO)δ8.21(s，2H)，7.91(dd，4H)，7.72(d，2H)，7.16(d，1H)，5.61(s，1H)，4.06(d，2H)，3.79(d，2H)，3.46(d，2H)，3.36(s，3H)，3.24(s，3H)，2.41(q，2H)，1.94-2.04(m，2H)，1.79(s，2H)，1.11(t，3H)，1.08-1.12(m，1H).
Embodiment 89
(1R, 5S)-3-(5-chloropyrimide-2-base)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
By crude product (1R; 5S)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 86a (50mg; 0.15mmol) be dissolved in 5mL N; in dinethylformamide; add 2,5-dichloro pyrimidine (22mg, 0.15mmol) and cesium carbonate (119mg successively; 0.36mmol), 120 DEG C of stirring reactions 2 hours are risen to.Add 10mL water; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous magnesium sulfate drying, filters, filtrate reduced in volume; obtain crude title product (1R; 5S)-3-(5-chloropyrimide-2-base)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 89 (10mg, yellow solid), productive rate: 15.0%.
MS m/z(ESI)：457.1[M+1]
1H NMR(400MHz，CDCl 3)δ8.23(s，2H)，7.97-7.99(m，2H)，7.72-7.74(m，2H)，7.55-7.57(m，2H)，7.00-7.02(m，2H)，3.94-3.99(m，4H)，3.58-3.60(m，2H)，3.09(s，3H)，1.78(s，2H)，1.21(s，1H).
Embodiment 90
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(the fluoro-4-methanesulfonylphenYl of 2-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
The first step
The fluoro-4-methylsulfonyl-benzene of the bromo-2-of 1-
By fluoro-for 2-4-methylsulfonyl-aniline 90a (1000mg; 5.29mmol) be dissolved in 30mL acetonitrile, add nitrite tert-butyl (1.2mL, 9.25mmol) and bromination ketone (1500mg successively; 6.60mmol), 65 DEG C of reactions 1 hour is risen to.Add the hydrochloric acid soln of 100mL 20%; be extracted with ethyl acetate (40mL × 3); merge organic phase; with saturated nacl aqueous solution washing (50mL × 2), anhydrous sodium sulfate drying, filter; filtrate reduced in volume; obtain the fluoro-4-methylsulfonyl-benzene 90b (1300mg, light yellow solid) of the bromo-2-of title product 1-, productive rate: 100%.
MS m/z(ESI)：252.0[M+1]
Second step
4-(fluoro-4 Metlianesulfonyl-phenyl of 2-) phenol
By fluoro-for bromo-for 1-2-4-methylsulfonyl-benzene 90b (250mg; 1mmol); 4-hydroxybenzene boric acid (150mg; 1.10mmol) be dissolved in 20mL 1 with 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (75mg, 0.10mmol); in 4-dioxane; add cesium carbonate (970mg, 3mmol) again, be warming up to 110 DEG C of stirring reactions 4 hours.Add 10mL water, extraction into ethyl acetate (20mL × 3), merge organic phase, anhydrous sodium sulfate drying, filters, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product 4-(2-methyl-6-methyl sulfo group-3-pyridyl) phenol 90c (170mg, white solid), productive rate: 63.0%.
MS m/z(ESI)：284.0[M+18]
3rd step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(the fluoro-4-methanesulfonylphenYl of 2-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
By 4-(2-methyl-6-methyl sulfo group-3-pyridyl) phenol 90c (130mg, 0.50mmol) be dissolved in 15mLN, in dinethylformamide, add crude product [(1R successively, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (150mg, 0.50mmol) with salt of wormwood (140mg, 0.10mmol), rise to 110 DEG C of stirring reactions 4 hours.Add 10mL water; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with eluent system A with silica gel column chromatography; obtain title product (1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(the fluoro-4-methanesulfonylphenYl of 2-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 90 (130mg; white solid), productive rate: 56.5%.
MS m/z(ESI)：468.1[M+1]
1H NMR(400MHz，d-DMSO)δ8.21(s，2H)，7.79-7.87(m，3H)，7.55-7.57(m，2H)，7.08-7.11(m，2H)，3.99-4.01(m，2H)，3.79-3.82(m，2H)，3.46-3.48(m，2H)，3.31(s，3H)，2.39-2.45(m，2H)，1.78(s，2H)，1.18(s，1H)，1.10-1.14(m，3H).
Embodiment 91
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(2-methyl-6-first sulfo group-3-pyridyl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
The first step
The bromo-2-methyl of 3--6-first sulfo group-pyridine
3,6-bis-bromine-2-methylpyridine 91a (300mg, 1.20mmol) is dissolved in 10mL dimethyl sulfoxide (DMSO), add methanesulfonic sodium (567mg successively, 4.80mmol) the sub-ketone (339mg, 1.60mmol) with iodate, rises to 125 DEG C of microwave reactions 40 minutes.Add 30mL water, be extracted with ethyl acetate (40mL × 2), merge organic phase, with saturated nacl aqueous solution washing (30mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains the bromo-2-methyl of title product 3--6-first sulfo group-pyridine 91b (80mg, yellow liquid), productive rate: 26.7%.
MS m/z(ESI)：251.0[M+1]
Second step
4-(2-methyl-6-methyl sulfo group-3-pyridyl) phenol
By bromo-for 3-2-methyl-6-first sulfo group-pyridine 91b (86mg, 0.34mmol), 4-hydroxybenzene boric acid (47mg, 0.34mmol) be dissolved in 5mL1 with 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (25mg, 0.03mmol), in 4-dioxane, add cesium carbonate (336g, 1.03mmol) again, be warming up to 120 DEG C of stirring reactions 2 hours.Add 10mL water, extraction into ethyl acetate (20mL × 3), merge organic phase, anhydrous sodium sulfate drying, filters, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product 4-(2-methyl-6-methyl sulfo group-3-pyridyl) phenol 91c (40mg, white solid), productive rate: 44.0%.
MS m/z(ESI)：263.9[M+1]
3rd step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(2-methyl-6-first sulfo group-3-pyridyl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
By 4-(2-methyl-6-methyl sulfo group-3-pyridyl) phenol 91c (45mg, 0.17mmol) be dissolved in 5mLN, in dinethylformamide, add crude product [(1R successively, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methylsulfonic acid 7g (51mg, 0.17mmol) with cesium carbonate (167mg, 0.50mmol), rise to 120 DEG C of stirring reactions 4 hours.Add 10mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product (1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(2-methyl-6-first sulfo group-3-pyridyl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 91 (15mg, white solid), productive rate: 18.9%.
MS m/z(ESI)：465.0[M+1]
1H NMR(400MHz，CDCl 3)δ8.25(s，2H)，7.97-7.95(m，1H)，7.75-7.73(m，1H)，7.26-7.24(m，2H)，7.00-6.98(m，2H)，4.12-3.92(m，4H)，3.67(m，2H)，3.27(s，3H)，2.60(s，3H)，2.52-2.50(m，2H)，1.82(s，2H)，1.26(s，1H)，1.25-1.19(m，3H)
Embodiment 92
2-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-5-(4-methanesulfonylphenYl) cyanophenyl
The first step
(the bromo-2-of 5-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group] cyanophenyl
By [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (500mg, 1.68mmol) be dissolved in 20mL N, in dinethylformamide, add salt of wormwood (460mg, 3.37mmol) with 2-cyano group-4-bromophenol (430mg, 2.19mmol), rise to 110 DEG C of stirring reactions 2.5 hours.Add 20mL water, be extracted with ethyl acetate (40mL × 2), merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtains title product (the bromo-2-of 5-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group] benzyl cyanide 92a (500mg, brown liquid), productive rate: 74.6%.
MS m/z(ESI)：400.9[M+1]
Second step
2-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-5-(4-methanesulfonylphenYl) cyanophenyl
By (the bromo-2-of 5-[[(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group] benzyl cyanide 92a (500mg; 1.25mmol); (4-methanesulfonylphenYl) boric acid (250mg; 1.25mmol); two (triphen phosphino-) palladium chloride (92mg; 0.13mmol) with cesium carbonate (1220mg; 3.75mmol) be dissolved in 30mL1; in 4-dioxane, rise to 110 DEG C of stirring reactions 5 hours.Filter; filtrate reduced in volume; gained resistates is purified with eluent system A with silica gel column chromatography; obtain title product 2-[[(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-5-(4-methanesulfonylphenYl) cyanophenyl 101 (350mg; white solid), productive rate: 59.3%.
MS m/z(ESI)：475.0[M+1]
1H NMR(400MHz，CDCl 3)δ8.21-8.20(m，3H)，8.05-7.98(m，5H)，7.40-7.38(m，1H)，4.21-4.19(m，2H)，3.82-3.79(m，2H)，3.48-3.46(m，2H)，3.31(s，3H)，2.44-2.38(m，2H)，1.83(s，2H)，1.14(s，1H)，1.13-1.09(m，3H)
Embodiment 93
(1R, 5S)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-isopropyl formate
By crude product (1R; 5S)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 86a (85mg; 0.22mmol) be dissolved in 5mL methylene dichloride; add triethylamine (70mg successively; 0.70mmol) with isopropyl chloroformate (30mg; 0.25mmol), stirring at room temperature reacts 12 hours.Add 10mL water; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous magnesium sulfate drying, filters, filtrate reduced in volume; obtain crude title product (1R; 5S)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-isopropyl formate 93 (40mg, white solid), productive rate: 40.0%.
MS m/z(ESI)：430.0[M+1]
1H NMR(400MHz，CDCl 3)δ7.99-7.97(m，2H)，7.75-7.72(m，2H)，7.57-7.53(m，2H)，7.01-6.98(m，2H)，4.94-4.89(m，1H)，4.00-3.88(m，2H)，3.76-3.67(m，2H)，3.47-3.44(m，2H)，3.09(s，3H)，1.62(s，2H)，1.25-1.23(m，6H)，1.17(s，1H)
Embodiment 94
(1R, 5S)-3-(5-methyl-2-pyridine)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
By crude product (1R; 5S)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 86a (100mg; 0.26mmol) be dissolved in 10mL 1; in 4-dioxane; add three (dibenzalacetone) two palladium (23mg successively; 0.03mmol); 2; 2 '-bis--(diphenyl phosphine)-1; 1 '-dinaphthalene (32mg; 0.05mmol) with the bromo-5-picoline (50mg, 0.29mmol) of 2-, rise to 100 DEG C of stirring reactions 8 hours.Filter; filtrate reduced in volume; gained resistates is purified with developping agent system A by thin-layer chromatography chromatography; obtain title product (1R; 5S)-3-(5-methyl-2-pyridine)-6-[[4-(4-methanesulfonylphenYl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 94 (30mg; white solid), productive rate: 26.5%.
MS m/z(ESI)：435.0[M+1]
1H NMR(400MHz，CDCl 3)δ7.99-7.97(m，3H)，7.74-7.72(m，2H)，7.57-7.54(m，2H)，7.28-7.27(m，2H)，7.02-7.00(m，2H)，3.99-3.97(m，2H)，3.83-3.81(m，2H)，3.49-3.46(m，2H)，3.09(s，3H)，2.19(s，3H)，1.78(s，2H)，1.33-1.29(m，1H)
Embodiment 95
3-sec.-propyl-5-[(1R, 5S)-6-[[4-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-1,2,4-oxadiazoles
By 4-(5-methylsulfonyl-2-pyridine) phenol 82b (42mg; 0.17mmol) be dissolved in 5mL N; in dinethylformamide; add crude product [[(1R successively; 5S)-3-(3-sec.-propyl-1; 2; 4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl methylsulfonate 48c (50mg; 0.17mmol) with cesium carbonate (108mg; 0.33mmol), 110 DEG C of stirring reactions 4 hours are risen to.Add 10mL water; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system A by thin-layer chromatography chromatography; obtain title product 3-sec.-propyl-5-[(1R; 5S)-6-[[4-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-1,2,4-oxadiazole 95 (40mg; white solid), productive rate: 53.0%.
MS m/z(ESI)：455.0[M+1]
1H NMR(400MHz，CDCl 3)δ9.16(s，1H)，8.24-8.22(m，1H)，8.07-8.05(m，2H)，7.87-7.85(m，1H)，7.02-7.01(m，2H)，4.02-4.00(m，2H)，3.92-3.90(m，2H)，3.73-3.70(m，2H)，3.14(s，3H)，2.96-2.90(m，1H)，1.81(s，2H)，1.32-1.30(m，6H)，1.26-1.24(m，1H)
Embodiment 96
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(the fluoro-4-methanesulfinyl-phenvl of 3-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
The first step
The fluoro-1-methylsulfinyl-benzene of the bromo-2-of 4-
Fluoro-for 1-2-methylthio phenyl 96a (5.12g, 35.30mmol) is dissolved in 40mL methylene dichloride, adds bromine (1.8mL, 35.30mmol) successively, stirring reaction 12 hours.Add 100mL saturated sodium bicarbonate aqueous solution, be extracted with ethyl acetate (100mL × 2), merge organic phase, with saturated nacl aqueous solution washing (50mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains the bromo-2-of title product 4-fluoro-1-methylsulfinyl-benzene 96b (1000mg, white solid), productive rate: 12.6%.
MS m/z(ESI)：236.8[M+1]
Second step
4-(the fluoro-4-methanesulfinyl-phenvl of 3-) phenol
By fluoro-for bromo-for 4-2-1-methylsulfinyl-benzene 96b (1000mg, 4.20mmol), 4-hydroxybenzene boric acid (582mg, 4.20mmol) be dissolved in 20mL 1 with 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (300mg, 0.40mmol), in 4-dioxane, add cesium carbonate (4.12g, 12.60mmol) again, be warming up to 120 DEG C of stirring reactions 2 hours.Add 20mL water; extraction into ethyl acetate (20mL × 2); merge organic phase; anhydrous sodium sulfate drying, filters, filtrate reduced in volume; gained resistates is purified with eluent system A with silica gel column chromatography; obtain title product 4-(the fluoro-4-methanesulfinyl-phenvl of 3-) phenol 96c (210mg, yellow solid), productive rate: 20.0%.
MS m/z(ESI)：250.9[M+1]
3rd step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(the fluoro-4-methanesulfinyl-phenvl of 3-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
By 4-(the fluoro-4-methanesulfinyl-phenvl of 3-) phenol 96c (50mg; 0.20mmol) be dissolved in 5mL N; in dinethylformamide; add crude product [(1R successively; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (59mg; 0.20mmol) with cesium carbonate (130mg, 0.40mmol), rise to 110 DEG C of stirring reactions 4 hours.Add 10mL water; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous sodium sulfate drying; filter; filtrate reduced in volume; purify gained resistates by thin-layer chromatography chromatography with developping agent system A and obtain title product (1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(the fluoro-4-methanesulfinyl-phenvl of 3-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 96 (50mg; white solid), productive rate: 45.0%.
MS m/z(ESI)：452.0[M+1]
1H NMR(400MHz，CDCl 3)δ8.18(s，2H)，7.90-7.86(m，1H)，7.58-7.51(m，3H)，7.31-7.28(m，1H)，7.27-6.99(m，2H)，3.98-3.97(m，4H)，3.60-3.58(m，2H)，2.87(s，3H)，2.50-2.45(m，2H)，1.77(s，2H)，1.26-1.24(m，1H)，1.23-1.17(m，3H)
Embodiment 97
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(the fluoro-4-Metlianesulfonyl-phenyl of 3-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
The first step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(the fluoro-4-Metlianesulfonyl-phenyl of 3-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
By (1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(the fluoro-4-methanesulfinyl-phenvl of 3-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 96 (40mg; 0.09mmol) be dissolved in 5mL methylene dichloride; add metachloroperbenzoic acid (23mg; 0.13mmol), stirring at room temperature reacts 3 hours.Add 10mL methylene dichloride; with saturated sodium carbonate solution washing (10mL × 2); anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system A by thin-layer chromatography chromatography; obtain title product (1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(the fluoro-4-Metlianesulfonyl-phenyl of 3-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 97 (10mg; white solid), productive rate: 25.0%.
MS m/z(ESI)：468.0[M+1]
1H NMR(400MHz，CDCl 3)δ8.22(s，2H)，7.99-7.95(m，1H)，7.55-7.49(m，3H)，7.43-7.40(m，1H)，7.01-6.99(m，2H)，3.99-3.97(m，4H)，3.66(m，2H)，3.25(s，3H)，2.50-2.49(m，2H)，1.80(s，2H)，1.26-1.25(m，1H)，1.20-1.18(m，3H)
Embodiment 98
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
The first step
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4,4,5,5-tetramethyl--1,3,2-dioxo boric acid-2-base) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
By (1R, 5S)-6-[(4-bromo-2,6-dilquoro-phenogy) methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 16c (2g, 5mmol), connection boric acid pinacol ester (1.90g, 7mmol), Potassium ethanoate (1.50g, 15mmol) He 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (360mg, 0.50mmol) is dissolved in 50mL Isosorbide-5-Nitrae-dioxane, be warming up to 95 DEG C, stirring reaction 2.5 hours.Add 30mL water, extraction into ethyl acetate (50mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtains crude title product (1R, 5S)-6-[[2, the fluoro-4-(4 of 6-bis-, 4,5,5-tetramethyl--1,3,2-dioxo boric acid-2-base) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 98a (2.20g, yellow oil), product is not purified directly carries out next step reaction.
MS m/z(ESI)：396.1[M-55]
Second step
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
By crude product (1R, 5S)-6-[[2, the fluoro-4-(4 of 6-bis-, 4, 5, 5-tetramethyl--1, 3, 2-dioxo boric acid-2-base) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 98a (2.20g, 4.87mmol), bromo-pyridine (the 1.20g of 3-methylsulfonyl-6-, 4.87mmol), cesium carbonate (4.70g, 14.60mmol) and 1, 1 '-two (diphenyl phosphine) ferrocene palladium chloride (3.50g, 0.40mmol) be dissolved in 50mL 1, in 4-dioxane, be warming up to 110 DEG C, stirring reaction 2 hours.Add 30mL water; extraction into ethyl acetate (50mL × 2); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system B by thin-layer chromatography chromatography; obtain title product (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 98 (1.90g, light yellow solid), productive rate: 82.0%.
MS m/z(ESI)：481.2[M+1]
1H NMR(400MHz，CDCl 3)δ9.17(s，1H)，8.30-8.28(m，1H)，7.85-7.83(m，1H)，7.70-7.68(m，2H)，4.14-4.12(m，2H)，3.60-3.57(m，2H)，3.38-3.35(m，2H)，3.15(s，3H)，1.72(s，2H)，1.44(s，9H)，1.14(s，1H)
Embodiment 99
3-ethyl-5-[(1R, 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base-1,2,4-oxadiazole
The first step
(1R, 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
By 6-(4-methanesulfonylphenYl) pyridine-3-alcohol 48e (2500mg; 10mmol) be dissolved in 50mL N; in dinethylformamide; add crude product (1R successively; 5S)-6-(Methanesulfonvloxvmethvl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 16b (2900mg; 10mmol) with salt of wormwood (4150mg, 30mmol), rise to 80 DEG C of stirring reactions 12 hours.Add 100mL water; filter; filter cake is dissolved in 100mL methylene dichloride; anhydrous sodium sulfate drying, filters, filtrate reduced in volume; obtain title product (1R; 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 99a (2600mg, faint yellow solid), productive rate: 60.0%.
Second step
(1R, 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane hydrochloride salt
By (1R; 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 99a (2600mg; 5.85mmol) be dissolved in 50mL ethyl acetate; add the ethyl acetate solution of 10mL 5M hydrogenchloride, stirring reaction 3 hours.Reaction solution concentrating under reduced pressure; obtain crude title product (1R; 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane hydrochloride 99b (2680mg; faint yellow solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：345.0[M+1]
3rd step
(1R, 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-formonitrile HCN
By crude title product (1R; 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane hydrochloride 99b (2680mg; 5.85mmol) be dissolved in 20mL methylene dichloride; 30mL sodium bicarbonate (3000mg is added under ice bath; aqueous solution 35.8mmol); stir 30 minutes; add 2mL cyanogen bromide (682mg again; dichloromethane solution 6.44mmol), stirring at room temperature reacts 12 hours.Add 20mL water; with dichloromethane extraction (60mL × 4); merge organic phase, anhydrous sodium sulfate drying, filter; filtrate reduced in volume; purify gained resistates with silica gel column chromatography with developping agent system A, obtain title product (1R, 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-formonitrile HCN 99c (1700mg; white solid), productive rate: 78.7%.
MS m/z(ESI)：370.0[M+1]
4th step
3-ethyl-5-[(1R, 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base-1,2,4-oxadiazole
By (1R; 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-formonitrile HCN 99c (369mg; 1.00mmol) be dissolved in 15mL tetrahydrofuran (THF); add N '-hydroxy-2-methyl-propylamine (106mg successively; 1.2mmol) with zinc chloride (1.2mL; tetrahydrofuran solution 1.2mmol), stirring reaction 12 hours.Reaction solution concentrating under reduced pressure, adds the mixing solutions (V/V=1: 1) of the second alcohol and water of 10mL 4M hydrogenchloride, refluxes 2 hours.Adding sodium bicarbonate to reaction solution pH is 7; filter; with dichloromethane extraction (20mL × 3); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; purify gained resistates by thin-layer chromatography chromatography with developping agent system A, obtain title product 3-ethyl-5-[(1R, 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base-1; 2; 4-oxadiazole 99 (60mg, white solid), productive rate: 13.6%.
MS m/z(ESI)：441.1[M+1]
1H NMR(400MHz，CDCl 3)δ8.40(d，1H)，8.13(d，2H)，8.01(d，2H)，7.72(d，1H)，7.28(dd，1H)，4.03(d，2H)，3.87(d，2H)，3.69(d，2H)，3.08(s，3H)，2.58(dd，2H)，1.89-1.70(m，3H)，1.27(t，3H)
Embodiment 100
3-cyclopropyl-5-[(1R, 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-1,2,4-oxadiazoles
By (1R; 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-formonitrile HCN 99c (300mg; 0.81mmol) be dissolved in 15mL tetrahydrofuran (THF); add ring propyl formamide oxime (98.0mg successively; 0.98mmol) with zinc chloride (1mL; 0.98mmol), stirring reaction 12 hours.Reaction solution concentrating under reduced pressure, adds the mixing solutions (V/V=1: 1) of the second alcohol and water of 10mL 4M hydrogenchloride, refluxes 2 hours.Adding sodium bicarbonate to reaction solution pH is 7; filter; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; purify gained resistates by thin-layer chromatography chromatography with developping agent system A, obtain title product 3-cyclopropyl-5-[(1R, 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base-1; 2; 4-oxadiazole 99 (50mg, white solid), productive rate: 11.0%.
MS m/z(ESI)：453.1[M+1]
1H NMR(400MHz，CDCl 3)δ8.41(s，1H)，8.15(d，2H)，8.02(d，2H)，7.75(d，1H)，7.32(d，1H)，4.03(d，2H)，3.84(d，2H)，3.65(d，2H)，3.08(s，3H)，1.87-1.86(m，1H)，1.79-1.77(m，2H)，1.26-1.22(m，1H)，0.96-0.93(m，4H)
Embodiment 101
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(the fluoro-4-pyridine of 3-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
The first step
(1R, 5S)-6-[(4-bromine phenoxy group) methyl]-3-(5-ethyl-pyrimidine 2-yl)-3-azabicyclo also [3.1.0] hexane
By [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (800mg, 2.69mmol) be dissolved in 5mL N, in dinethylformamide, add cesium carbonate (1750mg, 5.38mmol) with 4-bromophenol (465mg, 2.69mmol), rise to 120 DEG C of stirring reactions 6 hours.Add 20mL water, be extracted with ethyl acetate (40mL × 2), merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtains title product (1R, 5S)-6-[(4-bromine phenoxy group) methyl]-3-(5-ethyl-pyrimidine 2-yl)-3-azabicyclo also [3.1.0] hexane 101a (990mg, white solid), productive rate: 98.0%.
MS m/z(ESI)：376.1[M+1]
Second step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(the fluoro-4-pyridine of 3-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
By (1R, 5S)-6-[(4-bromine phenoxy group) methyl]-3-(5-ethyl-pyrimidine 2-yl)-3-azabicyclo also [3.1.0] hexane 101a (100mg, 0.27mmol), (the fluoro-4-pyridine of 3-) boric acid (38mg, 0.27mmol), two (triphen phosphino-) palladium chloride (4mg, 0.01mmol) He three hypophosphite monohydrate potassium (215mg, 0.81mmol) be dissolved in 5mL 1, in 4-dioxane, rise to 100 DEG C of stirring reactions 12 hours.Filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product (1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(the fluoro-4-pyridine of 3-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 101 (65mg, white solid), productive rate: 62.0%.
MS m/z(ESI)：391.0[M+1]
1H NMR(400MHz，CDCl 3)δ8.91-8.44(m，2H)，8.19(s，2H)，7.59-7.57(m，2H)，7.40-7.37(m，1H)，7.02-7.00(m，2H)，4.00-3.98(m，4H)，3.61-3.58(m，2H)，2.50-2.45(m，2H)，1.77(s，2H)，1.27-1.23(m，1H)，1.21-1.17(m，3H)
Embodiment 102
1-[4-[5-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-2-pyridine] phenyl] ethyl ketone
The first step
1-[4-(5-hydroxyl-2-pyridine) phenyl] ethyl ketone
By bromo-for 2-5-Hydroxy-pyridine (213mg, 1.22mmol), 4-phenyl methyl ketone boric acid (200mg, 1.22mmol) be dissolved in 5mL N with 1,1 '-two (triphen phosphino-) palladium chloride (50mg, 0.12mmol), in dinethylformamide, add 2M sodium carbonate solution (1mL, 3.66mmol) again, be warming up to 120 DEG C of microwave reactions 1 hour.Add 20mL water, dripping 5M hydrochloric acid is 3 ~ 5 to reaction solution pH, extraction into ethyl acetate (20mL × 2), merges organic phase, use water (20mL × 1) successively, saturated nacl aqueous solution washing (20mL × 1), anhydrous sodium sulfate drying, filters, filtrate reduced in volume, obtain title product 1-[4-(5-hydroxyl-2-pyridine) phenyl] ethyl ketone 102a (300mg, yellow solid), productive rate: 100%.
Second step
1-[4-[5-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-2-pyridine] phenyl] ethyl ketone
By 1-[4-(5-hydroxyl-2-pyridine) phenyl] ethyl ketone 102a (180mg, 0.84mmol) be dissolved in 8mL N, in dinethylformamide, add crude product [(1R successively, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (250mg, 0.84mmol) with salt of wormwood (235mg, 1.70mmol), rise to 85 DEG C of stirring reactions 3 hours.Add 50mL water, be extracted with ethyl acetate (50mL × 2), merge organic phase, use water (50mL × 1) successively, saturated nacl aqueous solution washing (50mL × 1), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by thin-layer chromatography chromatography, obtain title product 1-[4-[5-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-2-pyridine] phenyl] ethyl ketone 102 (120mg, white solid), productive rate: 34.6%.
MS m/z(ESI)：415.1[M+1]
1H NMR(400MHz，CDCl 3)δ8.56(d，1H)，8.50(d，1H)，8.46(d，1H)，8.17(s，2H)，7.36(d，2H)，7.18(d，2H)，4.04(d，2H)，3.99(d，2H)，3.60(d，2H)，2.47(q，2H)，2.15(s，3H)，1.80-1.78(m，2H)，1.27-1.25(m，1H)，1.19(t，3H)
Embodiment 103
(1R, 5S)-3-(5-methylpyrimidine-2-base)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
The first step
[(1R, 5S)-3-(5-methylpyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol
By crude product [(1R, 5S)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 7e (453mg, 4mmol) be dissolved in 5mL N, in N-N,N-DIMETHYLACETAMIDE, add the chloro-5-methyl-pvrimidine of 2-(514mg successively, 4mmol) with salt of wormwood (829mg, 6mmol), rise to 140 DEG C of stirring reactions 2 hours.Add 50mL water, be extracted with ethyl acetate (30mL × 3), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A, obtain title product [(1R, 5S)-3-(5-methylpyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 103a (0.41g, light yellow solid), productive rate: 51.0%.
MS m/z(ESI)：206.0[M+1]
Second step
[(1R, 5S)-3-(5-methylpyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate
By (1R, 5S)-3-(5-methylpyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 103a (0.41g, 2mmol) be dissolved in 20mL anhydrous methylene chloride, add triethylamine (0.8mL, 6mmol), be added dropwise to methylsulfonyl chloride (0.3mL, 3mmol), stirring reaction 12 hours.Add saturated sodium bicarbonate solution 30mL, dichloromethane extraction (10mL × 3), merge organic phase, use water (20mL × 3) successively, saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtain crude title product [(1R, 5S)-3-(5-methylpyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 103b (400mg, white solid), productive rate: 70.0%.
MS m/z(ESI)：284.0[M+1]
3rd step
(1R, 5S)-3-(5-methylpyrimidine-2-base)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By crude product [(1R; 5S)-3-(5 methylpyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 103b (130mg; 0.46mmol) with 6-(4-methanesulfonylphenYl) pyridine-3-alcohol 48e (114mg; 0.46mmol) be dissolved in 10mL N; in N-N,N-DIMETHYLACETAMIDE; add salt of wormwood (127mg, 0.92mmol) again, be warming up to 80 DEG C of stirring reactions 1 hour.Add 25mL water, extraction into ethyl acetate (20mL × 3), merge organic phase, use saturated ammonium chloride solution (10mL × 3) successively, saturated nacl aqueous solution washing (10mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by thin-layer chromatography chromatography, obtain title product (1R, 5S)-3-(5-methylpyrimidine-2-base)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 103 (110mg, white solid), productive rate: 56.0%.
MS m/z(ESI)：437.0[M+1]
1H NMR(400MHz，CDCl 3)δ8.42-8.40(m，1H)，8.16-8.12(m，4H)，8.02-8.00(m，2H)，7.74-7.72(m，1H)，7.31-7.29(m，1H)，4.04(d，2H)，3.98(d，2H)，3.60(d，2H)，3.08(s，3H)，2.12(s，2H)，1.78(s，2H)，1.26-1.25(m，2H)
Embodiment 104
(1R, 5S)-3-(5-chloropyrimide-2-base)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
The first step
[(1R, 5S)-3-(5-chloropyrimide-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol
By crude product [(1R, 5S)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 7e (350mg, 3.10mmol) be dissolved in 15mL N, in N-N,N-DIMETHYLACETAMIDE, add 2,5-Dichloro-pyrimidin (462mg, 3.10mmol) and salt of wormwood (641mg successively, 4.60mmol), 140 DEG C of stirring reactions 1 hour is risen to.Add 50mL water, be extracted with ethyl acetate (30mL × 3), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A, obtain title product [(1R, 5S)-3-(5-chloropyrimide-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 104a (0.40g, white solid), productive rate: 60.0%.
MS m/z(ESI)：226.0[M+1]
Second step
[(1R, 5S)-3-(5-chloropyrimide-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate
By (1R, 5S)-3-(5-chloropyrimide-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 104a (0.38g, 1.68mmol) be dissolved in 20mL anhydrous methylene chloride, add triethylamine (0.7mL, 5.04mmol), be added dropwise to methylsulfonyl chloride (0.2mL, 2.52mmol), stirring reaction 1 hour.Add saturated sodium bicarbonate solution 30mL, dichloromethane extraction (10mL × 3), merge organic phase, use water (20mL × 3) successively, saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtain crude title product [(1R, 5S)-3-(5-chloropyrimide-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 104b (370mg, white solid), productive rate: 72.5%.
MS m/z(ESI)：304.1[M+1]
3rd step
(1R, 5S)-3-(5-chloropyrimide-2-base)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By crude product [(1R; 5S)-3-(5-chloropyrimide-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 104b (180mg; 0.60mmol) with 6-(4-methanesulfonylphenYl) pyridine-3-alcohol 48e (150mg; 0.60mmol) be dissolved in 15mL N; in N-N,N-DIMETHYLACETAMIDE; add salt of wormwood (165mg, 1.20mmol) again, be warming up to 80 DEG C of stirring reactions 1 hour.Add 25mL water, extraction into ethyl acetate (20mL × 3), merge organic phase, use saturated ammonium chloride solution (10mL × 3) successively, saturated nacl aqueous solution washing (10mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by thin-layer chromatography chromatography, obtain title product (1R, 5S)-3-(5-chloropyrimide-2-base)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 104 (120mg, white solid), productive rate: 44.0%.
MS m/z(ESI)：4570[M+1]
1H NMR(400MHz，CDCl 3)δ8.41(d，1H)，8.23(s，2H)，8.12(d，2H)，8.00(d，2H)，7.73(d，1H)，7.31-7.29(m，1H)，4.02(d，2H)，3.93(d，2H)，3.58(d，2H)，3.08(s，3H)，1.80(s，2H)，1.25-1.21(m，1H)
Embodiment 105
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(6-methylsulfonyl-3-pyridyl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
The first step
The bromo-2-methylsulfanyl-pyridin of 5-
2,5-dibromo pyridine 105a (1g, 4.20mmo1) is dissolved in 10mL DMF, adds methyl sodium sulphite (300mg, 4.20mmol), room temperature reaction 0.5 hour.Add 30mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (20mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product 5-bromo-2-methylsulfanyl-pyridin 105b (800mg, white solid), productive rate: 100%.
MS m/z(ESI)：203.8[M+1]
Second step
The bromo-2-methanesulfonyl-pyridine of 5-
Bromo-for 5-2-methylsulfanyl-pyridin 105b (800mg, 3.90mmol) is dissolved in 8mL Virahol, adds potassium hydrogen persulfate (4.80g, 7.80mmol), stirring reaction 12 hours.Reaction solution concentrating under reduced pressure, purifies gained resistates by thin-layer chromatography chromatography with developping agent system B, obtains title product 5-bromo-2-methanesulfonyl-pyridine 105c (120mg, yellow solid), productive rate: 13.0%.
MS m/z(ESI)：235.9[M+1]
3rd step
4-(6-methylsulfonyl-3-pyridyl) phenol
By bromo-for 5-2-methanesulfonyl-pyridine 105c (400mg; 1.70mmol); (4-hydroxybenzene) boric acid (234mg; 1.70mmol); two (triphen phosphino-) palladium chlorides (25mg, 0.03mmol) and three hypophosphite monohydrate potassium (1400mg, 5.10mmol) are dissolved in 5mL 1; in 4-dioxane, rise to 100 DEG C of stirring reactions 12 hours.Filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 4-(6-methylsulfonyl-3-pyridyl) benzene 105d (400mg, white solid), productive rate: 95.2%.
MS m/z(ESI)：250.0[M+1]
4th step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(6-methylsulfonyl-3-pyridyl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
By 4-(6-methylsulfonyl-3-pyridyl) benzene 105d (100mg; 0.40mmol) be dissolved in 5mL N; in dinethylformamide; add crude product [(1R successively; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (119mg; 0.40mmol) with cesium carbonate (260mg, 0.80mmol), rise to 80 DEG C of stirring reactions 12 hours.Add 10mL water; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous sodium sulfate drying; filter; filtrate reduced in volume; purify gained resistates by thin-layer chromatography chromatography with developping agent system A and obtain title product (1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[4-(6-methylsulfonyl-3-pyridyl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 105 (120mg; white solid), productive rate: 66.7%.
MS m/z(ESI)：451.1[M+1]
1H NMR(400MHz，CDCl 3)δ8.90(s，1H)，8.31(s，2H)，8.13-8.06(m，2H)，7.56-7.54(m，2H)，7.04-7.02(m，2H)，4.16-4.14(m，2H)，4.00-3.98(m，2H)，3.78-3.75(m，2H)，3.26(s，3H)，2.55-2.54(m，2H)，1.87(s，1H)，1.24-1.23(m，5H)
Embodiment 106
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[1-(4-methanesulfonylphenYl)-4-piperidines] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
The first step
4-hydroxy piperidine-1-carboxylic acid tert-butyl ester
4-oxo-piperidine-1-carboxylic acid tert-butyl ester 106a (10g, 50mmol) is dissolved in 100mL methyl alcohol, adds sodium borohydride (2.84g, 75mmol), stirring reaction 2 hours.Add 30mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (20mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product 4-hydroxy piperidine-1-carboxylic acid tert-butyl ester 106b (10.50g, white solid), productive rate: 100%.
MS m/z(ESI)：102.1[M+1-100]
Second step
4-hydroxy piperidine trifluoroacetate
4-hydroxy piperidine-1-carboxylic acid tert-butyl ester 106b (4650mg, 23.10mmol) is dissolved in 100mL methylene dichloride, adds trifluoroacetic acid (26.30g, 231mmol), stirring reaction 2 hours.Reaction solution concentrating under reduced pressure, obtains title product 4-hydroxy piperidine trifluoroacetate 106c (5200mg, pale yellow oil), productive rate: 100%.
3rd step
1-(4-methanesulfonylphenYl) piperidines-4-alcohol
By 4-hydroxy piperidine trifluoroacetate 106c (3230mg, 15mmol), 1-fluoro-4-methylsulfonyl benzene (2610mg; 15mmol) and salt of wormwood (6220mg, 45mmol) be dissolved in 50mL DMF; rise to 90 DEG C, stirring reaction 12 hours.Add 300mL water; be extracted with ethyl acetate (100mL × 3); merge organic phase; anhydrous sodium sulfate drying, filters, filtrate reduced in volume; gained resistates is purified with eluent system A with silica gel column chromatography; obtain title product 1-(4-methanesulfonylphenYl) piperidines-4-alcohol 106d (3400mg, light yellow solid), productive rate: 78.3%.
MS m/z(ESI)：250.0[M+1]
4th step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[1-(4-methanesulfonylphenYl)-4-piperidines] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By 1-(4-methanesulfonylphenYl) piperidines-4-alcohol 106d (100mg; 0.39mmol) be dissolved in 3mL tetrahydrofuran (THF); be cooled to 0 DEG C; add 15-successively and be preced with-5 (86mg; 0.39mmol) with sodium hydride (16mg; 0.39mmol); stir 30 minutes; add crude product [(1R again; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (116mg; 0.39mmol), microwave rises to 100 DEG C of stirring reactions 0.5 hour.Add 10mL saturated ammonium chloride solution; be extracted with ethyl acetate (15mL × 3); merge organic phase; anhydrous sodium sulfate drying; filter; filtrate reduced in volume; purify gained resistates with silica gel column chromatography with developping agent system A and obtain title product (1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[1-(4-methanesulfonylphenYl)-4-piperidines] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 106 (62mg; white solid), productive rate: 34.6%.
MS m/z(ESI)：457.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.16(s，2H)，7.74(d，2H)，6.92(d，2H)，3.90(d，2H)，3.69-3.65(m，2H)，3.56-3.52(m，3H)，3.45(d，2H)，3.18-3.15(m，2H)，3.00(s，3H)，2.48-2.42(dd，2H)，1.97-1.93(m，2H)，1.71-1.68(m，2H)，1.25(s，2H)，1.17(t，3H)，0.99(t，1H)
Embodiment 107
[2-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo [3.1.0] hexane-6-base] methoxyl group]-5-(4-methanesulfonylphenYl) phenyl] methylamine
By 2-[[(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-5-(4-methanesulfonylphenYl) phenyl aldehyde 87c (100mg; 0.20mmol) with ammoniacal liquor (5mg; 0.30mmol) be dissolved in 10mL methyl alcohol; rise to return stirring and react 20 minutes; add sodium borohydride (16mg, 0.40mmol), continue return stirring and react 2.5 hours.Add 20mL water; with dichloromethane extraction (30mL × 2); merge organic phase; anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with eluent system A by thin-layer chromatography chromatography; obtain title product 1-[2-[[(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-5-(4-methanesulfonylphenYl) phenyl]-N-methyl-methylamine 88 (10mg; white solid), productive rate: 10.0%.
MS m/z(ESI)：479.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.20-8.18(m，2H)，7.99-7.94(m，5H)，7.77-7.75(m，1H)，7.19-7.17(m，1H)，4.14(m，4H)，4.08-4.07(m，4H)，3.84-3.81(m，2H)，3.24(s，3H)，2.42-2.38(m，2H)，1.83(s，2H)，1.16(s，1H)，1.12-1.09(m，3H)
Embodiment 108
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(4-methylsulfinyl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
The first step
6-(4-methylsulfinyl phenyl) pyridine-3-alcohol
6-(4-methyl thio phenyl) pyridine-3-alcohol (0.04g, 0.20mmol) is dissolved in 5mL methylene dichloride, adds metachloroperbenzoic acid (28mg, 0.12mmol), react 1 hour.Add 100mL saturated sodium bicarbonate aqueous solution, be extracted with ethyl acetate (100mL × 2), merge organic phase, with saturated nacl aqueous solution washing (5mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system A, obtains title product 6-(4-methylsulfinyl phenyl) pyridine-3-alcohol 108a (18.40mg, white solid), productive rate: 39.0%.
MS m/z(ESI)：234.0[M+1]
Second step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(4-methylsulfinyl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By 6-(4-methylsulfinyl phenyl) pyridine-3-alcohol 108a (115mg, 0.50mmol) be dissolved in 15mL N, in dinethylformamide, add crude product [(1R successively, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (149mg, 0.50mmol) with salt of wormwood (138mg, 1mmol), rise to 80 DEG C of stirring reactions 4 hours.Add 10mL water; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous sodium sulfate drying; filter; filtrate reduced in volume; purify gained resistates by thin-layer chromatography chromatography with developping agent system A and obtain title product (1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(4-methylsulfinyl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 108 (120mg; white solid), productive rate: 55.0%.
MS m/z(ESI)：435.2[M+1]
1H NMR(400MHz，d-DMSO)δ8.39(d，1H)，8.21(s，2H)，8.08(d，2H)，7.72-7.69(m，3H)，7.29-7.27(m，1H)，4.02(d，3H)，3.65(s，2H)，2.75(s，3H)，2.50-2.48(m，2H)，1.82(s，2H)，1.24-1.17(m，5H)
Embodiment 109
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(the fluoro-4-pyridine of 3-)-3-pyridyl] oxygen methyl]-3 azabicyclos also [3.1.0] hexane
By 6-(the fluoro-4-pyridine of 3-) pyridine-3-alcohol 109a (100mg, 0.53mmol) be dissolved in 5mL N, in dinethylformamide, add crude product [(1R successively, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (150mg, 0.53mmol) with salt of wormwood (220mg, 1.58mmol), rise to 85 DEG C of stirring reactions 3 hours.Add 30mL water, be extracted with ethyl acetate (20mL × 3), merge organic phase, use water (30mL × 1) successively, saturated nacl aqueous solution washing (30mL × 1), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with developping agent system A and obtain title product (1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(the fluoro-4-pyridine of 3-)-3-pyridyl] oxygen methyl]-3 azabicyclos also [3.1.0] hexane 109 (100mg, white solid), productive rate: 48.8%.
MS m/z(ESI)：392.1[M+1]
1H NMR(400MHz，CDCl 3)δ8.53(d，1H)，8.49(d，1H)，8.44(d，1H)，8.18(s，2H)，7.99(dd，1H)，7.87(d，1H)，7.28(dd，1H)，4.03(d，2H)，3.99(d，2H)，3.59(d，2H)，2.46(q，2H)，1.78-1.76(m，2H)，1.25-1.23(m，1H)，1.18(t，3H)
Embodiment 110
(1R, 5S)-3-(5-cyclopropyl-pyrimidine-2-base)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
The first step
The chloro-5-cyclopropyl-pyrimidine of 2-
By bromo-for chloro-for 2-5-pyrimidine (387mg, 2mmol) be dissolved in 7.6mL toluene, add cyclopropylboronic acid (223mg successively, 2.60mmol), potassiumphosphate (1.48g, 7mmol), three cyclohexyl phosphorus (56mg, 0.20mmol) with palladium (22.40mg, 0.10mmol), rise to 120 DEG C of microwave reactions 0.2 hour.Be chilled to room temperature, add 10mL water, be extracted with ethyl acetate (20mL × 3), merge organic phase, with saturated nacl aqueous solution washing (50mL × 1), anhydrous magnesium sulfate drying, filter concentrating under reduced pressure filtrate, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 2-chloro-5-cyclopropyl-pyrimidine 11a (270mg, white solid), productive rate: 87.7%.
MS m/z(ESI)：155.0[M+1]
Second step
[(1R, 5S)-3-(5-cyclopropyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol
By crude product [(1R, 5S)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 7e (373mg, 3.30mmol) be dissolved in 10mL N, in dinethylformamide, add 2-chloro-5-cyclopropyl-pyrimidine 110a (510mg successively, 3.30mmol) with salt of wormwood (684mg, 4.95mmol), rise to 150 DEG C of stirring reactions 2 hours.Reaction solution concentrating under reduced pressure, add 20mL water, be extracted with ethyl acetate (20mL × 6), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product [(1R, 5S)-3-(5-cyclopropyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 110b (0.63g, yellow solid), productive rate: 82.7%.
MS m/z(ESI)：232.1[M+1]
3rd step
[(1R, 5S)-3-(5-cyclopropyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate
By [(1R, 5S)-3-(5-cyclopropyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 110b (0.63g, 2.73mmol) be dissolved in 10mL anhydrous methylene chloride, add triethylamine (750mg, 5.46mmol), be added dropwise to methylsulfonyl chloride (0.3mL, 4.08mmol), stirring reaction 0.5 hour.Add 30mL water, stir 30 minutes, separatory, aqueous phase is with dichloromethane extraction (10mL × 3), merge organic phase, wash with water (10mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtains crude title product [(1R, 5S)-3-(5-cyclopropyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 110c (760mg, yellow solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：310.1[M+1]
4th step
(1R, 5S)-3-(5-cyclopropyl-pyrimidine-2-base)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By crude product [(1R; 5S)-3-(5-cyclohexyl pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 110c (223mg; 0.72mmol) with 6-(4-methanesulfonylphenYl) pyridine-3-alcohol 48e (180mg; 0.72mmol) be dissolved in 2mL N; in dinethylformamide; add salt of wormwood (300mg, 2.17mmol) again, be warming up to 90 DEG C of stirring reactions 5 hours.Add 20mL water; dichloromethane extraction (20mL × 3); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system A by thin-layer chromatography chromatography; obtain title product (1R; 5S)-3-(5-cyclopropyl-pyrimidine-2-base)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 110 (160mg; white solid), productive rate: 47.9%.
MS m/z(ESI)：463.1[M+1]
1H NMR(400MHz，CDCl 3)δ8.45(s，1H)，8.16(d，4H)，8.03(d，2H)，7.76(d，1H)，7.32(d，1H)，4.06(d，2H)，3.99(d，2H)，3.60(d，2H)，3.11(s，3H)，1.81(s，2H)，1.74-1.72(m，1H)，1.27-1.25(m，1H)，0.93(d，2H)，0.60(d，2H)
Embodiment 111
(1R, 5S)-3-(5-cyclopropyl-pyrimidine-2-base)-6-[[6-(the fluoro-4-pyridine of 3-)-3-pyridyl] oxygen methyl]-3 azabicyclos also [3.1.0] hexane
By 6-(the fluoro-4-pyridine of 3-) pyridine-3-alcohol 109a (150mg, 0.79mmol) be dissolved in 5mL N, in dinethylformamide, add crude product [(1R successively, 5S)-3-(5-cyclopropyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 110c (244mg, 0.79mmol) with salt of wormwood (327mg, 2.37mmol), rise to 80 DEG C of stirring reactions 12 hours.Reaction solution concentrating under reduced pressure, add 10mL water, with dichloromethane extraction (15mL × 3), merge organic phase, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A and obtain title product (1R, 5S)-3-(5-cyclopropyl-pyrimidine-2-base)-6-[[6-(the fluoro-4-pyridine of 3-)-3-pyridyl] oxygen methyl]-3 azabicyclos also [3.1.0] hexane 110 (150mg, faint yellow solid), productive rate: 47.2%.
MS m/z(ESI)：404.1[M+1]
1H NMR(400MHz，CDCl 3)δ8.49-8.47(m，3H)，8.12(s，2H)，7.99(t，1H)，7.87(d，1H)，7.26(d，1H)，4.03(d，2H)，3.96(d，2H)，3.57(d，2H)，1.77(s，2H)，1.69-1.67(m，1H)，1.25(m，1H)，0.89(d，2H)，0.56(d，2H)
Embodiment 112
(1R, 5S)-3-(5-methylpyrimidine-2-base)-6-[[6-(the fluoro-4-pyridine of 3-)-3-pyridyl] oxygen methyl]-3 azabicyclos also [3.1.0] hexane
By 6-(the fluoro-4-pyridine of 3-) pyridine-3-alcohol 109a (150mg, 0.79mmol) be dissolved in 5mL N, in dinethylformamide, add crude product [(1R successively, 5S)-3-(5-methylpyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 103b (224mg, 0.79mmol) with salt of wormwood (327mg, 2.37mmol), rise to 80 DEG C of stirring reactions 12 hours.Reaction solution concentrating under reduced pressure, add 10mL water, with dichloromethane extraction (15mL × 3), merge organic phase, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A and obtain title product (1R, 5S)-3-(5-methylpyrimidine-2-base)-6-[[6-(the fluoro-4-pyridine of 3-)-3-pyridyl] oxygen methyl]-3 azabicyclos also [3.1.0] hexane 112 (150mg, faint yellow solid), productive rate: 50.3%.
MS m/z(ESI)：378.0[M+1]
1H NMR(400MHz，CDCl 3)δ8.49-8.47(m，3H)，8.15(s，2H)，7.99(t，1H)，7.87(d，1H)，7.26(d，1H)，4.03(d，2H)，3.96(d，2H)，3.58(d，2H)，2.12(s，3H)，1.78(s，2H)，1.25-1.23(m，1H)
Embodiment 113
(1R, 5S)-3-(5-propyl group pyrimidine-2-base)-6-[[6-(the fluoro-4-pyridine of 3-)-3-pyridyl] oxygen methyl]-3 azabicyclos also [3.1.0] hexane
The first step
[(1R, 5S)-3-(5-propyl group pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol
By crude product [(1R, 5S)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 7e (566mg, 5mmol) be dissolved in 10mL N, in N-N,N-DIMETHYLACETAMIDE, add the chloro-5-propyl-pyrimidin of 2-(783mg successively, 5mmol) with salt of wormwood (1040mg, 7.50mmol), rise to 140 DEG C of stirring reactions 4 hours.Reaction solution concentrating under reduced pressure, add 20mL water, be extracted with ethyl acetate (20mL × 3), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A, obtain title product [(1R, 5S)-3-(5-propyl group pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 113a (0.88g, yellow solid), productive rate: 75.6%.
MS m/z(ESI)：234.1[M+1]
Second step
[(1R, 5S)-3-(5-propyl group pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate
By (1R, 5S)-3-(5-propyl group pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 113a (0.88g, 3.77mmol) be dissolved in 10mL anhydrous methylene chloride, add triethylamine (1.1mL, 7.54mmol), under ice bath, be added dropwise to methylsulfonyl chloride (0.4mL, 5.66mmol), stirring reaction 0.5 hour.Add 30mL water, stir 30 minutes, aqueous phase is with dichloromethane extraction (20mL × 1), merge organic phase, use water (10mL × 1) successively, saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtains crude title product [(1R, 5S)-3-(5-propyl group pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 113b (1200mg, yellow solid), productive rate: 100%.
MS m/z(ESI)：312.1[M+1]
3rd step
(1R, 5S)-3-(5-propyl group pyrimidine-2-base)-6-[[6-(the fluoro-4-pyridine of 3-)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By 6-(the fluoro-4-pyridine of 3-) pyridine-3-alcohol 109a (100mg, 0.53mmol) be dissolved in 5mL N, in dinethylformamide, add crude product [(1R successively, 5S)-3-(5-propyl group pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 113b (164mg, 0.53mmol) with salt of wormwood (218mg, 1.58mmol), rise to 80 DEG C of stirring reactions 12 hours.Reaction solution concentrating under reduced pressure, add 10mL water, with dichloromethane extraction (15mL × 3), merge organic phase, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A and obtain title product (1R, 5S)-3-(5-propyl group pyrimidine-2-base)-6-[[6-(the fluoro-4-pyridine of 3-)-3-pyridyl] oxygen methyl]-3 azabicyclos also [3.1.0] hexane 113 (100mg, light yellow solid), productive rate: 46.9%.
MS m/z(ESI)：406.1[M+1]
1H NMR(400MHz，CDCl 3)δ8.51-8.49(m，3H)，8.15(s，2H)，7.99(t，1H)，7.87(d，1H)，7.28(d，1H)，4.03(d，2H)，3.97(d，2H)，3.58(d，2H)，2.39(t，2H)，1.78(s，2H)，1.56-1.54(m，2H)，1.25-1.23(m，1H)，0.92(t，3H)
Embodiment 114
(1R, 5S)-3-(5-chloropyrimide-2-base)-6-[[6-(the fluoro-4-pyridine of 3-)-3-pyridyl] oxygen methyl]-3 azabicyclos also [3.1.0] hexane
By 6-(the fluoro-4-pyridine of 3-) pyridine-3-alcohol 109a (100mg, 0.53mmol) be dissolved in 5mL N, in dinethylformamide, add crude product [(1R successively, 5S)-3-(5-chloropyrimide-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 104b (160mg, 0.53mmol) with salt of wormwood (218mg, 1.58mmol), rise to 80 DEG C of stirring reactions 16 hours.Reaction solution concentrating under reduced pressure, add 10mL water, be extracted with ethyl acetate (15mL × 3), merge organic phase, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A and obtain title product (1R, 5S)-3-(5-chloropyrimide-2-base)-6-[[6-(the fluoro-4-pyridine of 3-)-3-pyridyl] oxygen methyl]-3 azabicyclos also [3.1.0] hexane 114 (160mg, faint yellow solid), productive rate: 76.4%.
MS m/z(ESI)：398.1[M+1]
1H NMR(400MHz，CDCl 3)δ8.49-8.47(m，3H)，8.22(s，2H)，7.99(t，1H)，7.87(d，1H)，7.26(d，1H)，4.03(d，2H)，3.95(d，2H)，3.58(d，2H)，1.79(s，2H)，1.23-1.21(m，1H)
Embodiment 115
4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] p-methoxy-phenyl] ethyl benzoate
By (1R, 5S)-6-[(4-bromine phenoxy group) methyl]-3-(5-ethyl-pyrimidine 2-yl)-3-azabicyclo also [3.1.0] hexane 101a (150mg, 0.40mmol), 4-boric acid-ethyl benzoate (78mg, 0.40mmol), two (triphen phosphino-) palladium chloride (6mg, 0.01mmol) He three hypophosphite monohydrate potassium (319mg, 1.20mmol) be dissolved in 5mL 1, in 4-dioxane, rise to 100 DEG C of stirring reactions 12 hours.Filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product 4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] p-methoxy-phenyl] ethyl benzoate 115 (93mg, white solid), productive rate: 52.0%.
MS m/z(ESI)：444.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.19(s，2H)，8.13(d，2H)，7.62(d，2H)，7.57(d，2H)，6.99(d，2H)，4.43-4.38(m，2H)，4.00-3.97(m，4H)，3.61-3.59(m，2H)，2.50-2.45(m，2H)，1.77(s，2H)，1.42(t，3H)，1.26-1.23(m，1H)，1.19(t，3H).
Embodiment 116
4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] p-methoxy-phenyl] phenylformic acid
By 4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] p-methoxy-phenyl] ethyl benzoate 115 (50mg, 0.13mmol) be dissolved in 2mL tetrahydrofuran (THF), add the lithium hydroxide aqueous solution of 2mL 10%, rise to 50 DEG C of stirring reactions 4 hours.Add the hydrochloric acid of 2mL 2M, be extracted with ethyl acetate (5mL × 3), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by thin-layer chromatography chromatography, obtain title product 4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] p-methoxy-phenyl] phenylformic acid 116 (23mg, white solid), productive rate: 50.0%.
MS m/z(ESI)：416.1[M+1]
1H NMR(400MHz，CDCl 3)δ11.05(s，1H)，8.35(s，2H)，8.02(d，2H)，7.64(d，2H)，7.59(d，2H)，6.99(d，2H)，4.25-4.22(m，4H)，3.68-3.56(m，2H)，2.78-2.73(m，2H)，1.97(s，2H)，1.62-1.59(m，1H)，1.29(t，3H).
Embodiment 117
(1R, 5S)-6-[[6-(4-m methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo [3.1.0] hexane-3-isopropyl formate
The first step
(1R, 5S)-6-(methylol)-3-azabicyclo is [3.1.0] hexane-3-isopropyl formate also
By crude product [(1R, 5S)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 7e (650mg, 5.70mmol) is dissolved in 15mL pyridine, adds isopropyl chlorocarbonate (0.7mL, 5.70mmol), stirring reaction 4 hours.Add 50mL water, be extracted with ethyl acetate (30mL × 3), merge organic phase, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, obtain title product (1R, 5S)-6-(methylol)-3-azabicyclo also [3.1.0] hexane-3-isopropyl formate 117a (0.99g, yellow liquid), productive rate: 95.0%.
MS m/z(ESI)：200.1[M+1]
Second step
(1R, 5S)-6-(methanesulfonyloxymethyl)-3-azabicyclo is [3.1.0] hexane-3-isopropyl formate also
By (1R, 5S)-6-(methylol)-3-azabicyclo also [3.1.0] hexane-3-isopropyl formate 117a (0.96g, 4.80mmol) be dissolved in 15mL anhydrous methylene chloride, add triethylamine (2mL, 14.40mmol), be added dropwise to methylsulfonyl chloride (0.6mL, 7.20mmol), stirring reaction 12 hours.Add saturated sodium bicarbonate solution 30mL; dichloromethane extraction (10mL × 3); merge organic phase; use water (20mL × 3) successively; saturated nacl aqueous solution washing (20mL × 3); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; obtain crude title product (1R; 5S)-6-(methanesulfonyloxymethyl)-3-azabicyclo also [3.1.0] hexane-3-isopropyl formate 117b (1300mg, yellow liquid), productive rate: 97.0%.
MS m/z(ESI)：278.0[M+1]
3rd step
(1R, 5S)-6-[[6-(4-m methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo [3.1.0] hexane-3-isopropyl formate
By 6-(4-methanesulfonylphenYl) pyridine-3-alcohol 48e (249mg; 1mmol) be dissolved in 12mL N; in dinethylformamide; add crude product (1R successively; 5S)-6-(methanesulfonyloxymethyl)-3-azabicyclo also [3.1.0] hexane-3-isopropyl formate 117b (1277mg; 1mmol) with salt of wormwood (276mg, 2mmol), rise to 80 DEG C of stirring reactions 12 hours.Add 10mL water; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous sodium sulfate drying; filter; filtrate reduced in volume; purify gained resistates by silica gel thin-layer chromatography with eluent system A and obtain title product (1R; 5S)-6-[[6-(4-m methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo [3.1.0] hexane-3-isopropyl formate 117 (150mg; light yellow solid), productive rate: 35.0%.
MS m/z(ESI)：431.1[M+1]
1H NMR(400MHz，CDCl 3)δ8.40(d，1H)，8.15-8.12(m，2H)，8.02-8.00(m，2H)，7.74-7.72(m，1H)，7.31-7.29(m，1H)，4.93-4.86(m，1H)，4.06-3.93(m，2H)，3.76-3.66(m，2H)，3.47-3.41(m，2H)，3.08(s，3H)，1.63(s，2H)，1.25-1.19(m，6H)，1.18-1.15(m，1H)
Embodiment 118
5-[(1R, 5S)-6-[[4-(the fluoro-4-methanesulfinyl-phenyl of 3-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole
By 4-(the fluoro-4-methanesulfinyl-phenvl of 3-) phenol 96c (50mg; 0.20mmol) be dissolved in 5mL N; in dinethylformamide; add crude product [[(1R successively; 5S)-3-(3-sec.-propyl-1; 2; 4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl methylsulfonate 48c (60mg; 0.20mmol) with cesium carbonate (130mg; 0.42mmol), 110 DEG C of stirring reactions 4 hours are risen to.Add 10mL water; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous sodium sulfate drying; filter; filtrate reduced in volume; purify gained resistates by thin-layer chromatography chromatography with developping agent system A and obtain title product 5-[(1R; 5S)-6-[[4-(the fluoro-4-methanesulfinyl-phenyl of 3-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1; 2; 4-oxadiazole 118 (10mg, white solid), productive rate: 15.0%.
MS m/z(ESI)：456.2[M+1]
1H NMR(400MHz，CDCl 3)δ7.90-7.88(m，1H)，7.58-7.52(m，3H)，7.31-7.27(m，1H)，6.98-6.96(m，2H)，3.98-3.94(m，4H)，3.76-3.74(m，2H)，2.98-2.96(m，1H)，2.87(s，3H)，1.83(s，2H)，1.34-1.32(m，6H)，1.26-1.24(m，1H)
Embodiment 119
(1R, 5S)-6-[[6-(5-methanesulfonylindole quinoline-1-base) pyrimidine-4-yl] amido]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
The first step
(1R, 5S)-3-azabicyclo is [3.1.0] hexane-6-amine also
By [(1R, 5S)-3-benzyl-3-azabicyclo also [3.1.0] hexane-6-nitro 119a (5.50g, 25.20mmol) be dissolved in 100mL methyl alcohol, add palladium hydroxide (1000mg successively, 10%), hydrogenation 36 hours.Filter, concentrating under reduced pressure filtrate, obtains crude title product (1R, 5S)-3-azabicyclo also [3.1.0] hexane-6-amine 119b (1.70g, colorless oil), and product is not purified directly carries out next step reaction.
MS m/z(ESI)：141.2[M+42]
Second step
(1R, 5S)-6-(amino)-3-azabicyclo is [3.1.0] hexane-3-carboxylic acid tert-butyl ester also
By (1R, 5S)-3-azabicyclo also [3.1.0] hexane-6-amine 119b (1.70g, 17.30mmol) be dissolved in 60mL toluene, add phenyl aldehyde (2.50g, 25.40mmol), intensification 130 DEG C of stirring reactions 3 hours..Add tert-Butyl dicarbonate (3.80g, 17.30mmol), stirring reaction 12 hours.Reaction solution concentrates, add the saturated sodium bisulfate of 10mL, stirring reaction is after 0.5 hour, add the sodium hydroxide solution of 5mL1M, dichloromethane extraction (20mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A, obtain title product (1R, 5S)-6-(amino)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 119c (140g, yellow solid), productive rate: 50.0%.
MS m/z(ESI)：199.1[M+1]
3rd step
1-(6-chloropyrimide-4-base)-5-methylsulfonyl-indoline
By 5-methylsulfonyl-indoline 119d (210mg, 1.06mol), sodium hydride (64mg, 1.60mmol) and 4,6-dichloro pyrimidine (313mg, 2.10mmol) are dissolved in 10mL tetrahydrofuran (THF), and stirring at room temperature reacts 4 hours.Add 20mL water; extraction into ethyl acetate (20mL × 2); merge organic phase; anhydrous magnesium sulfate drying, filters, filtrate reduced in volume; gained resistates is purified with eluent system A with silica gel column chromatography; obtain title product 1-(6-chloropyrimide-4-base)-5-methylsulfonyl-indoline 119e (300mg, yellow solid), productive rate: 90.9%.
MS m/z(ESI)：310.0[M+1]
4th step
(1R, 5S)-6-[[6-(5-methanesulfonylindole quinoline-1-base) pyrimidine-4-yl] amido]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
By (1R; 5S)-6-(amino)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 119c (280mg; 0.90mmol) be dissolved in 5mLN; in dinethylformamide; add 1-(6-chloropyrimide-4-base)-5-methylsulfonyl-indoline 119e (140mg successively; 0.71mmol) with salt of wormwood (250mg, 1.80mmol), rise to 80 DEG C of stirring reactions 3 hours.Add 20mL water; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with eluent system A with silica gel column chromatography; obtain title product (1R; 5S)-6-[[6-(5-methanesulfonylindole quinoline-1-base) pyrimidine-4-yl] amido]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 119 (70mg; white solid), productive rate: 21.0%.
MS m/z(ESI)：472.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.58(d，1H)，8.32(s，1H)，7.79-7.72(m，2H)，5.78(s，1H)，4.12(t，2H)，3.76(d，1H)，3.65(d，1H)，3.52-3.46(m，2H)，3.34-3.30(m，2H)，3.03(s，3H)，2.34(s，1H)，1.85(d，1H)，1.46-1.41(m，10H)
Embodiment 120
(1R, 5S)-6-[ethyl-[6-(5-methanesulfonylindole quinoline-1-base) pyrimidine-4-yl] amido]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
By (1R; 5S)-6-[[6-(5-methanesulfonylindole quinoline-1-base) pyrimidine-4-yl] amido]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 119 (60mg; 0.13mmol) be dissolved in 5mL N; in dinethylformamide, add 60% sodium hydride (26mg, 0.65mmol); stirring reaction 0.5 hour; add iodoethane (0.1mL, 0.26mmol) again, stirring reaction 4 hours.Add 5mL water; with dichloromethane extraction (5mL × 2); merge organic phase; with saturated nacl aqueous solution washing (5mL × 1); anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system A by thin-layer chromatography chromatography; obtain title product (1R; 5S)-6-[ethyl-[6-(5-methanesulfonylindole quinoline-1-base) pyrimidine-4-yl] amido]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 120 (60mg, faint yellow solid), productive rate: 90.0%.
MS m/z(ESI)：500.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.54(d，1H)，8.43(s，1H)，7.78-7.74(m，2H)，5.92(s，1H)，4.10(t，2H)，3.91-3.90(m，1H)，3.76(d，1H)，3.65(d，1H)，3.58-3.55(m，3H)，3.29(q，2H)，3.02(s，3H)，2.30(s，1H)，2.01(s，1H)，1.98(s，1H)，1.47(s，9H)，1.18(t，3H)
Embodiment 121
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
The first step
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4,4,5,5-tetramethyl--1,3,2-dioxo boric acid-2-base) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By [(1R, 5S)-6-[(4-bromo-2,6-dilquoro-phenogy) methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 8a (85mg, 0.15mol), connection boric acid pinacol ester (93mg, 0.36mmol) He 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (18mg, 0.02mmol) be dissolved in 5mL dimethyl sulfoxide (DMSO), add Potassium ethanoate (72mg again, 0.73mmol), intensification 110 DEG C of stirring reactions 6 hours.Add 20mL water, extraction into ethyl acetate (20mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, obtain title product (1R, 5S)-6-[[the fluoro-4-(4 of 2,6-bis-, 4,5,5-tetramethyl--1,3,2-dioxo boric acid-2-base) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 121a (70mg, white solid), productive rate: 67.1%.
Second step
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By (1R, 5S)-6-[[2, the fluoro-4-(4 of 6-bis-, 4, 5, 5-tetramethyl--1, 3, 2-dioxo boric acid-2-base) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 121a (70mg, 0.15mmol) be dissolved in 5mL N, in dinethylformamide, add cesium carbonate (150mg again, 0.46mmol), the bromo-5-methanesulfonyl-pyridine of 2-(36mg, 0.15mmol) and 1, 1 '-two (diphenyl phosphine) ferrocene palladium chloride (12mg, 0.02mmol), , be warming up to 110 DEG C of stirring reactions 4 hours.Add 20mL water; extraction into ethyl acetate (20mL × 2); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system B by thin-layer chromatography chromatography; obtain title product (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 121 (10mg, white solid), productive rate: 13.5%.
MS m/z(ESI)：487.2[M+1]
1H NMR(400MHz，CDCl 3)δ9.17-9.16(m，1H)，8.29-8.28(m，1H)，8.27(s，2H)，7.84-7.82(m，1H)，7.70-7.67(m，2H)，4.19-4.17(m，2H)，3.88-3.85(m，2H)，3.55-3.52(m，2H)，3.15(s，3H)，2.48-2.42(m，2H)，1.71(s，2H)，1.26(s，1H)，1.19-1.15(m，3H)
Embodiment 122
(1R, 5S)-6-[[4-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
The first step
4-(4-hydroxy-pheny)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester
By bromo-for 4-phenol 122a (519mg, 3mmol) with 4-(4,4,5,5-tetramethyl--1,3,2-dioxy boric acid ester-2-base)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (973g, 3.15mmol) is dissolved in 50mL ethanol and toluene (V/V=1: 4) mixed solvent, adds saturated sodium carbonate solution (3.3mL successively, 6.60mmol) with ferrocene palladium chloride (220mg, 0.30mmol), be warming up to 100 DEG C, stirring reaction 2 hours.Add 50mL water, extraction into ethyl acetate (50mL × 3), merge organic phase, use water (50mL × 1) successively, saturated nacl aqueous solution washing (50mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 4-(4-hydroxy-pheny)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 122b (0.60mg, white solid), productive rate: 73.2%.
MS m/z(ESI)：274.3[M-1]
Second step
4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esters
By 4-(4-hydroxy-pheny)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 122b (412mg, 1.50mmol) be dissolved in 10mL N, in dinethylformamide, add [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (404mg, 1.36mmol) with salt of wormwood (563mg, 4.08mmol), be warming up to 100 DEG C, stirring reaction 3 hours.Add 50mL water, extraction into ethyl acetate (50mL × 4), merge organic phase, use water (50mL × 1) successively, saturated nacl aqueous solution washing (50mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product 4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-phenyl]-3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 122c (467mg, white solid), productive rate: 79.2%.
MS m/z(ESI)：477.2[M+1]
3rd step
(1R, 5S)-6-[[4-(1,2,3,6-tetrahydropyridine-4-base) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By 4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 122c (450mg, 0.95mmol) be dissolved in 10mL methylene dichloride, add 1mL trifluoracetic acid, stirring reaction 2 hours.Dripping 1M saturated sodium carbonate solution is 10 to reaction solution pH, extraction into ethyl acetate (50mL × 4), merge organic phase, use water (50mL × 1) successively, saturated nacl aqueous solution washing (50mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtain crude title product (1R, 5S)-6-[[4-(1, 2, 3, 6-tetrahydropyridine-4-base) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 122d (396mg, yellow solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：377.3[M+1]
4th step
(1R, 5S)-6-[[4-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By crude product (1R, 5S)-6-[[4-(1,2,3,6-tetrahydropyridine-4-base) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 122d (356mg, 0.94mmol) be dissolved in 10mL methylene dichloride, add triethylamine (287mg, 2.84mmol), under ice bath, slowly drip methylsulfonyl chloride (161mg, 1.41mmol), 0 DEG C of stirring reaction 1 hour.Add 50mL water, dichloromethane extraction (60mL × 4), merge organic phase, use water (60mL × 1) successively, saturated nacl aqueous solution washing (60mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product (1R, 5S)-6-[[4-(1-methylsulfonyl-3, 6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 122 (67mg, white solid), productive rate: 15.7%.
MS m/z(ESI)：455.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.22(s，2H)，7.33(d，2H)，6.90(d，2H)，6.02(s，1H)，4.01-3.95(m，6H)，3.63(d，2H)，3.57-3.55(t，2H)，2.89(s，3H)，2.67(s，2H)，2.53-2.48(q，2H)，1.78(s，2H)，1.24-1.20(m，4H)
Embodiment 123
5-[(1R, 5S)-6-[[4-(the fluoro-4-Metlianesulfonyl-phenyl of 3-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole
By 5-[(1R; 5S)-6-[[4-(the fluoro-4-methanesulfinyl-phenyl of 3-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1; 2; 4-oxadiazole 118 (5mg; 0.01mmol) be dissolved in 5mL DMF, add metachloroperbenzoic acid (5mg; 0.02mmol), stirring reaction 12 hours.Add the saturated sulfurous acid solution of 10mL; be extracted with ethyl acetate (10mL × 2); merge organic phase; anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system A by thin-layer chromatography chromatography; obtain title product 5-[(1R; 5S)-6-[[4-(the fluoro-4-Metlianesulfonyl-phenyl of 3-) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole 123 (3mg; white solid), productive rate: 60.0%.
MS m/z(ESI)：472.1[M+1]
1H NMR(400MHz，CDCl 3)δ7.99-7.97(m，1H)，7.55-7.51(m，3H)，7.49-7.43(m，1H)，7.00-6.98(m，2H)，3.98-3.85(m，4H)，3.69-3.67(m，2H)，3.25(s，3H)，2.92-2.88(m，1H)，1.79(s，2H)，1.33-1.26(m，6H)，1.25(m，1H)
Embodiment 124
5-[(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole
The first step
5-[(1R, 5S)-6-[(bromo-2, the 6-dilquoro-phenogy of 4-) methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole
By crude product [(1R, 5S)-3-(3-sec.-propyl-1,2,4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl methylsulfonate 48c (1600mg, 5.31mmol) be dissolved in 15mLN, in dinethylformamide, stir, add 2, bromo-phenol (the 1100mg of the fluoro-4-of 6-bis-, 5.31mmol) with cesium carbonate (3460mg, 10.60mmol), be warming up to 90 DEG C of stirring reactions 4 hours.Add 100mL water, extraction into ethyl acetate (80mL × 2), merge organic phase, wash with water (50mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product 5-[(1R, 5S)-6-[(4-bromo-2,6-dilquoro-phenogy) methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole 124a (1100mg, white solid), productive rate: 50.0%.
MS m/z(ESI)：416.1[M+1]
Second step
5-[(1R, 5S)-6-[[fluoro-4-of 2,6-bis-(4,4,5,5-tetramethyl--1,3,2-dioxo boric acid ester-2-base) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole
By 5-[(1R, 5S)-6-[(4-bromo-2,6-dilquoro-phenogy) methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole 124a (1100mg, 2.70mol), connection boric acid pinacol ester (1010mg, 3.90mmol) He 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (194mg, 0.50mmol) is dissolved in 20mL dimethyl sulfoxide (DMSO), then adds Potassium ethanoate (781mg, 7.80mmol), intensification 110 DEG C of stirring reactions 6 hours.Add 50mL water, extraction into ethyl acetate (50mL × 2), merge organic phase, anhydrous magnesium sulfate drying, filters, filtrate reduced in volume, obtain title product 5-[(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(4,4,5,5-tetramethyl--1,3,2-dioxo boric acid ester-2-base) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole 124b (1200mg, brown liquid), productive rate: 67.1%
MS m/z(ESI)：462.2[M+1]
3rd step
5-[(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole
By 5-[(1R, 5S)-6-[[2, the fluoro-4-(4 of 6-bis-, 4, 5, 5-tetramethyl--1, 3, 2-dioxo boric acid ester-2-base) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1, 2, 4-oxadiazole 124b (400mg, 0.19mmol) be dissolved in 5mL N, in dinethylformamide, add cesium carbonate (848mg again, 2.60mmol), the bromo-5-methanesulfonyl-pyridine of 2-(205mg, 0.86mmol) and 1, 1 '-two (diphenyl phosphine) ferrocene palladium chloride (63mg, 0.08mmol), , be warming up to 110 DEG C of stirring reactions 4 hours.Add 20mL water; extraction into ethyl acetate (20mL × 2); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system B by thin-layer chromatography chromatography; obtain title product 5-[(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1; 2; 4-oxadiazole 124 (20mg, white solid), productive rate: 5.0%.
MS m/z(ESI)：491.1[M+1]
1H NMR(400MHz，CDCl 3)δ9.17(s，1H)，8.29-8.27(m，1H)，7.85-7.83(m，1H)，7.70-7.68(m，2H)，4.17-4.16(m，2H)，3.78-3.76(m，2H)，3.65-3.63(m，2H)，3.15(s，3H)，2.90-2.87(m，1H)，1.76(s，2H)，1.29-1.27(m，6H)，1.20-1.18(m，1H)
Embodiment 125
2-methyl isophthalic acid-[(1R, 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base] propyl group-2-alcohol
By (1R; 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane hydrochloride 99b (0.41g; 1mmol) be dissolved in the mixed solvent of 15mL methyl alcohol and methylene dichloride (V/V=2: 1); add triethylamine (0.4mL; 3mmol), 2,2-dimethyl ethylene oxide (316mL is added; 4.40mmol), stirring reaction 72 hours.Reaction solution concentrating under reduced pressure, add water 10mL, dichloromethane extraction (20mL × 2), merge organic phase, use water (20mL × 1) successively, saturated nacl aqueous solution washing (20mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product (2-methyl isophthalic acid-[(1R, 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base] propyl group-2-alcohol 125 (270mg, yellow solid), productive rate: 64.9%.
MS m/z(ESI)：417.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.40(s，1H)，8.13(d，2H)，8.00(d，2H)，7.73(d，2H)，7.27(d，1H)，3.93(d，2H)，3.33(br.s，2H)，3.08(s，3H)，2.73-2.55(m，4H)，1.79(br.s，1H)，1.55(s，2H)，1.19(s，6H)
Embodiment 126
(1R, 5S)-3-(the fluoro-2-methyI-oropvD of 2-)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By (2-methyl isophthalic acid-[(1R; 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base] propyl group-2-alcohol 125 (0.21g; 0.50mmol) be dissolved in 5mL methylene dichloride; add two (2-methoxy ethyl) amino sulfur trifluoride (133mg; 0.60mmol), stirring reaction 2 hours.Dripping saturated sodium bicarbonate solution is 7 to reaction solution pH; dichloromethane extraction (10mL × 3); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system A by thin-layer chromatography chromatography; obtain title product (1R; 5S)-3-(the fluoro-2-methyI-oropvD of 2-)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 126 (80mg; white solid), productive rate: 38.3%.
MS m/z(ESI)：419.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.41(d，1H)，8.13(d，2H)，8.00(d，2H)，7.72(d，1H)，7.28(d，1H)，3.91(d，2H)，3.17(d，2H)，3.08(s，3H)，2.57-2.47(m，4H)，1.72(br.s，1H)，1.44(s，2H)，1.32(d，6H)
Embodiment 127
(1R, 5S)-6-[[4-(5-methylsulfonyl 1-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
By 4-(5-methylsulfonyl-2-pyridine) phenol 82b (450mg; 1.81mmol) be dissolved in 5mL N; in dinethylformamide; add crude product (1R successively; 5S)-6-(Methanesulfonvloxvmethvl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 16b (526mg; 1.81mmol) with cesium carbonate (1180mg, 3.61mmol), rise to 110 DEG C of stirring reactions 4 hours.Add 10mL water; be extracted with ethyl acetate (20mL × 2); merge organic phase, anhydrous sodium sulfate drying, filter; filtrate reduced in volume; purify gained resistates with silica gel column chromatography with eluent system A, obtain title product (1R, 5S)-6-[[4-(5-methylsulfonyl 1-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 127 (600mg; white solid), productive rate: 74.8%.
MS m/z(ESI)：445.2[M+1]
1H NMR(400MHz，CDCl 3)δ9.17(s，1H)，8.27-8.24(m，1H)，8.08-8.06(m，2H)，7.89-7.86(m，1H)，7.03-7.01(m，2H)，4.02-3.90(m，4H)，3.41-3.39(m，2H)，3.14(s，3H)，1.60(s，2H)，1.45(s，9H)，1.19-1.15(m，1H)
Embodiment 128
(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-(((1 '-(methylsulfonyl)-1 '; 2 '; 3 '; 6 '-tetrahydrochysene-[2,4 '-bipyridyl]-5-base) oxygen base) methyl)-3-azabicyclo [3.1.0] hexane
The first step
4-(5-hydroxyl-2-pyridine)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester
By bromo-for 5-hydroxyl-2-pyridine (2.56g, 14.70mmol) be dissolved in the mixed solvent of 80mL ethanol and toluene (V/V=1: 3), add 4-(4 successively, 4,5,5-tetramethyl--1,3,2-dioxy boric acid ester-2-base)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (5g, 16.20mmol), sodium carbonate (14.7mL, the 29.40mmol) aqueous solution of 2M, ferrocene palladium chloride (1.08g, 1.47mmol), be warming up to 100 DEG C, stirring reaction 3 hours.Concentrating under reduced pressure reaction solution, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 4-(5-hydroxyl-2-pyridine)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 128a (3.6g, white solid), productive rate: 90.0%.
MS m/z(ESI)：277.1[M+1]
Second step
4-[5-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-2-pyridine]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esters
By 4-(5-hydroxyl-2-pyridine)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 128a (2g, 7.20mmol) be dissolved in 20mL N, in dinethylformamide, add [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (2.15mg, 7.20mmol) and salt of wormwood (2.98mg, 21.60mmol), 80 DEG C of stirring reactions 4 hours are risen to.Cooling, add 10mL water to stir, separate out solid, filter, filter cake normal hexane (50mL) washing, vacuum-drying obtains title product 4-[5-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-2-pyridine]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 128b (2.10g, white solid), productive rate: 61.0%.
3rd step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(1,2,3,6-tetrahydropyridine-4-base)-3-pyridyl] oxygen methyl]-3-azabicyclo [3.1.0] hexane hydrochloride salt
By 4-[5-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-2-pyridine]-3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 128b (2.10g, 4.40mmol) be dissolved in the mixed solvent of 120mL ethyl acetate and methylene dichloride (V/V=5: 1), slowly add the hydrochloric ethyl acetate solution of 50mL 5M, stirring reaction 2 hours, concentrating under reduced pressure, obtain title product (1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(1, 2, 3, 6-tetrahydropyridine-4-base)-3-pyridyl] oxygen methyl]-3-azabicyclo [3.1.0] ethane 128c (2.4g, white solid), productive rate: 100%.
4th step
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-(((1 '-(methylsulfonyl)-1 ', 2 ', 3 ', 6 '-tetrahydrochysene-[2, 4 '-bipyridyl]-5-base) oxygen base) methyl)-3-azabicyclo [3.1.0] hexane is by (1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(1, 2, 3, 6-tetrahydropyridine-4-base)-3-pyridyl] oxygen methyl]-3-azabicyclo [3.1.0] hexane hydrochloride salt 128c (268mg, 0.65mmol) be dissolved in 15mL methylene dichloride, add triethylamine (270 μ L, 1.95mmol), under ice bath, be added dropwise to methylsulfonyl chloride (80 μ L again, 0.97mmol), rise to room temperature, stirring reaction 6 hours.Add water 10mL, dichloromethane extraction (20mL × 3), merge organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product (1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-(((1 '-(methylsulfonyl)-1 ', 2 ', 3 ', 6 '-tetrahydrochysene-[2, 4 '-bipyridyl]-5-base) oxygen base) methyl)-3-azabicyclo [3.1.0] hexane 128 (20mg, white solid), productive rate: 6.8%.
MS m/z(ESI)：456.3[M+1]
1H NMR(400MHz，CDCl 3)δ8.26(s，1H)，8.17(s，2H)，7.32(d，1H)，7.17(d，1H)，6.49(s，1H)，4.08-3.88(m，6H)，3.58-3.50(m，4H)，2.85(s，3H)，2.76(s，2H)，2.46(t，2H)，1.75(s，2H)，1.25-1.18(m，4H)
Embodiment 129
5-[(1R, 5S)-6-[[6-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole
The first step
4-[5-[[(1R, 5S)-3-(3-sec.-propyl-1,2,4-oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-2-pyridine]-3,6--dihydro-2H-pyridine-1-carboxylic acid tert-butyl esters
By crude product [(1R, 5S)-3-(3-sec.-propyl-1,2,4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl methylsulfonate 48c (263mg, 0.87mmol), 4-(5-hydroxyl-2-pyridine)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 128a (200mg, 0.73mmol) with salt of wormwood (302mg, 2.19mmol) be dissolved in 10mL N, in dinethylformamide, stir, be warming up to 80 DEG C of stirring reactions 2 hours.Add 50mL water, extraction into ethyl acetate (50mL × 2), merge organic phase, with saturated nacl aqueous solution washing (50mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtain crude title product 4-[5-[[(1R, 5S)-3-(3-sec.-propyl-1,2,4-oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-2-pyridine]-3,6--dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 129a (350mg, yellow oil), product is not purified directly carries out next step reaction.
Second step
5-[(1R, 5S)-6-[[6-(1,2,3,6-tetrahydropyridine-4-base)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole hydrochloride
By crude product 4-[5-[[(1R, 5S)-3-(3-sec.-propyl-1,2,4-oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-2-pyridine]-3,6--dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 129a (350mg, 0.73mmol) be dissolved in 20mL methyl alcohol, add 10mL 5M hydrochloric ethyl acetate solution, stirring reaction 6 hours.Reaction solution concentrating under reduced pressure, obtain crude title product 5-[(1R, 5S)-6-[[6-(1,2,3,6-tetrahydropyridine-4-base)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole hydrochloride 129b (305mg, yellow solid), product is not purified directly carries out next step reaction.
3rd step
5-[(1R, 5S)-6-[[6-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole
By 5-[(1R, 5S)-6-[[6-(1,2,3,6-tetrahydropyridine-4-base)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole hydrochloride 129b (305mg, 0.73mmol) is dissolved in 20mL methylene dichloride, adds triethylamine (305 μ L, 2.19mmol), under ice bath, then be added dropwise to methylsulfonyl chloride (84 μ L, 1.10mmol), rise to room temperature, stirring reaction 6 hours.Add water 50mL, dichloromethane extraction (10mL × 3), merge organic phase, with saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product 5-[(1R, 5S)-6-[[6-(1-methylsulfonyl-3, 6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1, 2, 4-oxadiazole 129 (40mg, white solid), productive rate: 11.9%.
MS m/z(ESI)：460.1[M+1]
1H NMR(400MHz，CDCl 3)δ8.29(d，1H)，7.39(d，1H)，7.24(d，1H)，6.57(s，1H)，4.06(d，2H)，4.02(d，2H)，3.89(d，2H)，3.71(d，2H)，3.58(t，2H)，2.94(q，1H)，2.90(s，3H)，2.81(d，2H)，1.82(s，2H)，1.32(d，6H)，1.25(t，1H)
Embodiment 130
(1R, 5S)-3-(the fluoro-2-methyI-oropvD of 2-)-6-[[4-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
The first step
(1R, 5S)-6-[[4-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
By (1R; 5S)-6-[[4-(5-methylsulfonyl l-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 127 (350mg; 0.78mmol) be dissolved in 5mL methanol hydrochloride solution, stirring reaction 5 hours.Add 10mL saturated sodium bicarbonate solution; be extracted with ethyl acetate (20mL × 2); merge organic phase; anhydrous sodium sulfate drying, filters, filtrate reduced in volume; obtain title product (1R; 5S)-6-[[4-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 130a (170mg, white solid), productive rate: 62.0%.
MS m/z(ESI)：445.2[M+1]
Second step
2-methyl isophthalic acid-[(1R, 5S)-6-[[4-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base] propane-2-alcohol
By (1R; 5S)-6-[[4-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 130a (0.07g; 0.20mmol) be dissolved in 5mL methyl alcohol; add 2; 2-dimethyl ethylene oxide (22mg; 0.30mmol), stirring reaction 16 hours.Add water 10mL, dichloromethane extraction (10mL × 3), merge organic phase, use water (20mL × 3) successively, saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product 2-methyl isophthalic acid-[(1R, 5S)-6-[[4-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base] propane-2-alcohol 130b (130mg, yellow solid), productive rate: 64.9%.
MS m/z(ESI)：417.1[M+1]
3rd step
(1R, 5S)-3-(the fluoro-2-methyI-oropvD of 2-)-6-[[4-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane
By 2-methyl isophthalic acid-[(1R; 5S)-6-[[4-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base] propane-2-alcohol 130b (0.13g; 0.30mmol) be dissolved in 5mL methylene dichloride; add two (2-methoxy ethyl) amino sulfur trifluoride (69mg; 0.30mmol), stirring reaction 2 hours.Add water 10mL, dichloromethane extraction (10mL × 3), merge organic phase, use water (20mL × 3) successively, saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by thin-layer chromatography chromatography, obtain title product (1R, 5S)-3-(the fluoro-2-methyI-oropvD of 2-)-6-[[4-(5-methylsulfonyl-2-pyridine) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane 130 (20mg, white solid), productive rate: 38.3%.
MS m/z(ESI)：419.1[M+1]
1H NMR(400MHz，CDCl 3)δ9.14(s，1H)，8.22-8.20(m，1H)，8.05-8.03(m，2H)，7.86-7.83(m，1H)，7.02-7.00(m，2H)，3.89-3.87(m，2H)，3.18-3.16(m，2H)，3.13(s，3H)，2.57(s，1H)，2.51-2.46(m，2H)，1.71(s，2H)，1.43-1.26(m，8H)
Embodiment 131
1-[(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-2-methyl-propan-2-alcohol
The first step
4-(the fluoro-4-hydroxy-pheny of 3,5-bis-)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester
Bromo-for fluoro-for 2,6-bis-4-phenol (1040mg, 5mmol) is dissolved in 6mL ethanol, add 4-(4,4,5,5-tetramethyl--1,3,2-dioxy boric acid ester-2-base)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1700g, 5.50mmol), adds 2M sodium carbonate (5mL, aqueous solution 10mmol), ferrocene palladium chloride (366mg, 0.5mmol), be warming up to 100 DEG C, microwave stirring reaction 1 hour.Concentrating under reduced pressure reaction solution, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product 4-(3, the fluoro-4-hydroxy-pheny of 5-bis-)-3, the tertiary fourth 131a of 6-dihydro-2H-pyridine-1-formic acid (772mg, white solid), productive rate: 49.5%.
MS m/z(ESI)：312.2[M+1]
Second step
The fluoro-4-of 2,6-bis-(1,2,3,6-tetrahydropyridine-4-base) phenol
By 4-(the fluoro-4-hydroxy-pheny of 3,5-bis-)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 131a (0.77g, 2.47mmol) be dissolved in 5mL ethyl acetate, slowly add the hydrochloric ethyl acetate solution of 5M, room temperature reaction 1.5 hours, concentrating under reduced pressure, obtain the fluoro-4-of title product 2,6-bis-(1,2,3,6-tetrahydropyridine-4-base) phenol 131b (0.611g, yellow solid), productive rate: 100%.
MS m/z(ESI)：204.2[M+1]
3rd step
The fluoro-4-of 2,6-bis-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl) phenol
By 2, the fluoro-4-(1 of 6-bis-, 2,3,6-tetrahydropyridine-4-base) phenol 131b (0.61g, 2.47mmol) be dissolved in 10mL methylene dichloride, under ice bath, add triethylamine (1200mg, 9.88mmol) and methylsulfonyl chloride (621mg, 5.43mmol), stirring reaction 12 hours.Add 10mL water, with dichloromethane extraction (50mL × 3), merge organic phase, concentrating under reduced pressure, purify gained resistates with silica gel column chromatography with eluent system B, the dissolution of solid obtained, in 3mL methylene dichloride, adds 10mL methyl alcohol, add 3mL 2M sodium hydroxide solution again, stirring reaction 1 hour.Reaction solution concentrating under reduced pressure, adds 10mL water, and dripping 2M hydrochloric acid is 2 ~ 3 to reaction solution pH; with dichloromethane extraction (50mL × 3); merge organic phase, anhydrous magnesium sulfate drying, filter; filtrate reduced in volume; the fluoro-4-of title product 2,6-bis-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl) phenol 131c (0.50g; white solid), productive rate: 89.0%.
4th step
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
By 2; the fluoro-4-of 6-bis-(1-methylsulfonyl-3; 6-dihydro-2H-pyridin-4-yl) phenol 131c (377mg, 1.30mmol) is dissolved in 7mL DMF; add (1R; 5S)-6-(Methanesulfonvloxvmethvl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 16b (415mg, 1.42mmol) and salt of wormwood (518mg, 3.75mmol); rise to 80 DEG C, stirring reaction 16 hours.Reaction solution concentrating under reduced pressure; add 50mL water; be extracted with ethyl acetate (50mL × 3); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; purify gained resistates with silica gel column chromatography with eluent system B, obtain title product (1R, 5S)-6-[[2; the fluoro-4-of 6-bis-(1-methylsulfonyl-3; 6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 131d (0.50g, white solid), productive rate: 82.6%.
MS m/z(ESI)：220.2[M+1]
5th step
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-azabicyclo [3.1.0] ethane
By (1R, 5S)-6-[[2, the fluoro-4-of 6-bis-(1-methylsulfonyl-3, 6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 131d (0.50g, 1.10mmol) be dissolved in 5mL ethyl acetate, slowly add the hydrochloric ethyl acetate solution of 5M, stirring reaction 1 hour, concentrating under reduced pressure, obtain title product (1R, 5S)-6-[[2, the fluoro-4-of 6-bis-(1-methylsulfonyl-3, 6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-azabicyclo [3.1.0] ethane 131e (0.45g, yellow solid thing), productive rate: 100%.
MS m/z(ESI)：385.1[M+1]
6th step
1-[(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-2-methyl-propan-2-alcohol
By (1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(1-methylsulfonyl-3; 6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-azabicyclo [3.1.0] ethane 131e (450mg; 1mmol) be dissolved in 10mL methyl alcohol and methylene dichloride (V/V=1: 1) mixed solvent; add triethylamine (0.4mL; 3mmol); add 2; 2-dimethyl ethylene oxide (560mL; 7.76mmol), stirring reaction 72 hours.Reaction solution concentrating under reduced pressure; add water 10mL; dichloromethane extraction (10mL × 3); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; purify gained resistates with silica gel column chromatography with eluent system A, obtain title product 1-[(1R, 5S)-6-[[2; the fluoro-4-of 6-bis-(1-methylsulfonyl-3; 6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-2-methyl-propan-2-alcohol 131 (460mg, yellow solid), productive rate: 100%.
MS m/z(ESI)：457.2[M+1]
1H NMR(400MHz，CDCl 3)δ6.90-6.88(m，2H)，6.05-6.03(m，1H)，3.95-3.93(m，4H)，3.51(t，2H)，3.00(br.s，2H)，2.86(s，3H)，2.50-2.35(m，6H)，1.79-1.77(m，1H)，1.50(br.s，1H)，1.35(s，2H)，1.32(s，6H)
Embodiment 132
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(1 methylsulfonyl 1-3,6-dihydro-2H-pyridin-4-yl) phenoxymethyl]-3-(the fluoro-2-methyI-oropvD of 2-)-3-azabicyclo also [3.1.0] hexane
By 1-[(1R; 5S)-6-[[2; the fluoro-4-of 6-bis-(1-methylsulfonyl-3; 6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-2-methyl-propan-2-alcohol 131 (0.37g; 0.80mmol) be dissolved in 5mL methylene dichloride; add two (2-methoxy ethyl) amino sulfur trifluoride (221mg, 1mmol), stirring reaction 2 hours.Dripping saturated sodium bicarbonate solution is 7 to reaction solution pH; dichloromethane extraction (10mL × 3); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system A by thin-layer chromatography chromatography; obtain title product (1R; 5S)-6-[[the fluoro-4-of 2,6-bis-(1 methylsulfonyl 1-3,6-dihydro-2H-pyridin-4-yl) phenoxymethyl]-3-(the fluoro-2-methyI-oropvD of 2-)-3-azabicyclo also [3.1.0] hexane 132 (150mg; white solid), productive rate: 40.9%.
MS m/z(ESI)：459.1[M+1]
1H NMR(400MHz，CDCl 3)δ6.90-6.88(m，2H)，6.05-6.03(m，1H)，3.95-3.90(m，4H)，3.51(t，2H)，3.10(br.s，2H)，2.86(s，3H)，2.60-2.45(m，6H)，1.67(br.s，1H)，1.37-1.25(m，8H)
Embodiment 133
5-[(1R, 5S)-6-[[6-(the fluoro-4-Metlianesulfonyl-phenyl of 3-)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole
The first step
2-(the sub-Metlianesulfonyl-phenyl of the fluoro-4-of 3-)-4,4,5,5-tetramethyl--1,3,2-dioxo boric acid
By fluoro-for bromo-for 4-2-1-methylsulfinyl-benzene 96b (230mg, 0.97mmol), connection boric acid pinacol ester (302mg, 1.19mmol), Potassium ethanoate (291mg, 2.97mmol) He 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (72mg, 0.01mmol) is dissolved in 25mL Isosorbide-5-Nitrae-dioxane, be warming up to 95 DEG C, stirring reaction 2 hours.Add 30mL water, extraction into ethyl acetate (50mL × 2), merge organic phase; anhydrous magnesium sulfate drying, filters, filtrate reduced in volume; purify gained resistates by thin-layer chromatography chromatography with developping agent system B, obtain title product 2-(the sub-Metlianesulfonyl-phenyl of the fluoro-4-of 3-)-4,4; 5; 5-tetramethyl--1,3,2-dioxo boric acid 133a (195mg; yellow solid), productive rate: 71.0%.
MS m/z(ESI)：285.1[M+1]
Second step
6-(the sub-Metlianesulfonyl-phenyl of the fluoro-4-of 3-) pyridine-3-hydroxyl
By 2-(the sub-Metlianesulfonyl-phenyl of the fluoro-4-of 3-)-4,4,5; 5-tetramethyl--1,3,2-dioxo boric acid 133a (190mg; 0.67mmol), the bromo-pyridine (116mg, 0.67mmol) of 3-hydroxyl-6-; cesium carbonate (654mg, 2mmol) and 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (49mg; 0.01mmol) be dissolved in 5mL 1; in 4-dioxane, be warming up to 110 DEG C, stirring reaction 4 hours.Add 30mL water; extraction into ethyl acetate (50mL × 2); merge organic phase; anhydrous magnesium sulfate drying; filter, filtrate reduced in volume, obtain crude title product 6-(the sub-Metlianesulfonyl-phenyl of the fluoro-4-of 3-) pyridine-3-hydroxyl 133b (90mg; brown oil), product is not purified directly carries out next step reaction.
MS m/z(ESI)：252.0[M+1]
3rd step
5-[(1R, 5S)-6-[[6-(the sub-Metlianesulfonyl-phenyl of the fluoro-4-of 3-)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole
By crude product 6-(the sub-Metlianesulfonyl-phenyl of the fluoro-4-of 3-) pyridine-3-hydroxyl 133b (90mg; 0.30mmol); [(1R; 5S)-3-(3-sec.-propyl-1; 2; 4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl methylsulfonate 48c (108mg; 0.30mmol) with cesium carbonate (233mg; 0.60mmol) be dissolved in 5mL N; in dinethylformamide; be warming up to 110 DEG C, stirring reaction 4 hours.Add 30mL water; extraction into ethyl acetate (50mL × 2); merge organic phase; anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; obtain crude title product 5-[(1R; 5S)-6-[[6-(the sub-Metlianesulfonyl-phenyl of the fluoro-4-of 3-)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1; 2; 4-oxadiazole 133c (163mg, gray solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：457.2[M+1]
4th step
5-[(1R, 5S)-6-[[6-(the fluoro-4-Metlianesulfonyl-phenyl of 3-)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole
By crude product 5-[(1R; 5S)-6-[[6-(the sub-Metlianesulfonyl-phenyl of the fluoro-4-of 3-)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1; 2; 4-oxadiazole 133c (163mg; 0.35mmol) be dissolved in 5mL methylene dichloride; add metachloroperbenzoic acid (184mg, 0.90mmol), stirring reaction 12 hours.Reaction solution concentrating under reduced pressure; gained resistates is purified with developping agent system B by thin-layer chromatography chromatography; obtain title product 5-[(1R; 5S)-6-[[6-(the fluoro-4-Metlianesulfonyl-phenyl of 3-)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1; 2; 4-oxadiazole 133 (5mg, white solid), productive rate: 3.0%.
MS m/z(ESI)：473.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.40-8.39(m，1H)，8.00-7.92(m，1H)，7.89-7.87(m，2H)，7.74-7.72(m，1H)，7.30-7.27(m，1H)，4.05-4.03(m，2H)，3.90-3.87(m，2H)，3.70-3.68(m，2H)，3.26(s，3H)，2.92-2.89(m，1H)，1.82(s，2H)，1.30-1.28(m，6H)，1.26(s，1H)
Embodiment 134
5-[(1R, 5S)-6-[[6-(5-methylsulfonyl-2-pyridyl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole
The first step
(5-bromo-2-pyridyl base)-tributyl-Xi
Under the dry ice bath, by 2, the bromo-pyridine 134a of 5-bis-(0.20g, 0.84mmol) be dissolved in 10mL toluene, drip 2M butyllithium (0.5mL, 0.93mmol), stir 1 hour, drip tributyltin chloride (286mg again, 0.88mmol), stirring reaction 1 hour, rise to room temperature, add 10mL saturated ammonium chloride solution, extraction into ethyl acetate (30mL × 3), merge organic phase, with saturated nacl aqueous solution washing (10mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtain crude title product (5-bromo-2-pyridyl base)-tributyl-Xi 134b (0.31g, colourless liquid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：448.0[M+1]
Second step
The bromo-2-of 5-(5-methylsulfonyl-2-pyridyl) pyridine
By crude product (5-bromo-2-pyridyl base)-tributyl-Xi 134b (189mg; 0.42mmol); bromo-pyridine (the 100mg of 5-methylsulfonyl-2-; 0.42mmol) with tetra-triphenylphosphine palladium (10mg; 0.01mmol) be dissolved in 10mL toluene; be warming up to 120 DEG C, stirring reaction 15 hours.Add 100mL ethyl acetate; with saturated nacl aqueous solution washing (20mL × 2); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains the bromo-2-of title product 5-(5-methylsulfonyl-2-pyridyl) pyridine 134c (83mg; white solid), productive rate: 63.4%.
MS m/z(ESI)：312.9[M-1]
3rd step
6-(5-methylsulfonyl-2-pyridyl) pyridine-3-hydroxyl
By bromo-for 5-2-(5-methylsulfonyl-2-pyridyl) pyridine 134c (200mg; 0.64mmol); connection boric acid pinacol ester (211mg, 0.83mmol), Potassium ethanoate (188mg; 1.92mmol) He 1; 1 '-two (diphenyl phosphine) ferrocene palladium chloride (26mg, 0.03mmol) is dissolved in 10mL Isosorbide-5-Nitrae-dioxane; be warming up to 95 DEG C, stirring reaction 2 hours.Add 80mL ethyl acetate, with saturated nacl aqueous solution washing (20mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, the dissolving crude product obtained is in 10mL tetrahydrofuran (THF), ice bath cools, drip 0.4mL 5M sodium hydroxide solution successively, 0.3mL 30% superoxol, stirring at room temperature reacts 15 hours.Add 10mL water; separatory, dripping 1M hydrochloric acid is 7 to water layer pH, extraction into ethyl acetate (30mL × 3); merge organic phase; with saturated nacl aqueous solution washing (20mL × 2), anhydrous magnesium sulfate drying, filter; filtrate reduced in volume; obtain crude title product 6-(5-methylsulfonyl-2-pyridyl) pyridine-3-hydroxyl 134d (30mg, gray solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：251.0[M+1]
4th step
5-[(1R, 5S)-6-[[6-(5-methylsulfonyl-2-pyridyl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1,2,4-oxadiazole
By crude product 6-(5-methylsulfonyl-2-pyridyl) pyridine-3-hydroxyl 134d (30mg; 0.12mmol); [(1R; 5S)-3-(3-sec.-propyl-1; 2; 4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl methylsulfonate 48c (39mg; 0.13mmol) with cesium carbonate (78mg; 0.24mmol) be dissolved in 10mLN; in dinethylformamide; be warming up to 110 DEG C, stirring reaction 2 hours.Add 20mL water, extraction into ethyl acetate (30mL × 3), merge organic phase, with saturated nacl aqueous solution washing (20mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by thin-layer chromatography chromatography, obtain title product 5-[(1R, 5S)-6-[[6-(5-methylsulfonyl-2-pyridyl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-3-sec.-propyl-1, 2, 4-oxadiazole 134 (8mg, white solid), productive rate: 14.5%.
MS m/z(ESI)：456.2[M+1]
1H NMR(400MHz，CDCl 3)δ9.13(s，1H)，8.56-8.54(m，1H)，8.47-8.45(m，1H)，8.39(s，1H)，8.29-8.27(m，1H)，7.33-7.31(m，1H)，4.07-4.05(m，2H)，3.90-3.87(m，2H)，3.71-3.68(m，2H)，3.14(s，3H)，2.90-2.89(m，1H)，1.65-1.63(m，1H)，1.30-1.28(m，6H)，1.27-1.25(m，2H)
Embodiment 135
(1R, 5S)-3-sec.-propyl-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By (1R; 5S)-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane hydrochloride 99b (110mg; 0.32mmol) be dissolved in 20mL methylene dichloride; add isobutyric aldehyde (35mg successively; 0.48mmol) with acetic acid (38mg; 0.64mmol), stirring reaction 30 minutes.Add sodium triacetoxy borohydride (135mg, 0.64mmol) again, stirring reaction 12 hours.Add water 10mL; dichloromethane extraction (20mL × 3); merge organic phase; with saturated nacl aqueous solution washing (20mL × 1); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with developping agent system A by thin-layer chromatography chromatography; obtain title product (1R; 5S)-3-sec.-propyl-6-[[6-(4-methanesulfonylphenYl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 135 (60mg, white solid), productive rate: 46.9%.
MS m/z(ESI)：401.1[M+1]
1H NMR(400MHz，CDCl 3)δ8.37(s，1H)，8.13(d，2H)，8.00(d，2H)，7.73(d，1H)，7.29(s，1H)，3.99(d，2H)，3.08(s，3H)，2.90(s，2H)，2.73(s，2H)，2.17(s，1H)，2.09(s，3H)，1.81(s，2H)，1.05(d，6H)
Embodiment 136
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
The first step
4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-3,5-difluorophenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esters
By 4-(3, the fluoro-4-hydroxy-pheny of 5-bis-)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 131a (466mg, 1.50mmol) be dissolved in 10mL N, in dinethylformamide, add [(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 7g (404mg, 1.36mmol) with salt of wormwood (563mg, 4.08mmol), be warming up to 100 DEG C, stirring reaction 3 hours.Add 25mL water, extraction into ethyl acetate (50mL × 4), merge organic phase, use water (50mL × 1) successively, saturated nacl aqueous solution washing (50mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product 4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-3, 5-difluorophenyl]-3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 136a (380mg, colourless viscous liquid), productive rate: 59.8%.
MS m/z(ESI)：513.2[M+1]
Second step
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(1,2,3,6-tetrahydropyridine-4-base) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By 4-[4-[[(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-3,5-difluorophenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 136a (380mg, 0.74mmol) be dissolved in 10mL methylene dichloride, add 1mL trifluoracetic acid, stirring reaction 2 hours.Dripping 1M saturated sodium carbonate solution is 10 to reaction solution pH, extraction into ethyl acetate (50mL × 4), merge organic phase, use water (50mL × 1) successively, saturated nacl aqueous solution washing (30mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtain crude title product (1R, 5S)-6-[[2, the fluoro-4-(1 of 6-bis-, 2, 3, 6-tetrahydropyridine-4-base) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 136b (0.27g, yellow oil), product is not purified directly carries out next step reaction.
MS m/z(ESI)：413.3[M+1]
3rd step
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane
By crude product (1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(1,2,3,6-tetrahydropyridine-4-base) phenoxy group] methyl] and-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 136b (270mg, 0.65mmol) be dissolved in 10mL methylene dichloride, add triethylamine (197mg, 1.95mmol), methylsulfonyl chloride (112mg, 0.98mmol) is slowly dripped, 0 DEG C of stirring reaction 1 hour under ice bath.Add 50mL water, dichloromethane extraction (50mL × 3), merge organic phase, use water (50mL × 1) successively, saturated nacl aqueous solution washing (50mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product (1R, 5S)-6-[[2, the fluoro-4-of 6-bis-(1-methylsulfonyl-3, 6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane 136 (130mg, white solid), productive rate: 40.8%.
MS m/z(ESI)：491.1[M+1]
1H NMR(400MHz，d-DMSO)δ8.21(s，2H)，6.94(d，2H)，6.10(s，1H)，4.10(d，2H)，4.00(s，2H)，3.89(d，2H)，3.58-3.54(m，4H)，2.90(s，3H)，2.62(s，2H)，2.53-2.47(q，2H)，1.71(s，2H)，1.30-1.20(m，4H)
Embodiment 137
(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(1-methylsulfonyl-4-piperidyl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By (1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(1-methylsulfonyl-3; 6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 128 (100mg; 0.22mmol) be dissolved in 20mL methyl alcohol; add palladium/carbon (20mg; 10%), stirring reaction 12 hours.Filter; filter cake is with washed with dichloromethane (20mL × 3); filtrate reduced in volume; gained resistates is purified with eluent system A with silica gel column chromatography; obtain title product (1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-6-[[6-(1-methylsulfonyl-4-piperidyl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 137 (30mg, white solid), productive rate: 29.8%.
MS m/z(ESI)：458.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.27(d，1H)，8.21(s，2H)，7.22(d，1H)，7.13(d，1H)，3.99(dd，5H)，3.61(d，2H)，2.94-2.74(m，5H)，2.50(q，2H)，2.20-2.00(m，3H)，1.98-1.85(m，2H)，1.78(s，2H)，1.22(t，3H)，0.92(t，2H)
Embodiment 138
(1R, 5S)-3-(5-chloropyrimide-2-base)-6-[[6-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
The first step
6-(1,2,3,6-tetrahydropyridine-4-base) pyridine-3-hydroxyl
4-(5-hydroxyl-2-pyridine)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 128a (552mg, 2mmol) are dissolved in 20mL methylene dichloride, add 2mL trifluoracetic acid, stirring reaction 12 hours.Reaction solution concentrating under reduced pressure, obtains crude title product 6-(1,2,3,6-tetrahydropyridine-4-base) pyridine-3-hydroxyl 138a (500mg, yellow-green colour oily matter), and product is not purified directly carries out next step reaction.
MS m/z(ESI)：177.0[M+1]
Second step
[6-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl] methanesulfonates
By 6-(1,2,3,6-tetrahydropyridine-4-base) pyridine-3-hydroxyl 138a (352mg, 2mmol) is dissolved in 10mL methylene dichloride, under ice bath, add methylsulfonyl chloride (344mg, 3mmol) and triethylamine (607mg, 6mmol), 0 DEG C of stirring reaction 2 hours.Add 50mL water; with dichloromethane extraction (50mL × 3); merge organic phase; use water (50mL × 1) successively; saturated sodium chloride solution washing (50mL × 1); anhydrous magnesium sulfate drying; filter; filtrate reduced in volume; purify gained resistates with silica gel column chromatography with eluent system B, obtain title product [6-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl] methanesulfonates 138b (339mg; faint yellow solid), productive rate: 51.1%.
MS m/z(ESI)：333.0[M+1]
3rd step
6-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl) pyridine-3-alcohol
By [6-(1-methylsulfonyl-3; 6-dihydro-2H-pyridin-4-yl)-3-pyridyl] methanesulfonates 138b (1g; 3mmol) be dissolved in 3mL methylene dichloride; add 10mL methyl alcohol; add sodium hydroxide (360mg successively again; 9mmol) with 2mL water, rise to 40 DEG C, stirring reaction 2 hours.Add 20mL water, dripping 1M hydrochloric acid is 6 to reaction solution pH, reaction solution concentrating under reduced pressure; filter, dry, obtain title product 6-(1-methylsulfonyl-3; 6-dihydro-2H-pyridin-4-yl) pyridine-3-alcohol 138c (620mg, white solid), productive rate: 81.3%.
MS m/z(ESI)：255.2[M+1]
4th step
(1R, 5S)-3-(5-chloropyrimide-2-base)-6-[[6-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By 6-(1-methylsulfonyl-3; 6-dihydro-2H-pyridin-4-yl) pyridine-3-alcohol 138c (381mg; 1.50mmol) be dissolved in 15mL N; in dinethylformamide; add [(1R successively; 5S)-3-(5-chloropyrimide-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl mesylate 104b (501mg; 1.65mmol) with salt of wormwood (518mg; 3.75mmol); be warming up to 100 DEG C, stirring reaction 1.5 hours.Be cooled to 85 DEG C, stirring reaction 12 hours.Add 50mL water, dichloromethane extraction (60mL × 3), merge organic phase, use water (30mL × 1) successively, saturated nacl aqueous solution washing (30mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product (1R, 5S)-3-(5-chloropyrimide-2-base)-6-[[6-(1-methylsulfonyl-3, 6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 138 (380mg, white solid), productive rate: 54.8%.
MS m/z(ESI)：462.2[M+1]
1H NMR(400MHz，d-DMSO)δ8.26(s，1H)，8.22(s，2H)，7.31(d，1H)，7.16(d，1H)，6.49(s，1H)，4.00-3.91(m，6H)，3.53-3.52(m，4H)，2.86(s，3H)，2.76(m，2H)，1.77(m，2H)，1.19(m，1H)
Embodiment 139
(1R, 5S)-3-(the fluoro-2-methyl-propan of 2-)-6-[[6-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
The first step
(1R, 5S)-6-[[6-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester
By 6-(1-methylsulfonyl-3; 6-dihydro-2H-pyridin-4-yl) pyridine-3-hydroxyl 138c (280mg; 1.10mmol); (1R, 5S)-6-(Methanesulfonvloxvmethvl)-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 16b (417mg, 1.43mmol) and salt of wormwood (455mg; 3.30mmol) be dissolved in 8mL N; in dinethylformamide, rise to 60 DEG C, stirring reaction 8 hours.Add 100mL water; be extracted with ethyl acetate (50mL × 3); merge organic phase; with saturated nacl aqueous solution washing (50mL × 1); anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with eluent system A with silica gel column chromatography; obtain title product (1R, 5S)-6-[[6-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 139a (360mg; white solid), productive rate: 73.0%.
MS m/z(ESI)：394.1[M-55]
Second step
1-[(1R, 5S)-6-[[6-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base] propane-2-alcohol
By (1R; 5S)-6-[[6-(1-methylsulfonyl-3; 6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-carboxylic acid tert-butyl ester 139a (360mg; 0.80mmol) be dissolved in 15mL 4M hydrochloric acid 1; in 4-dioxane solution; stirring reaction 1 hour; reaction solution concentrating under reduced pressure; in resistates, add 20mL methyl alcohol and triethylamine (242mg, 2.40mmol), then add 2; 2-dimethyl ethylene oxide (173mg; 2.40mmol), rise to 33 DEG C, stirring reaction 12 hours.Reaction solution concentrating under reduced pressure; gained resistates is purified with eluent system A with silica gel column chromatography; obtain title product 1-[(1R; 5S)-6-[[6-(1-methylsulfonyl-3; 6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base] propane-2-alcohol 139b (200mg; white solid), productive rate: 60.0%.
MS m/z(ESI)：422.2[M+1]
3rd step
(1R, 5S)-3-(the fluoro-2-methyl-propan of 2-)-6-[[6-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
Under the dry ice bath; by 1-[(1R; 5S)-6-[[6-(1-methylsulfonyl-3; 6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane-3-base] propane-2-alcohol 139b (200mg; 0.47mmol) be dissolved in 20mL methylene dichloride, add two (2-methoxy ethyl) amino sulfur trifluoride (157mg, 0.71mmol); rise to room temperature, stirring reaction 2 hours.Add 50mL saturated sodium bicarbonate solution, dichloromethane extraction (50mL × 3), merge organic phase, with saturated nacl aqueous solution washing (50mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product (1R, 5S)-3-(the fluoro-2-methyl-propan of 2-)-6-[[6-(1-methylsulfonyl-3, 6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 139 (99mg, white solid), productive rate: 50.0%.
MS m/z(ESI)：424.2[M+1]
1H NMR(400MHz，CDCl 3)δ8.25(d，1H)，7.32(d，1H)，7.16(dd，1H)，6.63-6.37(m，1H)，4.20-3.94(m，2H)，3.94-3.77(m，2H)，3.53(t，2H)，3.16(d，2H)，3.00-2.83(m，3H)，2.83-2.72(m，2H)，2.56(s，1H)，2.53-2.37(m，3H)，1.77-1.59(m，1H)，1.42(br.s，2H)，1.38-1.17(m，6H)
Embodiment 140
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane
The first step
4-[4-[[(1R, 5S)-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-3,5-difluorophenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esters
By 4-(3, the fluoro-4-hydroxy-pheny of 5-bis-)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 131a (684mg, 2.20mmol) is dissolved in 20mL DMF, add [(1R, 5S)-3-(5-chloropyrimide-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methylsulfonic acid 104 (607mg, 2mmol) and salt of wormwood (829mg, 6mmol), be warming up to 90 DEG C, stirring reaction 12 hours.Add 50mL water, dichloromethane extraction (50mL × 4), merge organic phase, use water (50mL × 1) successively, saturated nacl aqueous solution washing (50mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product 4-[4-[[(1R, 5S)-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-3, 5-difluorophenyl]-3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 140a (797mg, white solid), productive rate: 76.8%.
MS m/z(ESI)：519.2[M+1]
Second step
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(1,2,3,6-tetrahydropyridine-4-base) phenoxy group] methyl]-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane
By 4-[4-[[(1R, 5S)-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-3,5-difluorophenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 140a (780mg, 1.50mmol) be dissolved in 20mL methylene dichloride, add 2mL trifluoracetic acid, stirring reaction 1 hour.Add 50mL water, dripping 1M saturated sodium carbonate solution is 9 ~ 10 to reaction solution pH, dichloromethane extraction (60mL × 4), merge organic phase, use water (50mL × 1) successively, saturated nacl aqueous solution washing (50mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtain crude title product (1R, 5S)-6-[[2, the fluoro-4-(1 of 6-bis-, 2, 3, 6-tetrahydropyridine-4-base) phenoxy group] methyl]-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane 140b (622mg, faint yellow solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：419.1[M+1]
3rd step
(1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane
By crude product (1R, 5S)-6-[[the fluoro-4-of 2,6-bis-(1,2,3,6-tetrahydropyridine-4-base) phenoxy group] methyl] and-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane 140b (610mg, 1.50mmol) be dissolved in 20mL methylene dichloride, add triethylamine (455mg, 4.50mmol), methylsulfonyl chloride (258mg, 2.25mmol) is slowly dripped, 0 DEG C of stirring reaction 2 hours under ice bath.Add 100mL water, dichloromethane extraction (60mL × 4), merge organic phase, use water (100mL × 1) successively, saturated nacl aqueous solution washing (100mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product (1R, 5S)-6-[[2, the fluoro-4-of 6-bis-(1-methylsulfonyl-3, 6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane 140 (470mg, white solid), productive rate: 63.4%.
MS m/z(ESI)：497.1[M+1]
1H NMR(400MHz，d-DMSO)δ8.22(s，2H)，6.92(d，2H)，6.05-6.07(m，1H)，4.02(d，1H)，3.95-3.97(m，2H)，3.83(d，2H)，3.49-3.54(m，4H)，2.86(s，3H)，2.57-2.58(m，2H)，1.69(s，2H)，1.11-1.16(m，1H)
Embodiment 141
(1R, 5S)-6-[[4-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane
The first step
4-[4-[[(1R, 5S)-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esters
By 4-(4-hydroxy-pheny)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 122b (500mg, 1.82mmol) be dissolved in 20mL N, in dinethylformamide, add [(1R, 5S)-3-(5-chloropyrimide-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methylsulfonic acid 104 (607mg, 2mmol) with salt of wormwood (753mg, 5.46mmol), be warming up to 100 DEG C, stirring reaction 2 hours.Add 50mL water, dichloromethane extraction (50mL × 4), merge organic phase, use water (50mL × 1) successively, saturated nacl aqueous solution washing (50mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product 4-[4-[[(1R, 5S)-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-phenyl]-3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 141a (566mg, white solid), productive rate: 64.4%.
MS m/z(ESI)：483.5[M+1]
Second step
(1R, 5S)-6-[[4-(1,2,3,6-tetrahydropyridine-4-base) phenoxy group] methyl]-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane
By 4-[4-[[(1R, 5S)-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane-6-base] methoxyl group]-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester 141a (540mg, 1.12mmol) be dissolved in 20mL methylene dichloride, add 2mL trifluoracetic acid, stirring reaction 2 hours.Dripping 1M saturated sodium carbonate solution is 9 ~ 10 to reaction solution pH, dichloromethane extraction (60mL × 4), merge organic phase, use water (50mL × 1) successively, saturated nacl aqueous solution washing (50mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtain crude title product (1R, 5S)-6-[[4-(1, 2, 3, 6-tetrahydropyridine-4-base) phenoxy group] methyl]-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane 141b (306mg, white solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：383.2[M+1]
3rd step
(1R, 5S)-6-[[4-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane
By crude product (1R, 5S)-6-[[4-(1,2,3,6-tetrahydropyridine-4-base) phenoxy group] methyl]-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane 141b (300mg, 0.78mmol) be dissolved in 20mL methylene dichloride, add triethylamine (237mg, 2.34mmol), under ice bath, slowly drip methylsulfonyl chloride (134mg, 1.17mmol), 0 DEG C of stirring reaction 2 hours.Add 50mL water, dichloromethane extraction (60mL × 4), merge organic phase, use water (50mL × 1) successively, saturated nacl aqueous solution washing (50mL × 1), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product (1R, 5S)-6-[[4-(1-methylsulfonyl-3, 6-dihydro-2H-pyridin-4-yl) phenoxy group] methyl]-3-(the chloro-pyrimidine-2-base of 5-)-3-azabicyclo also [3.1.0] hexane 141 (227mg, white solid), productive rate: 63.2%.
MS m/z(ESI)：461.5[M+1]
1H NMR(400MHz，d-DMSO)δ8.26(s，2H)，7.33(d，2H)，6.91(d，2H)，6.02(br，1H)，3.95-3.99(m，6H)，3.54-3.62(m，4H)，2.89(s，3H)，2.67(br，2H)，1.78(s，2H)，1.22(br，1H)
Embodiment 142
Cis-(1R, 5S)-3-(5-ethyl-pyrimidine base-2-base)-6-[[6-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
The first step
Cis-(1R, 5S)-3-benzyl 2,4-dicarbapentaborane-3-azabicyclo also [3.1.0] hexane-6-ethyl formate
By 5-benzyl-4,6-dicarbapentaborane-3a, 6a-dihydro-1H-pyrrolo-[3,4-c] pyrazoles-3-ethyl formate 7b (2.10g, 7mmol) is placed in reaction flask, is heated to 190 DEG C, reacts 1 hour at 190 DEG C.Be chilled to room temperature, add 200mL ethyl acetate, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product cis-(1R, 5S)-3-benzyl 2,4-dicarbapentaborane-3-azabicyclo is [3.1.0] hexane-6-ethyl formate 142a (2g, white solid) also, productive rate: 12.8%.
MS m/z(ESI)：274.1[M+1]
Second step
[cis-(1R, 5S)-3-benzyl-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol
By Lithium Aluminium Hydride (1.12g, 29.28mmol) be dissolved in 35mL tetrahydrofuran (THF), be cooled to 0 DEG C, slowly add 15mL cis-(1R, 5S)-3-benzyl 2,4-dicarbapentaborane-3-azabicyclo is [3.1.0] hexane-6-ethyl formate 142a (2g also, tetrahydrofuran solution 7.32mmol), finishes, and rises to room temperature, stir 10 minutes, be heated to back flow reaction 3 hours.Add 5mL 1M sodium hydroxide solution, add 5mL ethanol again, filter, use 10mL methyl alcohol successively, 10mL washed with dichloromethane filter cake, merging filtrate, concentrating under reduced pressure filtrate, add 20mL water, be extracted with ethyl acetate (30mL × 3), merge organic phase, use water (20mL × 3) successively, saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtain crude title product [cis-(1R, 5S)-3-benzyl-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 142b (1.45g, pale yellow oil), product is not purified directly carries out next step reaction.
MS m/z(ESI)：204.5[M+1]
3rd step
[cis-(1R, 5S)-3-azabicyclo is [3.1.0] hexane-6-base also] methyl alcohol
By crude product [cis-(1R, 5S)-3-benzyl-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 142b (1.45g, 7.13mmol) be dissolved in 50mL methyl alcohol, add palladium/carbon (300mg successively, 10%), hydrogen exchange 3 times, stirring reaction 12 hours.Filter, concentrating under reduced pressure filtrate, obtains crude title product [cis-(1R, 5S)-3-azabicyclo is [3.1.0] hexane-6-base also] methyl alcohol 142c (0.8g, pale yellow oil), product is not purified directly carries out next step reaction.
MS m/z(ESI)：114.4[M+1]
4th step
[cis-(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol
By crude product [cis-(1R, 5S)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 142c (300mg, 2.65mmol) be dissolved in 20mL acetonitrile, add the chloro-5-ethyl-pyrimidin of 2-(451mg successively, 3.18mmol) with salt of wormwood (1.10g, 7.95mmol), be warming up to backflow, stirring reaction 4 hours.Concentrating under reduced pressure reaction solution, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product [cis-(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 142d (324mg, white solid), productive rate: 56.0%.
MS m/z(ESI)：220.5[M+1]
5th step
Methylsulfonic acid [cis-(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl ester
Under ice bath, by crude product [cis-(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 142d (159g, 0.72mmol) be dissolved in 15mL methylene dichloride, add triethylamine (183mg, 1.81mmol), be added dropwise to methylsulfonyl chloride (124mg again, 1.08mmol), rise to room temperature, stirring reaction 1 hour.Add 10mL saturated sodium bicarbonate solution, with dichloromethane extraction (20mL × 3), merge organic phase, use water (20mL × 3) successively, saturated nacl aqueous solution washing (20mL × 3), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtain crude title product methylsulfonic acid [cis-(1R, 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl ester 142e (180mg, white solid), product is not purified directly carries out next step reaction.
MS m/z(ESI)：298.1[M+1]
6th step
Cis-(1R, 5S)-3-(5-ethyl-pyrimidine base-2-base)-6-[[6-(1-methylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane
By 6-(1-methylsulfonyl-3; 6-dihydro-2H-pyridin-4-yl) pyridine-3-alcohol 138c (3160mg; 0.63mmol); methylsulfonic acid [cis-(1R; 5S)-3-(5-ethyl-pyrimidine-2-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl ester 142e (180mg; 0.63mmol) with salt of wormwood (174mg; 1.26mmol) be dissolved in 8mL N; in dinethylformamide; be warming up to 90 DEG C, stirring reaction 3 hours.Concentrating under reduced pressure reaction solution, add 25mL water, with dichloromethane extraction (60mL × 3), merge organic phase, use water (30mL × 1) successively, saturated nacl aqueous solution washing (30mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product cis-(1R, 5S)-3-(5-ethyl-pyrimidine base-2-base)-6-[[6-(1-methylsulfonyl-3, 6-dihydro-2H-pyridin-4-yl)-3-pyridyl] oxygen methyl]-3-azabicyclo also [3.1.0] hexane 142 (50mg, white solid), productive rate: 20%.
MS m/z(ESI)：456.2[M+1]
1H NMR(400MHz，d-DMSO)δ8.22(d，1H)，7.86(s，2H)，7.28(dd，1H)，7.12(dd，1H)，6.45(s，1H)，4.12-3.93(m，4H)，3.81-3.73(m，4H)，3.56-3.45(m，2H)，2.85(s，3H)，2.73(s，2H)，2.46(m，2H)，2.00(s，2H)，1.54-1.46(m，1H)，1.18(t，3H)
Embodiment 143
3-sec.-propyl-5-[cis-(1R, 5S)-6-[[4-(5-methylsulfonyl-2-pyridyl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-1,2,4-oxadiazoles
The first step
Cis-(1R, 5S)-(6-methylol)-3-azabicyclo also [3.1.0] hexane-3-formonitrile HCN
Under ice bath, by [cis-(1R, 5S)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 142c (500mg, 4.41mmol) be dissolved in 48mL water and methylene dichloride (V/V=1: 5) mixed solvent, add salt of wormwood (1.52g, 11.02mmol) and cyanogen bromide (537mg, 5.07mmol), stirring reaction 1 hour, rises to room temperature, stirs 1 hour.Add 20mL water, separatory, aqueous phase, with dichloromethane extraction (30mL × 3), merges organic phase, anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtains crude title product cis-(1R, 5S)-(6-methylol)-3-azabicyclo also [3.1.0] hexane-3-formonitrile HCN 143a (400mg, pale yellow oil), product is not purified directly carries out next step reaction.
MS m/z(ESI)：139.1[M+1]
Second step
[cis-(1R, 5S)-3-(3-sec.-propyl-1,2,4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol
By crude product cis-(1R, 5S)-(6-methylol)-3-azabicyclo also [3.1.0] hexane-3-formonitrile HCN 143a (410mg, 2.97mmol) be dissolved in 15mL tetrahydrofuran (THF), add N '-hydroxy-2-methyl-propylamine (334mg, 3.27mmol) with zinc chloride (445mg, 3.27mmol), stirring reaction 1 hour.Concentrating under reduced pressure reaction solution, adds 10mL water and ethanol (V/V=1: 1) mixed solvent, then adds 1mL concentrated hydrochloric acid, be warming up to 80 DEG C, stirring reaction 1 hour.Concentrating under reduced pressure reaction solution, dripping saturated sodium bicarbonate solution is 7 ~ 8 to reaction solution pH, add 20mL water, be extracted with ethyl acetate (50mL × 3), merge organic phase, with saturated nacl aqueous solution washing (30mL × 2), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product [cis-(1R, 5S)-3-(3-sec.-propyl-1, 2, 4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 143b (380mg, pale yellow oil), productive rate: 57.0%.
MS m/z(ESI)：224.1[M+1]
3rd step
[cis-(1R, 5S)-3-(3-sec.-propyl-1,2,4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl methylsulfonate
Under ice bath, by [cis-(1R, 5S)-3-(3-sec.-propyl-1,2,4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl alcohol 143b (350mg, 1.57mmol) be dissolved in 15mL methylene dichloride, add triethylamine (397mg, 3.92mmol), be added dropwise to methylsulfonyl chloride (233mg, 2.04mmol), stirring reaction 1 hour.Add 20mL saturated sodium bicarbonate solution, with dichloromethane extraction (30mL × 3), merge organic phase, with saturated nacl aqueous solution washing (30mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, obtain crude title product [cis-(1R, 5S)-3-(3-sec.-propyl-1,2,4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl methylsulfonate 143c (392mg, pale yellow oil), product is not purified directly carries out next step reaction.
MS m/z(ESI)：302.5[M+1]
4th step
3-sec.-propyl-5-[cis-(1R, 5S)-6-[[4-(5-methylsulfonyl-2-pyridyl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-1,2,4-oxadiazoles
By crude product [cis-(1R; 5S)-3-(3-sec.-propyl-1; 2; 4--oxadiazole-5-base)-3-azabicyclo also [3.1.0] hexane-6-base] methyl methylsulfonate 143c (392mg; 1.57mmol); 4-(5-methylsulfonyl-2-pyridine) phenol 82b (473mg; 1.57mmol) with salt of wormwood (433mg; 3.14mmol) be dissolved in 10mL N; in dinethylformamide; be warming up to 90 DEG C, stirring reaction 3 hours.Add 50mL water, with dichloromethane extraction (80mL × 2), merge organic phase, with saturated nacl aqueous solution washing (30mL × 2), anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product 3-sec.-propyl-5-[cis-(1R, 5S)-6-[[4-(5-methylsulfonyl-2-pyridyl) phenoxy group] methyl]-3-azabicyclo also [3.1.0] hexane-3-base]-1, 2, 4-oxadiazole 143 (400mg, white solid), productive rate: 56.0%.
MS m/z(ESI)：455.1[M+1]
1H NMR(400MHz，d-DMSO)δ9.14(d，1H)，8.21(dd，1H)，8.06-7.98(m，2H)，7.84(d，1H)，7.02-6.95(m，2H)，4.03(d，2H)，3.88-3.80(m，2H)，3.80-3.73(m，2H)，3.13(s，3H)，2.87(td，1H)，2.07-2.00(m，2H)，1.60(t，1H)，1.26(d，6H)
Test case:
biological assessment
Following methods is used for measuring the compounds of this invention to the agonist activity of GPR119.Experimental technique is summarized as follows:
In 96 orifice plates, inoculate hamster beta islet cells (HIT-T15) (being purchased from ATCC, article No. CRL-1777), inoculating cell density is 2x10 4.Cell at 37 DEG C, 5%CO 2cultivate after 48 hours under condition, remove nutrient solution, adding 100 μ L stimulates damping fluid (Hanks, 5mM HEPES, 0.5mM IBMX, 0.1%BSA, pH 7.4), and in incubated at room 15 minutes.In hole, add different concns medicine, after hatching 30 minutes, remove damping fluid, add the lysate of 75 μ L precoolings, and hatch 20 minutes on ice, suitably vibrate.By 96 orifice plates with the rotating speed of 13000rpm centrifugal 10 minutes.Get 50 μ L Sample supernatants, detect cAMP content according to cAMP ELISA kit (Cell Biolabs, Inc.) standard step, the EC of compound 50value draws by cAMP cubage.
The EC of test-compound 50be worth as shown in the table:
Compound number EC 50(HIT-T15)/(μM)
Embodiment 4 0.021
Embodiment 8 0.004
Embodiment 12 0.006
Embodiment 13 0.012
Embodiment 25 0.020
Embodiment 33 0.009
Embodiment 34 0.012
Embodiment 41 0.027
Embodiment 48 0.071
Embodiment 52 0.061
Embodiment 56 0.042
Embodiment 74 0.062
Embodiment 75 0.094
Embodiment 78 0.062
Embodiment 80 0.071
Embodiment 81 0.078
Embodiment 82 0.028
Embodiment 89 0.038
Embodiment 90 0.027
Embodiment 91 0.011
Embodiment 93 0.028
Embodiment 95 0.036
Embodiment 96 0.051
Embodiment 97 0.046
Embodiment 103 0.048
Embodiment 104 0.038
Embodiment 105 0.064
Embodiment 108 0.047
Embodiment 110 0.016
Embodiment 113 0.075
Embodiment 118 0.043
Embodiment 121 0.052
Embodiment 122 0.005
Embodiment 123 0.056
Embodiment 124 0.038
Embodiment 126 0.058
Embodiment 127 0.048
Embodiment 128 0.011
Embodiment 129 0.069
Embodiment 130 0.068
Embodiment 132 0.009
Embodiment 133 0.052
Embodiment 134 0.057
Embodiment 136 0.004
Embodiment 137 0.058
Embodiment 138 0.005
Embodiment 139 0.021
Conclusion: it is active that embodiment of the present invention compound all has good insulin agonist.
Pharmacodynamics is tested
1. research purpose
With ICR mouse for animal subject, observe the present invention's embodiment compound to be measured single single dose administration to the impact of glucose load mouse blood sugar value.
2. test-compound
Embodiment compound 8,13,25,33,82,95,97,121,122,128,136 and 138
3. experimental animal
Healthy ICR mouse (about body weight 20-24g) 130, male and female half and half, purchased from Shanghai western pul-Bi Kai laboratory animal company limited, animal productiong credit number: SCXK (Shanghai) 2008-0016.
4. Pharmaceutical formulations
Take appropriate compound becomes 3mg/ml suspension with 0.5% sodium cellulose glycolate solution.
5. test method
5.1 grouping
Male and female mouse totally 130, overnight fast 16 hours.Measure basal plasma glucose value after weighing, according to blood sugar height random packet be Blank group (5 female 5 male), 12 testing compounds of the present invention are divided into 12 groups (5 female 5 is male respectively).
5.2 dosage are arranged
Dosage is that 30mg/kg, Blank group gives the 0.5% sodium cellulose glycolate aqueous solution.
5.3 medication
Gastric infusion, administration gives the glucose solution (every mouse gives 0.4mL) of 20% by 4g/kg after 15 minutes.
The mensuration of 5.4 blood glucose values
According to dosage administration, measures blood glucose value (-15 minutes).
Administration gives the glucose solution of 20% by 4g/kg after 15 minutes, and 0,15,30,45,60 and 120 minute time, use the full Instrument for Measuring Blood Sugar of Roche Luo Kang to measure the blood glucose value of each mouse.
5.5 data statistics
Use Excel statistical software: mean value calculates with avg; SD value calculates with STDEV; Group difference P value calculates with TTEST.
AUC calculation formula:
AUC＝(t 15min+t 0min)x0.25/2+(t 30min+t 15min)x0.25/2+(t 45min+t 30min)x0.25/2+(t 60min+t 45min)x0.25/2+(t 120min+t 60min)x1/2
Wherein t 0min, t 15min, t 30min, t 45min, t 60min, t 120minfor the blood glucose value that different time points records.
6. test-results
Embodiment is numbered Blood sugar rate of descent % in 30 minutes
8 15.62
13 16.92
25 10.12
33 11.09
82 10.75
95 16.11
97 10.78
121 14.55
122 14.96
128 17.51
136 16.70
138 18.66
Result shows: the compound of the present invention's test all has the effect significantly reducing mouse blood sugar and raise.

Claims (17)

1. the compound shown in a general formula (I) or its pharmaceutically useful salt:
Wherein, L 1for key, L 2for-(CH 2) 1-4-, a wherein arbitrary-CH 2-optional further by one or more O or N (R 7) replaced, or an arbitrary-CH 2-be optionally selected from C by one or more further 1-6the substituting group of alkyl or halogen replaced;
Ring C is cyclopropyl pyrrolizine base;
Ring A is:
Ring B is selected from heterocyclic radical, C 6-10aryl or heteroaryl, wherein said C 6-10aryl or heteroaryl are optionally selected from halogen, cyano group, nitro, C by one or more independently of one another further 1-6alkyl, C 1-6haloalkyl, C 1-6hydroxyalkyl ,=O ,-OR 2,-(CH 2) mnR 3r 4,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4,-NR 3c (O) R 4or-S (O) mr 2substituting group replaced;
R 1for heteroaryl, wherein said heteroaryl is optionally selected from halogen, C by one or more further 1-6alkyl, C 3-10cycloalkyl or C 1-6the substituting group of haloalkyl replaced;
R 10be selected from halogen, cyano group, C identical or differently 1-6alkyl, C 1-6hydroxyalkyl, C 3-10cycloalkyl or C 1-6the substituting group of haloalkyl replaced;
R 11be selected from hydrogen atom, halogen, cyano group, nitro, C 1-6alkyl ,-C (O) R 2,-C (O) OR 2,-C (O) NR 3r 4or-S (O) mr 2;
R 2be selected from hydrogen atom, C 1-6alkyl, C 3-10cycloalkyl;
R 3and R 4be selected from hydrogen atom or C independently of one another 1-6alkyl;
R 7be selected from hydrogen atom or C 1-6alkyl;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
Described heteroaryl is comprise the heteroatoms that 1 to 4 is selected from N or O, the heteroaromatic group of 5 to 10 annular atomses.
2. the compound shown in general formula according to claim 1 (I) or its pharmaceutically useful salt, it is the compound shown in general formula (VI) or its pharmaceutically useful salt:
Wherein: ring B, R 1, R 10or the definition of n as described in the appended claim 1.
3. the compound shown in general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein ring B is selected from:
R 10be selected from halogen, cyano group, C identical or differently 1-6alkyl, C 1-6hydroxyalkyl, C 3-10cycloalkyl or C 1-6the substituting group of haloalkyl replaced; N is 0,1,2,3 or 4.
4. the compound shown in general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein ring B is phenyl.
5. the compound shown in general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein ring B is
r 10for halogen, n is 0,1,2,3 or 4.
6. the compound shown in general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein R 1for
R 10be selected from halogen, C identical or differently 1-6alkyl, C 3-10cycloalkyl or C 1-6the substituting group of haloalkyl replaced; And
N is 0,1,2,3 or 4.
7. the compound shown in general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein this compound is:
8. prepare a method for the compound or pharmaceutically acceptable salt thereof shown in general formula according to claim 1 (I), the method comprises:
General formula (IA) compound and general formula (IB) compound are reacted, obtains general formula (I) compound;
Wherein: PG is leavings group;
Ring A, ring B, ring C, R 1, L 1and L 2definition as described in the appended claim 1.
9. preparation method according to claim 8, wherein PG is halogen or alkylsulfonyl.
10. prepare a method for the compound or pharmaceutically acceptable salt thereof shown in general formula according to claim 1 (I), the method comprises:
General formula (IC) compound and general formula (ID) compound are reacted, obtains general formula (I) compound;
Wherein L 1it is a key; X is halogen; Ring A, ring B, ring C, R 1and L 2definition as described in the appended claim 1.
11. 1 kinds of methods preparing the compound or pharmaceutically acceptable salt thereof shown in general formula according to claim 1 (I), the method comprises:
General formula (IE) compound and general formula (IF) compound are reacted, obtains general formula (I) compound;
Wherein PG is leavings group;
Ring A, ring B, ring C, R 1, L 1and L 2definition as described in the appended claim 1.
12. preparation methods according to claim 11, wherein PG is halogen or alkylsulfonyl.
13. 1 kinds of methods preparing the compound or pharmaceutically acceptable salt thereof shown in general formula according to claim 1 (I), the method comprises:
General formula (IH) compound and general formula (IJ) compound are reacted, obtains general formula (I) compound;
Wherein L 1it is a key; X is halogen; Ring A, ring B, ring C, R 1and L 2definition as described in the appended claim 1.
14. 1 kinds of pharmaceutical compositions, described pharmaceutical composition contains the compound according to the general formula (I) in claim 1 ~ 7 described in any one or its pharmaceutically useful salt and pharmaceutically useful carrier for the treatment of effective dose.
15. compounds according to the general formula (I) of claim 1 ~ 7 described in any one or its pharmaceutically useful salt, or the purposes of pharmaceutical composition according to claim 14 in preparation GPR119 agonist.
16. compounds according to the general formula (I) of claim 1 ~ 7 described in any one or its pharmaceutically useful salt, or the purposes of pharmaceutical composition according to claim 14 in the medicine of the disease of preparation treatment diabetes and metabolic syndrome.
17. compounds according to the general formula (I) of claim 1 ~ 7 described in any one or its pharmaceutically useful salt, or the purposes of pharmaceutical composition according to claim 14 in the medicine of preparation as adjustment Regular Insulin.
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