CN101061113A - 2,3,4,6-substituted pyridyl derivative compounds useful as beta-secretase inhibitors for the treatment of alzheimer's disease - Google Patents
2,3,4,6-substituted pyridyl derivative compounds useful as beta-secretase inhibitors for the treatment of alzheimer's disease Download PDFInfo
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- CN101061113A CN101061113A CN 200580039720 CN200580039720A CN101061113A CN 101061113 A CN101061113 A CN 101061113A CN 200580039720 CN200580039720 CN 200580039720 CN 200580039720 A CN200580039720 A CN 200580039720A CN 101061113 A CN101061113 A CN 101061113A
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Abstract
The present invention is directed to 2,3,4,6-substituted pyridyl derivative compounds which are inhibitors of the beta-secretase enzyme and that are useful in the treatment of diseases in which the beta-secretase enzyme is involved, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which the beta-secretase enzyme is involved.
Description
Related application
According to 35 U.S.C. § 119 (e), the application requires following U.S. Provisional Application No.: on November 23rd, 2004 was filed an application application number 60/630539; On February 15th, 2005 was filed an application application number 60/653,037; And on June 23rd, 2005 file an application application number 60/693,271.
Technical field
The present invention relates to a class new 2,3,4, the pyridine derivate that 6-replaces, the inhibitor of their useful as beta-secretase enzymes is applicable to treatment and beta-secretase diseases associated, such as Alzheimer's.
Background technology
The feature of Alzheimer's is amyloid form abnormal deposition with neurofibrillary tangles in extracellular plaque and the cell in brain.The speed that amyloid is accumulated is to form, assemble and from the combination of the excessive speed of brain.People are generally accepted to be that the main composition of amyloid plaque is 4kD amyloid (β A4 is also referred to as A β, beta-protein and β AP), and it is the proteolysis product of more macromolecule precursor protein.Amyloid precursor protein has the acceptor spline structure, has big ectodomain, strides film district and short cytoplasmic tail.A beta structure territory comprises a plurality of parts of the outer and membrane spaning domain of the born of the same parents of APP, so its release means that two kinds of different proteolysis approach of existence produce its NH
2-and the COOH-end.At least there are two kinds of mechanism of secretion that discharge the solubility COOH-clipped form (APPs) of APP and generation APP from film.Be called Secretases from film release APP and segmental proteolytic enzyme thereof.Most of APPs are discharged by the alpha-secretase enzyme of generally acknowledging, it separates the release that discharges α-APPs and stoped complete A β in a implosion.The APPs albumen of small part is discharged by beta-secretase (" beta-secretase "), and it is at the NH of APP
2-terminal cracking and generation comprise whole COOH-terminal fragments (CTFs).
Therefore, the activity of beta-secretase or β-site amyloid precursor protein lyase (" BACE ") causes the unusual cracking of APP, produce A β, and the amyloid-beta plaque is accumulated in the brain, the latter be Alzheimer's feature (referring to R.N.Rosenberg, Arch.Neurol., vol.59, Sep 2002, pp.1367-1368; H.Fukumoto etc., Arch.Neurol., vol.59, Sep 2002, pp.1381-1389; J.T.Huse etc., J.Biol.Chem., vol.277, No.18, on May 3rd, 2002 published, pp.16278-16284; K.C.Chen and W.J.Howe, Biochem.Biophys.Res.Comm, vol.292, pp 702-708,2002).So the therapeutical agent that can suppress beta-secretase or BACE can be used for the treatment of Alzheimer's.
Compound of the present invention is by suppressing the activity of beta-secretase or BACE, prevents that thus insoluble A β from forming and stop the generation of A β and can be used in the treatment Alzheimer's.
Summary of the invention
The present invention relates to 2,3,4 shown in the general formula (I), the pyridinyl derivatives that 6-replaces and its single enantiomorph and diastereomer, with and pharmaceutically-acceptable salts, the inhibitor of their useful as beta-secretase enzymes:
The invention still further relates to the pharmaceutical composition that comprises significant quantity formula (I) compound or its pharmaceutically-acceptable salts and pharmaceutically acceptable carrier.The present invention also relates to treat method and the compound of the present invention and the application of composition in this class disease of treatment of Mammals and beta-secretase diseases associated (as Alzheimer's).
Detailed Description Of The Invention
The present invention relates to formula (I) compound:
Wherein:
X is selected from group:
Y is selected from group:
(1) halogen,
(2) cyano group,
(3)-C
1-6Alkyl and
(4)-C
6-10Aryl;
A is selected from:
(1) hydrogen,
(2)-C
1-10Alkyl and
(3)-C
2-10Alkenyl,
Wherein said alkyl or alkenyl are unsubstituted or are replaced by one or more following groups:
(a) halogen,
(b)-C
3-12Cycloalkyl,
(c)-OH，
(d)-CN，
(e)-O-C
1-10Alkyl,
(f) phenyl, or
(g) heteroaryl,
And described phenyl and heteroaryl are unsubstituted or are replaced by one or more following groups:
(i) halogen,
(ii)-OH，
(iii)-CN，
(iv)-O-C
1-10Alkyl,
(v)-C
1-10Alkyl, or
(vi)-C
3-12Cycloalkyl;
Q is-C
0-3Alkyl, wherein this alkyl is unsubstituted or is replaced by one or more following groups:
(1) halogen,
(2)-C
3-12Cycloalkyl,
(3)-OH，
(4)-CN，
(5)-O-C
1-10Alkyl and
(6)-C
1-10Alkyl;
R
1Be selected from:
(1) be selected from the aryl of phenyl and naphthyl,
(2) heteroaryl,
(3)-C
1-10Alkyl and
(4)-C
3-8Cycloalkyl, the optional and C of this cycloalkyl
6-10It is aryl-condensed,
Wherein said alkyl, cycloalkyl, aryl or heteroaryl are unsubstituted or are replaced by one or more following groups:
(a) halogen,
(b)-C
1-10Alkyl, wherein this alkyl is unsubstituted or is replaced by halogen,
(c)-OH，
(d)-CN，
(e)-O-C
1-10Alkyl,
(f)-C
3-12Cycloalkyl, or
(g)-NR
10R
11, R wherein
10And R
11Be selected from:
(i) hydrogen,
(ii)-C
1-10Alkyl and
(iii)-C
0-6Alkylidene group-C
6-10Aryl;
R
8And R
9Be selected from:
(1) hydrogen,
(2) C
1-10Alkyl and
(3) C
0-6Alkylidene group-C
6-10Aryl;
R
4Be selected from group:
(1)-C
1-10Alkyl,
(2) heteroaryl and
(3)-NR
12R
13, R wherein
12And R
13Be selected from:
(a) hydrogen,
(b) C
1-10Alkyl and
(c) C
0-6Alkylidene group-C
6-10Aryl,
Perhaps R
12And R
13Represent 4,5 or 6 to be selected from CR
aR
b, S, NR
cWith the annular atoms of O, and constitute non-aromatic ring with the nitrogen that they connected, wherein said alkyl, alkylidene group and heteroaryl are unsubstituted or are replaced by one or more following groups:
(a) halogen,
(b)-OH，
(c)-CN，
(d)-O-C
1-10Alkyl,
(e)-C
1-10Alkyl
(f)-C
3-12Cycloalkyl,
(g) be selected from the aryl of phenyl and naphthyl,
(h) heteroaryl, or
(i)-C (=O)-C
1-10Alkyl,
And wherein said aryl and heteroaryl are unsubstituted or are replaced by one or more following groups:
(i) halogen,
(ii)-OH，
(iii)-CN，
(iv)-O-C
1-10Alkyl,
(v)-C
3-12Cycloalkyl, or
(vi)-C
1-10Alkyl;
R
7Be selected from group:
(1) hydrogen,
(2)-C
1-10Alkyl,
(3)-C
3-7Cycloalkyl,
(4)-C
6-10Aryl and
(5) heteroaryl,
Wherein said alkyl, cycloalkyl, aryl and heteroaryl are unsubstituted or are replaced by one or more following groups:
(a) halogen,
(b)-OH，
(c)-CN，
(d)-O-C
1-10Alkyl,
(e)-C
3-12Cycloalkyl,
(f) be selected from CR by 4,5 or 6
aR
b, S, NR
cThe non-aromatics cyclic group that constitutes with the annular atoms of O,
(g) be selected from the aryl of phenyl and naphthyl, or
(h)-C
5-12Heteroaryl,
Wherein said cycloalkyl, aryl or heterocyclic radical are unsubstituted or are replaced by one or more following groups:
(i) halogen,
(ii)-OH，
(iii)-CN，
(iv)-O-C
1-10Alkyl,
(v)-C
3-12Cycloalkyl, or
(vi) be selected from the aryl of phenyl and naphthyl;
Perhaps, R
4And R
7Can connect into-CH
2CH
2CH
2-group;
R
5And R
6Be independently selected from:
(1) hydrogen,
(2)-C
1-10Alkyl,
(3)-C
2-10Thiazolinyl,
(4)-C
2-10Alkynyl and
(5)-C
1-10Alkylidene group-C
3-12Cycloalkyl;
Wherein said alkyl, alkylidene group, cycloalkyl, alkenyl or alkynyl are unsubstituted or are replaced by one or more following groups:
(a) halogen,
(b)-OH，
(c)-CN，
(d)-C
1-10Alkyl,
(e)-C
3-12Cycloalkyl,
(f)-O-C
1-10Alkyl, wherein this alkyl is unsubstituted or quilt-O-C
1-10Alkyl-(O-C
1-10Alkyl)
mReplace,
(g) heteroaryl, wherein this heteroaryl can be unsubstituted or be replaced by one or more following groups:
(A) halogen, or
(B)-C
1-10Alkyl,
(h) phenyl,
(i)-NR
14R
15, R wherein
14And R
15Be selected from:
(A) hydrogen,
(B)-C
1-10Alkyl and
(C)-C
0-6Alkyl-C
6-10Aryl,
(j)-C (=O)-OR
16, R wherein
16Be selected from:
(A) hydrogen,
(B)-C
1-10Alkyl and
(C)-C
0-6Alkylidene group-C
6-10Aryl and
(k)-C (=O)-NR
17R
18, R wherein
17And R
18Be selected from:
(A) hydrogen,
(B)-C
1-10Alkyl and
(C)-C
0-6Alkylidene group-C
6-10Aryl,
Perhaps, R
17And R
18Represent 4,5 or 6 to be selected from CR
aR
b, S, NR
cWith the annular atoms of O, and with the nitrogen that they connected constitute non-aromatic ring and (l)-C (=O)-R
19, R wherein
19Be selected from:
(A)-C
1-10Alkyl,
(B)-C
3-7Cycloalkyl and
(C)-C
0-6Alkylidene group-C
6-10Aryl, perhaps, R
5And R
6Connect into 4-6 unit ring with the nitrogen-atoms that they connected, this ring is unsubstituted or by one or more following groups replacements:
(a)-C
1-10Alkyl,
(b)-C
3-12Cycloalkyl,
(c)-(CH
2)
n-phenyl,
(d)-C
2-10Thiazolinyl, or
(e)-C
2-10Alkynyl,
Wherein said alkyl, thiazolinyl and alkynyl are unsubstituted or are replaced by one or more following groups:
(i) halogen,
(ii)-OH，
(iii)-CN，
(iv)-O-C
1-10Alkyl, or
(v)-C
3-12Cycloalkyl,
And described cycloalkyl and phenyl are unsubstituted or are replaced by one or more following groups:
(i) halogen,
(ii)-C
1-10Alkyl,
(iii)-OH，
(iv)-CN，
(v)-C
3-12Alkyl, or
(vi)-O-C
1-10Alkyl;
R
a, R
bAnd R
cBe selected from independently of one another:
(1) hydrogen,
(2) halogen,
(3)-C
1-6Alkyl and
(4)-C (=O)-C
1-6Alkyl;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
With its pharmaceutically-acceptable salts, with and single enantiomorph and diastereomer.
The invention further relates to preparation and be used for suppressing active medicine of human or animal body beta-secretase or method for compositions, comprise The compounds of this invention and pharmaceutically acceptable carrier or mixing diluents.The invention still further relates to preparation and be used for the treatment of the medicine or the method for compositions of human Alzheimer's, comprise The compounds of this invention and pharmaceutically acceptable carrier or mixing diluents.
In one embodiment, X is selected from following diazole:
In one embodiment, Y is a halogen, is preferably chlorine.
In one embodiment, the present invention relates to wherein R
1Be phenyl unsubstituted or that replace, and Q is preferably CH
2Formula (I) compound.Preferred R
1Be unsubstituted phenyl or 4-fluorophenyl.
In one embodiment, R
1It is heteroaryl.Preferred R
1Heteroaryl comprises pyridyl, furyl, azoles base and benzoxazol base.
In other embodiments, R
1Be C
1-12Alkyl or C
3-8Cycloalkyl.Preferred C
1-12Alkyl R
1Group comprises C
1-6Alkyl (preferred unsubstituted C
1-6Alkyl comprises methyl and sec.-propyl).Preferred C
3-8Cycloalkyl comprises cyclopropyl, cyclopentyl and cyclohexyl, and is preferably unsubstituted.Two ring carbon atoms of cycloalkyl can be connected to form C
6-12Aryl.The representativeness of this embodiment condenses group:
In another embodiment, the present invention relates to wherein R
8And R
9It all is formula (I) compound of hydrogen.
In another embodiment of formula (I) compound, A is unsubstituted or replaces (preferably unsubstituted) C
1-10Alkyl, preferred unsubstituted or (preferably unsubstituted) C of replacing
1-6Alkyl, more preferably methyl.
In other selectable embodiment, A can be a hydrogen.
In one embodiment, R
6Be-C
1-10Alkylidene group-C
3-12Cycloalkyl, wherein this cycloalkyl is preferably by C
1-10Alkyl replaces.In preferred embodiments, R
6Be-C
1-3Alkylidene group-C
3-6Cycloalkyl, wherein this cycloalkyl is preferably by C
1-3Alkyl replaces.
In one embodiment, R
5Be C
1-10Alkyl, it is optional by one or more following groups replacements:
(a) halogen,
(b)-OH，
(c)-CN，
(d)-O-C
1-10Alkyl, or
(e) heteroaryl.
In another embodiment of formula (I) compound, R
5And R
6The nitrogen-atoms that the two connected with them is connected to form pyrrolidine ring.
In another embodiment of formula (I) compound, R
4And R
7Be C
1-10Alkyl, preferred C
1-6Alkyl.More preferably, R
4Be methyl or sec.-propyl and R
7It is methyl.
In another embodiment, R
4Be-C
0-3Alkylidene group-heteroaryl.Preferred R
4Heteroaryl comprises pyridyl, different azoles base, imidazolyl and azoles base.
In another embodiment, R
7Be-C
0-3Alkylidene group-heteroaryl.Preferred R
7Heteroaryl comprises pyridyl, different azoles base and tetrazyl.
In another embodiment, the present invention relates to formula (II) compound and its pharmaceutically-acceptable salts with and single enantiomorph and diastereomer:
Wherein Y is a halogen, and A, X, Q, R
1, R
4, R
5, R
7, R
8And R
9As above definition.
In one embodiment, X is the di azoly:
In one embodiment, Y is a halogen, is preferably chlorine.
In an embodiment of formula (II) compound, R
1Be that phenyl and Q are CH
2Preferred R
1Be unsubstituted phenyl or 4-fluorophenyl.
In another embodiment, the present invention relates to wherein R
8And R
9It all is formula (II) compound of hydrogen.
In another embodiment of formula (II) compound, A is C
1-10Alkyl, preferred C
1-6Alkyl, more preferably methyl.
In another embodiment of formula (II) compound, R
4And R
7Be C
1-10Alkyl, preferred C
1-6Alkyl.More preferably, R
4Be methyl or sec.-propyl and R
7It is methyl.
In one embodiment, R
5Be C
1-10Alkyl, it is chosen wantonly and is replaced by one or more following groups:
(a)-O-C
1-10Alkyl, wherein this alkyl is unsubstituted or quilt-O-C
1-10Alkyl-(O-C
1-10Alkyl)
mReplace,
(b) heteroaryl, or
(c)-C (=O)-R
19, R wherein
19Be selected from:
(i)-C
1-10Alkyl,
(ii)-C
3-7Cycloalkyl, or
(iii)-C
0-6Alkylidene group-C
6-10Aryl.
In another selectable embodiment, R
5Be hydrogen.
In the preferred embodiment of formula (II) compound, X is the diazole, promptly the compound shown in following (III) and its pharmaceutically-acceptable salts with and single enantiomorph and diastereomer:
In an embodiment of formula (III) compound, Y is a chlorine.
In an embodiment of formula (III) compound, R
1Be that phenyl and Q are CH
2
In another embodiment of formula (III) compound, R
8And R
9Be hydrogen.
In another embodiment of formula (III) compound, A is a methyl.
In another embodiment of formula (III) compound, R
4And R
7Be C
1-10Alkyl, preferred C
1-6Alkyl.More preferably, R
4Be methyl or sec.-propyl and R
7It is methyl.
In one embodiment, R
5Be C
1-10Alkyl, it is chosen wantonly and is replaced by one or more following groups:
(a)-O-C
1-10Alkyl, wherein this alkyl is unsubstituted or quilt-O-C
1-10Alkyl-(O-C
1-10Alkyl)
mReplace,
(b) heteroaryl, or
(c)-C (=O)-R
19, R wherein
19Be selected from:
(i)-C
1-10Alkyl,
(ii)-C
3-7Cycloalkyl, or
(iii)-C
0-6Alkylidene group-C
6-10Aryl.
In another selectable embodiment, R
5Be hydrogen.
The preferred enantiomorph configuration of formula (II) and formula (III) compound has trans-S at methyl-cyclopropyl-methyl moiety, the S-configuration, as shown in following formula (II ') and (III '):
Another embodiment of the present invention comprises title compound and the pharmacy acceptable salt thereof that is selected from back embodiment.
As used herein, term " alkyl " itself or as another substituent integral part is meant and has the straight or branched saturated hydrocarbyl that specifies number carbon atom (C for example
1-10Alkyl is meant the alkyl with 1-10 carbon atom).Say that for of the present invention should being used for preferred alkyl is the C with 1-6 carbon atom
1-6Alkyl.The example of alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc.
As used herein, term " alkylidene group " itself or as another substituent integral part is meant to have saturated straight chain or the side chain bivalent hydrocarbon radical that specifies number carbon atom.Term C
0Alkylidene group is (for example, at group " C
0Alkylidene group-C
6-10Aryl " in) be meant that alkylidene group does not exist.
As used herein, term " thiazolinyl " itself or as another substituent integral part is meant straight or branched alkyl (for example, the C that has a carbon-to-carbon double bond and specify number carbon atom
2-10Thiazolinyl is meant the thiazolinyl with 2-10 carbon atom).For application of the present invention, preferred thiazolinyl is the C with 2-6 carbon atom
2-6Thiazolinyl.The example of thiazolinyl comprises vinyl and propenyl.
As used herein, term " alkynyl " itself or as another substituent integral part is meant straight or branched alkyl (for example, the C that has a carbon-to-carbon triple bond and specify number carbon atom
2-10Alkynyl is meant the alkynyl with 2-10 carbon atom).For application of the present invention, preferred alkynyl is the alkynyl with 2-6 carbon atom.The example of alkynyl comprises ethynyl and proyl.
As used herein, term " cycloalkyl " itself or as another substituent integral part is meant to have the saturated monocycle that specifies number carbon atom, encircle or bridged cyclic hydrocarbon group (for example, C more
3-12Cycloalkyl is meant the cycloalkyl with 3-12 carbon atom).Preferred cycloalkyl comprises C
3-8Cycloalkyl, especially C
3-8Monocyclic cycloalkyl.The example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.Typical bridge shape cycloalkyl comprises adamantyl and norcamphyl.
As used herein, term " aryl " itself or as another substituent integral part is meant to have aromatics or cyclic group (for example, the C that specifies number carbon atom
6-10Aryl is meant the aryl with 6-10 carbon atom).For application of the present invention, preferred aryl groups comprises phenyl and naphthyl.
Term " halogen " or " halogen " comprise fluorine, chlorine, bromine and iodine.
As used herein, term " heteroaryl " itself or as another substituent integral part is meant the aromatics cyclic group with ring carbon atom and at least one ring hetero atom (O, N or S).Preferred heteroaryl has 5-12 annular atoms.Preferred heteroaryl has 5 or 6 annular atomses.For application of the present invention, representational heteroaryl comprises benzopyranyl, furyl, benzofuryl, isobenzofuran-base, imidazolyl, benzimidazolyl-, indazolyl, indyl, indynyl, di azoly, azoles base, benzoxazol base, different azoles base, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, quinolyl, isoquinolyl, tetrazyl, thiazolyl, thienyl (thienyl), thienyl (thiophenyl), benzothienyl, triazinyl and triazolyl.
Term " heteroaryl " also comprise the part aromaticity fused aromatic ring-type group (that is, one of fused rings be aromaticity and other ring is non-aromaticity).The heteroaryl example of part aromaticity comprises tetrahydric quinoline group, dihydro benzo furyl and indolinyl.
When the heteroaryl of this paper definition is substituted, described substituting group can with the ring carbon atom bonding of heteroaryl, or key is connected on the ring hetero atom (being nitrogen), they have and allow the valency that replaces.Preferably, described substituting group and ring carbon atom bonding.Similarly, when heteroaryl was defined herein as substituting group, link position can be on the ring carbon atom of heteroaryl, or on ring hetero atom (being nitrogen, oxygen or sulphur), and they have and allow the valency that replaces.
Compounds more of the present invention have at least one asymmetric center.May there be other asymmetric center in character according to different substituents on the molecule.Compound with asymmetric center produces enantiomer (optically active isomer), diastereomer (configurational isomer) or both, and all possible enantiomer and diastereomer, no matter be in mixture or, estimate all to comprise within the scope of the present invention as purifying or partially purified compound form.The present invention includes all these type of isomeric form of these compounds.
The independence of enantiomerism or diastereo-isomerism enrichment compound is synthetic, or its chromatographic separation, can obtain by suitably improving method disclosed herein according to methods known in the art.Their absolute stereo chemistry can utilize crystallized product or intermediate crystalline x-radiocrystallgraphy to measure, in case of necessity, and the reagent derivatize of the asymmetric center that contains configuration known of intermediate wherein.
If desired, can the racemic mixture of described compound be separated, thereby emanate out single enantiomer.Separation can adopt method well known in the art to carry out, and for example makes the racemic mixture of compound and enantiopure compound coupling form non-enantiomer mixture, adopts standard method to separate single diastereomer subsequently, for example fractional crystallization or chromatography.Linked reaction utilizes the acid of enantiomer-pure or alkali to form salt usually.Non-enantiomer derivative can be converted into pure enantiomorph by the additional chirality residue of cracking then.The racemic mixture of compound also can directly adopt chiral stationary phase to separate by chromatographic process, and these class methods are well known in the art.
On the other hand, use the pure raw material of optically-active of configuration known or reagent to pass through stereospecific synthesis, also can obtain any enantiomer of compound of Formula I.
In formula (I) and compound (II), with R
2, A and Q bonding carbon atom be generally chiral carbon.As a result, formula (I) and (II) compound can be with the racemic modification form, perhaps with pure (R) of stereochemistry or (S) form exist.The isomeric form of formula (I) compound is as follows:
First kind of configuration shown in above preferred (be generally (R) configuration, for example, when A is CH
3, R
2Be NH
2, Q is-CH
2-and R
1When being phenyl).
Compound of the present invention can be according to following universal method and the described preparation of specific embodiment.
Compound of the present invention can be according to following universal method preparation.
In route plan 1, the amino acid derivative of 1.1 types is converted into corresponding Boc-acid 1.2.For obtaining there is not commercially available amino acid derivative, can adopt two step alkylated reactions of glycine Schiff's base 1.3.Be used for synthetic 1.4 and 1.3 the alkylated reaction that carries out as described in the document by the enantioselectivity mode finish (referring to K.Maruoka etc., J.Am.Chem.Soc.2000,122,5228-5229 and M.North etc., Tetrahedron Lett.2003,44,2045-2048).
Route plan 1
In route plan 2, use the BH that produces on the spot
3Reducing amino acid 1.1 generates corresponding amino alcohol, carries out the N-protected reaction then and obtains compound 2.1.Oxidation 2.1 generates aldehyde 2.2.Carry out epoxidation reaction with 2.2, then use the ammonia open loop, amino alcohol 2.3.
Route plan 2
Route plan 3 has been summarized cyclopropyl methyl amine derivatives (NR
5R
6) synthetic, this compounds is used for the route plan of back.Cyclopropyl-carboxylic acid with 3.1 types is a raw material, generates benzyl amine 3.2 through EDC coupling and borane reduction.Hydrogenation obtains primary amine 3.3.Through reduction methylate, hydrogenation generates methylamine 3.3.To 3.2 further processing, generate the replacement amine of 3.6 types through acid amides coupling, borane reduction and hydrogenation benzyl, it is also as coupling.Other method is with different aldehyde reductive aminations 3.2, then hydrogenation, to generate the amine of 3.7 types.
Route plan 3
Route plan 4 has been described the preparation of intermediate 4.2a-c and 4.3a-c, and these intermediates are used for the processing of different sorts heterocyclic.Although c class intermediate has fully been introduced R in position
7NSO
2R
4And R
6R
5The N part, but a and b class intermediate still can introduced these parts to heterocycle processing back.
Route plan 4
Route 5 has been described the preparation of 5.1a-c and 5.2a-c type diazole, the amino acid derivative of promptly first coupling 1.2 types and hydrazides 4.3a-c, then carries out dehydrocyclization with triphenyl phosphine and carbon tetrabromide and reacts.Muriate 5.1a, b turns into successively change into 5.1c and 5.2c with deprotection through palladium.
Route plan 5
Route plan 6 has been described the preparation of 6.2 type azoles: coupling amino alcohol 2.3 and acid 4.2, then be oxidized to keto-amide 6.1, and carry out the dehydrocyclization reaction again.
Route plan 6
Route plan 7 has been described the preparation of the furans of 7.5 types.
Route plan 7
Route 8 has been described the chlorination reaction of diazole, azoles and the furan derivatives of NCS mediation, generates derivative 8.1-4.
Route plan 8
Route 9 has been described fluoridation and the cyanogenation (latter finishes through the cyanogenation of bromination and Pd mediation) that is generated the 9.2-4 type compound by the oxadiazole derivative.What note is that intermediate 9.3 provides the functionalization through the Pd mediation to obtain the approach of a large amount of 3-substituted pyridine compounds, thereby obtains the 3-alkyl and the 3-aryl substituted derivatives of 9.5 types.
Route plan 9
Route plan 10 has been described the preparation of the diazole-Schiff's base of 10.2 types, and this compounds allows the later stage through alkylated reaction introducing-Q-R
1
Route plan 10
Term " pure substantially " is meant by analytical technology known in the art and measures that the purity of separate substance is at least 90%, preferred at least 95% purity, more preferably at least 99% purity.
Term " pharmacy acceptable salt " is meant the salt by pharmaceutically useful nontoxic alkali or acid (comprising inorganic or organic bases and inorganic or organic acid) preparation.The compounds of this invention can be single, two or three salt, and this depends on the number of the acid functional group that exists in the free alkali form compound.Free alkali and comprise aluminium salt, ammonium salt, calcium salt, mantoquita, molysite, ferrous salt, lithium salts, magnesium salts, manganic salt, manganous salt, sylvite, sodium salt, zinc salt etc. by mineral alkali deutero-salt.Preferred especially ammonium salt, calcium salt, magnesium salts, sylvite and sodium salt.The salt of solid form may exist more than a kind of crystalline structure, and can be the form of hydrate.Comprise primary amine by the pharmaceutically useful non-toxic organic alkali salt that obtains of deriving, secondary amine or tertiary amine, replace amine and comprise naturally occurring replacement amine, the salt of cyclammonium and deacidite, the salt of following amine for example: arginine, trimethyl-glycine, trimethyl-xanthine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, the 2-DEAE diethylaminoethanol, the 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine, breathe out amine, Isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, the polyamines resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol etc.When The compounds of this invention was alkalescence, salt can prepare with pharmaceutically acceptable nontoxic acid (comprising inorganic and organic acid).These acid comprise acetate, trifluoroacetic acid, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, mandelic acid, methylsulfonic acid, glactaric acid, nitric acid, pounce on acid, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, tosic acid etc.Special optimization citric acid, Hydrogen bromide, hydrochloric acid, trifluoroacetic acid, toxilic acid, phosphoric acid, sulfuric acid, fumaric acid and tartrate.
The present invention relates to compound described herein as beta-secretase activity or the active inhibitor of β-site amyloid precursor protein-lyase (" BACE ") in for example application in the Mammals of this inhibiting patient of needs or curee, comprise the described compound of using significant quantity.Term " beta-secretase ", " β-site amyloid precursor protein-lyase " and " BACE " can exchange use in this manual.Except the mankind, multiple other Mammalss also can be treated according to the inventive method.
The compounds of this invention has effectiveness in the danger for the treatment of, alleviate, control or alleviating Alzheimer's.For example, The compounds of this invention can be used to prevent Alzheimer type dementia, and be used for the treatment of early stage, mid-term or late period Alzheimer type dementia.The compounds of this invention also can be used for the treatment of, alleviates, controls or alleviate the danger of the disease that the unusual cracking of amyloid precursor protein (claiming APP again) causes, and other illnesss that can treat or prevent by suppressing the 2-Secretases.These illnesss comprise paralysis, head trauma, apoplexy, Down's syndrome, pancreatitis, embedding gonosome myositis, other periphery amyloidosiss, diabetes and atherosclerosis on mild cognitive damage, Trisomy 21 (Down's syndrome), brain amyloid blood vessel disease, sex change dementia, the hereditary cerebral hemorrhage (HCHWA-D) of following Dutch-type amyloidosis, Creutzfeld-Jakob disease, prion disease, amyotrophic lateral sclerosis, the carrying out property nuclear.
The curee of administration The compounds of this invention or patient normally need to suppress the active mankind of beta-secretase (sex), but can comprise that also needs suppress the beta-secretase activity or treat other Mammalss of above-mentioned illness, for example dog, cat, mouse, rat, ox, horse, sheep, rabbit, monkey, chimpanzee or other apes or primates.
The compounds of this invention can be united with one or more other drugs and is used for disease or the treatment of conditions that The compounds of this invention is suitable for, and wherein coupling is more safer or more effective with any medicine than single together for these medicines.In addition, The compounds of this invention can be used for the treatment of, prevents, controls, alleviates or alleviate the side effect of The compounds of this invention with one or more or the other drug of risk of toxicity is united use.This type of other drug can pass through its normally used approach and consumption and The compounds of this invention administration simultaneously or sequentially.In addition, pharmaceutical composition of the present invention comprises those compositions that also contain one or more other activeconstituentss except that The compounds of this invention.This class coupling medicine can be used as a part of administration of unit dosage joint product, and perhaps as medicine box or the administration of treatment set meal (treatment protocol), wherein one or more medications are to separate a part of administration of formulation as treatment plan.
The example of the unitary dose that The compounds of this invention and other drug are formed or the coupling medicine of medicament forms comprises the coupling medicine that forms with anti-Alzheimer's agent, for example other beta-secretase inhibitor or inhibitors of gamma-secretase; The tau phosphorylation inhibitor; The positive allosteric modulators of M1 acceptor; A β oligomer forms blocker; The 5-HT conditioning agent, PRX-03140 for example, GSK742467, SGS-518, FK-962, SL-65.0155, SRA-33 and xaliproden (xaliproden); P25/CDK 5 inhibitor; The NK1/NK3 receptor antagonist; Cox 2 inhibitor; The HMG-CoA reductase inhibitor; The NSAIDs that comprises Ibuprofen BP/EP; Vitamin-E; Anti-amyloid antibody comprises the anti-amyloid Humanized monoclonal antibodies; Anti-inflammatory compound is as (R)-flurbiprofen, nitro flurbiprofen (nitroflurbiprofen), rosiglitazone, ND-1251, VP-025, HT-0712 and EHT-202; CB-1 receptor antagonist or CB-1 receptor inverse agonists; Microbiotic such as doxycycline and Rifampin; N-methyl-D-aspartate (NMDA) receptor antagonist, for example Memantine hydrochloride and neramexane; Anticholinesterase such as lycoremine, thunder department is for bright, only Buddhist nun time, tacrine, pheneserine, ladostigil and ABT-089; Tethelin succagoga such as ibutamoren, methylsulfonic acid ibutamoren, and capromorelin; Histamine H
3Antagonist such as ABT-834, ABT829 and GSK 189254; AMPA agonist or AMPA conditioning agent, CX-717 for example, LY 451395 and S-18986; PDE IV inhibitor; GABA
AInverse agonist; Neuronal nicotinic sample agonist; Selectivity M1 agonist; Microtubule is affine adjusting kinases (MARK) part; Or influence the other drug of acceptor or enzyme, they otherwise can improve effectiveness, security, the accessibility of The compounds of this invention, or can reduce the adverse side effect or the toxicity of The compounds of this invention.The combination medicine of listing above only illustrates, and limits and produce never in any form.
The same with many proteinase inhibitor, it is believed that The compounds of this invention is in vivo by the metabolism of cytochrome P-450 monooxygenase institute.Cytochrome P-450 is the isozyme family that influences drug metabolism.Cytochrome P-450 isozyme (comprising the CYP3A4 isozyme) transforms drug molecule by oxidation in vivo usually.The metabolism that cytochrome P-450 causes usually produces undesirable pharmacokinetics, compares the more dosage of frequent drug administration and Geng Gao like this with the situation of expectation.These medicines with can suppress the metabolic medicament that cytochrome P-450 causes and unite the pharmacokinetics (promptly increase the transformation period, increase the time that reaches the blood peak concentration of drug, increase blood levels) that use can improve medicine.
In one embodiment, the present invention relates to associating or co-administered The compounds of this invention and cytochrome P-450 inhibitor.The invention still further relates to improvement by the pharmacokinetics of the metabolic The compounds of this invention of cytochrome P-450 monooxygenase, comprise administration The compounds of this invention and cytochrome P-450 inhibitor simultaneously.
The coupling medicine of P-450 inhibitor and The compounds of this invention can be used as the integral part administration of unit dosage joint product, perhaps as medicine box or the administration of treatment set meal, wherein one or more P450 inhibitor are to separate a part of administration of formulation as treatment plan.
Representational p450 inhibitor comprises KETOKONAZOL, erythromycin, erythromycin, vazadrine, fluoxetine, Dormicum, ground La Weiding, Indinavir, ritonavir, nepresol, isoptin, troleomycin, tamoxifen and irinotecan.Other p450 inhibitor is open in following document: Pea etc., and Clin Pharmacokinet 2001,40 (11), 833-868; Zhou etc., Current Drug Metabolism 2004,5,415-442; And Wienkers, J.Pharm.Toxicol Methods 2001,45:79-84.Preferred p450 inhibitor is a ritonavir.
Term used herein " composition " comprises the product of the specific components that contains predetermined amount or ratio, and any product that is obtained directly or indirectly by the combination of the specific components of certain content.This term relevant with pharmaceutical composition comprised the product (described carrier comprises inert fraction) of the carrier that comprises one or more activeconstituentss and choose wantonly, and it is any directly or indirectly by the combination of any two or more components, compound or assemble the product that obtains, the perhaps product that is obtained by the disassociation of one or more components is perhaps by the other types reaction of one or more components or the product that interacts and obtain.Usually, pharmaceutical composition prepares by equal even densely activeconstituents and liquid vehicle or subdivided solids carrier or the two being mixed together, and optionally product is molded into the formulation that needs subsequently.In pharmaceutical composition, active target compound exists with the amount that is enough to the process of disease or situation are produced predictive role.Therefore, pharmaceutical composition of the present invention comprises by mixing any composition that The compounds of this invention and pharmaceutically acceptable carrier are made.
The pharmaceutical composition that Gong orally uses can be according to any method preparation of pharmaceutical compositions known in the art, and this based composition can comprise one or more materials that is selected from sweeting agent, seasonings, tinting material and sanitas, so that pharmaceutically attractive in appearance and good to eat preparation is provided.Tablet can comprise activeconstituents and be suitable for preparing the nontoxic pharmaceutically acceptable vehicle that tablet is used with its blended.These vehicle can be inert excipients for example, such as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example W-Gum or alginic acid; Tackiness agent, for example starch, gelatin or gum arabic, and lubricant, for example Magnesium Stearate, stearic acid or talcum.Tablet can be a dressing not, and perhaps they can carry out dressing postponing disintegration and the absorption in gi tract with known technology, thereby obtain longer slow releasing function.
The composition that Gong orally uses also can be the form of hard gelatin capsule, wherein activeconstituents mixes with inert solid diluent such as lime carbonate, calcium phosphate or kaolin, or the form of soft gelatin capsule, activeconstituents wherein and water or oily medium be peanut oil, whiteruss or mixed with olive oil for example.
Other pharmaceutical composition comprises water suspension, and it comprises and is suitable for preparing the activeconstituents of water suspension with mixed with excipients.In addition, the oiliness suspensoid can be by being suspended in activeconstituents vegetables oil for example in peanut oil, sweet oil, sesame oil or the Oleum Cocois or be suspended in mineral oil and for example prepare in the whiteruss.The oiliness suspensoid can also comprise various vehicle.Pharmaceutical composition of the present invention also can be an oil-in-water emulsion, and it also can contain vehicle for example sweeting agent and seasonings.
Pharmaceutical composition of the present invention can be the water-based of sterile injectable or the form of oiliness suspensoid, and it can be prepared according to methods known in the art, perhaps the suppository form administration that can use with rectal administration.
Compound of the present invention can also be by suction apparatus inhalation known in the art or by the transdermal patch administration.
" pharmaceutically acceptable " is meant that carrier, thinner or vehicle must be compatible with other compositions in the preparation, and harmless to the recipient.
Term " administration of compound " or " giving drug compound " are interpreted as being meant The compounds of this invention is offered the individuality that needs treatment with such forms, even compound can have the mode of consumption to enter in the individual body with treatment useful form and treatment, such form includes but not limited to oral dosage form, for example tablet, capsule, syrup, suspensoid etc.; Injectable dosage formulations, for example IV, IM or IP etc.; The transdermal formulation comprises creme, gelatum agent, pulvis or patch; Through buccal dosage form; Suck pulvis, sprays, suspensoid etc.; And rectal suppository.
Term " significant quantity " or " treatment significant quantity " are meant that the host compound that is searched out by researchist, animal doctor, doctor or other clinicist causes the amount of biology or medical response in tissue, system, animal or human's body.
Term used herein " ... treatment " or " treatment ... " be meant administration compound of the present invention and comprise (1) experience show the pathology of disease or the animal of symptom in suppress this disease (promptly stoping further developing of pathology and/or symptom), or (2) experience show the pathology of disease or the animal of symptom in improve disease (promptly reversing this pathology and/or symptom).Term " control " comprises prophylactic treatment, elimination, improvement or reduces the seriousness of controlled illness.
The composition that contains The compounds of this invention should exist with unit dosage forms, and can be by the preparation of pharmaceutical field known method.Term " unit dosage " is meant that wherein all active and non-active ingredients are combined into the single formulation of suitable system, thereby make the patient maybe this drug administration can be opened single container or the packing that wherein contains all dosage in patient's people, and any component that does not need to take from two or more containers or packing mix.The representative instance of unit dosage has the tablet or the capsule of pro ore, injection single dose bottle, or rectal administration suppository.Above-named unit dosage does not produce any qualification effect, only is the representative example of unit dosage.
The composition that contains The compounds of this invention should exist with the form of medicine box, two or more components thus, it can be activeconstituents or non-active ingredient, carrier, thinner etc., offers the patient or gives the people of patient's administration with the specification sheets of preparation actual dosage form.This class medicine box provides all essential material and components therein, and perhaps they can comprise that these materials and component are patient or independently acquisition of the people who delivers medicine to the patient for the specification sheets that uses or preparation institute's material of wanting or component are used.
In treatment, improve, control or reduce Alzheimer's or during other diseases that The compounds of this invention is pointed dangerous, when The compounds of this invention can obtain satisfied result during with the per daily dose administration of the about 100mg/kg the weight of animals of about 0.1mg-usually, these dosage preferably with single per daily dose or every day 2-6 divided dose form or put form to usefulness with slowly-releasing.Total per daily dose is the about 2000mg of the about 1.0mg-of every kg body weight, the about 20mg of preferably about 0.1mg-.For the adult of 70kg, total per daily dose is generally about 1,400 mg of about 7mg-.For obtaining optimum therapeutic response, can adjust this dosage.The compounds of this invention can adopt 1-4 time scheme administration every day, preferred administration every day 1 or 2 times.
The concrete dosage of The compounds of this invention or its pharmacy acceptable salt comprises 1mg, 5mg, 10mg, 30mg, 80mg, 100mg, 150mg, 300mg and 500mg.Pharmaceutical composition of the present invention can provide to contain the 0.5mg-1000mg formulations of active ingredients form of having an appointment; More preferably it comprises about 0.5mg-500mg activeconstituents; Or 0.5mg-250mg activeconstituents; Or 1mg-100mg activeconstituents.The certain drug composition that is used for the treatment of can comprise about 1mg, 5mg, 10mg, 30mg, 80mg, 100mg, 150mg, the activeconstituents of 300mg and 500mg.
But be to be understood that, for any concrete patient, concrete dosage level and administration number of times can change, and depend on multiple factor, comprise the activity of used particular compound, metabolic stability and effect length, age, body weight, healthy state, sex, diet situation, administering mode and time, excretion rate, drug combination situation, the severity of particular disorder and the therapy that the host accepts of this compound.
The compounds of this invention can confirm with the known methodology of the present invention as the effectiveness of beta-secretase activity inhibitor.Enzyme inhibition is measured as follows.
ECL assay method: adopt homogeneous phase terminal point electrochemistry spectral photometry method, use biotinylation BACE substrate.The Km of substrate is greater than 100 μ M and owing to the restriction of this substrate solubleness can not be measured.Typical reactant comprises about 0.1nM enzyme, 0.25 μ M substrate, and damping fluid (50mMNaOAc, pH4.5,0.1mg/ml BSA, 0.2%CHAPS, 15mM EDTA and 1mM Deferoxamine), total reaction volume 100 μ l.Reaction was carried out 30 minutes, added 25 μ L 1MTris-HCl subsequently, and pH8.0 ends.Gained enzyme product is analyzed the C-terminal residue of this this product of antibody capable specific recognition by adding ruthenium antibody.Add Streptomycin sulphate dressing magnetic bead in solution, sample is carried out M-384, and (Igen Inc., Gaithersburg MD) measure.Under these conditions, handled by BACE 1 less than 10% substrate.The enzyme that uses in these researchs is solubility (not comprising collapse membrane structure territory and kytoplasm extension) the people's albumen that produces in the baculovirus expression system.Tire for the inhibition of measuring compound, contain the solution (12 kind inhibitor concentration since 100 μ Ms by three times serial dilutions prepare) of inhibitor in DMSO in the reaction mixture (the DMSO final concentration is 10%).All tests all are at room temperature to adopt above-mentioned standard reaction condition to carry out.For measuring the IC of compound
50, use four parametric equations to carry out curve fitting.The error of reproducing dissociation constant is generally less than twice.
The HPLC assay method: homogeneous phase terminal point HPLC measures the employing substrate, and (tonka bean camphor-CO-REVNFEVEFR), it is discharged the N-terminal fragment that is connected with tonka bean camphor by BACE 1 cracking.The Km of this substrate is greater than 100 μ M and because the restriction of this substrate solubleness can not be determined.Typical reactant comprises about 2nM enzyme, 1.0 μ M substrates, and damping fluid (50mMNaOAc, pH4.5,0.1mg/ml BSA, 0.2%CHAPS, 15mM EDTA and 1mM Deferoxamine), total reaction volume 100 μ l.Reaction was carried out 30 minutes, added 25 μ L 1MTris-HCl subsequently, and pH8.0 ends.The gained reaction mixture is loaded on the HPLC, product and substrate is separated by 5 minutes linear gradient elutions.Under these conditions, handled by BACE 1 less than 10% substrate.The enzyme that uses in these researchs is solubility (not comprising collapse membrane structure territory and kytoplasm extension) the people's albumen that produces in the baculovirus expression system.Tire for the inhibition of measuring compound, contain the solution (prepare 12 kind inhibitor concentration, concentration range depend on tiring according to ECL prediction) of inhibitor in DMSO in the reaction mixture (the DMSO final concentration is 10%).All tests all are at room temperature to adopt above-mentioned standard reaction condition to carry out.For measuring the IC of compound
50, use four parametric equations to carry out curve fitting.The error of reproducing dissociation constant is generally less than twice.
Specifically, the compound of the following example has the activity that suppresses beta-secretase in one or both said determinations, generally has the IC of about 1nM-100 μ M
50Such result is the index of The compounds of this invention intrinsic activity when using as the beta-secretase activity inhibitor.
Route plan and embodiment illustrated that the Several Methods that the preparation The compounds of this invention is used provides at this paper.Starting raw material is according to method well known in the art or method cited herein preparation.The invention provides following examples in order more fully to understand, but these embodiment only are illustrative, must not be interpreted as by any way is limitation of the present invention.
Intermediate 1.2.1:N 2-[(tert-butoxycarbonyl) amino]-2-methyl-3-pyridin-4-yl propionic acid
(route plan 1)
Steps A: the formation of Schiff's base
To alanine methyl ester hydrochloride (10.0g 71.6mmol) at 100mL CH
2Cl
2In solution in add benzophenone imines (12.0mL, 71.6mmol).Reaction was at room temperature carried out 15 hours, separated out white precipitate in the solution gradually.Reactant H
2O and CH
2Cl
2Dilution separates each layer, and with organic layer salt water washing, dried over sodium sulfate is filtered, concentrated, and obtains N-(phenylbenzene methylene radical) alanine methyl ester, is the viscosity oil body, and it need not to be further purified and can use.
1H?NMR(CDCl
3，400MHz)δ7.62(m，2H)，7.47-7.29(m，6H)，7.19-7.16(m，2H)，4.16(q，J＝6.8Hz，1H)，3.7(s，3H，1.40(d，J＝6.8Hz，3H).
Step B: alkylation
In 0 ℃, 20 minutes, to the N-of steps A (phenylbenzene methylene radical) alanine methyl ester (9.78g, 36.6mmol) add in the solution in 60ml DMF two (trimethyl silyl) ammonification sodium of 1M THF solution (45.72ml, 45.72mmol).After 30 minutes, in 25 minutes, in reactant, add 4-chloromethyl pyridine hydrochloride (3.00g, 18.29mmol) thermal source in 40ml DMF by sleeve pipe.Warm reactant stirred 5 hours to room temperature.Use the saturated aqueous ammonium chloride stopped reaction, continue and extract with EtOAc (3x).The organic layer that merges 3M LiCl (2x) and salt water washing, dried over sodium sulfate is filtered vacuum concentration.Through silica gel chromatography (0-40% EtOAc/ hexane) purifying, obtain 2-[(phenylbenzene methylene radical) amino]-2-methyl-3-pyridin-4-yl methyl propionate, be white solid (5.28g, 81%).
LCMS[M+H]＝359.2.
1H?NMR(d
4-MeOH)δ8.51(dd，J＝4.5，1.5Hz，2H)，7.56(dd，J＝8.4，1.4Hz，2H)，7.40-7.37(m，4H)，7.34-7.30(m，2H)，7.26-7.23(m，2H)，7.10-7.07(m，2H)，3.33(A?of?AB，d，J＝13.0Hz，1H)，3.27(s，3H)，3.18(B?of?AB，d，J＝12.9Hz，1H)，1.32(s，3H).
Step C: the removing of Schiff's base
To the 2-[(of step B phenylbenzene methylene radical) amino]-2-methyl-3-pyridin-4-yl methyl propionate (5.28g, 14.73mmol) add in the suspension in 1: 1 MeOH/THF of 75ml 6NHCl (3.68ml, 22.10mmol).After the stirring at room 1.5 hours, the vacuum concentration reactant.Use ion-exchange chromatography (SCX tube) purifying to obtain 2-amino-2-methyl-3-pyridin-4-yl methyl propionate, be yellow oil body (2.76g, 97%).
LCMS[M+H]＝195.3.
1H?NMR(d
4-MeOH)δ8.43(dd，J＝4.6，1.6Hz，2H)，7.24(dd，J＝4.6，1.5Hz，2H)，3.70(s，3H)，3.09(A?of?AB，d，J＝12.9Hz，1H)，2.90(B?of?AB，d，J＝13.0Hz，1H)，1.39(s，3H).
Step D:Boc protection
In 0 ℃, to the 2-of step C amino-2-methyl-3-pyridin-4-yl methyl propionate (2.76g, 14.21mmol) add in the suspension in 70ml THF tert-Butyl dicarbonate (4.03g, 18.47mmol).After 30 minutes, the warm ambient temperature overnight that is reacted to.Reactant dilutes with EtOAc, continues with saturated aqueous ammonium chloride, water, salt water washing.The organic layer dried over sodium sulfate is filtered vacuum concentration.Through silica gel chromatography (0-60% EtOAc/CH
2Cl
2) purifying obtains the 2-[(tert-butoxycarbonyl) amino]-2-methyl-3-pyridin-4-yl methyl propionate, be yellow solid (3.22g, 77%).
LCMS[M+H]＝295.2.
1H?NMR(400MHz，d
4-MeOH)δ8.43(d，J＝5.1Hz，2H)，7.21(d，J＝5.9Hz，2H)，3.73(s，3H)，3.44(A?of?AB，d，J＝13.2Hz，1H)，3.12(B?of?AB，d，J＝13.2Hz，1H)，1.46(s，9H)，1.30(s，3H).
Step e: saponification
To the 2-[(of step D tert-butoxycarbonyl) amino]-2-methyl-3-pyridin-4-yl methyl propionate (0.25g, 0.85mmol) add in the solution in 1: 1 MeOH/THF of 4.25ml 3NNaOH (0.43ml, 1.27mmol).Make to be reflected at 50 ℃ and to carry out 1 hour, cool to room temperature then is with 6N HCl (0.21ml, 1.27mmol) stopped reaction.The vacuum concentration reactant obtains the 2-[(tert-butoxycarbonyl) amino]-2-methyl-3-pyridin-4-yl propionic acid NaCl, be white solid.
LCMS[M+H]＝281.3.
1H?NMR(400MHz，d
4-MeOH)δ8.44(d，J＝5.3Hz，2H)，7.28(d，J＝5.9Hz，2H)，3.43(A?of?AB，d，J＝12.6Hz，1H)，3.33(B?of?AB，d，J＝12.3Hz，1H)，1.47(s，9H)，1.41(s，3H).
Intermediate 1.2.2:N-(tertbutyloxycarbonyl)-2,5-dimethyl n leucine (route plan 1)
N-(tertbutyloxycarbonyl)-2,5-dimethyl n leucine are that raw material is according to the described method preparation of preparation intermediate 1.2.1 with isobutyl iodide and L-Ala Schiff's base.
Intermediate 2.3.1:(3R-amino-1-benzyl-2RS-hydroxyl-1-methyl-propyl) t-butyl carbamate (route plan 2)
Steps A: reduction
Under the room temperature, to D-Alpha-Methyl-phenylalanine (1.74g, 9.71mmol) disposable adding NaBH in the solution in 30mL THF
4(0.92g, 24.27mmol).Cooling gained solution to 0 ℃.In 30 minutes, dropwise be added in iodine among the 5mL THF (2.46g, 9.71mmol).Behind reinforced the finishing, heating reflux reaction 2 days.With postcooling reactant to 0 ℃, come stopped reaction until stopping bubbling by adding methyl alcohol.Reaction mixture is acidified to pH1 by adding 6N HCl, stirs vacuum concentration 30 minutes in 50 ℃.Utilize ion-exchange chromatography (SCX tube) to carry out purifying, obtain white solid 2R-amino-2-methyl-3-phenyl third-1-alcohol.
1H?NMR(400MHz，CDCl
3)δ7.35-7.18(m，5H)，3.36(A?of?AB，d，J＝10.4Hz，1H)，3.31(B?of?AB，d，J＝10.4Hz，1H)，2.70(s，2H)，1.04(s，3H).
Step B:Boc protection
Stir 2R-amino-2-methyl-3-phenyl third-1-alcohol (4.14g under the room temperature, 25mmol) with tert-Butyl dicarbonate (7.1g, 32.5mmol) solution 16 hours, concentrate and obtain (1-benzyl-2R-hydroxyl-1-methylethyl) t-butyl carbamate, be white solid.
1H?NMR(400MHz，CDCl
3)δ7.35-7.15(m，5H)，4.48(br?s，1H)，4.17(br?s，1H)，3.76-3.62(m，2H)，3.19(A?of?AB，d，J＝13.6Hz，1H)，2.81(B?of?AB，d，J＝13.6Hz，1H)，1.47(s，9H)，1.07(s，3H).
Step C: oxidation
To (1-benzyl-2R-hydroxyl-1-methylethyl) t-butyl carbamate (6.7g, 25.2mmol) in the solution among DCM (100mL) and the DMSO (25mL) the adding triethylamine (10.5mL, 75.7mmol) and sulphur trioxide-pyridine (10g, 63.1mmol).At room temperature stirred reaction mixture is 3.5 hours, with the EtOAc dilution, continues and uses 10%KHSO
4, saturated NaHCO
3, water, salt solution and LiCl solution washing, dried over sodium sulfate, vacuum concentration, and by purification by flash chromatography (silica gel, 0-20% EtOAc/ hexane), obtain (1-benzyl-1-methyl-2R-oxoethyl) t-butyl carbamate is white solid.
1H?NMR(400MHz，CDCl
3)δ?9.53(s，1H)，7.35-7.22(m，3H)，7.12-7.00(m，2H)，4.84(br?s，1H)，3.17(A?of?AB，d，J＝13.6?Hz，1H)，3.08(B?of?AB，d，J＝13.6Hz，1H)，1.51(s，9H)，1.27(s，3H).
Step D: epoxidation reaction
To (1-benzyl-1-methyl-2R-oxoethyl) t-butyl carbamate (1g, add in acetonitrile 3.80mmol) (15mL) solution 6 drip, trimethyl sulfonium iodide (775mg, 3.80mmol) and potassium hydroxide (511mg, 9.11mmol).This is reflected at 60 ℃ of lower seals stirred 1.5 hours, add again trimethyl sulfonium iodide (775mg, 3.80mmol) and potassium hydroxide (511mg 9.11mmol), and will be reflected at 60 ℃ of lower seals stirrings 3 hours.Reaction mixture is diluted with EtOAc, and with saturated sodium bicarbonate aqueous solution, salt water washing, dried over mgso and vacuum concentration obtain oily matter (1-methyl isophthalic acid-oxyethane-2R-base-2-phenylethyl) t-butyl carbamate.MS(ES，M+H)278.
Step e: the open loop of epoxide
(986mg is 3.56mmol) at EtOH (35mL) and NH with (1-methyl isophthalic acid-oxyethane-2R-base-2-phenylethyl) t-butyl carbamate
4Solution among the OH (35mL) stirred 16 hours in 60 ℃ of sealings, vacuum concentration and by purification by flash chromatography (silica gel, 0-30% (10% NH
4OH/MeOH)/CH
2Cl
2), obtain (3R-amino-1-benzyl-2RS-hydroxyl-1-methyl-propyl) t-butyl carbamate, be the thickness oil body.
1H NMR (400MHz, CD
3OD, 1: 1 non-enantiomer mixture) δ 7.30-7.14 (m, 5H), 4.01 (br d, J=9.2Hz, 0.5H), 3.54 (dd, J=10.0,2Hz, 0.5H), 3.39 (br s, 0.5H), 3.36 (br s, 0.5H), 2.94-2.56 (m, 4H), 1.47 (s, 9H), 1.03 (s, 1.5H), 0.99 (s, 1.5H).
Intermediate 3.2.1:N-benzyl-1-(2-trans-methyl cyclopropyl) methylamine (route plan 3)
Steps A: coupling
With 2-methyl cyclopropane carboxylic acid (77.74g, 777mmol), benzylamine (93.3mL, 854mmol) and DIPEA (141.5mL 854mmol) is dissolved in the 1200mL methylene dichloride.At room temperature add solid EDC-HCl in this solution (163.7g, 854mmol), stirring is spent the night in batches.Reaction mixture is poured among the 0.3M HCl.Separate each layer, once more once with 0.3M HCl washing, and with the saturated sodium bicarbonate aqueous solution washing once.Organic layer is water, salt water washing successively subsequently, dried over sodium sulfate, and residue obtains the coupling affixture with EtOAc/ hexane recrystallization, is white crystals.
1H NMR (400MHz, CDCl
3) δ 7.28 (m, 5H), 5.81 (br s, 1H), 4.43 (dd, J=5.6,2.4Hz, 2H), 1.37 (m, 1H), 1.17 (m, 1H), 1.07 (d, J=6.0Hz, 3H), 1.04 (overlapping multimodal m, 1H), 0.56 (m, 1H).
Choose wantonly and be prepared chirality HPLC, obtain preferably trans-S, the S enantiomer.In following intermediate and embodiment, no matter be preferably trans-S, the S enantiomer still is trans-S, and S and trans-R, the racemic mixture of R need not to differentiate and can use.For simplicity, methyl-cyclopropyl-methyl moiety is depicted as trans-racemic form.
Step B: reduction
In the 500mL flask, add N-benzyl-trans-2-methyl cyclopropane methane amide (step B, 3.9g, THF 20.6mmol) (80mL) solution.Drip BH by dropping funnel
3-THF (1.0M, 105mL, 105mmol).Backflow mixture is 5 hours after reinforced finish (10 minutes).Make the mixture cool to room temperature, carefully use MeOH (15mL) to end.Enriched mixture is dissolved in methylene dichloride again to doing, with 3M KOH washing.Separate organic layer, use the salt water washing, use dried over sodium sulfate then, reconcentration is to doing.Thick material was handled 1 hour down at 50 ℃ with 1N HCl/ two alkane.Enriched mixture obtains hydrochloride, is white solid.This solid is dissolved in saturated sodium bicarbonate aqueous solution (80mL), uses CHCl
3(2 * 150mL) extract.The organic layer salt water washing that merges, dried over sodium sulfate except that desolvating, obtains N-benzyl-1-(2-trans-methyl cyclopropyl) methylamine by rotary evaporation after the vacuum-drying, be canescence semisolid (quantitatively).
1H NMR (400MHz, CDCl
3) δ 7.28 (m, 5H), 3.80 (s, 2H), 2.50 (d, J=6.8Hz, 2H), 2.4 (br s, 1H), 1.02 (d, J=6.0Hz, 3H), 0.69 (m, 1H), 0.52 (m, 1H), 0.23 (m, 2H). intermediate 3.3.1:N-methyl isophthalic acid-(2-trans-methyl cyclopropyl) methylamine (route plan 3)
In N-benzyl-1-(2-trans-methyl cyclopropyl) solution of methylamine (8g, 45.6mmol, intermediate VI) in DCE (240mL) and MeOH (120mL), add formaldehyde (34mL, 456mmol, 37% aqueous solution) and NaBH (OAc)
3(19.3g, 91mmol).Stirring at room reaction mixture 1 hour is handled with saturated sodium bicarbonate aqueous solution, concentrates near doing, and dilute with water continues and extracts with EtOAc (3x).The organic layer salt water washing that merges, dried over sodium sulfate is used HCl (50mL, 50mmol, 1M Et again
2O) handle, vacuum concentration obtains the hydrochloride of N-benzyl-methyl isophthalic acid-(2-trans-methyl cyclopropyl) methylamine, and then at 20%Pd (OH)
2Under the existence of/C (616mg) in EtOH (400mL) in 60 ℃ and 1atm H
2Following hydrogenation 2 hours.Filter, vacuum concentration obtains the hydrochloride of N-methyl isophthalic acid-(2-trans-methyl cyclopropyl) methylamine.
1H?NMR(400MHz，CD
3OD)δ2.88(d，J＝7.3Hz，2H)，2.69(s，3H)，1.09(d，J＝5.7Hz，3H)，0.78-0.70(m，2H)，0.52-0.50(m，1H)，0.50-0.40(m，1H).
Intermediate 3.4.1:2-is trans-the methyl cyclopropyl) and methylamine (route plan 3)
To N-benzyl-1-(2-trans-methyl cyclopropyl) methylamine (intermediate 3.2.1,255mg, add in EtOH 1.46mmol) (20mL) solution 1N HCl (1.53mL, 1.53mmol).With this solution argon-degassed, add Pd (OH) then
2(30mg).Under the 1atm hydrogen-pressure in 60 ℃ of stirred reaction mixtures 16 hours.On diatomite, filter, concentrate obtain 2-trans-the methyl cyclopropyl) hydrochloride of methylamine.
1H?NMR(400MHz，CD
3OD+CDCl
3)δ2.90-2.60(m，2H)，1.09(bs，3H)，0.90-0.70(m，2H)，0.60-0.35(m，2H).
Intermediate 3.6.1:(2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amine (route plan 3)
Steps A: coupling
To N-benzyl-1-(2-trans-methyl cyclopropyl) methylamine hydrochloride (intermediate 3.2.1,10g, CHCl 47.2mmol)
3(150mL) add in the solution diisopropylethylamine (9.87mL, 56.7mmol), methoxyacetic acid (4.35mL, 56.7mmol), HOAt (1.29g, 9.5mmol) and EDC (10.87g, 56.7mmol), stirring at room reaction mixture 18 hours.The vacuum concentration reaction mixture with the EtOAc dilution, continues and uses 10%KHSO
4, NaHCO
3The aqueous solution and salt water washing, dried over sodium sulfate and vacuum concentration obtain trans N-benzyl-2-methoxyl group-N-[(2-methyl cyclopropyl) methyl] ethanamide, it is directly used in next step.
Step B: reduction
To the trans N-benzyl-2-methoxyl group-N-[(2-methyl cyclopropyl that is cooled to 0 ℃) methyl] (12.18g slowly adds borine-THF (123.1mL, 123.1mmol, 1M THF) to ethanamide in THF 49.2mmol) (100mL) solution.Reaction mixture was stirred 2 hours down at 70 ℃.Reaction mixture to 0 ℃ is carefully ended with MeOH.Add MeOH (20mL) again, under reflux state, stirred the gained mixture 0.5 hour.Vacuum concentration adds the saturated MeOH (25mL) of HCl (g) to about 200mL, mixture stirred 1 hour in 50 ℃.Add the saturated MeOH (25mL) of HCl (g) again, and stirred the mixture 1 hour in 50 ℃.The vacuum concentration reaction mixture, reconcentration obtains trans N-benzyl-2-methoxyl group-N-[(2-methyl cyclopropyl for several times from EtOH, MeOH and DCM) methyl] ethylamine hydrochloride, being colourless thickness oil body, it is directly used in next step.
Step C: hydrogenation
With trans N-benzyl-2-methoxyl group-N-[(2-methyl cyclopropyl) methyl] (16g, the solution argon-degassed of EtOH 59.3mmol) (400mL) add Pd (OH) to ethylamine hydrochloride then
2(830mg, 20%), with mixture at 1atm H
2Following stirring at room 4 hours.Reaction mixture N
2Flushing is at N
2Diatomite filtration is passed through in protection down, vacuum concentration, and under vacuum, use P
2O
5Drying obtains trans (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amine hydrochlorate, is the white foam body.
1H?NMR(400MHz，CDCl
3)δ9.46(bs，2H)，3.84(t，J＝5.1Hz，2H)，3.40(s，3H)，3.23(bt，J＝5.1Hz，2H)，3.08-2.88(m，2H)，1.09(d，J＝6.1Hz，3H)，1.02-0.91(m，1H)，0.86-0.78(m，1H)，0.65-0.57(m，1H)，0.50-0.42(m，1H).
Intermediate 3.6.2:(2,2-two fluoro ethyls) [(2-methyl cyclopropyl) methyl] amine
With N-benzyl-1-(2-trans-methyl cyclopropyl) methylamine hydrochloride and difluoroacetic acid is raw material, adopts the similar approach preparation of describing in the intermediate 3.6.1 preparation.
1H?NMR(400MHz，CD
3OD)d6.35(tt，48，3Hz，1H)，3.56(td，J＝15.6，3.1Hz，2H)，3.03(m，2H)，1.11(d，J＝5.9Hz，3H)，0.83(m，2H)，0.60(m，1H)，0.50(m，1H).
The intermediate 3.6.3:(2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl) [(2-methyl cyclopropyl)-methyl] amine
With (tertiary butyl) (dimethyl) siloxy-) ethamine and 2-methyl cyclopropane carboxylic acid be raw material, adopts the described similar approach preparation of preparation intermediate 3.2.1.
1H?NMR(400MHz，CD
3OD)δ3.74(t，J＝5.3Hz，2H)，2.76(m，2H)，2.52(m，2H)，1.04(d，J＝6.0Hz，3H)，0.90(s，9H)，0.68(m，1H)，0.55(m，1H)，0.29(m，1H)，0.24(m，1H)，0.07(s，6H).
Intermediate 3.6.4:{ (1S)-[(1S, 2S)-2-methyl cyclopropyl] ethyl } amine
Steps A: (2E)-1,1-diethoxy but-2-ene
With crotonaldehyde (23.64mL, 285.35mmol), triethyl orthoformate (57.02mL, 342.42mmol) and ammonium nitrate (2.28g 28.54mmol) mixes in 60mL EtOH.After at room temperature 22 hours, this reactant with EtOAc (60mL) dilution, is continued with saturated sodium bicarbonate solution (40mL) washing.Water layer extracts with EtOAc (20mL) is anti-.The organic phase that merges is washed with salt solution (40mL), and dried over sodium sulfate is filtered and vacuum concentration, obtains 36.5g% (89%) 1,1-diethoxy but-2-ene.
1H?NMR(CDCl
3，400MHz)5.84(m，1H)；5.54(m，1H)；4.82(d，J＝5.7Hz，1H)；3.64(m，2H)；3.49(m，2H)；1.73(m，3H)；1.21(m，6H).
Step B. (4S, 5S)-2-[(1E)-third-1-thiazolinyl]-1,3-dioxolane-4,5-dicarboxylic acid diisopropyl ester
With (2E)-1,1-diethoxy but-2-ene (32.20g, 223.27mmol), D-tartrate (-)-diisopropyl ester (64.64mL, 245.60mmol) and toluenesulphonic acids pyridine (2.24g, 8.93mmol) solution in 100mL benzene is heated to 95 ℃, distillation removes the EtOH that desolvates and generate.At 95 ℃ after following 7 hours, reactant is cooled to room temperature, vacuum concentration.Through normal-phase chromatography purifying (10-＞30% EtOAc/ hexane) obtain 35.37g (55%) (4S, 5S)-2-[(1E)-third-1-thiazolinyl]-1,3-dioxolane-4,5-dicarboxylic acid diisopropyl ester is orange oil body.
1H?NMR(CDCl
3，400MHz)6.03(m，1H)；5.86(m，2H)；5.12(m，2H)；4.71(d，J＝3.84Hz，1H)；4.63(d，J＝3.84Hz，1H)；1.78(m，3H)；1.30(d，J＝6.23Hz，12H)；LC/MS[M+H]
+＝287.
Step C. (4S, 5S)-2-[(1S, 2S)-2-methyl cyclopropyl]-1,3-dioxolane-4,5-dicarboxylic acid diisopropyl ester
To intermediate (4S, 5S)-2-[(1E)-third-1-thiazolinyl]-1,3-dioxolane-4,5-dicarboxylic acid diisopropyl ester (4.10g, 14.32mmol) add in-20 ℃ of solution in the 60mL hexane 1M the zinc ethyl hexane solution (42.96mL, 42.96mmol).Under vigorous stirring, drip methylene iodide (6.92mL, 85.92mmol).At-20 ℃ after following 1 hour, that this reactant is freezing down at-5 ℃.At-5 ℃ after following 17 hours, in 0 ℃ of stirring reaction 5 hours, use saturated ammonium chloride cold soln (100mL) to end then again, continue and use Et
2O (100mL * 3) extracts.The organic phase that merges is filtered with sodium thiosulfate solution (100mL) and salt solution (100mL) washing, and dried over sodium sulfate is filtered, then vacuum concentration once more.Through normal-phase chromatography purifying (10-＞30%EtOAc/ hexane) obtain 3.85g (89%) (4S, 5S)-2-[(1S, 2S)-2-methyl cyclopropyl]-1,3-dioxolane-4,5-dicarboxylic acid diisopropyl ester is yellow oil body.
1H?NMR(CDCl
3，400MHz)5.12(m，2H)；4.78(d，J＝6.41Hz，1H)；4.66(d，J＝4.21Hz，1H)；4.57(d，J＝4.22Hz，1H)；1.30(m，12H)；1.09(d，J＝5.68Hz，3H)；0.94(m，2H)；0.67(m，1H)；0.39(m，1H)；LC/MS[M+H]
+＝301.
Step D.2-methyl-N-{ (1E)-[(1S, 2S)-2-methyl cyclopropyl] methylene radical propane-2-sulfinyl amine
To (4S, 5S)-2-[(1S, 2S)-2-methyl cyclopropyl]-1,3-dioxolane-4, (0.450g is 1.50mmol) at 5mL CH for 5-dicarboxylic acid diisopropyl ester
2Cl
2/ 200 μ L H
2Adding tosic acid in the solution among the O (0.071g, 0.38mmol).This is reflected at 50 ℃ of following reflux.At 50 ℃ after following 16 hours, cooling is reacted to room temperature.Remove the water droplet that generates at this reactant top.Add copper sulfate (II) (0.507g, 2.85mmol) and (R)-(+)-tertiary butyl sulfinyl amine (0.173g, 1.43mmol).After at room temperature 5.5 hours, by Celite pad filtering reaction thing.With this diatomite CH
2Cl
2(200mL) washing and vacuum concentrated filtrate.Through normal-phase chromatography purifying (10-＞50% EtOAc/ hexane) obtain 0.235g (92%) 2-methyl-N-{ (1E)-[(1S, 2S)-2-methyl cyclopropyl] methylene radical propane-2-sulfinyl amine, be limpid colourless residue.
1H?NMR(CDCl
3，400MHz)7.46(d，J＝7.69Hz，1H)；1.62(m，1H)；1.25(m，2H)；1.10(m，12H)；0.82(m，1H)；LC/MS[M+H]
+＝188.
Step e .2-methyl-N-{ (1S)-1-[(1S, 2S)-2-methyl cyclopropyl] ethyl } propane-2-sulfinyl amine
To 2-methyl-N-{ (1E)-[(1S, 2S)-2-methyl cyclopropyl] methylene radical (0.300g is 1.60mmol) at 5mL CH for propane-2-sulfinyl amine
2Cl
2In-78 ℃ of solution in add 3M at Et
2Methyl-magnesium-bromide among the O (1.07mL, 3.20mmol).At-78 ℃ after following 2 hours, the warm reaction to room temperature.After at room temperature 1 hour,, continue and extract with EtOAc (30mL * 2) with saturated ammonium chloride solution (15mL) stopped reaction.The organic phase that merges is washed with salt solution (15mL), and dried over sodium sulfate is filtered and vacuum concentration.Through normal-phase chromatography purifying (0-＞80% EtOAc/ hexane) obtain 0.224g (69%) 2-methyl-N-{ (1S)-[(1S, 2S)-2-methyl cyclopropyl] ethyl propane-2-sulfinyl amine, be limpid colourless residue.
1H?NMR(CDCl
3，400MHz)2.77(m，1H)；1.31(d，J＝6.50Hz，3H)；1.21(s，9H)；1.03(d，J＝5.77Hz，3H)；0.54(m，3H)；0.30(m，1H)；LC/MS[M+H]
+＝204.
Step F. (1S)-[(1S, 2S)-2-methyl cyclopropyl] the ethane chlorination ammonium
To 2-methyl-N-{ (1S)-[(1S, 2S)-2-methyl cyclopropyl] ethyl (0.210g 1.03mmol) adds 2M at Et to propane-2-sulfinyl amine in 0 ℃ of solution in 4mL MeOH
2HCl among the O (0.52mL, 1.03mmol).Reacted 18 hours from 0 ℃ to stirring at room, vacuum concentration is dissolved in Et with the gained material then
2O (4mL), vacuum concentration twice, obtain (1S)-[(1S, 2S)-2-methyl cyclopropyl] the ethane chlorination ammonium, be white solid.
1H?NMR(CDCl
3，400MHz)2.60(m，1H)；1.37(d，J＝6.59Hz，3H)；1.08(d，J＝6.04Hz，3H)；0.77(m，1H)；0.64(m，2H)；0.42(m，1H)；LC/MS[M+H]
+＝100.
Intermediate 3.6.5:{ (1R)-1-[(1S, 2S)-2-methyl cyclopropyl] ethyl } amine
Adopt the described method preparation of preparation intermediate 3.6.4, its improvements are to use (S)-(+)-uncle's butane sulfinyl amine in step D.LC/MS[M+H]
+＝100。
Intermediate 3.6.6:(2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amine
With 2-(2-methoxy ethoxy) ethamine and trans-2-methyl cyclopropane carboxylic acid is raw material, utilizes steps A and B preparation in the described method of synthetic intermediate 3.6.1.
Intermediate 3.6.7:(2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amine
With 2-[2-(2-methoxy ethoxy) oxyethyl group] ethamine and trans-2-methyl cyclopropane carboxylic acid be raw material, utilizes steps A and B preparation in the described method of synthetic intermediate 3.6.1.MS(ES，M+H)232。
Intermediate 3.6.8:(1-(trans-2-methyl cyclopropyl (N-[(1-methyl isophthalic acid H-pyrazole-3-yl) methyl] methylamine
With intermediate 3.4.1 with 1-methyl isophthalic acid H-pyrazoles-the 3-carboxylic acid is a raw material, utilize steps A and B preparation in the described method of synthetic intermediate 3.6.1.
Intermediate 3.6.9:1-(trans-2-methyl cyclopropyl)-N-[(1-methyl isophthalic acid H-imidazoles-2-yl) methyl] methylamine
With intermediate 3.4.1 with 1-methyl isophthalic acid H-imidazoles-the 2-carboxylic acid is a raw material, utilize steps A and B preparation in the described method of synthetic intermediate 3.6.1.
Intermediate 3.6.10:1-(trans-2-methyl cyclopropyl)-N-[(1-methyl isophthalic acid H-pyrazoles-4-yl) methyl] methylamine
With intermediate 3.4.1 with 1-methyl isophthalic acid H-pyrazoles-the 4-carboxylic acid is a raw material, utilize steps A and B preparation in the described method of synthetic intermediate 3.6.1.
Intermediate 3.7.1:N-[(is trans-2-methyl cyclopropyl) and methyl] glycine ethyl ester
Steps A: reductive amination
(2.0g, DCE solution (50mL) 9.45mmol) is cooled to 0 ℃, uses glyoxylic acid ethyl ester (1.01g, 2.2mL, 9.92mmol, 50% toluene solution), NaHB (OAc) successively with the hydrochloride of intermediate 3.2.1
3(2.83g 13.2mmol) handles.Warm gained solution is to room temperature, and stirring is spent the night.Add bicarbonate aqueous solution this moment, further stirred this solution 20 minutes.Mixture is repeated to extract the salt water washing of the organic layer of merging with EtOAc.Remove after with dried over sodium sulfate and desolvate, further drying under reduced pressure again, obtain 2.0g N-benzyl-N-[(trans-2-methyl cyclopropyl) methyl] glycine ethyl ester, be that white is semi-solid.LC/MS[M+H]＝262.2。
Step B: hydrogenation
(2.0g 7.6mmol), uses N to be added in above-mentioned reactant among the 75mL EtOH in the 250mL flask
2Washed 10 minutes.In this solution, add 10%Pd (OH) successively
2(80mg), HCl (2.0mL, 7.6mmol, 4.0N two alkane solution).Utilize hydrogen gas tank that content is placed atmosphere of hydrogen.After stirring is spent the night mixture is passed through diatomite filtration.The HCl that adds equivalent again concentrates the gained mixture, and vacuum-drying obtains the hydrochloride (pale solid) of the above-mentioned title product of 1.6g:
1H?NMR(CD
3OD，400MHz)δ4.28(q，J＝7.2Hz，2H)；3.95(s，2H)；2.95(m，2H)；1.29(t，J＝7.2Hz，3H)；1.07(d，J＝5.6Hz，3H)；0.82(m，2H)；0.55(m，1H)；0.45(m，2H)；LC/MS[M+H]＝176.3.
Intermediate 4.2a.1:2-chloro-6-[methyl (methylsulfonyl) amino] Yi Yansuan (route plan 4)
With 2,6-dichloro-isonicotinic acid methyl esters and methyl (methylsulfonyl) amine is steps A and the B described preparation of raw material according to preparation intermediate 4.2c.1.
Intermediate 4.2b.1:2-chloro-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } Yi Yansuan (route plan 4)
With 2,6-dichloro-isonicotinic acid and intermediate 3.6.1 are that raw material is according to preparing intermediate 4.2c.1, the described similarity method preparation of step C.MS?M+1＝299。
Intermediate 4.2b.2:2-chloro-6-{ (2-methyl) [(trans-2-methyl cyclopropyl) methyl] amino } Yi Yansuan (route plan 4)
With 2,6-dichloro-isonicotinic acid and intermediate 3.3.1 are that raw material is according to preparing intermediate 4.2c.1, the described similarity method preparation of step C.MS?M+1＝255。
Intermediate 4.2c.1:2-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] Yi Yansuan (route plan 4)
Steps A: sulphonamide is introduced
In the dry flask that argon cleaning is crossed, add 2; 6-dichloro-isonicotinic acid methyl esters (25g; 121.3mmol), methyl (methylsulfonyl) amine (3.18g; 29.12mmol), potassiumphosphate (38.6g; 182mmol), Xantphos (4.2g; 7.28mmol) and three (dibenzalacetones), two palladiums (2.22g, 2.43mmol).Add two alkane (1200mL),, be heated to 100 ℃ of reactions 16 hours then gained solution argon-degassed.Cooling is reacted to room temperature, by diatomite filtration, and vacuum-evaporation.Flash chromatography (silica gel, 0-50%0-40% EtOAc/ hexane) obtains 2-chloro-6-[methyl (methylsulfonyl) amino] iso methyl nicotinate, be yellow oil body:
1H NMR (400MHz, CDCl
3) δ 7.88 (s, 1H), 7.68 (s, 1H), 3.96 (s, 3H), 3.44 (s, 3H), 3.11 (s, 3H).
Step B: hydrolysis
To 2-chloro-6-[methyl (methylsulfonyl) amino] iso methyl nicotinate (90.2g, 323.6mmol) add in the solution in 1: 1 THF: MeOH (1L) NaOH (388mL, 388mmol, 1N).Stirring at room reaction mixture 2 hours is acidified to pH3-4 with 1N HCl, extracts with methylene dichloride (x2), and dried over sodium sulfate and vacuum concentration obtain 2-chloro-6-[methyl (methylsulfonyl) amino] Yi Yansuan (intermediate 4.2c.1), be white solid.
1H?NMR(400MHz，CD
3OD)δ7.88(s，1H)，7.63(s，1H)，3.39(s，3H)，3.13(s，3H).
Step C: the introducing of amine
With 2-chloro-6-[methyl (methylsulfonyl) amino] Yi Yansuan (20g; 75.6mmol), trans (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amine hydrochlorate (17.65g; 98.2mmol), (48.12g, 226.7mmol) suspension in DMA (300mL) was with argon-degassed 10 minutes for potassiumphosphate.Add Pd (PtBu
3)
2(1.93g 3.78mmol), uses argon-degassed 10 minutes with reaction mixture again.Then in 110 ℃ of stirred reaction mixtures 24 hours.Cooling is reacted to room temperature, and by diatomite filtration, with the EtOAc flushing, thin up is regulated pH to 3-4 with 1N HCl, uses EtOAc (x3) to extract again.Organic layer LiCl solution washing, dried over sodium sulfate and vacuum concentration obtain 2-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] Yi Yansuan.
1H?NMR(400MHz，CDCl
3)δ7.05(s，1H)，7.02(s，1H)，3.76(t，J＝6.3Hz，2H)，3.60(t，J＝6.3Hz，2H)，3.52-3.43(m，1H)，3.39(s，3H)，3.36(s，3H)，3.38-3.30(m，1H)，3.18(s，3H)，1.23(d，J＝6.1Hz，3H)，0.82-0.64(m，2H)，0.46-0.39(m，1H)，0.32-0.25(m，1H).
Intermediate 4.2c.2:2-{ benzyl [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] Yi Yansuan (route plan 4)
With 2,6-dichloro-isonicotinic acid methyl esters, methyl (methylsulfonyl) amine and intermediate 3.2.1 are that raw material is according to the described similarity method preparation of preparation intermediate 4.2c.1.
1H?NMR(400MHz，CD
3OD)δ7.88(s，1H)，7.63(s，1H)，3.39(s，3H)，3.13(s，3H).
Intermediate 4.2c.3:2-{ methyl [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] Yi Yansuan (route plan 4)
With 2,6-dichloro-isonicotinic acid methyl esters, methyl (methylsulfonyl) amine and intermediate 3.3.1 are that raw material is according to the described similarity method preparation of preparation intermediate 4.2c.1.
1H?NMR(400MHz，CD
3OD)δ7.02(s，1H)，6.96(s，1H)，3.55(A?of?ABX，dd，J＝14.4，6.0Hz，1H)，3.29(B?of?ABX，dd，J＝14.4，7.2Hz，1H)，3.35(s，3H)，3.15(s，3H)，3.12(s，3H)，1.03(d，J＝6.0Hz，3H)，0.82-0.66(m，2H)，0.48-0.41(m，1H)，0.28-0.22(m，1H).
Intermediate 4.2c.4:2-{ (2,2-two fluoro ethyls) [(2-trans-methyl cyclopropyl) methyl] amino }-the 6-[(2-methoxy ethyl) (methylsulfonyl) amino] Yi Yansuan (route plan 4)
With 2,6-dichloro-isonicotinic acid methyl esters, 2-methoxy ethyl (methylsulfonyl) amine and intermediate 3.6.2 are that raw material is according to the described similarity method preparation of preparation intermediate 4.2c.1.MS?M+1＝422.
Intermediate 4.2c.5:2-{ (2-methoxy ethyl) [(2-trans-methyl cyclopropyl) methyl] amino }-the 6-[(2-methoxy ethyl) (methylsulfonyl) amino] Yi Yansuan (route plan 4)
With 2,6-dichloro-isonicotinic acid methyl esters, 2-methoxy ethyl (methylsulfonyl) amine and intermediate 3.6.1 are that raw material is according to the described similarity method preparation of preparation intermediate 4.2c.1.MS?M+1＝416.
Intermediate 4.2c.6:2-{ (2-methoxy ethyl) [(2-trans-methyl cyclopropyl) methyl] amino }-the 6-[(2-methoxy ethyl) (methylsulfonyl) amino] Yi Yansuan (route plan 4)
With 2,6-dichloro-isonicotinic acid methyl esters, 2-methoxy ethyl (methylsulfonyl) amine and intermediate 3.3.1 are that raw material is according to the described similarity method preparation of preparation intermediate 4.2c.1.MS?M+1＝372.
Intermediate 4.2c.7:2-(1,1-titanium dioxide isothiazolidine-2-yl)-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } Yi Yansuan (route plan 4)
With 2,6-dichloro-isonicotinic acid methyl esters, isothiazolidine 1,1-dioxide and intermediate 3.6.1 are that raw material is according to the described similarity method preparation of preparation intermediate 4.2c.1.MS?M+1＝384.
Intermediate 4.2c.8:2-{ benzyl [(trans-2-methyl cyclopropyl) methyl] amino }-6-(1,1-titanium dioxide isothiazolidine-2-yl) Yi Yansuan (route plan 4)
With 2,6-dichloro-isonicotinic acid methyl esters, isothiazolidine 1,1-dioxide and intermediate 3.2.1 are that raw material is according to the described similarity method preparation of preparation intermediate 4.2c.1.MS?M+1＝416.
Intermediate 4.2c.9:2-{ (the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl) [(trans-2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] Yi Yansuan (route plan 4)
With 2,6-dichloro-isonicotinic acid methyl esters, methyl (methylsulfonyl) amine and intermediate 3.6.3 are that raw material is according to the described similarity method preparation of preparation intermediate 4.2c.1.MS?M+1＝472.
Intermediate 4.2c.10:2-((1R)-1-[(2S)-and 2-methyl cyclopropyl) ethyl] amino }-6-[methyl (methylsulfonyl) amino] Yi Yansuan (route plan 4)
With 2,6-dichloro-isonicotinic acid methyl esters, methyl (methylsulfonyl) amine and intermediate 3.6.5 are that raw material is according to the described similarity method preparation of preparation intermediate 4.2c.1.MS?M+1＝328.
Intermediate 4.2c.11:2-{ benzyl [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (sec.-propyl alkylsulfonyl) amino] Yi Yansuan (route plan 4)
With 2,6-dichloro-isonicotinic acid methyl esters, methyl (sec.-propyl alkylsulfonyl) amine and intermediate 3.2.1 are that raw material is according to the described similarity method preparation of preparation intermediate 4.2c.1.MS?M+1＝432.
Intermediate 4.2c.12:2-{ benzyl [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (ethylsulfonyl) amino] Yi Yansuan (route plan 4)
With 2,6-dichloro-isonicotinic acid methyl esters, methyl (ethylsulfonyl) amine and intermediate 3.2.1 are that raw material is according to the described similarity method preparation of preparation intermediate 4.2c.1.MS?M+1＝418.
Intermediate 4.2c.13:2-[benzyl (methylsulfonyl) amino]-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } Yi Yansuan (route plan 4)
With 2,6-dichloro-isonicotinic acid methyl esters, benzyl (methylsulfonyl) amine and intermediate 3.6.1 are that raw material is according to the described similarity method preparation of preparation intermediate 4.2c.1.MS?M+1＝448.
2-chloro-6-(methylamino) iso methyl nicotinate
Steps A: methylamine coupling
To 2, (25g 130.2mmol) adds 60mL 40% aqueous methylamine solution to the 6-dichloro-isonicotinic acid in the solution in 52mL water.At 100 ℃ of following heating reflux reaction things.After 16 hours, the cooling reactant is to room temperature.Reactant with 1N HCl (200mL) acidifying, is continued and extracts with EtOAc (300mL * 4).The organism that merges washs with salt solution (150mL), and dried over mgso is filtered, and vacuum concentration obtains 24.2g (100%) 2-chloro-6-(methylamino) Yi Yansuan, is brown solid.LC/MS[M+H]
+＝187.0.
Step B: esterification
(18.1g, (7.783mL 107mmol) (acutely disengages HCl gas) 97mmol) to add thionyl chloride in the solution in 600mL MeOH extremely lentamente to 2-chloro-6-(methylamino) Yi Yansuan.Back flow reaction to 65 ℃ 2 hours.After 2 hours, the vacuum concentration reaction.Residue is dissolved in EtOAc (400mL), uses saturated NaHCO
3Solution (300mL) neutralization.This aqueous solution is extracted with EtOAc (150mL * 3).The organic phase that merges is washed with salt solution (150mL), and dried over mgso is filtered and vacuum concentration.Obtain 11.3g (58%) 2-chloro-6-(methylamino) iso methyl nicotinate by normal-phase chromatography (5%EtOAc/ hexane, 20%EtOAc/ hexane then) purifying, be pale brown look solid.
1H?NMR(CDCl
3，400mHz)7.08(d，J＝0.91Hz，1H)；6.84(d，J＝0.73Hz，1H)；5.09(s，NH)；3.92(s，3H)；2.96(d，J＝5.31Hz，3H)；LC/MS[M+H]
+＝201.0.
Intermediate 4.2.c.14:2-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino }-6-[methyl (pyridin-3-yl alkylsulfonyl) amino] Yi Yansuan
Steps A: sulfonation
(2.00g is 9.97mmol) at 3: 1 CH to 2-chloro-6-(methylamino) iso methyl nicotinate
2Cl
2: add in the solution in the pyridine (amount to 100mL) 3-pyridine SULPHURYL CHLORIDE hydrochloride (6.40g, 29.9mmol) and Dimethylamino pyridine (0.609g, 4.98mmol).At 50 ℃ of heating reflux reactions.After 36 hours, cooling is reacted to room temperature.Add CH
2Cl
2(200mL) dilution continues with 1N HCl (150mL) solution washing.Aqueous solution CH
2Cl
2Extract (100mL * 2).The organic phase that merges is washed with salt solution (100mL), and dried over mgso is filtered vacuum concentration.Obtain 3.12g (92%) 2-chloro-6-[methyl (pyridin-3-yl alkylsulfonyl) amino through normal-phase chromatography purifying (20-＞40%EtOAc/ hexane)] iso methyl nicotinate, be yellow residue.
1H?NMR(CDCl
3，400MHz)8.95(d，J＝0.64Hz，1H)；8.82(m，1H)；8.03(m，2H)；7.67(m，1H)；7.45(m，1H)；3.99(s，3H)；3.39(s，3H)；LC/MS[M+H]
+＝341.9.
Step B: hydrolysis
To 2-chloro-6-[methyl (pyridin-3-yl alkylsulfonyl) amino] iso methyl nicotinate (3.12g, 9.13mmol) adding 1N NaOH solution in the solution in 1: 1 MeOH: THF (amount to 60mL) (27mL, 27.4mmol).After 1 hour, the vacuum concentration reaction.Reactant is diluted with EtOAc (100mL), and then with the acidifying of 1N HCl (50mL) solution.The aqueous solution extracts with EtOAc (100mL * 3).The organic phase that merges is with salt solution (100mL) washing, and dried over mgso is filtered and carried out vacuum concentration, obtains 2.63g (88%) 2-chloro-6-[methyl (pyridin-3-yl alkylsulfonyl) amino] Yi Yansuan, be white solid.LC/MS[M+H]
+＝328.1.
Intermediate 4.2c.15:2-[[(3, the different azoles of 5-dimethyl-4-yl) alkylsulfonyl] (methyl) amino]-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } Yi Yansuan
With 2-chloro-6-(methylamino) iso methyl nicotinate and 3, the different azoles of 5-dimethyl-4-SULPHURYL CHLORIDE is that raw material is according to the described method preparation of preparation intermediate 4.2c.14.MS?M+1＝453.
Intermediate 4.2c.16:2-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino }-6-{ methyl [(1-methyl isophthalic acid H-imidazol-4 yl) alkylsulfonyl] amino } Yi Yansuan
With 2-chloro-6-(methylamino) iso methyl nicotinate and 1-methyl isophthalic acid H-imidazoles-4-SULPHURYL CHLORIDE is that raw material is according to the described method preparation of preparation intermediate 4.2c.14.MS?M+1＝438.
Intermediate 4.2c.17:2-[({4-[(benzyloxy) carbonyl] piperazine-1-yl } alkylsulfonyl) (methyl) amino]-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } Yi Yansuan (route plan 4)
With 2,6-dichloro-isonicotinic acid methyl esters, 4-[(methylamino) alkylsulfonyl] piperazine-1-benzyl carboxylate and intermediate 3.6.1 be that raw material is according to the described similarity method preparation of preparation intermediate 4.2c.1.MSM+1＝576.
Intermediate 4.2c.18:2-[[(1,2-dimethyl-1H-imidazol-4 yl) alkylsulfonyl] (methyl) amino]-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } Yi Yansuan
With 2-chloro-6-(methylamino) iso methyl nicotinate and 1,2-dimethyl-1H-imidazoles-4-SULPHURYL CHLORIDE is that raw material is according to the described method preparation of preparation intermediate 4.2c.14.MS?M+1＝576.
Intermediate 4.2c.19:2-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino }-6-[methyl (morpholine-4-base alkylsulfonyl) amino] Yi Yansuan (route plan 4)
With 2,6-dichloro-isonicotinic acid methyl esters, N-methylmorpholine-4-sulphonamide and intermediate 3.6.1 are that raw material is according to the described similarity method preparation of preparation intermediate 4.2c.1.MS?M+1＝443.
Intermediate 4.2c.20:2-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino }-6-(methyl { [(the different azoles of 3-methyl-5-yl) methyl] alkylsulfonyl } amino) Yi Yansuan
With 2,6-dichloro-isonicotinic acid methyl esters, N-methyl isophthalic acid-(the different azoles of 3-methyl-5-yl) Toluidrin and intermediate 3.6.1 are that raw material is according to the described similarity method preparation of preparation intermediate 4.2c.1.
MS?M+1＝453.
Intermediate 4.2c.21:2-[[(dimethylamino) alkylsulfonyl] (methyl) amino]-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } Yi Yansuan
With 2,6-dichloro-isonicotinic acid methyl esters, N, N, N '-trimethylammonium sulphonamide and intermediate 3.6.1 are that raw material is according to the described similarity method preparation of preparation intermediate 4.2c.1.MS?M+1＝401.
Intermediate 4.2c.22:2-{ (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (tetramethyleneimine-1-base alkylsulfonyl) amino] Yi Yansuan
With 2,6-dichloro-isonicotinic acid methyl esters, N-methylpyrrolidin-1-sulphonamide and intermediate 3.6.1 are that raw material is according to the described similarity method preparation of preparation intermediate 4.2c.1.MS?M+1＝427.
Intermediate 4.3c.1:N-(4-(diazanyl carbonyl)-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (route plan 4)
Steps A: coupling
To 2-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] Yi Yansuan (14.05g; 37.8mmol) DCM (150mL) solution in add diisopropylethylamine (7.91mL; 45.4mmol), Boc-hydrazine (6g; 45.4mmol), HOAt (1.03g; 7.6mmol) and EDC (8.7g; 45.4mmol), and stirred reaction mixture 16 hours at room temperature.Reaction mixture adds the EtOAc dilution, continues and uses 10%KHSO
4, sodium bicarbonate aqueous solution and salt water washing; dried over sodium sulfate; vacuum concentration; and by purification by flash chromatography (silica gel; the 30%-70%EtOAc/ hexane), obtain 2-{2-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] different nicotinoyl } hydrazine carboxylic acid's tert-butyl ester.MS?M+1＝486.
Step B:Boc removes
To 2-{2-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino that is cooled to 0 ℃ }-6-[methyl (methylsulfonyl) amino] different nicotinoyl } (13.6g feeds HCl (g) in DCM 28mmol) (50mL) solution to hydrazine carboxylic acid's tert-butyl ester.After LC confirmed that reaction is finished, the vacuum concentration reaction mixture obtained N-(4-diazanyl carbonyl)-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino }-hydrochloride of N-methyl Toluidrin.
1HNMR(400MHz，CD
3OD)δ6.89(s，1H)，6.88(s，1H)，3.79(t，J＝6.1Hz，2H)，3.62(t，J＝6.3Hz，2H)，3.52-3.48(m，1H)，3.42-3.35(m，1H)，3.33(s，3H)，3.31(s，3H)，3.16(s，3H)，1.04(d，J＝5.9Hz，3H)，0.85-0.70(m，2H)，0.51-0.42(m，1H)，0.31-0.23(m，1H).
Note: the sour intermediate of each 4.2c type can be converted into the hydrazides of corresponding 4.3c type.
Intermediate 5.2c.1:N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (route plan 5)
Step: coupling
To N-(4-(diazanyl carbonyl)-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin hydrochloride (intermediate 4.3c.1,11.81g, add diisopropylethylamine (9.75mL in DMF 28mmol) (100mL) solution, 56mmol), Boc-D-Alpha-Methyl-phenylalanine (8.6g, 30.8mmol), HOAt (1.9g, 14mmol) and EDC (8.05g 42mmol), and at room temperature stirred reaction mixture 16 hours.Reaction mixture adds the EtOAc dilution, continues and uses 10%KHSO
4, sodium bicarbonate aqueous solution and LiCl solution washing; dried over sodium sulfate; vacuum concentration and by purification by flash chromatography (silica gel; the 30%-70%EtOAc/ hexane), obtain [(1R)-1-benzyl-2-oxo-(2-{2-{ (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] different nicotinoyl } diazanyl)-the 1-methylethyl] t-butyl carbamate.MS?M+1＝647.
Step B: cyclodehydration
To [(1R)-1-benzyl-2-oxo-(2-{2-{ (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] different nicotinoyl } diazanyl)-the 1-methylethyl] t-butyl carbamate (16.2g; 25mmol), triphenyl phosphine (7.88g; 30.1mmol) and imidazoles (2.05g; 30.1mmol) add carbon tetrabromide (9.97g in 0 ℃ of cold soln in DCM (150mL); 30.1mmol), reaction mixture was at room temperature stirred 16 hours.The vacuum concentration reaction mixture; by purification by flash chromatography (silica gel; the 20%-50%EtOAc/ hexane) obtain [(1R)-1-(5-{2-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] pyridin-4-yl }-1; 3,4- diazole-2-yl)-1-methyl-2-phenylethyl] t-butyl carbamate.MS?M+1＝629.
Step C:Boc removes
To be cooled to 0 ℃ [(1R)-1-(5-{2-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] pyridin-4-yl-1; 3; 4- diazole-2-yl)-and 1-methyl-2-phenylethyl] t-butyl carbamate (14.65g; 23.3mmol) DCM (95mL) solution in add TFA (35mL); stirring at room reaction mixture 3 hours; vacuum concentration; utilize MeOH to concentrate again; utilize DCM to concentrate for several times subsequently again; obtain N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1; 3,4- diazole-2-yl]-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-tfa salt of N-methyl Toluidrin.
MS?M+1＝529.
1H?NMR(400MHz，CDCl
3)δ7.32-7.26(m，3H)，7.21(s，1H)，7.09(s，1H)，7.08-7.02(m，2H)，3.82(t，J＝5.5Hz，2H)，3.75(t，J＝5.5Hz，2H)，3.54-3.47(m，2H)，3.45(s，3H)，3.42(s，3H)，3.42-3.36(m，2H)，3.16(s，3H)，1.96(s，3H)，1.05(d，J＝5.8Hz，3H)，0.79-0.70(m，2H)，0.50-0.44(m，1H)，0.42-0.35(m，1H).
Intermediate 5.2c.2:N-(4-{5-[(1R)-1-amino-2-(4-fluorophenyl)-1-methylethyl]-1,3,4- diazole-2-yl]-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (route plan 5)
Step: coupling
To N-(4-(diazanyl carbonyl)-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin hydrochloride (intermediate 4.3c.1,10.16g, 24.1mmol) DMF (240mL) solution in add diisopropylethylamine (8.39mL, 48.2mmol), Boc-D-Alpha-Methyl-4-fluorophenylalanine (7.88g, 26.5mmol), HOAt (1.64g, 12.0mmol) and EDC (6.92g, 36.1mmol), and reaction mixture at room temperature stirred 16 hours.Reaction mixture adds the EtOAc dilution, continues and uses 10%KHSO
4, the washing of sodium bicarbonate aqueous solution and the LiCl aqueous solution (x3); dried over sodium sulfate, vacuum concentration obtain [(1R)-1-(4-fluorophenyl methyl)-2-oxo-(2-{2-{ (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] different nicotinoyl diazanyl)-the 1-methylethyl] t-butyl carbamate.MS?M+1＝665.
Step B: cyclodehydration
To [(1R)-1-(4-fluorophenyl methyl)-2-oxo-(2-{2-{ (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] different nicotinoyl } diazanyl)-the 1-methylethyl] t-butyl carbamate (16.64g; 25.0mmol), triphenyl phosphine (7.89g; 30.1mmol) and imidazoles (2.05g; 30.1mmol) add carbon tetrabromide (9.98g in 0 ℃ of cold soln in DCM (150mL); 30.1mmol), reaction mixture was at room temperature stirred 16 hours.Filter reaction mixture; vacuum concentration; and by purification by flash chromatography (silica gel; the 20%-50%EtOAc/ hexane); thereby obtain [(1R)-2-(4-fluorophenyl)-1-(5-{2-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] pyridin-4-yl }-1; 3,4- diazole-2-yl)-1-methyl-2-phenylethyl] t-butyl carbamate.MSM+1＝647.
Step C:Boc removes
To be cooled to 0 ℃ [(1R)-2-(4-fluorophenyl)-1-(5-{2-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] pyridin-4-yl-1; 3; 4- diazole-2-yl)-and 1-methyl-2-phenylethyl] t-butyl carbamate (11.58g; 17.9mmol) DCM (75mL) solution in add TFA (25mL); stirring at room reaction mixture 16 hours; vacuum concentration; from DCM, concentrate for several times again; obtain N-(4-{5-[(1R)-1-amino-2-(4-fluorophenyl)-1-methylethyl]-1; 3,4- diazole-2-yl }-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-tfa salt of N-methyl Toluidrin.
MS M+1=547.
1H NMR (400MHz, CD
3OD) δ 7.10 (m, 5H), 7.01 (s, 1H), 3.82 (t, J=5.86Hz, 2H), 3.64 (t, J=5.86,2H), 3.50 (AB overlapping multimodal m, 4H), 3.39 (s, 3H), 3.35 (s, 3H), 3.18 (s, 3H), 1.88 (s, 3H), 1.05 (d, J=5.86,3H), 0.78 (m, 2H), 0.49 (m, 1H), 0.30 (m, 1H).
Wherein X is other intermediates preparation as described in Table 1 of diazole.
Table I: diazole intermediate
Intermediate 6.2.1:[(1R)-1-(2-{2-(benzyl { [trans-2-methyl cyclopropyl] methyl } amino)-6-[methyl (methylsulfonyl) amino] pyridin-4-yl }-1,3- azoles-5-yl)-1-methyl-2-phenylethyl] carbamate
Steps A: coupling
To intermediate 4.2c.2 (0.452g, 1.121mmol) and intermediate 2.3.1 (0.300g, 1.019mmol) add in the solution in 12mL DMF EDC (0.240g, 1.253mmol) and HOAt (0.153g, 1.121mmol).After 15 hours, add water and EtOAc diluting reaction, use 10%KHSO subsequently
4, saturated NaHCO
3, 3M LiCl (3x) and salt water washing.The organic phase dried over sodium sulfate; filter; concentrate; obtain [(1R)-({ (benzyl is { [trans-(1S for 2-for 1-benzyl-3-; 2S)-and the methyl cyclopropyl] methyl } amino)-6-[methyl (methylsulfonyl) amino] different nicotinoyl } amino)-2-hydroxyl-1-methyl-propyl] t-butyl carbamate; be the mixture of two kinds of diastereomers, this product need not to be further purified and directly uses.LCMS(M+H)＝680.
Step B: oxidation
To steps A [(1R)-({ (benzyl is { [trans-(1S for 2-for 1-benzyl-3-; 2S)-and the methyl cyclopropyl] methyl } amino)-6-[methyl (methylsulfonyl) amino] different nicotinoyl } amino)-2-hydroxyl-1-methyl-propyl] t-butyl carbamate (0.693g; 1.019mmol) and triethylamine (0.426mmL is 3.058mmol) at 10mL CH
2Cl
2In solution in be added in sulphur trioxide pyridine complex among the 2.5mL DMSO (0.406g, 2.55mmol).After 15 hours, add the EtOAc diluting reaction, use 10%KHSO subsequently
4, saturated NaHCO
3, 3M LiCl and salt water washing; use dried over sodium sulfate afterwards again; filter and concentrate; residue uses normal phase silica gel chromatography purifying (10-＞40%EA/ hexane); obtain [(1R)-({ (benzyl is { [trans-(1S for 2-for 1-benzyl-3-; 2S)-and the methyl cyclopropyl] methyl } amino)-6-[methyl (methylsulfonyl) amino] different nicotinoyl } amino)-1-methyl-2-oxopropyl] t-butyl carbamate, be the white foam body.
1H?NMR(400MHz，CDCl
3)δ7.32-7.26(m，5H)，7.23-7.19(m，3H)，7.10(d，J＝11.7Hz，2H)，6.81(s，1H)，6.80(s，2H)，4.86(m，2H)，4.62(m，2H)，4.48(m，2H)，3.56(m，2H)，3.33-3.28(m，5H)，3.05(d，J＝13.7Hz)，2.84(s，3H)，1.55(s，3H)，1.31(s，9H)，0.98(d，J＝5.9Hz，3H)，0.62(m，1H)，0.60(m，1H)，0.36(m，1H)，0.26(m，1H).LCMS(M+H)＝678.
Step C: dehydration
To [(1R)-({ (benzyl is { [trans-(1S for 2-for 1-benzyl-3-; 2S)-and the methyl cyclopropyl] methyl } amino)-6-[methyl (methylsulfonyl) amino] different nicotinoyl } amino)-1-methyl-2-oxopropyl] t-butyl carbamate (0.230g; 0.339mmol) at 4mL 1; add methoxycarbonyl amino-sulfonyl triethyl ammonium hydroxide (0.485g in the solution in the 2-ethylene dichloride; 2.04mmol, Burgess reagent).Be reflected at 100 ℃ and use microwave treatment 40 minutes down; then directly by normal phase silica gel chromatography purifying (10-＞40%EtOAc/ hexane); obtain [(1R)-1-(2-{2-(benzyl { [(1S; 2S)-and 2-methyl cyclopropyl] methyl } amino)-6-[methyl (methylsulfonyl) amino] pyridin-4-yl }-1; 3- azoles-5-yl)-and 1-methyl-2-phenylethyl] carbamate, be the white foam body.
1H?NMR(400MHz，CDCl
3)□7.31-7.19(m，9H)，7.05-7.02(m，3H)，6.93(s，1H)，4.89(m，2H)，3.57(dd，J＝14.8，5.9Hz，1H)，3.47(m，1H)，3.34-3.30(m，4H)，3.11(d，J＝13.2Hz，1H)，2.88(s，3H)，1.59(s，3H)，1.34(s，9H)，0.98(d，J＝5.9Hz，3H)，0.82(m，1H)，0.61(m，1H)，0.36(m，1H)，0.27(m，1H).LCMS(M+H)＝660.
Intermediate 6.2.2:[(1R)-1-(2-{2-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] pyridin-4-yl }-1,3- azoles-5-yl)-1-methyl-2-phenylethyl] the t-butyl carbamate ester
With intermediate 4.2c.1 and 2.3.1 is that raw material adopts the described similarity method preparation of preparation intermediate 6.2.1.MS?M+1＝628.
Intermediate 8.4.1:N-{4-(5-{ (1R)-1-[(tertbutyloxycarbonyl) amino]-1-methyl-2-phenylethyl }-1; 3,4- diazole-2-yl)-and 6-[methyl (methylsulfonyl) amino] pyridine-2-yl }-N-[(is trans-2-methyl cyclopropyl) and methyl] glycine (route plan 8)
Steps A: chlorination
Under the room temperature, be added with intermediate 5.2c.22 (1.9g, 3.41mmol) and add in the flask of DCM (34mL) N-chlorosuccinimide (455g, 3.41mmol).Till disappearing, stirring reaction to starting raw material (detects) according to LC/MS.This moment, enriched mixture was to doing use AcCN/H
2O linear gradient liquid is by the RP-HPLC purifying.Compile the part that contains product, freeze-drying obtains 780mg 3-chlorine product.
1H?NMR(CD
3OD，400MHz)δ7.27(m，3H)；7.13(s，1H)；7.08(m，2H)；4.37(s，2H)；4.17(q，J＝7.1Hz，2H)；3.55(dd，J＝14.8，5.9Hz，2H)；3.35(m，2H)；3.20(s，3H)；3.18(s，3H)；1.60(s，3H)；1.41(s，9H)，1.24(t，J＝7.1Hz，3H)；1.05(d，J＝6.7，3H)；0.80(m，2H)；0.47(m，1H)；0.32(m，1H)；LC/MS[M+H]＝691.0
Step B: hydrolysis
(750mg 1.09mmol) is dissolved in 11mL THF with the intermediate of top steps A.In this solution, add 5mL 4.0N LiOH.After spending the night, stirring uses the pH to 4.0 of 1N HCl neutralise mixt.Mixture is repeated (3 * 25mL) extractions, each of merging layer continuation sodium bicarbonate aqueous solution, water and salt water washing with EtOAc.Dried over sodium sulfate, removal of solvent under reduced pressure obtains the title intermediate subsequently, is yellow foams.
1H?NMR(CD
3OD，400MHz)δ7.27(m，3H)；7.18(m，3H)；4.32(s，2H)；3.50(m，2H)；3.35(m，2H)；3.20(s，3H)；3.18(s，3H)；1.60(s，3H)；1.41(s，9H)；1.09(d，J＝6.3，3H)；0.80(m，2H)；0.47(m，1H)；0.32(m，1H)；LC/MS[M+H]＝663.0.
Intermediate 8.4.2:[(1R)-1-(5-{2-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino }-the 6-[(methylsulfonyl) amino] pyridin-4-yl }-1; 3,4- diazole-2-yl)-1-methyl-2-phenylethyl] t-butyl carbamate (route plan 8)
Preparation according to intermediate 8.4.1 is described, is raw material with intermediate 5.1c.2, uses the NCS preparation.MS?M+1＝615.
Intermediate 9.1.1:3-fluoro-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino }-2-[methyl (methylsulfonyl) amino] Yi Yansuan (route plan 9)
With 2-{ (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] Yi Yansuan (intermediate 4.2c.1; 0.05g; 0.135mmol) acetonitrile (3mL) solution with 1-chloromethyl-4-fluoro-1; two (a tetrafluoro borate) (0.047g of 4-diazabicylo [2.2.2] octane; 0.134mmol) handle stirring at room 16 hours.Reaction obtains 3-fluoro-6-{ (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amino by anti-phase LC purifying }-2-[methyl (methylsulfonyl) amino] Yi Yansuan, be faint yellow solid: LCMS[M+H]
+=390.3.
Intermediate 9.1.2:6-{ benzyl [(trans-2-methyl cyclopropyl) methyl] amino }-3-fluoro-2-[methyl (methylsulfonyl) amino] Yi Yansuan (route plan 9)
With intermediate 4.2c.2 is that raw material adopts the described similarity method preparation of preparation intermediate 9.1.1.MS?M+1＝422.
Intermediate 9.3.1:[(1R)-and 1-(5-{3-bromo-6-{[(trans-2-methyl cyclopropyl) methyl] amino }-2-[methyl (methylsulfonyl) amino] pyridin-4-yl }-1; 3,4- diazole-2-yl)-1-methyl-2-phenylethyl] t-butyl carbamate (route plan 9)
To [(1R)-and 1-methyl isophthalic acid-(5-{2-{[(trans-2-methyl cyclopropyl) methyl] amino }-6-[methyl (methylsulfonyl) amino] pyridin-4-yl }-1; 3; 4- diazole-2-yl)-and the 2-phenylethyl] (Boc removes intermediate 5.2c.3 before to t-butyl carbamate; 250mg is 0.438mmol) at 8mL CH
2Cl
2In solution in add NBS (78mg, 0.438mmol).After 2 hours; concentrate this reactant; by normal phase silica gel chromatography purifying (20-＞40%EtOAc/ hexane); obtain [(1R)-and 1-(5-{3-bromo-6-{[(trans-2-methyl cyclopropyl) methyl] amino }-2-[methyl (methylsulfonyl) amino] pyridin-4-yl }-1; 3; 4- diazole-2-yl)-and 1-methyl-2-phenylethyl] t-butyl carbamate, be yellow solid.
1H NMR (CDCl
3, 400MHz) δ 7.31-7.26 (m, 3H), 7.06-7.04 (m, 2H), 6.90 (s, 1H), 4.94 (m, 1H), 3.57 (d, J=13.2Hz, 1H), 3.42 (d, J=13.1Hz, 1H), 3.24 (s, 3H), 3.23 (s, 3H), 3.18 (m, 1H), 3.07 (m, 1H), 1.71 (s, 3H), 1.43 (s, 9H), 1.09 (d, J=6.0Hz, 3H), 0.80 (m, 1H), 0.70 (m, 1H), 0.41 (m, 1H), 0.33 (m, 1H) .LCMS (M+H)=649,651 (bromine pattern).
Intermediate 10.2.1:N-[3-chloro-4-(5-{1-[(phenylbenzene methylene radical) amino] ethyl }-1,3,4- diazole-2-yl)-6-((3-methoxy-propyl) { trans-2-methyl cyclopropyl] methyl amino) pyridine-2-yl]-N-methyl Toluidrin (route plan 10)
Steps A: chlorination
To N-[4-[5-(1-amino-ethyl)-1,3,4- diazole-2-yl]-6-((2-methoxy ethyl) { [trans-2-methyl cyclopropyl] methyl } amino) pyridine-2-yl]-(intermediate 10.1.1,3.600g is 6.51mmol) at 100mL CH for N-methyl Toluidrin trifluoroacetate
2Cl
2In solution in add N-chlorosuccinimide (0.870g, 6.51mmol).After 12 hours, concentration response thing, gained residue were by expectation in 3: 1: the mixture of the chlorine positional isomers of non-expectation is formed, and (Sunfire C18 Prep OBD post, 30 * 150mm 35mL/min) obtains required compound to employing HPLC purifying.The component that will comprise required chlorine positional isomers is assigned to EtOAc and saturated NaHCO
3In, separate each layer, organic layer salt water washing, concentrate and obtain N-[4-[5-(1-amino-ethyl)-1,3,4- diazole-2-yl]-3-chloro-6-((2-methoxy ethyl) { [trans-2-methyl cyclopropyl] methyl } amino) pyridine-2-yl]-N-methyl Toluidrin, be yellow foams.
1H NMR (400MHz, CDCl
3) δ 7.12 (s, 1H), 4.40 (br s, 1H), 3.71 (m, 2H), 3.54 (m, 2H), 3.43 (dd, J=14.8,6Hz, 1H), 3.33-3.28 (m, 4H), 3.24 (s, 3H), 3.19 (s, 3H), 1.61 (d, J=5.9Hz, 3H), 1.02 (d, J=5.9Hz, 3H), 0.74-0.64 (m, 2H), 0.41 (m, 1H), 0.29 (m, 1H) .LCMS[M+H]
+=473 (chlorine patterns).
Step B: the formation of hydrochloride
Under 0 ℃, to N-[4-[5-(1-amino-ethyl)-1,3,4- diazole-2-yl]-3-chloro-6-((2-methoxy ethyl) { [trans-2-methyl cyclopropyl] methyl } amino) pyridine-2-yl]-(0.060g is 0.102mmol) at 1mL CH for N-methyl Toluidrin
2Cl
2In solution in add 4M HCl two alkane solution (0.038mL, 0.153mmol).Concentrate this reactant and obtain N-[4-[5-(1-amino-ethyl)-1,3,4- diazole-2-yl]-3-chloro-6-((2-methoxy ethyl) { [trans-2-methyl cyclopropyl] methyl } amino) pyridine-2-yl]-N-methyl Toluidrin hydrochloride, be yellow foams.LCMS[M+H]
+=473 (chlorine pattern (chlorine pattern)).
Step B: the formation of Schiff's base
Product (0.720g, CH 1.413mmol) to step B
2Cl
2Add in the solution benzophenone imine (0.356mL, 2.12mmol).At room temperature reacted 15 hours, thin up continues and extracts with EtOAc (3x) then.The organic phase salt water washing that merges, dried over sodium sulfate is filtered, and concentrates.Residue is passed through silica gel chromatography purifying (5-＞50%EtOAc/ hexane), obtain N-[4-(5-{1-[(phenylbenzene methylene radical) amino] ethyl }-1,3,4- diazole-2-yl)-6-((2-methoxy ethyl) { [trans-2-methyl cyclopropyl] methyl } amino) pyridine-2-yl]-N-methyl Toluidrin, be yellow foams.
1H NMR (400MHz, CDCl3) δ 7.62 (d, J=7.1Hz, 2H), 7.52-7.45 (m, 2H), 7.40-7.37 (m, 2H), 7.33-7.24 (m, 4H), 7.14 (s, 1H), 4.93 (q, J=6.4Hz, 1H), 3.71 (m, 2H), 3.54 (t, J=6.1Hz, 2H), 3.45-3.42 (m, 1H), 3.34-3.27 (m, 4H), 3.24 (s, 3H), 3.20 (s, 3H), 1.68 (d, J=6.6Hz, 3H), 1.01 (d, J=5.9Hz, 3H), 0.89-0.64 (m, 2H), 0.40 (m, 1H), 0.26 (m, 1H) .LCMS[M+H]
+=637 (chlorine patterns).
Embodiment 1
N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-3-chloro-6-{{ is trans-the 2-methoxy ethyl) and [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (route plan 8)
With N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methylpropane-2-sulphonamide trifluoroacetate (intermediate 5.2c.1,10.77g, 16.75mmol) DCM (145mL) solution with NCS (2.35g, 17.6mmol) handle, and at room temperature stirred this solution 24 hours.Add 115mg NCS again, at room temperature continued stirring reaction 8 hours.The vacuum-evaporation reactant, subsequently by the reversed-phase HPLC purifying, obtain N-(4-[5-(1R-amino-1-methyl-2-phenylethyl)-1,3,4- diazole-2-yl]-3-chloro-6-{ (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin trifluoroacetate, be faint yellow solid.
1H?NMR(400MHz，CD
3OD)δ7.34(t，J＝3.11，3H)，7.12(s，1H)，7.08(m，2H)，3.79(t，J＝5.9Hz，2H)，3.62(t，J＝5.7Hz，2H)，3.53(dd，J＝14.8，5.9Hz，1H)，3.44(s，2H)，3.40(dd，J＝15.0，7.0Hz，1H)，3.34(s，3H)，3.26(s，3H)，3.24(s，3H)，1.87(s，3H)，1.05(d，J＝5.9Hz，3H)，0.79(m，2H)，0.49(m，1H)，0.31(m，1H).LCMS[M+H]
+＝563.3.
Use intermediate 3.2.1, the preferably trans-S of steps A, the S enantiomorph is realized the S of preferred enantiomer-pure, S, the preparation of R embodiment.
Embodiment 2
N-(4-{5-[(1R)-1-amino-2-(4-fluorophenyl)-1-methylethyl]-1,3,4- diazole-2-yl }-3-chloro-6-{ (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin (route plan 8)
With N-(4-{5-[(1R)-1-amino-2-(4-fluorophenyl)-1-methylethyl]-1,3,4- diazole-2-yl }-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin trifluoroacetate (intermediate 5.2c.2,9.79g, 17.9mmol) solution in DCM (250mL) is with NCS (2.39g, 17.9mmol) handle, and at room temperature stirred this solution 60 hours.In the stirring at room reaction, in 72 hours, divide three parts again and add 360mg NCS.The vacuum-evaporation reactant separates the chlorine isomer of needs subsequently by the reversed-phase HPLC purifying.The gained material is further passed through purification by flash chromatography (silica gel, 0%-3% Virahol/CHCl
3), obtain N-(4-{5-[(1R)-1-amino-2-(4-fluorophenyl)-1-methylethyl]-1,3,4- diazole-2-yl }-3-chloro-6-{ (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl Toluidrin.
1H NMR (400MHz, CDCl
3) δ 7.13 (s, 1H), 7.02 (m, 2H), 6.93 (m, 2H), 3.74 (t, J=6.05,2H), 3.57 (t, J=6.04,2H), 3.41 (AB overlapping multimodal m, 5H), 3.28 (m, 4H), 3.22 (s, 3H), 3.07 (B of AB overlapping multimodal m, 1H), 1.86 (s, 2H), 1.64 (s, 3H), 1.05 (d, J=5.86,3H), 0.78-0.67 (m, 2H), 0.43 (m, 1H), 0.31 (m, 1H) .LCMS[M+H]
+=581.0.
The 3-Cl substituted pyridine derivative that more has the oxadiazole as preparation as described in the following table 2.
Table 2-3-Cl derivative
| Ex# | Intermediate | Preparation method | Structure | ES M+1 |
Embodiment 37
N-(4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3,4- diazole-2-yl }-3-chloro-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methyl isophthalic acid-pyridine-2-base Toluidrin
Steps A: Mitsunobu
Under 0 ℃; to (1R)-1-(5-{3-chloro-6-((2-methoxy ethyl) { [trans-2-methyl cyclopropyl] methyl } amino)-2-[(methylsulfonyl) amino] pyridin-4-yl }-1; 3; 4- diazole-2-yl)-1-methyl-2-phenylethyl t-butyl carbamate (intermediate 8.4.2; 0.028g; 0.043mmol) toluene (1ml) solution in add 2-(methylol) pyridine (0.004ml; 0.043mmol) and triphenyl phosphine (0.011g; 0.043mmol); then add the diisopropyl azo-2-carboxylic acid (0.008ml, 0.043mmol).Remove ice bath, stirring at room solution spends the night.Next day, this solution of vacuum concentration absorbed among the DMF again, filtered then.Product is by the reversed-phase HPLC purifying; obtain 0.015g (1R)-1-(5-{3-chloro-6-((2-methoxy ethyl) { [trans-2-methyl cyclopropyl] methyl } amino)-2-[(methylsulfonyl) (pyridine-2-ylmethyl) amino] pyridin-4-yl }-1; 3; 4- diazole-2-yl)-and 1-methyl-2-phenylethyl t-butyl carbamate, LCMS[M+H] 740.2.
Step B:Boc removes
To (1R)-1-(5-{3-chloro-6-((2-methoxy ethyl) { [trans-2-methyl cyclopropyl] methyl } amino)-2-[(methylsulfonyl) (pyridine-2-ylmethyl) amino] pyridin-4-yl }-1; 3,4- diazole-2-yl)-CH of 1-methyl-2-phenylethyl t-butyl carbamate
2Cl
2(1ml) add TFA (0.5ml) in the solution, at room temperature stirred 30 minutes.Evaporating solvent obtains 0.008g N-[4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3,4- diazole-2-yl }-3-chloro-6-((2-methoxy ethyl) { [trans-2-methyl cyclopropyl] methyl } amino) pyridine-2-yl]-N-(pyridine-2-ylmethyl) amsacrine.LCMS[M+H]640.2。C
31H
38ClN
7O
4The accurate mass spectrum calculated value of S: 640.2468; Measured value: 640.2482.
Table 3 3-Cl derivative
Embodiment 49
N-(4-{5-[1-amino-2-(3, the 5-dibromo phenyl)-and the 1-methylethyl]-1,3,4- diazole-2-yl }-3-ammonia-6-{ (2-methoxy ethyl) [(trans-2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methylmethane sulphonamide (route plan 10)
Under 0 ℃, to N-[4-(5-{1-[(phenylbenzene methylene radical) amino] ethyl }-1,3,4- diazole-2-yl)-((2-methoxy ethyl) is { [trans-(1S for 6-, 2S)-and 2-methyl cyclopropyl] methyl } amino) pyridine-2-yl]-N-methylmethane sulphonamide (0.106g, 0.162mmol) be added in the solution in 2mL DMF 1M NaHMDS among the THF (0.211mL, 0.211mmol).After 5 minutes, be added in 3 among the 1mL DMF by sleeve pipe in the dark blue solution that generates, (0.072g, 0.219mmol), solution is becoming yellow after finishing through sleeve pipe is reinforced to 5-dibromo-benzyl bromine.After 30 minutes, add 1mL 1N HCl, allow reaction carry out 15 hours to finish the hydrolysis of Schiff's base.Reactant is poured on the 10g SCX ion-exchange ketone, with 150mL MeOH wash-out, continued earlier with the 2M NH of 150mL in MeOH
3Wash-out, obtain analytically pure N-[4-{5-[(1R)-1-amino-2-(3, the 5-dibromo phenyl)-and the 1-methylethyl]-1,3,4- diazole-2-yl }-((2-methoxy ethyl) is { [trans-(1S for 3-chloro-6-, 2S)-and 2-methyl cyclopropyl] methyl } amino) pyridine-2-yl]-N-methylmethane sulphonamide, be yellow foams.The diastereomer that is produced by this alkylation can adopt ChiralPak AD chiral stationary phase to separate.
1H?NMR(400MHz，CDCl3)δ7.55(s，J＝7.1Hz，1H)，7.17(s，2H)，7.04(s，1H)，3.71(m，2H)，3.52(t，J＝5.9Hz，2H)，3.42(dd，J＝14.8，5.7Hz，1H)，3.33-3.29(m，4H)，3.24(s，3H)，3.19(s，3H)，1.80(s，3H)，1.01(d，J＝5.9Hz，3H)，0.72-0.65(m，2H)，0.40(m，1H)，0.28(m，1H)。LCMS [M+H]
+=721 (title complex patterns).C
26H
34Br
2ClN
6O
4The accurate mass spectrum calculated value of S: 719.0412; Measured value: 719.0446.
As described in following table 3, use suitable alkylating agent, prepare the Q-R that other have di azoly and replacement
1The 3-Cl substituted pyridine derivative of group.
Table 4-3-Cl derivative
| Ex# | Intermediate | Preparation method | Structure | ES M+1 |
Embodiment 66
N
2-4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3,4- diazole-2-yl }-5-chloro-6-[methyl (methylsulfonyl) amino] pyridine-2-yl }-N, N-dimethyl-N
2-[(trans-2-methyl cyclopropyl) methyl] amino] G-NH2
Steps A: coupling
To be equipped with intermediate 8.4.1 (25mg, 0.04mmol), dimethylamine (5.1mg, 0.11mmol), HOAt (2.6mg, 0.02mmol) and add in 13 * 100mm screw-cap developmental tube of DMF (0.2mL) EDC-HCl (10.2mg, 0.05mmol).Stir after 3 hours, add KHSO
4The diluting reaction thing, continuing, (2 * 10mL) extract with EtOAc.Organic layer salt water washing, dried over sodium sulfate is concentrated into driedly, obtains Boc-protection acid amides crude product: LC/MS[M+H]=689.1 (chlorine patterns)
Step B:Boc removes
The acid amides of top steps A is dissolved in 0.3mL CH
2Cl
2, on ice bath, cool off, (16 μ L 0.2mmol) handle with TFA.Starting raw material disappearance back concentration response thing under nitrogen gas stream, and by the RP-HPLC purifying.Freeze-drying comprises the part of product, obtains the white solid title compound:
1H?NMR(400MHz，CDCl3)δ7.32(m，3H)，7.10(s，1H)，7.08(m，2H)，4.54(s，2H)，3.55(dd，J＝(br?s，1H)，3.71(m，2H)，3.54(m，2H)，3.45(s，3H)，3.33-3.28(m，2H)，3.19(s，3H)，3.13(s，3H)，3.14(s，3H)，2.92(s，3H)，1.87(s，3H)，1.05(d，J＝5.9Hz，3H)，0.80(m，2H)，0.48(m，1H)，0.32(m，1H)；LC/MS[M+H]＝590.0
Table 5-amide derivatives
Embodiment 71
N-(4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3,4- diazole-2-yl }-3-chloro-6-{ (2-cyclopropyl-2-oxoethyl) [(trans-2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methylmethane sulphonamide
Steps A: the formation of Weinreb acid amides
Under embodiment 66 described conditions of similarities, coupling intermediate 8.4.1 and N, the O-dimethyl hydroxylamine obtains Weinreb acid amides: LC/MS[M+H]=706.0.
Step B: Ge Liya addition
Under the room temperature, containing the Weinreb reactant of steps A (40mg, disposable adding 5 normal cyclopropyl Ge Liya (0.29mmol, 1.0M ether) 0.06mmol) and in the flask of toluene (0.5mL).After 20 minutes, add 2mL NH
4The Cl aqueous solution adds H subsequently again
2O and EtOAc.Separate organic layer, use the salt water washing.With organic layer dried over sodium sulfate, concentrating under reduced pressure.The gained crude product obtains protected ketone: LC/MS[M+H through the RP-HPLC purifying]=680.7.
Step C:Boc removes
(10mg 0.01mmol) is dissolved in 1.0mL CH with the intermediate of step B
2Cl
2, in ice bath, cool off, and handle with TFA (10 μ L).Treat the concentrating under reduced pressure reaction under nitrogen gas stream of starting raw material disappearance back, again by the RP-HPLC purifying.Freeze-drying comprises the part of product, obtains the white solid title compound:
1H?MR(400MHz，CD
3OD)δ7.31(m，3H)，7.06(m，3H)，4.65(s，2H)，3.52(m，2H)，3.42(br?s，2H)，3.17(s，3H)，3.13(s，3H)，2.16(m，1H)，1.85(s，3H)，1.02(d，J＝6.0Hz，3H)，0.98(m，4H)，0.70(m，2H)，0.45(m，1H)，0.30(m，1H)；LC/MS[M+H]＝587.0.
Embodiment 72
N-(4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3,4- diazole-2-yl }-3-chloro-6-{[(is trans-2-methyl cyclopropyl) and methyl] [2-(5-methyl isophthalic acid, 3,4- diazole-2-yl)-2-oxoethyl] amino } pyridine-2-yl)-N-methylmethane sulphonamide
Steps A: coupling 8.4.1 and acethydrazide
Under embodiment 66 described conditions of similarities, coupling intermediate 8.4.1 and acethydrazide obtain two acidylate hydrazine: LC/MS[M+H]=719.0
Step B: cyclodehydration
To the reactant that contains steps A (60mg, 0.08mmol), polystyrene bonding triphenyl phosphine (100mg, 0.13mmol, 1.3mmol/g, 200 orders) and imidazoles (8mg, 0 ℃ of CH 0.12mmol)
2Cl
2Disposable adding CBr in the solution
4(39mg, 0.12mmol).Stirring reaction 48 disappears.Filter this mixture this moment, concentrates and by the RP-HPLC purifying.Compile the part that comprises product, after with sodium bicarbonate aqueous solution/EtOAc aftertreatment, separate.The salt water washing of last organic layer, dried over sodium sulfate concentrates the intermediate that obtains cyclisation: LC/MS[M+H]=701.0.
Step C:Boc removes
(56mg 0.08mmol) is dissolved in 6.0mL CH with the intermediate of step B
2Cl
2, in ice bath, cool off, and handle with TFA (100 μ L).Treat the concentrating under reduced pressure reaction under nitrogen gas stream of starting raw material disappearance back, again by the RP-HPLC purifying.Freeze-drying comprises the part of product, obtains white solid title compound: LC/MS[M+H]=600.9 (chlorine patterns).
Embodiment 73
N-(4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3,4- diazole-2-yl }-3-chloro-6-{[(2-methyl cyclopropyl) methyl] [2-(1,3,4- diazole-2-yl)-2-oxoethyl] amino } pyridine-2-yl)-N-methylmethane sulphonamide
According to preparation N-(4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3,4- diazole-2-yl }-3-chloro-6-{[(is trans-2-methyl cyclopropyl) and methyl] [2-(5-methyl isophthalic acid, 3,4- diazole-2-yl)-and the 2-oxoethyl] amino } pyridine-2-yl)-N-methylmethane sulphonamide (embodiment 72) is described, is feedstock production with intermediate 8.4.1 and formyl hydrazine.MS?M+1＝587.
Embodiment 74
N-(4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3- azoles-2-yl }-3-chloro-6-({ [trans-2-methyl cyclopropyl] methyl } amino) pyridine-2-yl]-N-methylmethane sulphonamide
Steps A: debenzylation
To [(1R)-((benzyl is { [trans-(1S for 2-{2-for 1-; 2S)-and 2-methyl cyclopropyl] methyl } amino)-6-[methyl (methylsulfonyl) amino] pyridin-4-yl }-1; 3- azoles-5-yl)-and 1-methyl-2-phenylethyl] t-butyl carbamate (intermediate 6.2.1; 0.050g; 0.076mmol) add in the solution in 5mL EtOH trifluoroacetic acid (0.006mL, 0.076mmol) and 20%Pd (OH)
2-carbon (0.011g).Connect hydrogen gas tank, the flask of finding time is opened H
2(3x).After 15 hours; the reactant of finding time once more; connect argon gas (3x); filter by Celite pad; concentrated obtaining [(1R)-the 1-methyl-(2-{2-is ({ [trans-(1S; 2S)-and 2-methyl cyclopropyl] methyl } amino)-6-[methyl (methylsulfonyl) amino] pyridin-4-yl }-1,3- azoles-5-yl)-the 2-phenylethyl] t-butyl carbamate.
1H?NMR(400MHz，CDCl
3)δ7.31-7.26(m，4H)，7.12(s，1H)，7.04-7.03(m，2H)，6.98(s，1H)，3.50(m，1H)，3.43-3.34(m，4H)，3.23-3.13(m，4H)，3.11(d，J＝13.2Hz，1H)，1.60(s，3H)，1.41(s，9H)，1.09(d，J＝5.9Hz，3H)，0.85(m，1H)，0.72(m，1H)，0.48(m，1H)，0.39(m，1H).LCMS(M+H)＝570.
Step B:Boc deprotection
To [(1R)-the 1-methyl-(2-{2-is ({ [trans-(1S; 2S)-and 2-methyl cyclopropyl] methyl } amino)-6-[methyl (methylsulfonyl) amino] pyridin-4-yl }-1; 3- azoles-5-yl)-and the 2-phenylethyl] (0.040g is 0.070mmol) at 0.5mL CH for t-butyl carbamate
2Cl
2In solution in add the 0.5mL trifluoroacetic acid.After 1 hour, this reactant of freeze-drying obtains N-[4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3- azoles-2-yl }-6-([(1S, 2S)-2-methyl cyclopropyl] methyl } amino) pyridine-2-yl]-N-methylmethane sulphonamide, be yellow solid.
1HNMR(400MHz，d
4-MeOH)δ7.29-7.26(m，3H)，7.22(s，1H)，7.06(d，J＝1.1Hz，1H)，7.03-7.01(m，2H)，6.95(d，J＝1.1Hz，1H)，3.47(d，J＝13.4Hz，1H)，3.37(s，3H)，3.28-3.23(m，3H)，3.19(s，3H)，1.72(s，3H)，1.06(d，J＝5.9Hz，3H)，0.85(m，1H)，0.71(m，1H)，0.43(m，1H)，0.27(m，1H).LCMS(M+H)＝470.
Step C: chlorination
To N-[4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3- azoles-2-yl }-6-([(1S, 2S)-2-methyl cyclopropyl] methyl } amino) pyridine-2-yl]-(0.009g is 0.015mmol) at 0.3mL CH for N-methylmethane sulphonamide
2Cl
2In solution in add the methylene dichloride stock solution of 0.09mL 0.15MNCS.After 15 hours, further add 0.10mL CH
2Cl
2Methylene dichloride stock solution with 0.1mL 0.15M NCS.After 24 hours, the concentration response thing, be dissolved in DMF again, obtain N-[4-{5-[(1R through preparation HPLC purifying)-1-amino-1-methyl-2-phenylethyl]-1,3- azoles-2-yl }-3-chloro-6-({ [(1S, 2S)-and 2-methyl cyclopropyl] methyl } amino) pyridine-2-yl]-N-methylmethane sulphonamide, be yellow solid.
1HNMR (400MHz, d
4-MeOH) δ 7.30-7.29 (m, 3H), 7.24 (s, 1H), 7.04-7.02 (m, 3H), 3.47 (d, J=13.3Hz, 1H), 3.28 (s, 3H), and 3.26-3.20 (m, 5H), 1.71 (s, 3H), 1.06 (d, J=5.9Hz, 3H), 0.85 (m, 1H), 0.71 (m, 1H), 0.43 (m, 1H), 0.27 (m, 1H) .LCMS (M+H)=505 (chlorine pattern).
Embodiment 75
N-(4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3- azoles-2-yl }-3-chloro-6{ (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methylmethane sulphonamide
With intermediate 6.2.2 is that raw material prepares in the following order: aforesaid Boc removes the chlorination with NCS.MS?M+1＝562.
Embodiment 76
N-(4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3- azoles-2-yl }-3-chloro-6-{ (2-methoxy ethyl) [(2-methyl cyclopropyl) methyl] amino } pyridine-2-yl)-N-methylmethane sulphonamide
With intermediate 9.1.1 and Boc-D-Alpha-Methyl-phenylalanine is raw material, adopts as the described similarity method preparation of preparation intermediate 5.2c.1.MS?M+1＝547.
Embodiment 77
N-(4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3,4- diazole-2-yl }-3-fluoro-6-{[(is trans-2-methyl cyclopropyl) and methyl] amino } pyridine-2-yl)-N-methylmethane sulphonamide (route plan 9)
With intermediate 9.1.2 and Boc-D-Alpha-Methyl-phenylalanine is raw material, adopt as the described similarity method preparation of preparation intermediate 5.2c.1, but the debenzylating reaction that before Boc removes, will carry out the hydrogenation mediation.MS?M+1＝489.
Embodiment 78
N-(4-{5-[(1R)-1-amino-1-methyl-2-phenylethyl]-1,3,4- diazole-2-yl }-3-cyano group-6-{[(is trans-2-methyl cyclopropyl) and methyl] amino } pyridine-2-yl)-N-methylmethane sulphonamide (route plan 9)
To [(1R)-and 1-(5-{3-bromo-6-{[(trans-2-methyl cyclopropyl) methyl] amino }-2-[methyl (methylsulfonyl) amino] pyridin-4-yl }-1; 3; 4- diazole-2-yl)-and 1-methyl-2-phenylethyl] t-butyl carbamate (intermediate 9.3.1; 18mg, 0.028mmol) the middle Zn (CN) that adds
2(7mg, 0.055mg), the Zn powder (scraper looking somebody up and down ,～1mg ,～0.014mmol) and Pd (t-Bu
3)
2(3mg, 0.006mmol).Add the N,N-DIMETHYLACETAMIDE (0.3mL) that took off gas.Reactant is further used argon-degassed, uses microwave treatment 90 minutes down at 130 ℃ then.The filtering reaction thing; obtain [(1R)-1-(5-{3-cyano group-6-{[(trans-2-methyl cyclopropyl) methyl] amino through anti-phase preparation HPLC purifying }-2-[methyl (methylsulfonyl) amino] pyridin-4-yl }-1; 3; 4- diazole-2-yl)-and 1-methyl-2-phenylethyl] t-butyl carbamate and final compound N-(4-{5-[(1R)-and 1-amino-1-methyl-2-phenylethyl]-1; 3,4- diazole-2-yl }-3-cyano group-6-{[(is trans-2-methyl cyclopropyl) and methyl] amino } pyridine-2-yl)-mixture of N-methylmethane sulphonamide.Use 1: 1 TFA/CH
2Cl
2Solution is processed into latter's derivative with the former.
1H?NMR(CDCl
3，400MHz)δ7.34-7.32(m，3H)，7.15(br?s)，7.10-7.07(m，3H)，3.45(s，，2H)，3.34(s，3H)，3.33(m，2H)，3.27(s，3H)，1.87(s，3H)，1.06(d，J＝5.9Hz，3H)，0.83(m，1H)，0.71(m，1H)，0.46(m，1H)，0.31(m，1H)；LCMS(2M+H)＝991；
C
24H
30N
7O
3The accurate mass spectrum calculated value of S: 496.126; Measured value: 496.2149.
Use following abbreviation herein:
Me: methyl
Bu: butyl
I-Bu: isobutyl-
T-Bu: the tertiary butyl
Et: ethyl
Pr: propyl group
I-Pr: sec.-propyl
Ar: aryl
Ph: phenyl
Py: pyridine
Ac: ethanoyl
NaHMDS: hexamethyldisilane base ammonification sodium
EDC: ethyl-3-(3-dimethylamino-propyl)-carbodiimide
HOAt:1-hydroxyl-7-azepine benzotriazole
DMF:N, the N1-dimethyl formamide
THF: tetrahydrofuran (THF)
DMSO: methyl-sulphoxide
EDTA: ethylenediamine tetraacetic acid (EDTA)
Boc: tertbutyloxycarbonyl
BOP: phosphofluoric acid benzotriazole-1-base oxygen base-three (dimethylamino) phosphorus
CHAPS:3-[(3-courage amidopropyl) dimethylammonio]-2-hydroxyl-1-propane sulfonate
TFA: trifluoroacetic acid
The NCS:N-chlorosuccinimide
DCE: ethylene dichloride
DIPEA: diisopropylethylamine
DCM: methylene dichloride
DMA:N, the N-N,N-DIMETHYLACETAMIDE
Aq: moisture
Rt: room temperature
HPLC: high performance liquid chromatography
Though the present invention is described and illustrates with reference to some specific embodiments, but those skilled in the art should be understood that, under the situation that does not depart from spirit of the present invention and scope, can carry out various modifications, change, modification, substitute, omit or add its method and scheme.Therefore, the present invention is limited by the scope of following claim, and the reasonably extensive interpretation of these claims.
Claims (19)
1. the compound of formula (I) and its pharmaceutically-acceptable salts, with and single enantiomorph and diastereomer:
Wherein
X is selected from:
Y is selected from:
(1) halogen,
(2) cyano group,
(3)-C
1-6Alkyl and
(4)-C
6-10Aryl;
A is selected from:
(1) hydrogen,
(2)-C
1-10Alkyl and
(3)-C
2-10Alkenyl,
Wherein said alkyl or alkenyl are unsubstituted or are replaced by one or more following groups:
(a) halogen,
(b)-C
3-12Cycloalkyl,
(c)-OH，
(d)-CN，
(e)-O-C
1-10Alkyl,
(f) phenyl, or
(g) heteroaryl,
And described phenyl and heteroaryl are unsubstituted or are replaced by one or more following groups:
(i) halogen,
(ii)-OH，
(iii)-CN，
(iv)-O-C
1-10Alkyl,
(v)-C
1-10Alkyl, or
(vi)-C
3-12Cycloalkyl;
Q is-C
0-3Alkyl, wherein this alkyl is unsubstituted or is replaced by one or more following groups:
(1) halogen,
(2)-C
3-12Cycloalkyl,
(3)-OH，
(4)-CN，
(5)-O-C
1-10Alkyl and
(6)-C
1-10Alkyl;
R
1Be selected from:
(1) be selected from the aryl of phenyl and naphthyl,
(2) heteroaryl,
(3)-C
1-10Alkyl and
(4)-C
3-8Cycloalkyl, the optional and C of this cycloalkyl
6-10It is aryl-condensed,
Wherein said alkyl, cycloalkyl, aryl or heteroaryl are unsubstituted or are replaced by one or more following groups:
(a) halogen,
(b)-C
1-10Alkyl, wherein this alkyl is unsubstituted or is replaced by halogen,
(c)-OH，
(d)-CN，
(e)-O-C
1-10Alkyl,
(f)-C
3-12Cycloalkyl, or
(g)-NR
10R
11, R wherein
10And R
11Be selected from:
(i) hydrogen,
(ii)-C
1-10Alkyl and
(iii)-C
0-6Alkylidene group-C
6-10Aryl;
R
8And R
9Be selected from:
(1) hydrogen,
(2) C
1-10Alkyl and
(3) C
0-6Alkylidene group-C
6-10Aryl;
R
4Be selected from:
(1)-C
1-10Alkyl,
(2) heteroaryl and
(3)-NR
12R
13, R wherein
12And R
13Be selected from:
(a) hydrogen,
(b) C
1-10Alkyl and
(c) C
0-6Alkylidene group-C
6-10Aryl,
Perhaps R
12And R
13Represent 4,5 or 6 to be selected from CR
aR
b, S, NR
cWith the annular atoms of O, and constitute non-aromatic ring with the nitrogen that they connected,
Wherein said alkyl, alkylidene group and heteroaryl are unsubstituted or are replaced by one or more following groups:
(a) halogen,
(b)-OH，
(c)-CN，
(d)-O-C
1-10Alkyl,
(e)-C
1-10Alkyl
(f)-C
3-12Cycloalkyl,
(g) be selected from the aryl of phenyl and naphthyl,
(h) heteroaryl, or
(i)-C (=O)-C
1-10Alkyl,
And wherein said aryl and heteroaryl are unsubstituted or are replaced by one or more following groups:
(i) halogen,
(ii)-OH，
(iii)-CN，
(iv)-O-C
1-10Alkyl,
(v)-C
3-12Cycloalkyl, or
(vi)-C
1-10Alkyl;
R
7Be selected from group:
(1) hydrogen,
(2)-C
1-10Alkyl,
(3)-C
3-7Cycloalkyl,
(4)-C
6-10Aryl and
(5) heteroaryl,
Wherein said alkyl, cycloalkyl, aryl and heteroaryl are unsubstituted or are replaced by one or more following groups:
(a) halogen,
(b)-OH，
(c)-CN，
(d)-O-C
1-10Alkyl,
(e)-C
3-12Cycloalkyl,
(f) be selected from CR by 4,5 or 6
aR
b, S, NR
cThe non-aromatics cyclic group that constitutes with the annular atoms of O,
(g) be selected from the aryl of phenyl and naphthyl, or
(h)-C
5-12Heteroaryl,
Wherein said cycloalkyl, aryl or heterocyclic radical are unsubstituted or are replaced by one or more following groups:
(i) halogen,
(ii)-OH，
(iii)-CN，
(iv)-O-C
1-10Alkyl,
(v)-C
3-12Cycloalkyl, or
(vi) be selected from the aryl of phenyl and naphthyl;
Perhaps, R
4And R
7Can connect into-CH
2CH
2CH
2-group;
R
5And R
6Be independently selected from:
(1) hydrogen,
(2)-C
1-10Alkyl,
(3)-C
2-10Thiazolinyl,
(4)-C
2-10Alkynyl and
(5)-C
1-10Alkylidene group-C
3-12Cycloalkyl;
Wherein said alkyl, alkylidene group, cycloalkyl, alkenyl or alkynyl are unsubstituted or are replaced by one or more following groups:
(a) halogen,
(b)-OH，
(c)-CN，
(d)-C
1-10Alkyl,
(e)-C
3-12Cycloalkyl,
(f)-O-C
1-10Alkyl, wherein this alkyl is unsubstituted or quilt-O-C
1-10Alkyl-(O-C
1-10Alkyl)
mReplace,
(g) heteroaryl, wherein this heteroaryl can be unsubstituted or be replaced by one or more following groups:
(A) halogen, or
(B)-C
1-10Alkyl,
(h) phenyl,
(i)-NR
14R
15, R wherein
14And R
15Be selected from:
(A) hydrogen,
(B)-C
1-10Alkyl and
(C)-C
0-6Alkyl-C
6-10Aryl,
(j)-C (=O)-OR
16, R wherein
16Be selected from:
(A) hydrogen,
(B)-C
1-10Alkyl and
(C)-C
0-6Alkylidene group-C
6-10Aryl and
(k)-C (=O)-NR
17R
18, R wherein
17And R
18Be selected from:
(A) hydrogen,
(B)-C
1-10Alkyl and
(C)-C
0-6Alkylidene group-C
6-10Aryl,
Perhaps, R
17And R
18Represent 4,5 or 6 to be selected from CR
aR
b, S, NR
cWith the annular atoms of O, and with the nitrogen that they connected constitute non-aromatic ring and
(l)-C (=O)-R
19, R wherein
19Be selected from:
(A)-C
1-10Alkyl,
(B)-C
3-7Cycloalkyl and
(C)-C
0-6Alkylidene group-C
6-10Aryl,
Perhaps, R
5And R
6Connect into 4-6 unit ring with the nitrogen-atoms that they connected, this ring is unsubstituted or by one or more following groups replacements:
(a)-C
1-10Alkyl,
(b)-C
3-12Cycloalkyl,
(c)-(CH
2)
n-phenyl,
(d)-C
2-10Thiazolinyl, or
(e)-C
2-10Alkynyl,
Wherein said alkyl, thiazolinyl and alkynyl are unsubstituted or are replaced by one or more following groups:
(i) halogen,
(ii)-OH，
(iii)-CN，
(iv)-O-C
1-10Alkyl, or
(v)-C
3-12Cycloalkyl,
And described cycloalkyl and phenyl are unsubstituted or are replaced by one or more following groups:
(i) halogen,
(ii)-C
1-10Alkyl,
(iii)-OH，
(iv)-CN，
(v)-C
3-12Alkyl, or
(vi)-O-C
1-10Alkyl;
R
a, R
bAnd R
cBe selected from independently of one another:
(1) hydrogen,
(2) halogen,
(3)-C
1-6Alkyl and
(4)-C (=O)-C
1-6Alkyl;
M is 0,1 or 2;
N is 0,1,2,3 or 4.
2. the compound of claim 1, wherein X is the oxadiazole:
3. claim 1 or 2 compound, wherein Y is a halogen.
4. each compound, wherein R among the claim 1-3
1Be phenyl, Q is CH
2, R
8And R
9All be hydrogen, and A is C
1-6Alkyl.
5. each compound, wherein R among the claim 1-4
4And R
7Be C
1-10Alkyl.
6. the compound of claim 5, wherein R
4Be methyl or sec.-propyl and R
7It is methyl.
7. the compound of claim 1, it is formula (II) compound
Wherein A, X, Y, Q, R
1, R
4, R
5, R
7, R
8And R
9As in the claim 1 definition and its pharmacy acceptable salt, with and single enantiomorph and diastereomer.
8. the compound of claim 7, wherein X is the oxadiazole:
9. claim 7 or 8 compound, wherein R
1Be phenyl, Q is CH
2, R
8And R
9All be hydrogen, and A is C
1-6Alkyl.
10. each compound, wherein R among the claim 7-9
5Be hydrogen or C
1-10Alkyl, wherein said C
1-10Alkyl is unsubstituted or is replaced by one or more following groups:
(a)-O-C
1-10Alkyl, wherein this alkyl is unsubstituted or quilt-O-C
1-10Alkyl-(O-C
1-10Alkyl)
mReplace,
(b) heteroaryl, or
(c)-C (=O)-R
19, R wherein
19Be selected from:
(i)-C
1-10Alkyl,
(ii)-C
3-7Cycloalkyl, or
(iii)-C
0-6Alkylidene group-C
6-10Aryl.
11. the compound of claim 1, it is formula (III) compound
Wherein A, X, Y, Q, R
1, R
4, R
5, R
7, R
8And R
9As in the claim 1 definition and its pharmacy acceptable salt, with and single enantiomorph and diastereomer.
12. the compound of claim 11, wherein R
1Be phenyl, Q is CH
2, R
8And R
9All be hydrogen, and A is C
1-10Alkyl.
13. the compound of claim 11 or 12, wherein R
5Be hydrogen or C
1-10Alkyl, wherein said C
1-10Alkyl is unsubstituted or is replaced by one or more following groups:
(a)-O-C
1-10Alkyl, wherein this alkyl is unsubstituted or quilt-O-C
1-10Alkyl-(O-C
1-10Alkyl)
mReplace,
(b) heteroaryl, or
(c)-C (=O)-R
19, R wherein
19Be selected from:
(i)-C
1-10Alkyl,
(ii)-C
3-7Cycloalkyl, or
(iii)-C
0-6Alkylidene group-C
6-10Aryl.
14. the compound of claim 13, it is selected from:
With its pharmacy acceptable salt.
15. a pharmaceutical composition, it comprises the compound of the claim 1 for the treatment of significant quantity or salt and pharmaceutically acceptable carrier that it is pharmaceutically accepted.
16. the pharmaceutical composition of claim 15, it further comprises the P-450 inhibitor.
17. the pharmaceutical composition of claim 16, wherein said P-450 inhibitor is a ritonavir.
18. a method for the treatment of patient's Alzheimer's, but this method comprises compound or its pharmacy acceptable salt to the claim 1 of patient's drug treatment significant quantity of this treatment of needs.
19. the method for claim 18, the compound of wherein said claim 1 is with the administration of P-450 inhibitor.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US63053904P | 2004-11-23 | 2004-11-23 | |
| US60/630,539 | 2004-11-23 | ||
| US60/653,037 | 2005-02-15 | ||
| US60/693,271 | 2005-06-23 |
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|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102471296A (en) * | 2009-07-09 | 2012-05-23 | 伊莱利利公司 | Bace inhibitors |
| CN113816858A (en) * | 2021-11-02 | 2021-12-21 | 四川汇宇制药股份有限公司 | Preparation method of trans-1, 2-diaminomethylcyclobutane and hydrochloride thereof |
-
2005
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102471296A (en) * | 2009-07-09 | 2012-05-23 | 伊莱利利公司 | Bace inhibitors |
| CN113816858A (en) * | 2021-11-02 | 2021-12-21 | 四川汇宇制药股份有限公司 | Preparation method of trans-1, 2-diaminomethylcyclobutane and hydrochloride thereof |
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