CN102574853B

CN102574853B - Heterocyclic oxime compounds

Info

Publication number: CN102574853B
Application number: CN201080047132.XA
Authority: CN
Inventors: 戴淼; 富兴年; 贺峰; L·江; 李悦; 梁芳; 刘磊; 米沅; 徐耀昌; 寻国良; 严小霞; Z·于; J·Y·张
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2009-08-20
Filing date: 2010-08-18
Publication date: 2015-01-21
Anticipated expiration: 2030-08-18
Also published as: CN102574853A

Abstract

The invention relates to compounds of formula (I) and salts thereof wherein the substituents are as defined in the specification; a compound of formula (I) for use in the treatment of the human or animal body, in particular with regard to c-Met tyrosine kinase mediated diseases or conditions; the use of a compound of formula (I) for manufacturing a medicament for the treatment of such diseases; pharmaceutical compositions comprising a compound of the formula (I), optionally in the presence of a combination partner, and processes for the preparation of a compound of formula (I).

Description

Heterocyclic oxime compounds

The present invention relates to bicyclic compound and the salt thereof of formula (I); The application of described compounds for treating human or animal body, particularly its proliferative disease; Comprise the pharmaceutical composition of described compound; The combination of contained (I) compound; With the method for the described compound of preparation.

Hepatocyte growth factor receptor, is called c-Met herein, is receptor tyrosine kinase, it shows process LAN and/or hereditary change in Several Kinds of Malignancy, particularly, gene amplification and a lot of c-Met sudden change are found in multiple solid tumor, see such as WO2007/126799.In addition, receptor tyrosine kinase c-Met participates in migration, invasion and attack and morphogenetic process, and these processes are with fetal development and tissue regeneration.C-met also participates in transfer process.Several evidence shows that c-Met plays a role in tumor invasion.The acquisition of the function germ line mutation of c-Met is relevant to the development of heredity Papillary Renal Cell Carcinoma (PRCC).Also report that the amplification of c-Met or sudden change are in the PRCC of sporadic form, Head and neck squamous cell carcinoma, cancer of the stomach, carcinoma of the pancreas and lung cancer.This type of changes to have shown in selected example gives the dependence of tumour to c-Met and/or the opposing to targeted therapy.The rising of the part HGF/SF level of c-Met and its uniqueness is often observed in various clinical related neoplasms.Expressing increases and progression of disease, relation between transfer and mortality have report in several types of cancers, and described cancer comprises bladder cancer, mammary cancer, squamous cell carcinoma and cancer of the stomach and leiomyosarcoma and glioblastoma multiforme.

WO 2008/008539 discloses some Hete rocyclic derivatives condensed, and it is used for the treatment of the disease of HGF mediation.WO 2007/013673 discloses the Hete rocyclic derivatives condensed as Lck inhibitor, and it is used as immunosuppressor.EP0490587 discloses some pyrazolopyrimidine, and it is used as angiotensin-ii antagonist.The disclosure of the publication quoted in this specification sheets is hereby incorporated by.

An object of the present invention is to provide other compound of adjustment (particularly suppressing) c-Met.Have been found that now that formula (I) compound described in literary composition is the inhibitor of c-Met and has many treatment use.Such as, formula (I) compound suitable examples depends on disease, the particularly solid tumor of c-Met activity or the transfer by its generation as being used for the treatment of.By suppressing c-Met, the compounds of this invention is also used as anti-inflammatory agent, such as, be used for the treatment of owing to infecting the inflammatory condition caused.

Preferably, the compounds of this invention is metabolic stability, nontoxic and show few side effect.In addition, preferred the compounds of this invention exists with physical form that is stable, nonhygroscopic and that be easy to prepare.One aspect of the present invention relates to formula (I) compound, and its activity is better than the activity of prior art compound or other similar compound.Another aspect of the present invention relates to formula (I) compound with good Kinase Selectivity.Preferred the compounds of this invention has favourable pharmacokinetic profile, such as, exposes and/or solvability in good body.

The present invention relates to formula (I) compound or its pharmacy acceptable salt,

Wherein

Y is C or N;

X is CH or N;

B is CH or N;

A is ring;

When X is CH and B is N, ring A is ring Ai or ring Aii;

When X is N and B is N, ring A is Aiii;

And when X is N and B is N, or X be N and B is CH time, ring A is Ai;

R ¹the group being selected from i, ii and iii:

Wherein R ⁵it is heteroaryl ¹,

R ⁶hydrogen, deuterium, OH, methyl or halogen;

R ⁷hydrogen, deuterium, halogen or (C ₁-C ₃) alkyl, wherein said (C ₁-C ₃) alkyl optionally replaces by one or more substituting group, described substituting group is independently selected from OH and halogen;

Or R ⁶and R ⁷cyclopropyl is formed together with the carbon that they connect;

N is 0,1 or 2;

R ²hydrogen, NH ₂or (C ₁-C ₄) alkyl, wherein said (C ₁-C ₄) alkyl optionally replaces by one or more substituting group, described substituting group is independently selected from OH, NH ₃and halogen;

And R ³be

● (C ₁-C ₆) alkyl, wherein said (C ₁-C ₆) alkyl optionally replaces by one or more substituting group, described substituting group independent selected from halo, hydroxyl and (C ₁-C ₃) alkoxyl group,

● heterocyclic radical ¹

● phenyl, wherein said phenyl is optionally replaced by one or more substituting group, described substituting group independent selected from halo, hydroxyl, (C ₁-C ₃) alkyl and (C ₁-C ₃) alkoxyl group, wherein said (C ₁-C ₃) alkyl and (C ₁-C ₃) alkoxyl group optionally replaces by one or more halogenic substituent separately,

●-CH ₂-heterocyclic radical ¹

●-CH ₂-phenyl, wherein said-CH ₂the phenyl of-phenyl is optionally replaced by one or more substituting group, described substituting group independent selected from halo, hydroxyl, (C ₁-C ₃) alkyl and (C ₁-C ₃) alkoxyl group, wherein said (C ₁-C ₃) alkyl and (C ₁-C ₃) alkoxyl group optionally replaces by one or more halogenic substituent separately,

● (C ₁-C ₄) alkyl CO ₂(C ₁-C ₂) alkyl,

● (C ₀-C ₄) alkyl CONH ₂,

● (C ₁-C ₄) alkyl NH ₂,

● (C ₁-C ₄) alkyl NHCONH ₂,

● (C ₁-C ₄) alkyl CO ₂h,

● (C ₁-C ₄) alkyl NHCO ₂cH ₃,

●-(C ₀-C ₄) alkyl (C ₃-C ₆) cycloalkyl or-(C ₀-C ₄) alkyl (C ₄-C ₆) cycloalkenyl group, or

● hydrogen.

Except as otherwise noted, general definition below will be suitable in this manual:

" the compounds of this invention " or " compound of the present invention " means formula (I) compound described in literary composition.

Term used herein " comprises ", " comprising " and " containing " herein with their opening, the application of unrestricted meaning.

When applying plural form (such as compound (compounds), salt (salts)), it comprises (such as individualized compound, the single salt) of odd number." compound (A compound) " does not get rid of (such as in pharmaceutical preparation) to be existed more than a kind of formula (I) compound (or its salt).

" treatment " comprises the progress of preventative (preventive) and therapeutic treatment and delay disease, illness or illness.

Any have more than 1 carbon atom acyclic carbon-containing group or part be straight or branched." alkyl " represents straight or branched alkyl group.Such as, (C ₁-C ₄) alkyl comprises methyl, ethyl, n-propyl or sec.-propyl and normal-butyl, isobutyl-, sec-butyl or the tertiary butyl.

Heteroaryl ¹be comprise 1,2,3 or 4 unsaturated or undersaturated bicyclic groups of part of the unit of 9-or 10-independently selected from the ring hetero atom of N, O and S, wherein the sum of ring S atom is no more than 1, and the sum of ring O atom is no more than 1, wherein heteroaryl ¹optionally by one or more substituting group preferably 1,2 or 3 substituting group replace, described substituting group independently selected from:

● halogen,

●OH，

● (C ₁-C ₃) alkyl, described (C ₁-C ₃) alkyl optionally replaces by one or more substituting group, described substituting group independently selected from OH and halogen,

● heterocyclic radical ²,

●-C (CH ₃)=NO (C ₁-C ₃) alkyl, wherein said C (CH ₃)=NO (C ₁-C ₃) (the C of alkyl ₁-C ₃) alkyl optionally replaces by one or more substituting group, described substituting group is independently selected from OH and halogen.

In another embodiment, heteroaryl ¹optionally by one or more substituting group preferably 1,2 or 3 substituting group replace, described substituting group independently selected from:

● halogen,

●OH，

● (C ₁-C ₃) alkyl, described (C ₁-C ₃) alkyl optionally replaces by one or more substituting group, described substituting group independently selected from OH and halogen, and

Heteroaryl ¹specific examples include but not limited to quinolyl, isoquinolyl, cinnolines base, quinazolyl, quinoxalinyl, phthalazinyl, 1, 5-naphthyridinyl, 1, 6-naphthyridinyl, 1, 7-naphthyridinyl, 1, 8-naphthyridinyl, 2, 6-naphthyridinyl, 2, 7-naphthyridinyl, pyrido [3, 2-d] pyrimidyl, pyrido [4, 3-d] pyrimidyl, pyrido [3, 4-d] pyrimidyl, pyrido [2, 3-d] pyrimidyl, pyrido [2, 3-b] pyrazinyl, pyrido [3, 4-b] pyrazinyl, Kui Linpyrimido quinoline [5, 4-d] pyrimidyl, pyrazine also [2, 3-b] pyrazinyl, Kui Linpyrimido quinoline [4, 5-d] pyrimidyl, benzofuryl, benzothienyl, indyl, benzimidazolyl-, benzo azoles base, indazolyl (indazoyl), benzotriazole base, pyrrolo-[2, 3-b] pyridyl, pyrrolo-[2, 3-c] pyridyl, pyrrolo-[3, 2-c] pyridyl, pyrrolo-[3, 2-b] pyridyl, imidazo [4, 5-b] pyridyl, imidazo [4, 5-c] pyridyl, pyrazolo [4, 3-d] pyridyl, pyrazolo [4, 3-c] pyridyl, pyrazolo [3, 4-c] pyridyl, pyrazolo [3, 4-b] pyridyl, pseudoindoyl, indazolyl, purine radicals, indolizine base, imidazo [1, 2-a] pyridyl, imidazo [1, 5-a] pyridyl, pyrazolo [1, 5-a] pyridyl, pyrrolo-[1, 2-b] pyridazinyl and imidazo [1, 2-c] equivalent of pyrimidyl and its fractional saturation.

" heteroaryl ³" mean to comprise 1 or 2 unsaturated or undersaturated bicyclic groups of part of ring N heteroatomic 9-or 10-unit.Heteroaryl ³optionally replaced by one or more substituting group, described substituting group independently selected from:

● halogen,

●OH，

● (C ₁-C ₃) alkyl, wherein said (C ₁-C ₃) alkyl optionally replaces by one or more substituting group, described substituting group independently selected from OH and halogen,

● heterocyclic radical ², and

In another embodiment, heteroaryl ³optionally replaced by one or more substituting group, described substituting group independently selected from:

● halogen,

●OH，

● (C ₁-C ₃) alkyl, wherein said (C ₁-C ₃) alkyl optionally replaces by one or more substituting group, described substituting group independently selected from OH and halogen, and

Heteroaryl ³specific examples include but not limited to quinolyl, isoquinolyl, cinnolines base, azepine quinazolyl, quinoxalinyl, phthalazinyl, 1, 5-naphthyridinyl, 1, 6-naphthyridinyl, 1, 7-naphthyridinyl, 1, 8-naphthyridinyl, 2, 6-naphthyridinyl, 2, 7-naphthyridinyl, indyl, benzimidazolyl-, indazolyl, pyrrolo-[2, 3-b] pyridyl, pyrrolo-[2, 3-c] pyridyl, pyrrolo-[3, 2-c] pyridyl, pyrrolo-[3, 2-b] pyridyl, pseudoindoyl, indazolyl, indolizine base (indolininyl), imidazo [1, 2-a] pyridyl, imidazo [1, 5-a] pyridyl, pyrazolo [1, 5-a] pyridyl and pyrrolo-[1, 2-b] pyridazinyl.

" heterocyclic radical ¹" mean to comprise 4,5 or 6 yuan of saturated or undersaturated monocyclic groups of part of 1 or 2 ring hetero atom independently selected from N, O and S.Heterocyclic radical ¹optionally by CONH ₂or (C ₁-C ₃) alkyl replacement.Heterocyclic radical ¹specific examples include but not limited to oxetanylmethoxy, Thietane base (thiatanyl), azetidinyl, tetrahydrofuran base, tetrahydro-thienyl, 1,2,3,4-tetrahydro pyridyl, 1,2,5,6-tetrahydro pyridyl, pyrrolidyl, piperidyl and piperazinyl.

" heterocyclic radical ²" mean to comprise 5 or 6 yuan of saturated, unsaturated or undersaturated monocyclic groups of part of 1,2 or 3 ring hetero atom independently selected from N, O and S, wherein the sum of ring S atom is no more than 1, and the sum of ring O atom is no more than 1.Heterocyclic radical ²optionally by (C ₁-C ₃) alkyl replacement.Heterocyclic radical ²specific examples include but not limited to tetrahydrofuran base, tetrahydro-thienyl, 1,2,3,4-tetrahydro pyridyl, 1,2,5,6-tetrahydro pyridyl, pyrrolidyl, piperidyl, piperazinyl, pyrryl, furyl, thienyl, pyrazolyl, imidazolyl, different azoles base, azoles base, isothiazolyl, thiazolyl, 1,2,3-triazoles base, 1,3,4-triazolyl, 1-oxa--2,3-di azoly, 1-oxa--2,4-di azoly, 1-oxa--2,5-di azoly, 1-oxa--3,4-di azoly, 1-thia-2,3-di azoly, 1-thia-2,4-di azoly, 1-thia-2,5-di azoly, 1-thia-3,4-di azoly, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyls and 2H-pyranyl.

" disease " used herein comprises illness or illness.

Halogen means fluorine, chlorine, bromine or iodine.In of the present invention one special embodiment, halogen is fluorine or chlorine.Preferably, halogen is fluorine.

In light of the disclosure herein, formula (I) compound is selected from any one in having structure (Ia) to (Ie):

In one embodiment of the invention, formula (I) compound is provided, wherein

B is N;

Y is C or N;

X is CH or N;

When x is ch, ring A is ring Ai or ring Aii

When X is N, ring A is Aiii;

And when X is N and B is CH, ring A is Ai.

These compounds have structure (Ia) disclosed in literary composition, (Ib), (Ic) or (Ie).

In another embodiment of the present invention, formula (I) compound is provided, wherein

B is N;

Y is C or N;

X is CH or N;

When x is ch, ring A is ring Ai or ring Aii

And when X is N, ring A is Aiii;

These compounds have structure (Ia) disclosed in literary composition, (Ib) or (Ic).

In of the present invention one special embodiment, provide the compound with formula (Ib) structure, wherein substituting group as in literary composition define.

In another embodiment of the present invention, R ¹i or ii:

In a preferred embodiment of the present invention, R ¹i:

In another embodiment of the present invention, R ¹the group being selected from i, ii and iii:

And R ⁵it is heteroaryl ³.

In another embodiment of the present invention, R ¹i:

And R ⁵it is heteroaryl ³.

In another embodiment of the present invention, heteroaryl ¹and heteroaryl ³optionally replaced by one or more substituting group separately, described substituting group independent selected from halo, 4-methylpiperazine-1-yl, ethyl ketone O-(2-hydroxyethyl) oxime and (C ₁-C ₂) alkyl.

In a preferred embodiment of the present invention, R ⁵be indazolyl or quinolyl, optionally replaced by one or more substituting group separately, described substituting group independent selected from halo, (C ₁-C ₃) alkyl, 4-methylpiperazine-1-yl and ethyl ketone O-(2-hydroxyethyl) oxime.Particularly, R ⁵optionally by the indazolyl of 1,2 or 3 substituting group replacement or quinolyl, described substituting group independent selected from halo and (C ₁-C ₃) alkyl.

In a preferred embodiment of the present invention, R ⁵that described substituting group is independently selected from methyl and fluorine, or R optionally by the indazolyl that 1,2 or 3 substituting group replaces ⁵optionally by quinolyl that one or two fluoro substituents replaces.

In of the present invention one special embodiment, R ⁵to be replaced by methyl substituents and optional in addition by the indazole-5-base that one or two fluoro substituents replaces at 1, or R ⁵optionally by quinoline-6-base that one or two fluoro substituents replaces.In an embodiment of the present invention, described fluoro substituents is positioned at 5 and/or 7 of quinolinyl group.

In of the present invention one special embodiment, R ⁵be quinoline-6-base, it is replaced by following group:

● heterocyclic radical ², or

●-C (CH ₃)=NO (C ₁-C ₃) alkyl, wherein said C (CH ₃)=NO (C ₁-C ₃) (the C of alkyl ₁-C ₃) alkyl optionally replaces by one or more substituting group, described substituting group independently selected from OH and halogen,

Wherein said heterocyclic radical ²with-C (CH ₃)=NO (C ₁-C ₃) alkyl substituent is positioned at the 3-position of quinolinyl group.

In another embodiment, R ⁵quinoline-6-the base replaced by 3-(4-methylpiperazine-1-yl) or the quinoline-6-base replaced by 3-ethyl ketone O-(2-hydroxy-ethyl) oxime.

In of the present invention one special embodiment, R ⁵the fluoro-quinoline of 7--6-base, quinoline-6-base, 5,7-difluoro-quinoline-6-base, 1-methyl isophthalic acid H-indazole-5-base, 6-fluoro-1-methyl isophthalic acid H-indazole-5-base, 4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-bases, 5-fluorine quinoline-6-base, 3-(4-methylpiperazine-1-yl) quinoline-6-base or 6-quinoline-3-base-ethyl ketone O-(2-hydroxy-ethyl) oxime.

In another embodiment of the present invention, R ⁶hydrogen, deuterium, OH or halogen, particularly hydrogen, deuterium or halogen, and in preferred embodiments, R ⁶hydrogen.

In another embodiment of the present invention, R ⁷be hydrogen, deuterium, halogen or methyl, wherein said methyl is optionally replaced by one or more substituting group, and described substituting group is independently selected from OH and halogen.In another embodiment of the present invention, R ⁷hydrogen, deuterium, halogen or methyl.In preferred embodiments, R ⁷hydrogen or methyl, more preferably hydrogen.

Work as R ¹be i and R ⁶and R ⁷when being not all hydrogen, formula (I) compound is at R ¹place is containing unsymmetrical carbon.Containing R ¹(R) of i or formula (I) compound of (S) enantiomer or its mixture comprise within the scope of the invention.In of the present invention one preferred embodiment, provide containing R ¹formula (I) compound of (S) enantiomer of i or comprise the mixture of (S) enantiomer as main component.

In of the present invention one preferred embodiment, n is 0.

In another embodiment of the present invention, R ²hydrogen or methyl.Preferably, R ²it is methyl.

In another embodiment of the present invention, R ³be selected from:

● heterocyclic radical ¹

●-CH ₂-heterocyclic radical ¹

● (C ₁-C ₂) alkyl CO ₂(C ₁-C ₂) alkyl,

● (C ₀-C ₂) alkyl CONH ₂,

● (C ₁-C ₄) alkyl NH ₂,

● (C ₁-C ₂) alkyl NHCONH ₂,

● (C ₁-C ₂) alkyl CO ₂h,

● (C ₁-C ₂) alkyl NHCO ₂cH ₃, or

● hydrogen,

In another embodiment of the present invention, R ³be selected from:

● (C ₁-C ₄) alkyl, wherein said (C ₁-C ₄) alkyl optionally replaces by one or more substituting group, described substituting group independent selected from halo, hydroxyl and methoxyl group,

● optionally by CONH ₂the pyrrolidyl replaced,

● piperidyl,

●-CH ₂-pyrrolidyl, wherein said pyrrolidyl is optionally by CONH ₂replace,

●-CH ₂-piperidyl,

●-CH ₂-phenyl, wherein said-CH ₂the phenyl of-phenyl is optionally replaced by one or more substituting group, described substituting group independent selected from halo, methyl and methoxyl group, and wherein said methyl is optionally replaced by 1,2 or 3 halogenic substituent,

● (C ₁-C ₂) alkyl CO ₂(C ₁-C ₂) alkyl,

● (C ₀-C ₂) alkyl CONH ₂,

● (C ₂-C ₄) alkyl NH ₂,

● (C ₁-C ₂) alkyl NHCONH ₂,

● (C ₁-C ₂) alkyl CO ₂h,

● oxetanylmethoxy

● (C ₁-C ₂) alkyl NHCO ₂cH ₃,

●-CH ₂-(C ₃-C ₆) cycloalkyl, and

● hydrogen

In of the present invention one special embodiment, R ³ethyl, methyl, 2-hydroxyethyl, 1,3-dihydroxyl third-2-base-, 2,3-dihydroxypropyl-, 2-hydroxyl-1,1-dimethyl-ethyI-, 2-hydroxy-2-methyl-propyl group-, pyrrolidin-3-yl-,-3-tetramethyleneimine-1-methane amide, hydrogen, benzyl, 4-methoxy-benzyl-, piperidin-4-yl-, piperidin-4-ylmethyl-,-CH ₂cO ₂cH ₃,-CH ₂cONH ₂, 2-amino-ethyl-, 1-hydroxyl third-2-base-,-CH ₂cH ₂nHCO ₂cH ₃,-CH ₂cH ₂nHCONH ₂; 3-trifluoromethyl-, phenyl, 2-fluoro ethyl-, 3-hydroxypropyl, 2-methoxy ethyl, 4-hydroxybutyl, 4-fluorine butyl, CONH ₂, 1-hydroxy-2-methyl third-2-base, oxa-ring fourth-3-base or-CH ₂cO ₂h, Cvclopropvlmethvl or hydrogen;

In another special embodiment of the present invention, R ³hydroxyethyl particularly 2-hydroxyethyl or hydrogen.

In another embodiment, formula (I) compound or its pharmacy acceptable salt is provided

Wherein

Y is C or N;

X is CH or N;

B is CH or N;

A is ring;

When X is CH and B is N, ring A is ring Ai or ring Aii;

When X is N and B is N, ring A is Aiii;

And when X is N and B is N, or X be N and B is CH time, ring A is Ai;

R ¹i:

R ⁵the fluoro-quinoline of 7--6-base, quinoline-6-base, 5,7-difluoro-quinoline-6-base, 1-methyl isophthalic acid H-indazole-5-base, 6-fluoro-1-methyl isophthalic acid H-indazole-5-base, 4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-bases, 5-fluorine quinoline-6-base, (4-methylpiperazine-1-yl) quinoline-6-base or 6-quinoline-3-base-ethyl ketone O-(2-hydroxy-ethyl) oxime

R ⁶hydrogen, deuterium, OH, methyl or halogen;

Or R ⁶and R ⁷cyclopropyl is formed together with the carbon atom that they connect;

R ²hydrogen, NH ₂or (C ₁-C ₄) alkyl,

And R ³ethyl, methyl, 2-hydroxyethyl, 1,3-dihydroxyl third-2-base-, 2,3-dihydroxypropyl-, 2-hydroxyl-1,1-dimethyl-ethyI-, 2-hydroxy-2-methyl-propyl group-, pyrrolidin-3-yl-,-3-tetramethyleneimine-1-methane amide, hydrogen, benzyl, 4-methoxy-benzyl-, piperidin-4-yl-, piperidin-4-ylmethyl-,-CH ₂cO ₂cH ₃,-CH ₂cONH ₂, 2-amino-ethyl-, 1-hydroxyl third-2-base-,-CH ₂cH ₂nHCO ₂cH ₃,-CH ₂cH ₂nHCONH ₂; 3-trifluoromethyl-, phenyl, 2-fluoro ethyl-, 3-hydroxypropyl, 2-methoxy ethyl, 4-hydroxybutyl, 4-fluorine butyl, CONH ₂, 1-hydroxy-2-methyl third-2-base, oxa-ring fourth-3-base, hydrogen, Cvclopropvlmethvl or-CH ₂cO ₂h.

In another embodiment of the present invention, provide have be selected from above (Ia), (Ib) or (Ic) structure formula (I) compound, wherein

R ¹i:

R ⁵that fluoro substituents is preferably at 5 and/or 7 optionally by the quinoline-6-base that one or two fluoro substituents replaces;

R ⁶hydrogen;

R ⁷hydrogen or methyl;

R ²it is methyl; And

R ³hydroxyethyl more especially 2-hydroxyethyl, or R ³hydrogen;

Various embodiments of the present invention are described in literary composition.To recognize, the characteristics combination that feature specified in each embodiment can indicate with other is to provide other embodiments.

In a special embodiment, the invention provides one or more compounds or its pharmacy acceptable salt of being selected from the disclosed embodiments compound in literary composition.

Fig. 1 herein shows the x-ray diffraction pattern of embodiment 53S amorphous form.Fig. 2 shows the x-ray diffraction pattern of embodiment 53S crystalline form I.Fig. 3 shows the x-ray diffraction pattern of embodiment 53S Form II.

As used herein, term " isomer " refers to have identical molecular formula but the arrangement of atom different compounds different with configuration.Also as used herein, term " optically active isomer " or " steric isomer " refer to any different stereoisomeric configurations that can exist for given the compounds of this invention, and comprise geometrical isomer.Should be appreciated that substituting group can be connected to the chiral centre place of carbon atom.Therefore, the present invention includes and isomer, diastereomer or racemoid are reflected to compound." enantiomer " is mutually a pair steric isomer of mirror image that can not be overlapping.1: 1 mixture of a pair enantiomer is " racemize " mixture.In due course, this term is for representing racemic mixture.But " diastereomer " has at least two asymmetric atoms be not mutually the steric isomer of mirror image.Absolute stereochemical is indicated according to Cahn-lngold-Prelog R-S system.When compound is pure enantiomer, the stereochemistry at each chiral carbon atom place can be appointed as R or S.The compound of the fractionation of absolute configuration the unknown can be appointed as (+) or (-) according to their directions (dextrorotation or left-handed) at sodium D-line wavelength Plane of rotation polarized light.Some compound described in literary composition contains one or more asymmetric center or axle, and therefore may produce enantiomer, diastereomer and other stereoisomer form, can be used for absolute stereochemical (R)-or (S)-be limited.This invention is intended to comprise all possible isomer, comprise racemic mixture, optical purity form and intermediate blend.(R)-of optically active and (S)-isomer can adopt chiral synthon or chiral reagent preparation or adopt routine techniques to split.If compound contains double bond, then substituting group can be E or Z configuration.If compound contains dibasic cycloalkyl, then naphthenic substituent may have cis-or trans-configuration.Also be intended to comprise all tautomeric forms.

Any asymmetric atom (such as carbon etc.) of compound of the present invention can with racemize or enantiomer enrichment such as (R)-, (S)-or (R, the form of S)-configuration exists, such as, for being present in R defined herein ¹unsymmetrical carbon in group (i) just can be like this.In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess or at least 99% enantiomeric excess with regard to (R)-or (S)-configuration.Preferably, for the asymmetric R defined in literary composition ¹group (i), (S) enantiomer is excessive with above-mentioned amount.

If possible, the substituting group had on the atom of unsaturated link(age) can exist with cis-(Z)-or trans-(E)-form.Preferably, hydrazone of the present invention has trans-(E)-form.

Therefore, as used herein, the compounds of this invention can be the form of possible isomer, rotational isomer, atropisomer, one of tautomer or its mixture, such as substantially pure geometry (cis or trans) isomer, diastereomer, optically active isomer (enantiomorph), racemoid or its mixture.

Any isomer mixture obtained can be separated into pure or substantially pure geometry or optically active isomer, diastereomer, racemoid based on the physical chemical differences of component, such as, be separated by chromatography and/or fractional crystallization.

By currently known methods, such as, being separated diastereoisomeric salt that the acid of itself and optically active or alkali are formed, then discharging acidity or the basic cpd of optically active, can be optically active enantiomorph by the racemate resolution of any end product of obtaining or intermediate.Particularly; therefore; the fractional crystallization of salt such as by being formed with the acid of optically active; basic moiety can be used for optically active enantiomorph the compounds of this invention being split as they; acid such as tartrate, dibenzoyl tartaric acid, acetyl tartaric acid, two-O, O '-p-toluoyl tartaric acid, amygdalic acid, oxysuccinic acid or the camphor-10-sulfonic acid of described optically active.High performance liquid chromatography (HPLC) the resolution of racemic product of chiral sorbent such as can also be adopted by chiral chromatography.

Any formula provided herein is also intended to the unmarked form and the isotope labelled form that represent compound.Isotope-labeled compound has the structure of the formula description provided herein, except one or more atom is replaced by the atom with selected nucleidic mass or total mass number.The isotopic example that can mix the compounds of this invention comprises the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, respectively such as ²h, ³h, ¹¹c, ¹³c, ¹⁴c, ¹⁵n, ¹⁸f, ³¹p, ³²p, ³⁵s, ³⁶cl, ¹²⁵i.Multiple isotope-labeled the compounds of this invention, such as by radio isotope such as ³h, ¹³c and ¹⁴c mix wherein those.This type of isotope-labeled compound can be used for metabolism research and (preferably uses ¹⁴c), reaction kinetics research (is used such as ²h or ³h), detection or imaging technique [such as positron emission tomography art (PET) or SPECT (single photon emission computed tomography) (SPECT)], comprise medicine or substrate tissue distributional analysis, or for the radiotherapy of patient.Particularly, ¹⁸the compound of F or mark can be particularly preferred for PET or SPECT research.In addition, with heavier isotropic substance, such as deuterium is (namely ²h) replace some treatment advantage can be provided, these advantages from higher metabolic stability, the Half-life in vivo such as increased or the volume requirements of reduction.Isotope-labeled the compounds of this invention and prodrug thereof usually can by carrying out method disclosed in schema described below or embodiment and preparation and replacing nonisotopically labelled reagent to prepare with the isotope labeling reagent easily obtained.

In addition, with heavier isotropic substance, particularly deuterium is (namely ²h or D) replace some treatment advantage can be provided, these advantages are from higher metabolic stability, and the Half-life in vivo such as increased or the volume requirements of reduction or therapeutic index are improved.Should be understood that, deuterium is considered to the substituting group of formula (I) compound in the text.The concentration of this type of heavier isotropic substance particularly deuterium can define by the isotopic enrichment factor.Term used herein " the isotopic enrichment factor " represents isotopic abundance and specifies the ratio between natural abundance of isotopes.If the substituting group in the compounds of this invention is designated as deuterium, so this compound is at least 3500 (having the deuterium of 52.5% to mix at each D atom place specified) for the isotopic enrichment factor of each D atom of specifying, at least 4000 (deuterium of 60% mixes), at least 4500 (deuterium of 67.5% mixes), at least 5000 (deuterium of 75% mixes), at least 5500 (deuterium of 82.5% mixes), at least 6000 (deuterium of 90% mixes), at least 6333.3 (deuterium of 95% mixes), at least 6466.7 (deuterium of 97% mixes), at least 6600 (deuterium of 99% mixes) or at least 6633.3 (deuterium of 99.5% mixes).In the compounds of this invention, do not specify as specific isotopic any atom represents any stable isotropic substance of this atom.Unless otherwise indicated, when a position is specified as " H " or " hydrogen ", this position should be understood to the hydrogen with natural abundance isotopics.Therefore, in the compounds of this invention, anyly to specify as the atom table example of deuterium (D) is as the deuterium in the scope provided above.

Isotope-labeled formula (I) compound can be prepared by routine techniques well known by persons skilled in the art usually, or by with the following examples and the similar method of the method that describes in preparing adopt suitable isotope-labeled reagent replace before the cold reagent applied prepare.

As used herein, term " pharmacy acceptable salt " refers to and retains the biological efficacy of the compounds of this invention and the salt of character, and it is not that biology or other side institute are less desirable usually.Salt can exist individually, or can exist with free formula (I) compound.In many cases, owing to there is amino group or similar group, the compounds of this invention can form hydrochlorate.

Pharmaceutically acceptable acid salt can be formed, such as acetate with mineral acid and organic acid, aspartate, benzoate, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, hydrosulfate/vitriol, camsilate (camphorsulfornate), muriate/hydrochloride, chlortheophyllonate, Citrate trianion, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydriodate/iodide, isethionate, lactic acid salt, Lactobionate, dodecyl sulfate, malate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, Polygalacturonate, propionic salt, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.Such as hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. can be comprised by its derivative mineral acid obtaining salt.Such as acetic acid, propionic acid, hydroxyethanoic acid, oxalic acid, toxilic acid, propanedioic acid, succsinic acid, fumaric acid, tartrate, citric acid, phenylformic acid, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, sulphosalicylic acid etc. can be comprised by its derivative organic acid obtaining salt.

Pharmaceutically acceptable base addition salt can be formed with mineral alkali and organic bases.Such as ammonium salt and the metal from periodictable I to XII race can be comprised by its derivative mineral alkali obtaining salt.In certain embodiments, salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; Salt suitable especially comprises ammonium salt, sylvite, sodium salt, calcium salt and magnesium salts.

The amine that can comprise such as primary, secondary and tertiary amine, replacement by its derivative organic bases obtaining salt comprises the amine, cyclammonium, deacidite etc. of naturally occurring replacement.Some organic amine comprises Isopropylamine, benzyl star (benzathine), choline salt (cholinate), diethanolamine, diethylamine, Methionin, meglumine, piperazine and tromethane.

Pharmacy acceptable salt of the present invention can be synthesized by conventional chemical processes by parent compound, alkalescence or acidic moiety (moiety).Usually, this type of salt can by making the acid-respons of the free alkali form of these compounds and the suitable of stoichiometric quantity to prepare.Typically, this type of reaction is carried out in water or organic solvent or in both mixtures.In general, when applicable, it is desirable for applying non-aqueous media such as ether, ethyl acetate, ethanol, Virahol or acetonitrile.The list of other suitable salt is found in such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985); " Handbook of Pharmaceutical Salts:Properties, Selection, and Use ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002)." salt ", " its salt " or " or its salt " can Individual existences or exist with mixture with free formula (I) compound.

For isolated or purified object, application pharmaceutically unacceptable salt such as picrate or perchlorate is also possible.For therepic use, only apply pharmacy acceptable salt or free cpds (when applying in the form of a pharmaceutical preparation), and therefore these are preferred.In view of the new compound of free form and their salt form compound (comprise such as at purifying or identify those salt that can be used as intermediate in new compound) between substantial connection, suitably with at one's leisure, any the mentioning for free cpds in context should be understood to also relate to corresponding salt.

The compounds of this invention can exist with nonsolvated forms and solvation form.Term " solvate " is in the text for describing the molecular complex comprising the compounds of this invention and one or more pharmaceutically acceptable solvent molecules such as ethanol.When described solvent is water, application term " hydrate ".Pharmaceutically acceptable solvate comprise hydrate and wherein recrystallisation solvent can be replaced (such as D by isotropic substance ₂o, d ₆-acetone, d ₆-DMSO) other solvate.Any formula provided in literary composition is intended to polymorphic form representing hydrate, solvate and described compound and composition thereof.

The compound of the present invention (i.e. formula (I) compound) comprising the group that can serve as hydrogen bond donor and/or acceptor may can form eutectic with suitable eutectic formation (co-crystal former).These eutectics can form operation by formula (I) compound by known eutectic to be prepared.This generic operation comprise grinding, heating, altogether distillation, congruent melting or make under crystallization condition formula (I) compound together brilliant formation contact in the solution and be separated the eutectic of so formation.Suitable eutectic formation comprise as described in WO 2004/078163 those.Therefore the present invention also provides contained (I) eutectic of compound.

Therefore, the compounds of this invention comprises formula I, its polymorphic form and the isomer (comprising optically-active, geometry and tautomer) and isotope-labeled formula I that define in literary composition.In preferred embodiments, it is that independently, jointly or preferred with any combination or sub-combination the present invention relates to formula (I) compound of free alkali form or acid addition salt form thereof, wherein substituting group is as herein defined.

The compounds of this invention can be used as prodrug.Therefore, some derivative of formula (I) compound itself may have very little or not have pharmacologically active, but when being administered in health or on health, it such as can be converted into formula (I) compound of tool activity in need by hydrolytic rupture.This analog derivative is called " prodrug ".[be found in ' as the prodrug (Pro-drugs as Novel Delivery Systems) of new delivery system about the further information of prodrug application, Vol.14, ACS Symposium Series (T Higuchi and W Stella) and ' the bio-reversible carrier (Bioreversible Carriers in Drug Design) ' in medicinal design, Pergamon Press, 1987 (ed.E B Roche, American Pharmaceutical Association) .].

Prodrug such as can by the suitable functional group existed with " front-partly (pro-moieties) " alternate form (I) compound described in some part well known by persons skilled in the art (such as H Bundgaard " prodrug design (Design of Prodrugs) " (Elsevier, 1985)).

Some examples of this type of prodrug comprise:

I (), when formula (I) compound contains carboxylic acid functional (-COOH), its ester, such as, use (C ₁-C ₈) alkyl replacement hydrogen;

(ii) when formula (I) compound contains alcohol functional group (-OH), its ether, such as, use (C ₁-C ₆) alkyloyl oxygen ylmethyl replacement hydrogen; With

(iii) when formula (I) compound contains primary amino or secondary amino functionalities (-NH ₂or-NHR wherein R ≠ H) time, its acid amides, such as, use (C ₁-C ₁₀) alkyloyl replaces one or all two hydrogen.

Some formula (I) compound itself can also as the prodrug of other formula (I) compound.

The invention still further relates to the pharmaceutically acceptable prodrug of formula (I) compound.The invention still further relates to the pharmaceutically acceptable meta-bolites of formula (I) compound.

" disease that C-Met is tyrosine kinase mediated " especially has the illness of response (such as improve one or more symptoms, postpone the outbreak of disease until temporary transient or complete cure diseases) to the kinase whose suppression of the suppression of protein tyrosine kinase, especially c-Met with beneficial manner.These illnesss comprise proliferative disease, such as tumor disease, particularly solid tumor and its derivative transfer, such as heredity Papillary Renal Cell Carcinoma (PRCC), the PRCC of sporadic form, head and neck cancer, squamous cell carcinoma, cancer of the stomach, carcinoma of the pancreas, lung cancer, bladder cancer, mammary cancer, leiomyosarcoma, glioblastoma multiforme, melanoma, alveolar soft part sarcoma.These illnesss comprise inflammatory conditions further, such as, by infecting the inflammatory conditions caused.

" combination " represents the fixed Combination in a dosage unit form, or for the cover box (kit of parts) of combined administration, its Chinese style (I) compound and the combination partner (other medicines of such as explained later, also referred to as " therapeutical agent " or " co-drug ") can be same time individual application or within the timed interval separate administration, particularly when these timed intervals make combination partner show cooperation such as act synergistically time.Term used herein " is used " jointly or " combined administration " etc. refers to comprise and use selected combination partner to the single individuality (such as patient) of needs, and be intended to comprise such treatment plan, wherein promoting agent is without the need to using by identical route of administration or in the identical time.Term used herein " drug regimen " represents by mixing or combining the product produced more than a kind of activeconstituents, and comprises the fixing of activeconstituents and non-fixed combinations.Term " fixed Combination " represents activeconstituents such as formula (I) compound and combination partner, is applied to patient with the form of single entity or dosage simultaneously.Term " non-fixed combinations " represents activeconstituents such as formula (I) compound and combination partner, be not applied to patient successively as the entity separated, wherein this is applied in patient body the two kinds of compounds providing treatment level of significance simultaneously, jointly or with having specified time restriction.The latter is also applicable to conjoint therapy (cocktail therapy), such as, use three kinds or various active composition.

Formula (I) compound and wherein said preparation method that there is provided in embodiment are provided.

As above hereinafter described in, formula (I) compound has valuable pharmacological property.

In another embodiment of the present invention, the method being used for the treatment of illness that c-Met is correlated with or illness is provided.Illness to be treated or illness are preferably proliferative disease such as cancer or inflammatory condition.Formula (I) compound also can be used for treating the disease relevant with the situation that c-Met is correlated with.

A: proliferative disease: formula (I) compound is used in particular for treating one or more following proliferative disease:

Formula (I) compound is used for the treatment of cancer, and wherein cancer is selected from the cancer of the brain, cancer of the stomach, anogenital cancer, uropoiesis device cancer, prostate cancer, bladder cancer (surface and muscle invasion), mammary cancer, cervical cancer, colorectal carcinoma, colorectal carcinoma, glioma (comprises glioblastoma multiforme, glioblastoma multiforme, few astrocytoma, oligodendroglioma), the esophageal carcinoma, cancer of the stomach, gastrointestinal cancer, liver cancer, hepatocellular carcinoma (HCC) comprises children HCC, head and neck cancer (comprises Head and neck squamous cell carcinoma, nasopharyngeal carcinoma), Hu Erteer (Hurthle) cell carcinoma, epithelial cancer, skin carcinoma, melanoma (comprising malignant melanoma), mesothelioma, lymphoma, myelomatosis (comprising multiple myeloma), leukemia, lung cancer (comprises nonsmall-cell lung cancer and (comprises all histological subtypes: gland cancer, squamous cell carcinoma, bronchovesicular cancer, large cell carcinoma and adenosquamous carcinoma mixed type), small cell lung cancer), ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney (including but not limited to Papillary Renal Cell Carcinoma), intestinal cancer, renal cell carcinoma (comprises heredity and sporadic papillary renal cell carcinoma, I type and II type and clear cell renal cell carcinoma), sarcoma is osteosarcoma particularly, clear cell sarcoma and soft tissue sarcoma (comprise alveolar shape and embryonal rhabdomyosarcoma, alveolar soft part sarcoma), thyroid carcinoma (corpora mammillaria and other hypotype).

Formula (I) compound is used for the treatment of cancer, and wherein cancer is cancer of the stomach, colorectal carcinoma, liver cancer, anogenital cancer, uropoiesis device cancer, melanoma or prostate cancer.In special embodiment, cancer is liver cancer or esophagus cancer.

Formula (I) compound is used for the treatment of colorectal carcinoma, comprises the transfer in such as liver, and nonsmall-cell lung cancer.

Formula (I) compound is also used for the treatment of heredity papillary renal carcinoma (Schmidt, L. people is waited, Nat.Genet.16,68-73,1997) and other proliferative disease, wherein c-MET is by sudden change (Jeffers and Vande Woude.Oncogene 18,5120-5125,1999; And the reference wherein quoted) or chromosome rearrangement (the people Nature 311,29-33,1984 such as such as TPR-MET, Cooper; Park. people is waited, Cell 45,895-904,1986) cause process LAN or composition activation.

Formula (I) compound is further used for provided herein or other cancer known in the art for the treatment of and illness.

B: inflammatory conditions: formula (I) compound is specially adapted to treat one or more inflammatory conditions.

In further embodiment, inflammatory conditions is caused by infection.In one embodiment, methods for the treatment of will block pathogenic infection.In special embodiment, infection is bacteriological infection, and such as Li Site (Listeria) bacterium infects.See, the people .Cell 103:501-10 such as such as Shen, (2000), wherein bacterial surface protein activates c-Met kinases by being combined with the extracellular domain of acceptor, thus simulates the effect of relevant part HGF/SF.

Formula (I) compound is further used for provided herein or other inflammatory conditions known in the art for the treatment of and illness.

C: combined therapy: in certain embodiments, any aforesaid method relates to further uses chemotherapeutic.

In relevant embodiment, chemotherapeutic is carcinostatic agent.Special combination provides in this application.

In embodiment relevant further, any aforesaid method relates to route of administration specific inhibitor further.Approach specific inhibitor can be chemotherapeutic or can be biological agents, such as antibody.Approach specific inhibitor includes but not limited to the inhibitor of EGFR, Her-2, Her-3, VEGFR, Ron, IGF-IR, PI-3K, mTOR, Raf.

In the further embodiment relevant to several aforesaid method, after being applied to individuality or exposing cell, these methods can relate to the improvement or delay of observing cancer development or transfer further.

Therefore, in one embodiment, the present invention relates to the method for the treatment c-Met illness of being correlated with or illness, it relates to formula (I) compound having the individuality of its needs to use significant quantity.

In further embodiment, the present invention relates to formula (I) compound or its pharmacy acceptable salt, it is used as medicine, is used in particular for treating the tyrosine kinase mediated disease of one or more C-Met.

In further embodiment, the present invention relates to formula (I) compound or the purposes of its pharmacy acceptable salt in the medicine preparing the tyrosine kinase mediated disease of one or more C-Met for the treatment of.

In further embodiment, the present invention relates to treatment and have the disease of response or the method for illness to the suppression of C-Met Tyrosylprotein kinase, the method comprises uses formula (I) compound or its pharmacy acceptable salt to the warm-blooded animal of this treatment of needs, particularly uses with the amount effectively resisting described disease.

In further embodiment, the present invention relates to pharmaceutical composition, this pharmaceutical composition comprises as formula (I) compound of activeconstituents and at least one pharmaceutical carrier or thinner.

In further embodiment, the present invention relates to pharmaceutical composition, this pharmaceutical composition comprises: formula (I) compound of (a) significant quantity and pharmacy acceptable salt, pharmaceutically acceptable prodrug and/or pharmaceutical active metabolite; (b) one or more pharmaceutically acceptable vehicle and/or thinners.

In further embodiment, the present invention relates to the pharmaceutical composition of the disease such as solid tumor or liquid tumor being used for the treatment of warm-blooded animal (comprising people), this pharmaceutical composition comprises above-mentioned formula (I) compound of the effective dosage of the described disease for the treatment of or the pharmacy acceptable salt of this compound, and pharmaceutically acceptable carrier (=carrier substance).

In another embodiment of the invention, provide pharmaceutical preparation (composition), it comprises the pharmacy acceptable salt of formula defined herein (I) compound or this compound or its hydrate or solvate, and the pharmaceutically acceptable carrier of at least one and/or thinner and one or more optional other therapeutical agents.

" pharmaceutically acceptable carrier " comprises any and all solvents as the term is employed herein, dispersion medium, coating material, tensio-active agent, antioxidant, sanitas (such as antiseptic-germicide, anti-mycotic agent), isotonic agent, absorption delay agent, salt, sanitas, medicine, drug stabilizing agent, tackiness agent, vehicle, disintegrating agent, lubricant, sweeting agent, correctives, dyestuff etc. and its combination, this is well-known to those skilled in the art (for example, see Remington ' s Pharmaceutical Sciences, 18thEd.Mack Printing Company, 1990, pp.1289-1329).Except with except the inconsistent carrier of activeconstituents, consider to use any conventional carrier in treatment or pharmaceutical composition.

" the treatment significant quantity " of term the compounds of this invention refers to the amount of such the compounds of this invention, it will cause biology or the medical response of experimenter, such as, reduce or inhibitory enzyme or protein active or improve symptom, alleviate illness, delay or postpone progression of disease or preventing disease etc.In one non-limiting embodiment, term " treatment significant quantity " refers to the amount of such the compounds of this invention, when being applied to experimenter, its effectively (1) alleviate at least partly, suppress, prevent and/or improve (i) mediated by cMet or (ii) and cMet active relevant or (iii) by the activity (normal or exception) of cMet to be the illness of feature or illness or disease; Or (2) reduce or suppress the activity of cMet or (3) reduce or suppress the expression of cMet.In another nonrestrictive embodiment, term " treatment significant quantity " refers to the amount of such the compounds of this invention, and when being applied to cell or tissue or acellular biomaterials or medium, it effectively reduces at least partly or suppresses the activity of cMet; Or reduce or suppress the expression of cMet at least partly.

" experimenter " refers to animal as the term is employed herein.Typically, animal is Mammals.Experimenter also means such as primate (such as people), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird etc.In certain embodiments, experimenter is primate.In yet another embodiment, experimenter is people.

As used herein, term " suppression " refers to the Baseline activity alleviating or constrain given illness, symptom or illness or disease or remarkable reduction biological activity or process.

As used herein, in one embodiment, " treatment " of any disease of term or illness refer to and improve described disease or illness (namely slow down or stop or lowering the development of described disease or at least one its clinical symptom).In another embodiment, " treatment " refer to alleviate or improve at least one body parameter comprises may not by those parameters of patient identification.In an other embodiment, " treatment " refers to health aspect (such as not recognizable symptom stable), physiology aspect (such as body parameter stable) or this two aspect regulation and control disease or illness.In another embodiment, " treatment " refer to prevention or delay the outbreak of disease or illness or development or progress.

As used herein, experimenter's " needs " treats, if this experimenter will be benefited in biology, medical science or quality of life from described treatment.

As used herein, the similar term that in term " (a/an) ", " being somebody's turn to do " and literary composition of the present invention, (especially in claims) use will be interpreted as comprising odd number or plural number, obviously contradicts unless otherwise indicated herein or with context.

On the other hand, the invention provides the pharmaceutical composition comprising the compounds of this invention and pharmaceutically acceptable carrier.Pharmaceutical composition can be prepared and use and rectal administration etc. for particular route of administration such as Orally administered, parenteral.In addition, pharmaceutical composition of the present invention (can include but not limited to capsule, tablet, pill, granule, powder or suppository) or liquid form (including but not limited to solution, suspensoid or emulsion) existence in solid form.Pharmaceutical composition can carry out conventional manner operational example as sterilizing and/or can comprise conventional inert diluent, lubricant or buffer reagent, and auxiliary agents is as sanitas, stablizer, wetting agent, emulsifying agent and buffer reagent etc.

Typically, pharmaceutical composition is tablet or gelatine capsule, its comprise activeconstituents and

A) thinner, such as lactose, glucose, sucrose, N.F,USP MANNITOL, sorbyl alcohol, Mierocrystalline cellulose and/or glycine;

B) lubricant, such as silicon-dioxide, talcum powder, stearic acid, stearic magnesium or calcium salt and/or polyoxyethylene glycol; Tablet is also had

C) tackiness agent, such as neusilin, starch paste, gelatin, tragacanth gum, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone; If necessary

D) disintegrating agent, such as starch, agar, Lalgine or Lalgine sodium salt or effervescent mixture; And/or

E) absorption agent, tinting material, correctives and sweeting agent.

Tablet can carry out film coating or enteric coating according to methods known in the art.

The compounds of this invention of the significant quantity in tablet, lozenge, water-based or Oil suspensions, dispersible powder or granule, emulsion, hard or soft capsule or syrup or elixirs is included in for Orally administered suitable composition.The composition be intended to for orally using is prepared according to any method for the preparation of pharmaceutical composition known in the art, and such composition can comprise the material that one or more are selected from sweeting agent, correctives, tinting material and sanitas, to provide pharmaceutically graceful and good to eat preparation.Tablet containing activeconstituents and avirulently pharmaceutically acceptablely can be suitable for the vehicle preparing tablet.These excipients are inert diluent such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate in this way; Granulation agent and disintegrating agent, such as W-Gum or Lalgine; Tackiness agent, such as starch, gelatin or gum arabic; And lubricant, such as Magnesium Stearate, stearic acid or talcum powder.Tablet not by dressing or with known technology dressing to postpone disintegration in the gastrointestinal tract and absorption, and therefore provide the continuous action of longer time.Such as, time delay material such as glyceryl monostearate or distearin can be used.The preparation orally used can exist as hard gelatin capsule, wherein activeconstituents and inert solid diluent such as calcium carbonate, calcium phosphate or kaolin mixes, or exist as soft gelatin capsule, wherein activeconstituents and water or oily medium such as peanut oil, whiteruss or mixed with olive oil.

Some Injectable composition is isotonic aqueous solution agent or suspensoid, and suppository is advantageously prepared by fatty emulsion or suspension.Described composition by sterilizing and/or can contain auxiliary agents as the salt of sanitas, stablizer, wetting agent or emulsifying agent, dissolution accelerator, adjustment osmotic pressure and/or buffer reagent.In addition, they can also have the material of therapeutic value containing other.Described composition respectively according to routine mixing, granulate or coating method preparation, and containing the activeconstituents of have an appointment 0.1-75% or about 1-50%.

The composition of suitable applied dermally includes the compounds of this invention of effective amount and suitable carrier.The carrier being suitable for dermal delivery comprises the acceptable solvent of absorbable pharmacology of the skin contributed to through host.Such as transcutaneous device is bandage form, its comprise backing components, reservoir containing compound and optional carrier, optional for controlled and predetermined speed within the time period extended by compound delivery to the rate-controlling barrier of the skin of host and the means described device being fixed to skin.

Suitable comprise aqueous pharmaceutical, suspensoid, ointment, emulsion, gelifying agent or sprayable preparation (such as passing through aerosol delivery) etc. for topical application to the composition of such as skin and eyes.This type of local delivery system is particularly suitable for dermal administration, such as, be used for the treatment of skin cancer, such as, for the prophylactic applications in sunscreen, lotion, sprays etc.Therefore they are specially adapted to local well-known in the art (comprising makeup) preparation.These can contain solubilizing agent, stablizer, tension-elevating agent, buffer reagent and sanitas.

As used herein, topical application also can relate to application in suction or nose.They can be (independent with the form of dried powder, as mixture such as with the dry mixture of lactose or such as with the mixing element particle of phosphatide) from Diskus, or in use or send easily from pressurizing vessel, pump, atomizer, spraying gun or fog device with arosol spray form under not using suitable propellent situation.

The invention still further relates to pharmaceutical composition, it includes (disease that especially effectively treatment is above-mentioned, the amount of one of illness or illness) formula (I) compound of effective amount or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers, and described carrier is suitable for carrier that local, intestines such as oral or rectum or parenteral use and can is inorganic or organic, solid or liquid.

The dosage of the activeconstituents of warm-blooded animal to be administered to depends on that many factors comprise the type of patient, species, age, body weight, sex and medical conditions; The severity of illness to be treated; Route of administration; The renal function of patient and liver function; And the particular compound applied.There is the doctor of ordinary skill, clinician or animal doctor can easily determine and the place's of opening prevention, antagonism or stop the significant quantity of the medicine needed for progress of illness.The best correct amount realizing producing effect and drug level in not toxigenous scope needs based on medicine to dynamic (dynamical) scheme of the availability of target position.This needs to consider the distribution of medicine, balance and elimination.The dosage of formula (I) compound or its pharmacy acceptable salt that are applied to the warm-blooded animal such as people of about 70kg body weight be preferably every day everyone be about 3mg to about 5g, more preferably from about 10mg to about 1.5g, be preferably divided into 1 to 3 single dose (it can be such as formed objects).Usually, children receive a half-value dose of adult human dose.

For the experimenter of about 50-70kg, pharmaceutical composition of the present invention or combination can be the unitary dose of the activeconstituents of about 1-1000mg activeconstituents or about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg or about 1-50mg.The treatment effective dose of compound, pharmaceutical composition or its combination depends on the species of experimenter, body weight, age and individual instances, the illness be treated or disease or its severity.There is the significant quantity that the doctor of ordinary skill, clinician or animal doctor easily can determine each activeconstituents needed for progress preventing, treat or suppress illness or disease.

Above-mentioned dosage character advantageously can be adopted Mammals such as mouse, rat, dog, monkey or its isolated organ, tissue and prepared product to be tested by vitro and in vivo and confirm.Compound of the present invention can be applied outward using the form body of the solution such as aqueous solution or such as apply in intestines, parenteral (advantageously intravenously) terrain as suspension or the aqueous solution.External dosage can be about 10 ^-3to 10 ^-9volumetric molar concentration.Depend on route of administration, the treatment significant quantity in body can be about 0.1-500mg/kg or about 1-100mg/kg.

In another embodiment of the invention, provide the combination of formula (I) compound and one or more other therapeutic activity agent.Therefore, formula (I) compound can be used separately or use with one or more other therapeutic combinations, possible combined therapy adopts the form of fixed Combination or the compounds of this invention to use with one or more other therapeutical agents are staggered or use independently of one another, or combined administration fixed Combination and one or more other therapeutical agents.

In addition, particularly for oncotherapy, formula (I) compound and chemotherapy, radiotherapy, immunotherapy, surgery can be got involved or their combination combined administration.As mentioned above, in other therapeutic strategy, as assisting therapy, long-term treatment is possible equally.Other possible treatment is the treatment maintaining patient's states after tumor regression, or or even is such as being in the chemopreventive therapy in dangerous patient.

Therefore, formula (I) compound can with other anti-proliferative compounds Combination application.This type of anti-proliferative compounds includes but not limited to aromatase inhibitor; Estrogen antagonist agent; Topoisomerase I inhibitor; Topoisomerase II inhibitors; Microtubule active compound; Alkylated compound; Histone deacetylase inhibitors; The compound of Cell differentiation inducing activity process; Cyclooxygenase inhibitors; MMP inhibitor; MTOR inhibitors; Antineoplastic antimetabolite; Platinum compound; The compound of target/reduction protein or lipid kinase activity; Anti-angiogenic compounds; The compound of target, reduction or arrestin matter or lipid phosphatase activity; Gonadorelin (gonadorelin) agonist; Antiandrogenic agents; Methionine Aminopeptidase inhibitor; Diphosphonate; Biological response conditioning agent; Antiproliferation antibodies; Heparanase inhibitors; Ras Ras oncogenic isoforms inhibitor; Telomerase inhibitor; Proteasome inhibitor; Be used for the treatment of the compound of malignant hematologic disease; Target, reduction or suppress the compound of Flt-3 activity; Hsp90 inhibitor; Spindle body kinesin inhibitor; Mek inhibitor; Formyl tetrahydrofolic acid (leucovorin); EDG bonding agent; Leukemia compound; Ribonucleotide reductase inhibitors; S adenosylmethionine decarboxylase inhibitor; Inhibiting angiogenesis steroid; Reflunomide; Other chemotherapy compound (as defined below), light-sensitive compound.

In addition, selectively or additionally, they can with other tumor therapeuticing method Combination application, comprise surgical operation, ionizing rays, optical dynamic therapy, implantation, such as, with reflunomide, hormone, or they are used as radiosensitizer.

Term used herein " aromatase inhibitor " relates to the compound suppressing oestrogenic hormon to produce, namely suppress substrate androstenedione and testosterone to transform respectively to oestrone and estradiol.This term includes but not limited to steroid, particularly Atamestane, Exemestane and Formestane, and particularly on-steroidal, particularly aminoglutethimide, Rogletimide (roglethimide), Racemic pyridoglutethimide (pyridogluthethimide), Win-24540, testolactone, KETOKONAZOL, R 83842, fadrozole, Anastrozole and letrozole.Exemestane can such as with commercially available, such as trade mark for AROMASIN form is used.Formestane can such as with commercially available, such as trade mark for LENTARON form is used.Fadrozole can such as with commercially available, such as trade mark for AFEMA form is used.Anastrozole can such as with commercially available, such as trade mark for ARIMIDEX form is used.Letrozole can such as with commercially available, such as trade mark for FEMARA or FEMAR form is used.Aminoglutethimide can such as with commercially available, such as trade mark for ORIMETEN form is used.The combination of the present invention being included as the chemotherapeutic of aromatase inhibitor is used in particular for the tumour for the treatment of hormone receptor positive, such as breast tumor.

Term used herein " estrogen antagonist agent " relates to the compound in the effect of Estrogen Receptor antagonising oestrogen.This term includes but not limited to tamoxifen, fulvestrant, raloxifene and RALOXIFENE HCL.Tamoxifen can such as with commercially available, such as trade mark for NOLVADEX form is used.RALOXIFENE HCL can such as with commercially available, such as trade mark for EVISTA form is used.Fulvestrant can as US 4,659, prepare like that disclosed in 516 or its can such as with commercially available, such as trade mark for FASLODEX form is used.The combination of the present invention being included as the chemotherapeutic of estrogen antagonist agent is used in particular for treating estrogen receptor positive tumors, such as breast tumor.

Term used herein " antiandrogenic agents " relates to any material that can suppress androgenic biological action, and includes but not limited to bicalutamide (CASODEX), and it can such as US4, and 636, prepare like that disclosed in 505.

Term used herein " gonadorelin agonist " includes but not limited to abarelix, goserelin and goserelin acetate.Goserelin is disclosed in US 4,100, in 274 and can such as with commercially available, such as trade mark for ZOLADEX form is used.Abarelix can such as US 5, and 843, prepare like that disclosed in 901.

Term used herein " topoisomerase I inhibitor " includes but not limited to Hycamtin, gefitinib (gimatecan), irinotecan, camptothecine and analogue thereof, 9-nitrocamptothecin and macromolecular camptothecin conjugate PNU-166148 (compd A 1 in WO99/17804).Irinotecan can such as with commercially available, such as trade mark for CAMPTOSAR form is used.Hycamtin can such as with commercially available, such as trade mark for HYCAMTIN form is used.

Term used herein " Topoisomerase II inhibitors " includes but not limited to anthracycline, such as Dx (comprises Liposomal formulation, such as CAELYX), daunorubicin, epirubicin, idarubicin and Nemorubicin, anthraquinones mitoxantrone and losoxantrone, and podophillotoxines etoposide and teniposide.Etoposide can such as with commercially available, such as trade mark for ETOPOPHOS form is used.Teniposide can such as with commercially available, such as trade mark for VM 26-BRISTOL form is used.Dx can such as with commercially available, such as trade mark for ADRIBLASTIN or ADRIAMYCIN form is used.Epirubicin can such as with commercially available, such as trade mark for FARMORUBICIN form is used.Idarubicin can such as with commercially available, such as trade mark for ZAVEDOS form is used.Mitoxantrone can such as with commercially available, such as trade mark for NOVANTRON form is used.

Term " microtubule active compound " relates to microtubule stabilization, microtubule unstability compound and microtubule polymerization inhibitor, include but not limited to taxanes (such as taxol and docetaxel), vinca alkaloids (such as vinealeucoblastine(VLB) particularly Vinblastine sulphate, vincristine(VCR) is vincristine sulphate and vinorelbine particularly), discodermolides, colchicine and ebormycine (epothilone) and derivative (such as epothilone B or D or derivatives thereof) thereof.Taxol can such as be used with commercially available TAXOL form.Docetaxel can such as with commercially available, such as trade mark for TAXOTERE form is used.Vinblastine sulphate can such as with commercially available, such as trade mark for VINBLASTIN R.P. form is used.Vincristine sulphate can such as with commercially available, such as trade mark for FARMISTIN form is used.Discodermolide can as US 5, and 010, obtain like that disclosed in 099.Also comprise epothilone derivatives, it is disclosed in WO 98/10121, US 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247.Particularly preferably ebomycin A and/or B.

Term used herein " alkylated compound " includes but not limited to endoxan, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel).Endoxan can such as with commercially available, such as trade mark for CYCLOSTIN form is used.Ifosfamide can such as with commercially available, such as trade mark for HOLOXAN form is used.

Term " histone deacetylase inhibitors " or " hdac inhibitor " relate to inhibition of histone deacetylase and have the compound of antiproliferative activity.It comprises compound disclosed in WO 02/22577, particularly N-hydroxyl-3-[4-[[(2-hydroxyethyl) [2-(1H-indol-3-yl) ethyl]-amino] methyl] phenyl]-2E-2-acrylamide, N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-base)-ethyl]-amino] methyl] phenyl]-2E-2-acrylamide and its pharmacy acceptable salt.It is also particularly including octanedioyl aniline hydroxamic acid (Suberoylanilide hydroxamic acid) (SAHA).The compound inhibitor that target, reduction or inhibition of histone deacetylase (HDAC) are active, such as Sodium propanecarboxylate and octanedioyl aniline hydroxamic acid (SAHA), suppress the activity being called the enzyme of histone deacetylase.Specificity hdac inhibitor comprises MS275, SAHA, FK228 (being FR901228 in the past), Trichostatin A and US 6, 552, compound disclosed in 065, particularly N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-base)-ethyl]-amino] methyl] phenyl]-2E-2-acrylamide or its pharmacy acceptable salt and N-hydroxyl-3-[4-[(2-hydroxyethyl) { 2-(1H-indol-3-yl) ethyl]-amino] methyl] phenyl]-2E-2-acrylamide or its pharmacy acceptable salt, particularly lactic acid salt.

Term " antineoplastic antimetabolite " includes but not limited to 5 FU 5 fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylation compound, such as 5-azacytidine and Decitabine, methotrexate and edatrexate and antifol, such as pemetrexed.Capecitabine can such as with commercially available, such as trade mark for XELODA form is used.Gemcitabine can such as with commercially available, such as trade mark for GEMZAR form is used.

Term used herein " platinum compound " includes but not limited to carboplatin, cis-platinum, cis-platinum and oxaliplatin.Carboplatin can such as with commercially available, such as trade mark for CARBOPLAT form is used.Oxaliplatin can such as with commercially available, such as trade mark for ELOXATIN form is used.

Term used herein " compound of target/reduction protein or lipid kinase activity " or " protein or lipid phosphatase active " or " other anti-angiogenic compounds " include but not limited to c-Met Tyrosylprotein kinase and/or Serine and/or threonine kinase inhibitor or lipid kinase inhibitors, such as

A) compound that target, reduction or suppression platelet derived growth factor receptor (PDGFR) are active, such as target, reduction or suppress the compound of PDGFR activity, particularly suppress the compound of pdgf receptor, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111;

B) target, reduce or be suppressed to the active compound of bfgf receptor (FGFR);

C) compound that target, reduction or suppression IGF-1 I (IGF-IR) are active, such as target, reduction or suppress the compound of IGF-IR activity, particularly suppress the compound of IGF-I kinase activation, such as those compounds disclosed in WO 02/092599, or the antibody of target IGF-I receptor extracellular domain or its somatomedin;

D) target, reduction or suppress the compound of Trk receptor tyrosine kinase family active, or ephrin kinase families inhibitor;

E) target, reduction or suppress the compound of Axl family active;

F) target, reduction or suppress the compound of Ret receptor tyrosine kinase activity;

G) target, reduction or suppress the compound of Kit/SCFR receptor tyrosine kinase activity, such as imatinib;

H) compound that target, reduction or suppression C-kit receptor tyrosine kinase (part of PDGFR family) are active, such as target, reduction or suppress the compound of c-Kit receptor tyrosine kinase family active, particularly suppress the compound of c-Kit acceptor, such as imatinib;

I) target, reduction or suppress the compound of c-Abl family member, their gene fusion product (such as BCR-Abl kinases) and mutant activity, such as target, reduction or suppress the compound of c-Abl family member and their gene fusion product activity, such as N-phenyl-2-pyrimidine-amine derivatives, the PD173955 of such as imatinib or AMN107 (AMN107), PD180970, AG957, NSC 680410, ParkeDavis or Dasatinib (BMS-354825);

J) compound of target, reduction or arrestin kinase c (PKC) member and serine/threonine kinase Raf family, the member of MEK, SRC, JAK, FAK, PDK1, PKB/Akt and the activity of Ras/MAPK family member and/or cell cycle protein dependent kinase family (CDK) member, particularly US 5,093, those staurosporine derivatives, such as midostaurin disclosed in 330; The example of other compound comprise such as UCN-01, Safingol, BAY 43-9006, bryostatin 1, Perifosine, Thio ALP, RO 318220 and RO 320432, GO 6976, Isis 3521, LY333531/LY379196, isoquinoline compound such as disclosed in WO 00/09495 those, FTIs, PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor);

K) compound of target, reduction or arrestin tyrosine kinase inhibitor activity, such as the compound of target, reduction or arrestin tyrosine kinase inhibitor activity, comprises imatinib mesylate (GLEEVEC) or tyrphostin.Tyrphostin is preferably lower molecular weight (Mr < 1500) compound or its pharmacy acceptable salt, be selected from the compound of benzylidene propane dinitrile class or S-aryl phenylpropyl alcohol dintrile or two substrate quinoline especially, particularly be selected from following any compound: TyrphostinA23/RG-50810, AG 99, Tyrphostin AG 213, Tyrphostin AG 1748, Tyrphostin AG 490, Tyrphostin B44, Tyrphostin B44 (+) enantiomer, Tyrphostin AG 555, AG 494, Tyrphostin AG 556, AG957 and adaphostin (4-{ [(2, 5-dihydroxy phenyl) methyl] amino-phenylformic acid diamantane ester, NSC 680410, adaphostin),

L) target, reduce or suppress the epidermal growth factor family of receptor tyrosine kinase (as EGFR that is same or heterodimer, ErbB2, ErbB3, and the compound of their mutant activity, such as target ErbB4), reduce or suppress the compound of Epidermal Growth Factor Receptor Family activity particularly to suppress EGF receptor tyrosine kinase family member (such as EGF acceptor, ErbB2, ErbB3 and ErbB4) or in conjunction with the compound of EGF or EGF associated ligands, protein or antibody, and particularly WO97/02266 (such as embodiment 39 compound) or EP 0 564 409, WO 99/03854, EP0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, US 5,747,498, WO98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and particularly WO96/30347 (being such as called the compound of CP 358774), general and concrete those disclosed compound in WO 96/33980 (such as compound ZD1839) and WO 95/03283 (such as compound ZM105180), protein or monoclonal antibody, such as Herceptin (Herceptin ^tM), Cetuximab (Erbitux ^tM), Iressa, tower Western method, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3 and 7H-pyrrolo--[2,3-d] pyrimidine derivatives (being disclosed in WO 03/013541), with

M) target, reduction or suppress the compound of c-Met receptor active, such as target, reduction or suppress the compound of c-Met activity particularly to suppress the compound of c-Met kinase activation, or target c-Met extracellular domain or the antibody in conjunction with HGF;

N) target, reduction or suppress the compound of Ron receptor tyrosine kinase activity.

Other anti-angiogenic compounds comprises the compound with other active mechanism such as suppressing irrelevant with protein or lipid kinase, such as Thalidomide (THALOMID) and TNP-470.

Term " compound of target, reduction or arrestin matter or lipid phosphatase " includes but not limited to the inhibitor of phosphatase 1, Phosphoric acid esterase 2A or CDC25, such as okadaic acid (okadaic acid) or derivatives thereof.

Term " compound of Cell differentiation inducing activity process " include but not limited to such as vitamin A acid, α-, γ-or Delta-Tocopherol or α-, γ-or δ-tocotrienols (tocotrienol).

Term used herein " cyclooxygenase inhibitors " includes but not limited to the 2-arylaminophenylacetic acid that such as Cox-2 inhibitor, 5-alkyl replace and derivative, such as celecoxib (CELEBREX), rofecoxib (VIOXX), Etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2 '-chloro-6 '-fluoroanilino) phenylacetic acid, Prexige.

Term used herein " diphosphonate " includes but not limited to hydroxyl ethyl phosphonic acid, clodronic acid, tiludronic acid, pamidronic acid, clinic effect of alendronate, Ibandronic acid, risedronic acid and Zoledronic acid." hydroxyl ethyl phosphonic acid " can such as with commercially available, such as trade mark for DIDRONEL form is used." clodronic acid " can such as with commercially available, such as trade mark for BONEFOS form is used." tiludronic acid " can such as with commercially available, such as trade mark for SKELID form is used." pamidronic acid " can such as with commercially available, such as trade mark for AREDIA ^tMform is used." clinic effect of alendronate " can such as with commercially available, such as trade mark for FOSAMAX form is used." Ibandronic acid " can such as with commercially available, such as trade mark for BONDRANAT form is used." risedronic acid " can such as with commercially available, such as trade mark for ACTONEL form is used." Zoledronic acid " can such as with commercially available, such as trade mark for ZOMETA form is used.

Term " mTOR inhibitors " relates to the Mammals target (mTOR) and the compound with antiproliferative activity that suppress rapamycin, such as sirolimus (rapammune ), everolimus (Certican ^tM), CCI-779 and ABT578.

Term used herein " heparanase inhibitors " relates to target, reduction or suppresses the compound of heparin sulfate degraded.This term includes but not limited to PI-88.

Term used herein " biological response conditioning agent " relates to lymphokine or Interferon, rabbit, such as interferon-gamma.

Term used herein " Ras Ras oncogenic isoforms inhibitor " (such as H-Ras, K-Ras or N-Ras) relates to target, reduction or suppresses the compound of Ras carcinogenic activity, such as " farnesyl tranfering enzyme inhibitor ", such as L-744832, DK8G557 or R115777 (Zarnestra).

Term used herein " telomerase inhibitor " relates to target, reduction or suppresses the compound of telomerase activation.Target, reduction or suppress the compound of telomerase activation particularly to suppress the compound of telornerase receptor, such as Telomerase element (telomestatin).

Term used herein " Methionine Aminopeptidase inhibitor " relates to target, reduction or suppresses the compound of Methionine Aminopeptidase activity.Target, reduction or suppress the compound of Methionine Aminopeptidase activity to be such as bengamide or derivatives thereof.

Term used herein " proteasome inhibitor " relates to the compound of target, reduction or proteasome enzyme inhibition activity.The compound of target, reduction or proteasome enzyme inhibition activity comprises such as Velcade (Bortezomid) (Velcade ^tM) and MLN 341.

Term used herein " matrix metallo-proteinase inhibitor " or (" MMP " inhibitor) include but not limited to that collagen intends peptide and non-plan inhibitor peptides, tetracycline derivant, and such as hydroxamate intends inhibitor peptides Batimastat and oral bio can utilize analogue Marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

Term used herein " is used for the treatment of the compound of malignant hematologic disease " and includes but not limited to FMS-sample tyrosine kinase inhibitor, such as target, reduction or the compound suppressing FMS-sample tyrosine kinase receptor (Flt-3R) active; Interferon, rabbit, 1-b-D-arabinofuranosyl adenin cytosine(Cyt) (ara-c) and busulfan; And ALK inhibitor, such as target, reduction or suppress the compound of Nucleophosmin-anaplastic lymphoma kinase.

Term " target, reduction or the compound suppressing FMS-sample tyrosine kinase receptor (Flt-3R) active " particularly suppresses the compound of Flt-3R receptor kinase family member, protein or antibody, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

Term used herein " HSP90 inhibitor " includes but not limited to target, reduction or suppresses the compound of the inherent atpase activity of HSP90; By the degraded of ubiquitin protein body approach, target, reduction or the compound suppressing HSP90 client protein (client protein).Target, reduction or suppress the compound of the inherent atpase activity of HSP90 particularly to suppress the compound of HSP90ATP enzymic activity, protein or antibody, such as 17-allyl amino, 17-demethoxygeldanamycin (17AAG, 17-DMAG), geldanamycin derivant; Other geldanamycin related compound; Radicicol and hdac inhibitor; The CNF1010 of IPI-504, CNF1010, CNF2024, Conforma Therapeutics; Temozolomide (TEMODAL ), the AUY922 of Novartis.

Term used herein " anti proliferative antibody " includes but not limited to Herceptin (Herceptin ^tM), Herceptin-DM1, Erbitux, Avastin (Avastin ^tM), Rituximab (Rituxan ), PRO64553 (anti-CD 40) and 2C4 antibody.Antibody refers to such as complete monoclonal antibody, polyclonal antibody, the multi-specificity antibody formed by least 2 complete antibodies and antibody fragment, as long as they show required biologic activity.

Term " leukemia compound " comprises such as Ara-C, pyrimidine analogue, and it is 2 '-Alpha-hydroxy ribose (cytosine arabinoside) derivative of Deoxyribose cytidine.Also comprise purine analogue: xanthoglobulin, Ismipur (6-MP) and fludarabine phosphate.For treatment acute myeloid leukaemia (AML), formula (I) compound can be applied with standard leukemia therapeutic combination, therapy Combination application particularly used with treatment AML.Specifically, formula (I) compound can with such as farnesyl transferase inhibitor and/or the other medicines combined administration being used for the treatment of AML, described other medicines are daunorubicin, Zorubicin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, Carboplatin and PKC412 such as.

Term used herein " somatostatin receptor antagonist " refers to the compound of target, treatment or Developing restraint inhibin receptor, such as Sostatin and SOM230.

" tumor cell damage method " refers to the method for such as ionizing rays.Term " ionizing rays " refers to the ionizing rays occurred with electromagnetic radiation (such as X-ray and gamma-rays) or particle (such as α and beta-particle) at context.Ionizing rays be without limitation provide with radiotherapy and be known in the art.See Hellman, Principles of Radiation Therapy (radiotherapy principle), Cancer, in Principles and Practice of Oncology, the people such as Devita edit, the 4th edition, 1st volume, 248-275 page (1993).

Term used herein " EDG bonding agent " represents that a class regulates the immunosuppressor of lymphocyte recirculation, such as FTY720.

Term " spindle body kinesin inhibitor " is known in the art and comprises SB715992 or SB743921 of GlaxoSmithKline, the pentamidine/chlorpromazine of CombinatoRx.

Term " mek inhibitor " is known in the art and comprises the PD181461 of AZD6244, Pfizer of ARRY142886, AstraZeneca of Array PioPharma, formyl tetrahydrofolic acid.

Term " ribonucleotide reductase inhibitors " includes but not limited to pyrimidine or purine nucleoside analogs, includes but not limited to fludarabine and/or Ara-C (ara-C), 6-Tioguanine, 5 FU 5 fluorouracil, CldAdo, Ismipur (particularly combine with ara-C and resist ALL) and/or pentostatin.Ribonucleotide reductase inhibitors is hydroxyurea or 2-hydroxyl-1H-isoindole-1 particularly, 3-derovatives, the people such as such as Nandy, Acta Oncologica, 33rd volume, 8th phase, PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8 of mentioning in 953-961 page (1994).

Term used herein " S adenosylmethionine decarboxylase inhibitor " includes but not limited to US5,461, compound disclosed in 076.

Also comprise particularly such as, with the monoclonal antibody of those compounds, protein or VEGF/VEGFR disclosed in Publication about Document: WO 98/35958 (such as 1-(4-chloroanilino)-4-(4-pyridylmethyl) phthalazines or its pharmacy acceptable salt, succinate) or WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0 769 947; The people such as Prewett, Cancer Res, the 59th volume, 5209-5218 page (1999); The people such as Yuan, Proc Natl Acad Sci USA, the 93rd volume, 14765-14770 page (1996); The people such as Zhu, Cancer Res, the 58th volume, 3209-3214 page (1998); With people such as Mordenti, Toxicol Pathol, the 27th volume, the 1st phase, 14-21 page (1999); In WO 00/37502 and WO 94/10202 describe those; Angiostatin, by people such as O ' Reilly, Cell, the 79th volume, 315-328 page (1994) describes; Endostatin, by people such as O ' Reilly, Cell, the 88th volume, 277-285 page (1997); Anthranilic amides; ZD4190; ZD6474; SU5416; SU6668; Avastin; Or anti-VEGF antibodies or anti-VEGF receptor antibody, such as rhuMAb and RHUFab, VEG aptamers, such as Macugon; FLT-4 inhibitor, FLT-3 inhibitor, VEGFR-2IgG1 antibody, blood vessel enzyme (Angiozyme) (RPI 4610) and Avastin (Avastin ^tM).

" optical dynamic therapy " used herein refers to and is called the chemical treatment of light-sensitive compound or the therapy of preventing cancer with some.The example of optical dynamic therapy comprises with compound, and such as VISUDYNE and porfimer sodium treat.

" inhibiting angiogenesis steroid " used herein refers to the compound of blocking-up or inhibiting angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-Biao hydrocortisone, 11-prednisolone (cortexolone), 17 α-hydroxyprogesterone, Kendall compound, Desoxycortone, testosterone, oestrone and dexamethasone.

" reflunomide " used herein includes but not limited to compound, such as fluocinolone acetonide (fluocinolone), dexamethasone, particularly implant form.

" other chemotherapy compound " includes but not limited to plant alkaloid, hormonal compounds and antagonist; Biological response conditioning agent, preferred lymphokine or Interferon, rabbit; Antisense oligonucleotide or oligonucleotide derivative; ShRNA or siRNA; Or mix (miscellaneous) compound or there is the compound of other or unknown role mechanism.

Formula (I) compound can also with one or more other medicines Combination application, described other medicines are selected from anti-inflammatory drug, antihistamine drug, bronchodilator, NSAID, chemokine receptor anagonists.

The compounds of this invention is also used as co-therapy compound, with other medicines Combination application, especially for treatment inflammatory diseases, such as mentioned above those, be such as used as the toughener of these pharmacological agent activity or be used as to reduce the instrument of these medicine required dosages or potential side effect.The compounds of this invention can mix with described other medicines in fixed drug composition, or its can use individually (namely before described other medicines, simultaneously or use afterwards).Therefore, the present invention includes formula (I) compound and one or more are selected from the combination of following other medicines: anti-inflammatory drug, antihistamine drug, bronchodilator, NSAID, chemokine receptor anagonists; Described formula (I) compound and described medicine are in identical or different pharmaceutical composition.

The antiphlogiston be applicable to comprises steroid, particularly glucocorticoids, such as budesonide, Viarox, fluticasone propionate, ciclesonide or furoic acid momisone, or WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (particularly embodiment 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, those in 99 and 101), WO 03/035668, WO 03/048181, WO 03/062259, WO 03/064445, the steroid described in WO03/072592, non-steroidal glucocorticoid receptor stimulant, such as WO00/00531, WO 02/10143, WO 03/082280, WO 03/082787, WO 03/104195, in WO 04/005229 describe those, LTB4 antagonist, such as, in LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247 and US 5451700 describe those, LTD4 antagonist, such as Singulair and Zafirlukast, PDE4 inhibitor, such as cilomilast (Ariflo glaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), arofylline (Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SelCID (TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo), and WO 92/19594, WO 93/19749, WO93/19750, WO 93/19751, WO 98/18796, WO 99/16766, WO 01/13953, WO 03/104204, WO 03/104205, WO 03/39544, WO 04/000814, WO04/000839, WO 04/005258, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/018431, WO 04/018449, WO 04/018450, WO04/018451, WO 04/018457, WO 04/018465, WO 04/019944, WO 04/019945, disclosed in WO 04/045607 and WO 04/037805 those, A2a agonist, such as EP409595A2, EP 1052264, EP 1241176, WO 94/17090, WO 96/02543, WO96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451, WO 99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO 00/23457, WO 00/77018, WO 00/78774, WO 01/23399, WO 01/27130, WO 01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO 02/96462, WO 03/086408, WO 04/039762, WO04/039766, disclosed in WO 04/045618 and WO 04/046083 those, A2b antagonist, such as, in WO 02/42298 describe those, and beta-2-adrenoceptor agonist, such as salbutamol, Orciprenaline, terbutaline, Salmeterol, Partusisten, procaterol, and particularly formoterol and pharmacy acceptable salt thereof, with formula (I) compound (free or salt or solvate form thereof) in WO 0075114, document is incorporated to as a reference herein, the compound of preferred embodiment, particularly following formula: compound

And pharmacy acceptable salt, and formula (I) compound in WO 04/16601 (free or salt or solvate form thereof), and the compound in WO 04/033412.

The bronchodilator be applicable to comprises anticholinergic compound or antimuscarinic compounds, particularly ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and Glycopyrronium Bromide, also have those that describe in WO 01/04118, WO 02/51841, WO 02/53564, WO 03/00840, WO03/87094, WO 04/05285, WO 02/00652, WO 03/53966, EP 424021, US5171744, US 3714357, WO 03/33495 and WO 04/018422.

The Chemokine Receptors be applicable to comprises, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonist, such as Schering-Plough antagonist SC-351125, SCH-55700 and SCH-D, Takeda antagonist is N-[[4-[[[6 such as, 7-dihydro-2-(4-aminomethyl phenyl)-5H-benzo-suberene-8-base] carbonyl] amino] phenyl]-methyl] tetrahydrochysene-N, N-dimethyl-2H-pyrans-4-ammonium chloride (TAK-770), with US 6166037 (particularly claim 18 and 19), WO 00/66558 (particularly claim 8), WO 00/66559 (particularly claim 9), the CCR-5 antagonist described in WO 04/018425 and WO 04/026873.

Be applicable to antihistaminic comprise cetrizine hcl, acetaminophen, clemastine fumarate, promethazine, Loratadine, Desloratadine, diphenhydramine and fexofenadine hydrochloride, acrivastine, astemizole, azelastine, ebastine, epinastine, mizolastine and Triludan, and disclosed in WO 03/099807, WO 04/026841 and JP 2004107299 those.

For therapeutical agent particularly one or more anti-proliferative compounds, cytostatic compounds or the cytotoxic compound of possible combination, such as one or several are selected from following material, it includes but not limited to polyamine biosynthesis inhibitor, kinases inhibitor, particularly serine/threonine protein kitase (such as protein kinase C) inhibitor or tyrosine protein kinase inhibitor (such as EGF receptor tyrosine kinase inhibitors such as Iressa vegf receptor tyrosine kinase inhibitor such as PTK787 or Avastin ), the antibody of anti-ligand VEGF, or the antibody of anti-pdgf receptor Tyrosylprotein kinase, such as STI571 (Glivec ), PI3K (BEZ235 of such as Novartis) and mToR inhibitor such as rapamycin, RAD001, cytokine, negative growth regulator such as TGF-β or IFN-β, aromatase inhibitor such as letrozole (Femara ) or Anastrozole, SH2 structural domain and the interactional inhibitor of phosphorylated protein, estrogen antagonist agent, topoisomerase I inhibitor such as irinotecan, Topoisomerase II inhibitors, microtube active such as taxol or ebormycine, alkylating agent, antiproliferative metabolic antagonist such as gemcitabine or capecitabine, platinum compound such as carboplatin or cis-platinum, diphosphonate such as AREDIA or ZOMETA with monoclonal antibody (such as anti-HER2's) such as Herceptin.

The structure of the promoting agent assert by coding, popular name or trade(brand)name from the standard summary " the Merck index " of current edition or from database, such as, can be obtained in Patents International (such as IMS World Pulication).Its corresponding content is incorporated to herein as a reference.

The above-claimed cpd can applied with formula (I) compound combination can be prepared and use as described in this area (such as above-cited document).

In combination therapy/combined therapy of the present invention, the compounds of this invention and another therapeutical agent can be prepared and/or preparation by identical or different manufacturers.In addition, the compounds of this invention and another therapeutical agent can be come together in combination therapy as follows: (i) be (such as, when comprising the medicine box of the compounds of this invention and another therapeutical agent) before combined prod is revealed in doctor; (ii) before being about to use by doctor oneself (or guidance under) doctor; (iii) by patient oneself, such as, during continuous administration the compounds of this invention and another therapeutical agent.

Therefore, the invention provides the purposes of disease that formula (I) compounds for treating mediates by cMet or illness, wherein said medicine is produced for using together with another therapeutical agent.The present invention also provides another therapeutical agent to be used for the treatment of the purposes of disease or the illness mediated by cMet, and wherein said medicine is used together with formula (I) compound.

Therefore, the present invention relates to combination in further embodiment, particularly pharmaceutical composition, it comprises the treatment free form of significant quantity or formula (I) compound of pharmacy acceptable salt form and for simultaneously or the second therapeutic activity agent of using successively.Described other therapeutical agent is preferably selected from carcinostatic agent, anti-inflammatory agent.

The invention further relates to the method for disease therapy or illness, described disease or illness respond C-Met Tyrosylprotein kinase, particularly proliferative disorders or disease, especially cancer, described method comprises the combination of using the drug substance of significant quantity to the experimenter having its needs (particularly people), described combination comprises (a) formula (I) compound, and (b) one or more pharmaceutically active agents.

What the invention further relates to drug substance is combined in treatment to the disease of C-Met Tyrosylprotein kinase response or illness particularly proliferative disorders or the disease purposes especially in cancer, the combination of described drug substance comprises (a) formula (I) compound, and (b) one or more pharmaceutically active agents.

The invention further relates to being combined in for the preparation for the treatment of the purposes in the medicine of the disease of C-Met Tyrosylprotein kinase response or illness particularly proliferative disorders or disease especially cancer of drug substance, the combination of described drug substance comprises (a) formula (I) compound, and (b) one or more pharmaceutically active agents.

The invention further relates to pharmaceutical composition, it comprises (a) formula (I) compound and (b) pharmaceutically active agents, and (c) pharmaceutically acceptable carrier; Wherein at least one pharmaceutically active agents is anticancer therapeutic agent.

The invention further relates to commercial package or product, it comprises (a) formula (I) compound, (b) pharmaceutical preparation of pharmaceutically active agents, its for simultaneously, common, separately or apply successively, wherein at least one pharmaceutically active agents is anticancer therapeutic agent.

Two or more successively, separately and the combination of simultaneously using also be possible, the drug component of preferably combination shows combination therapy effect, it exceedes when the drug component combined is with the effect produced during the enough large timed interval (can not find the interaction to treatment effect) individual application, particularly preferably acts synergistically.

The present invention also provides formula (I) compound to be used for the treatment of the purposes of disease or the illness mediated by cMet, wherein before patient (in such as 24 hours) by another therapeutic agent treats.The present invention also provides another therapeutical agent to be used for the treatment of the purposes of disease or the illness mediated by cMet, wherein before patient (in such as 24 hours) by formula (I) compounds for treating.

Term used herein " postpone progress " refers to being in early stage or early stage patient uses described combination, or use described combination to the patient initially manifesting institute's disease therapy or institute's disease therapy recurrence, wherein patient, be such as diagnosed as pre-formed phase of corresponding disease, or patient is in the situation of such as pharmacological agent or in the situation process that caused by accident, wherein corresponding advancing of disease is possible.

Term " combination therapy active " or " combination therapy effect " refer to compound can with their (preferably in treated warm-blooded animal particularly people) still show (preferably working in coordination with) interact (combination therapy effect) the timed interval separately (with long-term interlace mode, the particularly special mode of order) use.Combination therapy effect can measure by following the trail of blood level (demonstrate and at least there are two kinds of compounds in the blood of treated people within some timed interval) especially.

Term " medicine is effective " preferably relates to treats or effective amount resisting disease disclosed herein or disease progression in wider meaning or in prevention.

Term used herein " commercial package " or " product " represent " medicine box (kit of parts) of part " especially, in this meaning, component (a) defined above and (b) can by administration independently or by application containing the different component (a) of amount and the different fixed Combination of (b), namely simultaneously or administration in different time points.In addition, these terms comprise commercial package, described commercial package comprises (particularly combination have) as the component (a) of activeconstituents and (b), and (preferably interlocks for a long time in specified time order) simultaneously, successively in the progress delaying proliferative disease or its treatment or (more preferably) separately applies their specification sheets.Then each several part of the medicine box of part such as can be used simultaneously or interlock for a long time and use, and namely for any part of the medicine box of part, uses in different time points with the identical or different timed interval.It is most preferred that, access time interval in case in the Combination application of part to the effect of institute's disease therapy be greater than effect that in only application combination partner (a) or (b), any one obtains (as according to standard method measure).Treat that the total amount of combination partner (a) and the combination partner (b) used in combination preparation is more different than being, such as in order to the demand of the demand or single patient that meet treated patient subgroups, its different demand may owing to the specific disease of patient, age, sex, body weight etc.Preferably, there is the effect that at least one is useful, the effect of such as combination partner (a) and (b) strengthens mutually, particularly exceed summation action, therefore described effect can with than only obtaining by each in the medicinal composition of the more low dosage of allowing in single medicine (not combination) treatment situation, produce other advantageous effect, such as less side effect or produce combined therapy effects with one or both in the combination partner of non-effective dosage (component) (a) and (b), and the very preferably strong synergy of combination partner (a) and (b).

When combination and the commercial package of applied component (a) and (b), simultaneously, it is also possible for applying any combination successively and separately, this means that component (a) and (b) can use, after the component using only a kind of lower host toxicity on a time point simultaneously, or long-term (such as more than the per daily dose in 3-4 week) uses and use another component subsequently on slower time point, or on slower time point, use the combination (obtaining the best use of in combinational drug therapy process subsequently) etc. of two kinds of components.

In another embodiment of the invention, provide the method for preparation formula (I) compound and intermediate thereof.Formula (I) compound can be prepared by known method itself, but these methods are so far not used for new compound of the present invention, and therefore they form new method.Schema provides the General Introduction of the synthesis strategy for obtaining formula (I) compound.Obviously contradict unless otherwise indicated herein or with context, described all methods can be carried out with any order suitably.The application of any and all examples provided in literary composition or exemplary language (as " such as ") is only for illustrating the present invention better, instead of the of the present invention scope claimed to other places carries out any restriction.

Therefore, on the other hand, the present invention relates to method (preparation method) and its intermediate of preparation formula (I) compound comprising at least one reactions steps disclosed in literary composition.

Z ₁be selected from Cl, Br and I

Schema 2 provides the details of the synthesis strategy obtaining preferred formula (IA, IB, IC) compound through (IIA, IIB and IIC).

Z ₁and Z ₂independently selected from Cl, Br and I

Schema 3 provides the details of the synthesis strategy obtaining preferred formula (ID) compound through (IID).

Z ₁be selected from Cl, Br and I

Schema 4 provides the details of the synthesis strategy obtaining preferred formula (IE) compound through (IIE).

Z ₁be selected from Cl, Br and I

Schema 5 provides the details of the synthesis strategy obtaining preferred formula (IF) compound through (IIF).

Z ₁and Z ₂independently selected from Cl, Br and I

Use method well known to the skilled person to be oxidized to cause obtaining SO/SO ₂linker

Schema 6 provides the details of the synthesis strategy obtaining preferred formula (IG) and formula (IH) compound through (IIG) and (IIH) respectively.

Z ₁be selected from Cl, Br and I

Schema 7 provides the details of the alternative synthesis strategy obtaining preferred formula (IH) compound through (IIH).

Schema 8 provides the details of the synthesis strategy obtaining preferred formula (IK) compound through (IIK).

Z ₁be selected from Cl, Br and I

Schema 9 provides the details of the synthesis strategy obtaining preferred formula (IL) compound.

The following examples illustrate the present invention, and do not limit its scope.In the embodiment provided, temperature is with a degree Celsius measurement.Except as otherwise noted, react and carry out in room temperature (rt).In addition, if do not pointed out in addition, analyze and preparative HPLC condition as follows:

method A:

Liquid stream is the first alcohol and water (containing 0.5% acetic acid) of 0.5mL/min

The methyl alcohol of 0-4.0min:10% to 90%

The methyl alcohol of 4.0-6.0min:90%

Post: from GP C18 3 μm of 4.6x30mm of Sepax

Thermostat temperature: 30 DEG C

method B:

Liquid stream is the first alcohol and water (containing 0.5% acetic acid) of 1.2mL/min

The methyl alcohol of 0-2.0min:10% to 90%

2.0-3.0min the methyl alcohol of 90%

Post: from GP C18 3 μm of 4.6x30mm. of Sepax

Thermostat temperature: 30 DEG C

method C:

The methyl alcohol of 0-3.0min:60% to 90%

The methyl alcohol of 3.0-5.0min:90%

Post: from GP C18 3 μm of 4.6x30mm. of Sepax

Thermostat temperature: 30 DEG C

method D:

The methyl alcohol of 0-3.0min:10% to 50%

The methyl alcohol of 3.0-4.0min:50%

Post: from GP C18 3 μm of 4.6x30mm. of Sepax

Thermostat temperature: 30 DEG C

method E:

The methyl alcohol of 0-4.0min:10% to 90%

The methyl alcohol of 4.0-8.0min:90%

Post: from GP C18 3 μm of 4.6x30mm. of Sepax

Thermostat temperature: 30 DEG C

method F:

Liquid stream is the hexane/ethanol/diethylamine (Diethyleamine) 80/20/0.1, v/v/v of 1mL/min

Post: AD-H

Thermostat temperature: 25 DEG C

method G:

Liquid stream is the hexane/ethanol/diethylamine 70/30/0.1, v/v/v of 1mL/min

Post: AD-H

Thermostat temperature: 25 DEG C

method H:

Liquid stream is the hexane/isopropyl alcohol/diethylamine 70/30/0.1, v/v/v of 1mL/min

Post: CHIRALPAK OD-H

Thermostat temperature: 25 DEG C

method I:

SFC instrument: Thar SFC Prep 80

Liquid stream is the methyl alcohol/CO of 45g/min ₂70/30

Post: CHIRALPAK OD-H, 2.0x25cm

Wavelength: UV 254nm

Thermostat temperature: 35 DEG C

method J:

The methyl alcohol of 0-3.0min:60% to 90%

Post: from GP C18 3 μm of 4.6x30mm of Sepax

Thermostat temperature: 30 DEG C

method K

Liquid stream is the hexane/ethanol/diethylamine 80/20/0.1, v/v/v of 1mL/min

Post: OJ-H

Thermostat temperature: 25 DEG C

method L

SFC instrument: Thar SFC Prep 80

Liquid stream is the methyl alcohol/CO of 45g/min ₂75/25

Post: CHIRALPAK AD-H, 2.0x25cm

Wavelength: UV 254nm

Thermostat temperature: 35 DEG C

In the examples below that, the following abbreviation provided is employed:

the synthesis of intermediate:

intermediate A

3-bromo-6-chlorine imidazo [1,2-b] pyridazine

NBS (6.37g, 35.8mmol) and TFA (0.75mL) is added in acetonitrile (300mL) solution of 6-chlorine imidazo [1,2-b] pyridazine (5g, 32.6mmol).The solution obtained at room temperature is stirred and spends the night.Under reduced pressure remove desolventizing and residue is dissolved in EtOAc, using NaHCO ₃solution, water and salt water washing, use Na ₂sO ₄drying also concentrates under vacuo, obtains the title compound for faint yellow solid of 7.2g (92%). ¹h-NMR (400MHz, CDCl ₃) δ ppm 7.91 (d, 1H), 7.79 (s, 1H), 7.12 (d, 1H) .LCMS (method A): [MH] ⁺=232/234, t _r=4.48min.

intermediate B

2-(2,3-dihydroxyl propoxy-) isoindoline-1,3-diketone and 2-(1,3-dihydroxyl third-2-base oxygen base) isoindoline-1,3-diketone

At 0 DEG C, to containing phthalic imidine and PPh ₃glycerol THF solution in add DIAD.After at room temperature stirring 20h, mixture is under reduced pressure concentrated.Then add water and aqueous solution DCM is extracted.By the organic layer Na of merging ₂sO ₄drying also under reduced pressure concentrates.By residue by column chromatography eluting (the DCM solution of 2%MeOH), obtaining title compound (1: 1 mixture), is white solid.LCMS (method A): [MH] ⁺=238, t _r=3.39/3.46min.

intermediate C

1-methyl isophthalic acid H-indazole-5-formaldehyde

Bromo-1H-indazole (i) of 5-

By bromo-for 5-2-fluorobenzaldehyde (10.15g, 50mmol), MeONH ₂-HCl (4.07g, 50mmol) and K ₂cO ₃the 100mL DMF suspension of (7.59g, 55.0mmol) stirs 5h at 40 DEG C.Mixture is filtered.By the concentrated residue obtaining about 50mL under vacuo of the filtrate containing oxime intermediate.N is added in the oxime residue that this is concentrated ₂h ₄-H ₂o (50mL, 1.03mol) by mixture heated overnight at reflux.After having reacted, reaction mixture is concentrated under vacuo.Residue diluted with water is also used EtOAc extracting twice.Organic layer is merged, uses Na ₂sO ₄drying is also concentrated.By crude product, by purified by flash chromatography, (hexane: EtOAc=10: 1) obtain title compound is white solid (6.02g, 61.2%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 13.24 (bs, 1H), 9.85 (s, 1H), 8.05 (s, 1H), 7.99 (s, 1H), 7.52 (d, 1H), 7.44 (dd, 1H) .LCMS (method A): [MH] ⁺=197/199, t _r=4.94min.

5-bromo-1-methyl isophthalic acid H-indazole (ii) and the bromo-2-methyl of 5--2H-indazole (iii)

At 0 DEG C, in the 3mL THF solution of the bromo-1H-indazole (0.19g, 0.94mmol) of 5-, add NaH (0.04g, 1.03mmol).Reaction mixture is stirred 1h at such a temperature, then at 0 DEG C, adds methyl iodide (0.09mL, 1.41mmol).Sluggish is warming up to room temperature and stirs 2h, goes out with shrend and concentrate under vacuo.Residue diluted with water is also used DCM extracting twice.Organic layer is merged, uses Na ₂sO ₄drying is also concentrated.By crude product, by purified by flash chromatography, (hexane: EtOAc=10: 1), obtaining title compound ii (88.7mg, 42.5%) and iii (60.9mg, 29%), is white solid.Ii: ¹h-NMR (400MHz, DMSO-d ₆) ppm 8.02 (d, 1H), 7.99 (d, 1H), 7.64 (d, 1H), 7.50 (dd, 1H), 4.04 (s, 3H) .LCMS (method A): [MH] ⁺=211/213, t _r=5.19min.iii: ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.33 (s, 1H), 7.95 (d, 1H), 7.57 (d, 1H), 7.30 (dd, 1H), 4.16 (s, 3H) .LCMS (method A): [MH] ⁺=211/213, t _r=4.95min.

1-methyl isophthalic acid H-indazole-5-formaldehyde (intermediate C)

By n-BuLi (7.33mL, 11.73mmol) with ethylmagnesium bromide (5.76mL, toluene (30mL) suspension 5.76mmol) stirs 30min at-30 DEG C, then THF (5mL) solution of 5-bromo-1-methyl isophthalic acid H-indazole (2.25g, 10.66mmol) is added.After 1h, at-10 DEG C, add anhydrous DMF (4.95mL, 64.0mmol).Reaction mixture is warming up to room temperature and stirs 2h.By the saturated NH of reaction ₄the cancellation of the Cl aqueous solution reduced under vacuum.By residue diluted with water, use DCM extracting twice.Organic layer is merged, uses Na ₂sO ₄drying is also concentrated.By crude product, by purified by flash chromatography, (hexane: EtOAc=10: 1), obtains title compound, is white solid (1.37g, 76%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 10.02 (s, 1H), 8.41 (d, 1H), 8.31 (d, 1H), 7.86 (dd, 1H), 7.78 (d, 1H), 4.09 (s, 3H) .LCMS (method A): [MH] ⁺=161, t _r=4.00min.

intermediate D

Quinoline-6-base methylamine

Quinoline-6-base methyl alcohol (i)

In THF (80mL) solution of quinoline-6-methyl-formiate (14g, 74.8mmol), gradation adds LiAlH ₄(2.84g, 74.8mmol).Reaction is at room temperature stirred 20min.Then drip water (2.84mL) and the NaOH aqueous solution (10%, 4.26mL) and carry out cancellation reaction.After stirring 20min again, add ether and the mixture obtained is passed through diatomite filtration.Obtain residue by concentrated under vacuo for filtrate, it, by column chromatography using hexane/EtOAc purifying, obtains quinoline-6-base methyl alcohol (7.6g, 64%).

2-(quinoline-6-ylmethyl) isoindoline-1,3-diketone (ii)

30min is gone through at 0 DEG C, to isoindoline-1,3-diketone (6.47g, 44.0mmol) with triphenylphosphine (11.53g, quinoline-6-base methyl alcohol (7g is dripped in THF (70mL) solution 44.0mmol), THF (30mL) solution 44.0mmol) and (E)-diazene-1,2-dioctyl phthalate diisopropyl ester (8.89g, 44.0mmol).30 DEG C, mixture is heated and keeps stirring 20h.After cooling and concentrating, adopt hexane/EtOAc gradient to carry out purifying by Analogix silica gel the residue obtained, obtain 2-(quinoline-6-ylmethyl) isoindoline-1,3-diketone (12.04g, 95%).LCMS (method A): [MH] ⁺=289, t _r=4.89min.

Quinoline-6-base methylamine (intermediate D)

A hydrazine hydrate (3.47g, 69.4mmol) is added in MeOH (100mL) solution of 2-(quinoline-6-ylmethyl) isoindoline-1,3-diketone (20g, 69.4mmol).By vlil 3h, be then cooled to room temperature and pass through diatomite filtration.Filtrate is concentrated under vacuo.Then EtOAc to be joined in residue and the solution obtained filtered and concentrates under vacuo, obtaining the title compound of 5g (41%).LCMS (method B): [MH] ⁺=159, t _r=0.93min.

intermediate E and F

The fluoro-quinoline of 7--6-formaldehyde and 7-(the fluoro-quinoline of 7--6-base)-methylamine

Bromo-7-fluorine quinoline (i) of 6-

In the vitriol oil (290mL) suspension of the fluoro-phenyl amine (100.0g, 526mmol) of the bromo-3-of 4-, add glycerol (220.0g, 2.39mol, 4.5eq.), then add ferrous sulfate (30.0g, 0.2eq.).Reaction mixture is heated 14h at 130 DEG C, is cooled to room temperature and in impouring frozen water.Solution is adjusted to pH 8 with saturated ammonium hydroxide aqueous solution and extracts with DCM (2L × 3).By organic layer washed with brine (1L × 3) washing merged, use Na ₂sO ₄dry and under reduced pressure concentratedly obtains crude product, (sherwood oil: EtOAc=10: 1), obtains title compound, is white solid (45g, 39%) by column chromatography eluting for it. ¹H-NMR(400MHz，DMSO-d ₆)δppm 8.86(s，1H)，8.56(m，1H)，8.45(m，1H)，7.90(d，1H)，7.71(m，1H).

The fluoro-quinoline of 7--6-formaldehyde (intermediate E)

To Pd (PPh ₃) ₄dMSO (30mL) solution of 6-bromo-7-fluorine quinoline (5g, 22mmol) is added in acetonitrile (30mL) suspension of (1.27g, 1.1mmol) and sodium formiate (13.8g, 132mmol, 6eq.).By reaction mixture 120 DEG C, heat 4h under CO normal atmosphere (1MPa), be cooled to room temperature and under reduced pressure concentrate.Residue is distributed between water (100mL) and EtOAc (150mL).Organic layer is separated, with salt solution (100mL) washing, uses Na ₂sO ₄drying also under reduced pressure concentrates, and obtains residue, and it adopts the sherwood oil from 10: 1 to 3: 1 by column chromatography: EtOAc is gradient-purified, obtains title compound, is white solid (400mg, 10.4%). ¹H-NMR(400MHz，DMSO-d ₆)δppm 8.95(s，1H)，8.46(m，1H)，8.20(m，1H)，7.75(d，1H)，7.53(m，1H).

7-(the fluoro-quinoline of 7--6-base)-methylamine (intermediate F)

The fluoro-quinoline of 7--6-formaldehyde (500mg, 2.85mmol) is dissolved in ammonia solution (2M in methyl alcohol, 50mL).After stirring at room temperature 3h, gradation adds NaBH ₄(108.0mg, 2.85mmol).Reaction stirring is spent the night, with water cancellation in ice bath.After under reduced pressure removing methyl alcohol, by residue diluted with water, regulate pH to being about 8 with 1N HCl solution, and extract three times with DCM.The organic layer washed with water of merging is used Na ₂sO ₄drying, filters and reduced under vacuum.By crude product by chromatography purification (DCM: MeOH=50: 1), obtain title compound, be yellow solid (250.0mg, 49%). ¹H-NMR(400MHz，DMSO-d ₆)δppm 8.86(dd，1H)，8.36(d，1H)，8.07(d，1H)，7.68(d，1H)，7.49(dd，1H)，3.93(s，2H)，1.98(s，2H).

intermediate G

O-(4-methoxy-benzyl) azanol

Cs is added in DMSO (10mL) solution of 2-hydroxyisoindolin-1,3-diketone (1.0g, 6.13mmol) ₂cO ₃(1.997g, 6.13mmol).The mixture obtained at room temperature is stirred 30min.Then 1-brooethyl 4-methoxyl group-benzene (0.88mL, 6.13mmol) is dripped.After 50 DEG C of stirrings are spent the night, by reaction mixture NH ₄cl (aq) cancellation, with EtOAc extraction, uses NH ₄cl (aq) washs, and uses Na ₂sO ₄drying, filters and reduced under vacuum obtains crude product, and it adopts gradient hexane by silicagel column: EtOAc purifying, obtains 2-(benzyloxy) isoindoline-1,3-diketone, is white solid (0.9g, 49%). ¹H-NMR(400MHz，DMSO-d ₆)δppm 7.85(s，4H)，7.42(d，2H)，6.94(d，2H)，5.08(s，2H)，3.75(s，3H).

O-(4-methoxy-benzyl) azanol (intermediate G)

A hydrazine hydrate (35.3mg, 0.706mmol) is added in MeOH (5mL) solution of 2-(4-methoxyl group benzyloxy) isoindoline-1,3-diketone (200mg, 0.706mmol).Reaction mixture is stirred 1h at 65 DEG C.Solvent removed in vacuo, and residue EtOAc (5mL) dilution that will obtain.After stirring 20min, mixture is filtered.Title compound is obtained by concentrated under vacuo for filtrate. ¹H-NMR(400MHz，CDCl ₃)δppm 7.30(m，2H)，6.90(m，2H)，4.63(m，2H)，3.81(s，3H).

intermediate H

O-benzyl hydroxylamine

2-(benzyloxy) isoindoline-1,3-diketone (i)

Title compound adopts the identical method as described in the synthesis of intermediate G to prepare with 64% productive rate by 2-hydroxyisoindolin-1,3-diketone and (brooethyl) benzene.LCMS (method A): [MH] ⁺=254, t _r=5.19min.

O-benzyl hydroxylamine (intermediate H)

Title compound adopts the identical method as described in the synthesis of intermediate G to prepare with 64% productive rate by 2-(benzyloxy) isoindoline-1,3-diketone and a hydrazine hydrate. ¹H-NMR(400MHz，CDCl ₃)δppm 7.37(m，5H)，6.70(s，2H).

intermediate compound I

4-(amino oxygen base) piperidines-1-t-butyl formate

4-(1,3-dioxo isoindoline-2-base oxygen base) piperidines-1-t-butyl formate (i)

Triphenylphosphine (326mg, 1.242mmol) and 2-hydroxyisoindolin-1,3-diketone (203mg, 1.242mmol) is added in the solution of 4-hydroxy piperidine-1-t-butyl formate (250mg, 1.242mmol).After stirring at room temperature 10min, add (E)-diazene-1,2-dioctyl phthalate diisopropyl ester (251mg, 1.242mmol).Stir after spending the night at 30 DEG C, by reaction mixture NH ₄cl (aq) cancellation, with EtOAc extraction, uses NH ₄cl (aq) washs, and uses Na ₂sO ₄drying, filters and reduced under vacuum obtains crude product, and it adopts gradient hexane by silicagel column: EtOAc purifying, obtains title compound, is colorless oil (252mg, 59%).LCMS (method B): [MNa] ⁺=369, t _r=2.59min.

4-(amino oxygen base) piperidines-1-t-butyl formate (intermediate compound I)

Title compound adopts the identical method as described in the synthesis of intermediate G to prepare with 85% productive rate by 4-(1,3-dioxo isoindoline-2-base oxygen base) piperidines-1-t-butyl formate and a hydrazine hydrate.

intermediate J

4-(aminooxymethyl) piperidines-1-t-butyl formate

4-((1,3-dioxo isoindoline-2-base oxygen base) methyl) piperidines-1-t-butyl formate (i)

Title compound adopts the identical method as described in the synthesis of intermediate B to prepare with 80% productive rate by 4-(hydroxymethyl) piperidines-1-t-butyl formate and 2-hydroxyisoindolin-1,3-diketone.LCMS (method B): [MNa] ⁺=383, t _r=2.64min.

4-(aminooxymethyl) piperidines-1-t-butyl formate (intermediate J)

Title compound adopts the identical method as described in the synthesis of intermediate B to prepare with 85% productive rate by 4-((1,3-dioxo isoindoline-2-base oxygen base) methyl)-piperidines-1-t-butyl formate and a hydrazine hydrate.

intermediate K

2-(amino oxygen base) methyl acetate

2-(1,3-dioxo isoindoline-2-base oxygen base) methyl acetate (i)

Title compound adopts the identical method as described in the synthesis of intermediate G to prepare with 56% productive rate by 2-hydroxyisoindolin-1,3-diketone and 2-methyl bromoacetate.LCMS (method B): [MH] ⁺=236, t _r=1.82min.

2-(amino oxygen base) methyl acetate (intermediate K)

Title compound adopts the identical method as described in the synthesis of intermediate G to prepare with 67% productive rate by 2-(1,3-dioxo isoindoline-2-base oxygen base) methyl acetate and a hydrazine hydrate.

intermediate L

The bromo-6-of 5-fluoro-1-methyl isophthalic acid H-indazole

2-methyl-prop-2-potassium alcoholate (2.087g, 18.60mmol) is added in DMF (20mL) solution of the fluoro-1H-indazole (4g, 18.60mmol) of the bromo-6-of 5-.The suspended matter obtained is stirred 40min.Drip CH ₃i (3.17g, 22.32mmol).After stirring is spent the night, by reaction mixture NH ₄cl (aq) cancellation, with EtOAc extraction, uses NH ₄cl (aq) washs, and uses Na ₂sO ₄drying, filters and reduced under vacuum obtains crude product, and it adopts gradient hexane by silica gel column chromatography: EtOAc purifying, obtaining the bromo-6-of 5-fluoro-1-methyl isophthalic acid H-indazole (1.86g, 42%), is faint yellow solid.

intermediate M

1-(the chloro-imidazo of 6-[1,2-b] pyridazine-3-base)-ethyl ketone

N '-(the chloro-pyridazine of 6--3-base)-N, N-dimethyl-formamidine (i)

The mixture reflux 2h of 3-amino-6-chlorine pyridazine (1.3g, 10mmol) and dimethylformamide dimethyl acetal (1.35mL, 10.2mmol) is also concentrated under vacuo, obtains brown solid.After EtOAc recrystallization, obtain 1.5g N '-(the chloro-pyridazine of 6--3-base)-N, N-dimethyl-formamidine with 81% productive rate.

1-(the chloro-imidazo of 6-[1,2-b] pyridazine-3-base)-ethyl ketone (intermediate M)

NaI (1g, 6.7mmol) and monochloroacetone (1mL, 12.6mmol) is added in DMF (60mL) solution of N '-(the chloro-pyridazine of 6--3-base)-N, N-dimethyl-formamidine (1.3g, 7mmol).Mixture heated overnight at 80 DEG C is also under reduced pressure concentrated.By residue by column chromatography eluting, obtain 1-(the chloro-imidazo of 6-[1,2-b] pyridazine-3-base)-ethyl ketone (0.7g) with 51% productive rate. ¹H-NMR(400MHz，CDCl ₃)δppm 8.42(s，1H)，8.05(d，1H)，7.31(d，1H)，2.77(s，3H).

intermediate N

The chloro-imidazo of 6-[1,2-b] pyridazine-3-formaldehyde

(the chloro-imidazo of 6-[1,2-b] pyridazine-3-base)-methyl alcohol (i)

NaOAc (1.4g, 17.1mmol) and paraformaldehyde (1.5g) is added in AcOH (50mL) solution of 6-chlorine imidazo [1,2-b] pyridazine (1.5g, 9.8mmol).Mixture heating is flow through night next time and under reduced pressure concentrated.By residue alkalization to pH 12.Then mixture filtered and solid EtOH is washed, obtaining (the chloro-imidazo of 6-[1,2-b] pyridazine-3-base)-methyl alcohol (1.3g) with 72% productive rate.

The chloro-imidazo of 6-[1,2-b] pyridazine-3-formaldehyde (intermediate N)

The MnO of activation is added in DCM (50mL) solution of (the chloro-imidazo of 6-[1,2-b] pyridazine-3-base)-methyl alcohol (1.3g, 7.1mmol) ₂(3g, 34.5mmol).Mixture is at room temperature stirred and spends the night and filter.Filtrate concentrated under vacuo and residue EtOAc is washed, obtaining the chloro-imidazo of 6-[1,2-b] pyridazine-3-formaldehyde (0.7g) with 54% productive rate. ¹H-NMR(400MHz，CDCl ₃).δ 10.36(s，1H)，8.42(s，1H)，8.08(d，1H)，7.38(d，1H).

intermediate O

6-((6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-base) methyl) quinoline

Chloro-6-diazanyl pyridazine (i) of 3-

The 20mL THF solution of 3,6-dichloro-pyridazine (3g, 20.14mmol) and a hydrazine hydrate (1g, 20.14mmol) is heated 5h in sealed tube at 80 DEG C.Evaporating solvent, crude product does not need purifying namely for next step (3.56g, 100%).LCMS (method B): [MH] ⁺=145.1, t _r=0.574min.

N '-(6-chlorine pyridazine-3-base)-2-(quinoline-6-base) acethydrazide (ii)

DCC (5.14g, 24.90mmol) is added in DCM (200mL) suspension of 3-chloro-6-diazanyl pyridazine (3g, 20.75mmol) and 2-(quinoline-6-base) acetic acid (4.27g, 22.83mmol).By solution at room temperature stirred weekend.Collect the title compound containing-a little dicyclohexylurea (DCU), be white solid, it does not need to be further purified namely for next step (8g, 100%).LCMS (method A): [MH] ⁺=314.1, t _r=2.851min.

6-((6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-base) methyl) quinoline (intermediate O)

The 250mL acetic acid solution of N '-(6-chlorine pyridazine-3-base)-2-(quinoline-6-base) acethydrazide (8g crude product, 25.5mmol) is heated 5h at 50 DEG C.After having reacted, evaporating solvent is also taken at molten for residue in EtOAc.The solid (importantly dicyclohexylurea (DCU)) formed filtered and filtrate is evaporated, obtaining title compound, be yellow solid (4g, 53%). ¹h-NMR (400MHz, MeOH-d ₄) δ ppm 8.82 (d, 1H), 8.33 (d, 1H), 8.25 (d, 1H), 8.0 (d, 1H), 7.93 (s, 1H), 7.83 (d, 1H), 7.53 (m, 1H), 7.42 (d, 1H), 4.79 (s, 2H) .LCMS (method B): [MH] ⁺=296.0, t _r=1.876min.

intermediate P

4,6-bis-fluoro-1-methyl isophthalic acid H-indazole

N-methyl-N '-[1-(2,4,6-Trifluoro-phenyl)-methyl-(E)-subunit]-hydrazine (i)

The solution of the 20mL dehydrated alcohol of 2,4,6-trifluro benzaldehyde (3g, 18.74mmol) and methyl hydrazine (40% in water, 2.6mL, 18.74mmol) is at room temperature stirred 1h.Evaporating solvent obtains thick title compound, is white solid, and it does not need purifying namely for next step (3.95g, 100%).LCMS (method B): [MH] ⁺=189, t _r=2.16min.

4,6-bis-fluoro-1-methyl isophthalic acid H-indazole (intermediate P)

N-methyl-N '-[1-(2,4,6-Trifluoro-phenyl)-methyl-(E)-subunit]-hydrazine (3.85g, 20.46mmol) is heated 2h at 210 DEG C in sealed tube.After cooling, black residue to be dissolved in DCM and by purified by flash chromatography (EtOAc: hexane 10: 90), to obtain title compound, being pale yellow crystals (1.926g, 56%). ¹h-NMR (400MHz, MeOH-d ₄) δ ppm 8.05 (s, 1H), 7.16 (d, 1H), 6.75 (t, 1H), 3.32 (s, 3H) .LCMS (method B): [MH] ⁺=169, t _r=2.28min.

intermediate Q

2-(amino oxygen base) third-1-alcohol

2-(tertbutyloxycarbonylamino oxygen base) ethyl propionate (i)

At room temperature, to the hydroxy carbamic acid tert-butyl ester (530mg, 3.98mmol) and in EtOH (10mL) solution of potassium hydroxide (223mg, 3.98mmol) add 2 bromopropionic acid ethyl ester (600mg, 3.31mmol) lentamente.By reaction mixture heated overnight at reflux.White depositions is filtered and filtrate is concentrated.The residue obtained is dissolved in ether, with water and salt water washing, and uses Na ₂sO ₄dry.Evaporating solvent obtains title compound, is clear oil thing, and it does not need to be further purified namely for next step (825mg, 100%). ¹H-NMR(400MHz，CDCl ₃)δppm 7.62(s，1H)，4.46(q，1H)，4.24(q，2H)，1.46(d，3H)，1.48(s，9H)，1.28(t，3H).

1-hydroxyl third-2-base oxygen carbamate (ii)

At 0 DEG C, by LiAlH ₄anhydrous THF (8mL) solution of (213mg, 5.62mmol) joins in THF (15mL) solution of 2-(tertbutyloxycarbonylamino oxygen base) ethyl propionate (820mg, 3.52mmol) lentamente.Mixture is stirred 5h at 0 DEG C and at room temperature stirs and spend the night.By solution Na ₂sO ₄with the mixture cancellation of water, and stir 1.5h again.Mixture is filtered and concentrates.Crude product is dissolved in EtOAc, with water and salt water washing, then uses Na ₂sO ₄dry.Evaporating solvent obtains title compound, is clear oil thing (500mg, 74.4%). ¹H-NMR(400MHz，CDCl ₃)δppm 7.09(s，1H)，3.95(m，1H)，3.69(dd，1H)，3.47(m，1H)，1.51(s，9H)，1.21(d，3H).

2-(amino oxygen base) third-1-alcohol (intermediate Q)

The HCl bis-of 3mL is added in DCM (15mL) solution of 1-hydroxyl third-2-base oxygen carbamate (500mg, 2.61mmol) alkane solution.Then solution is at room temperature stirred and spend the night.Evaporating solvent obtains the title compound (365mg, 98%, purity 90%) into HCl salt. ¹H-NMR(400MHz，MeOH-d ₄)δppm 4.28(m，1H)，3.80(m，1H)，3.70(m，1H)，1.23(d，3H).

intermediate R

6-[(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-base)-two fluoro-2-methyl-s]-quinoline

Difluoro-quinolin-6-base-ethyl acetate (i)

By sodium iodide (4.32g, 28.8mmol), cuprous iodide (I) (137mg, 0.72mmol), the bromo-quinoline (3g, 14.4mmol) of 6-, N, N '-dimethyl-hexanaphthene (0.227mL, 1.44mmol) and two alkane puts into microwave tube (25mL).Effective nitrogen wash 10min is also used Teflon diaphragm seals.Reaction mixture is stirred 15h at 110 DEG C.After cooling, will extract with DCM in mixture impouring ice-water.By crude product by silica column purification, obtain the iodo-quinoline of 6-, be light green solid (3.5g, 92%).

The fluoro-ethyl acetate (893mg, 4.4mmol) of bromine two is added in the dry DMSO suspension of the iodo-quinoline of 6-(1.0g, 4mmol) and Cu (0) (559mg, 8.8mmol).By reaction mixture at N ₂, stir 15h at 55 DEG C.By mixture impouring K ₂cO ₃solution in and extract with EtOAc.Organic layer is collected and uses MgSO ₄dry.Crude product is obtained title compound by silica column purification, is red oil (310mg, 30%). ¹H-NMR(400MHz，CDCl ₃)δppm 1.33(t，3H)，4.334(q，2H)，7.52(m，1H)，7.93(m，1H)，8.15(s，1H)，8.20-8.23(m，2H)，9.03(s，1H).

Difluoro-quinolin-6-base-acethydrazide (ii)

Difluoro-quinolin-6-base-ethyl acetate (836mg, 3.33mmol) is dissolved in MeOH (13mL).Add a hydrazine hydrate (1.5mL, 16.8mmol).Mixture is heated 30min at 45 DEG C, is cooled to room temperature, concentrated, and get with DCM is molten.By organic layer MgSO ₄drying, filters and reduced under vacuum obtains crude product, and it obtains title compound by silica column purification, is pale orange solid (400mg, 51%). ¹H-NMR(400MHz，CDCl ₃) ppm 3.99(br s，2H)，7.51(m，1H)，7.92(m，1H)，8.15(s，1H)，8.20-8.26(q，2H)，9.02(m，1H).

6-[(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-base)-two fluoro-2-methyl-s]-quinoline (intermediate R)

3,6-dichloro-pyridazine (160mg, 1.07mmol) and difluoro-quinolin-6-base-acethydrazide (254mg, 1.07mmol) are joined in n-BuOH (20mL).Reaction mixture is heated 12h at 130 DEG C.Under reduced pressure except desolventizing.By crude product at K ₂cO ₃distribute between the aqueous solution and EtOAc.Merged by organic layer, and concentrated obtain solid, it obtains title compound by silica column purification, is black solid (190mg, 53%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 7.62 (m, 2H), 7.90 (m, 1H), 8.22 (m, 1H), 8.35 (m, 1H), 8.65 (m, 2H), 9.02 (m, 1H).

intermediate S

2-(amino oxygen base) ethylate hydrochlorate

2-'-hydroxyethoxy carbamate hydrochloride (i)

Title compound is according to the method preparation described in WO2006/10094.In the mixture of the hydroxy carbamic acid tert-butyl ester (11.27g, 85mmol) and DBU (12.8mL, 85mmol), add ethylene bromohyrin (15mL, 212mmol) lentamente, and reaction mixture is stirred 2.5 days at 40 DEG C.After cooling, reaction mixture DCM is diluted, and continuously with the cold 1N HCl aqueous solution, water and salt water washing.By organic over anhydrous Na ₂sO ₄drying, by column chromatography eluting (38%EtOAc in hexane), obtaining the title compound of 12.6g (70%), is colorless syrup. ¹H-NMR(400MHz，DMSO-d ₆)δppm 9.95(s br，1H)，4.55(t，1H)，3.70(t，2H)，3.45-3.55(m，2H)，1.38(s，9H).

2-(amino oxygen base) ethylate hydrochlorate (intermediate S)

To two of 2-'-hydroxyethoxy carbamate hydrochloride (5.82g, 32.8mmol) drip dense HCl (3.5mL) in alkane (60mL) solution, and reaction mixture is at room temperature stirred spend the night.Except desolventizing obtains the title compound of 3.78g (100%), it is colorless syrup. ¹H-NMR(400MHz，DMSO-d ₆)δppm 10.93(s br，2H)，3.70-4.80(s br，1H)，4.02(t，2H)，3.60(t，2H).

intermediate T

3-(amino oxygen base) third-1-alcohol hydrochloride

Title compound adopts the identical method preparation as described in the synthesis of intermediate S. ¹H-NMR(400MHz，DMSO-d ₆)δppm 10.89(s br，2H)，3.85-4.50(s br，1H)，4.05(t，2H)，3.45(t，2H)，1.68-1.74(m，2H).

intermediate U

O-(oxa-ring fourth-3-base) azanol

2-(oxa-ring fourth-3-base oxygen base) isoindoline-1,3-diketone (i)

Triphenylphosphine (4.25g, 16.20mmol) and 2-hydroxyisoindolin-1,3-diketone (2.42g, 14.85mmol) is added in the solution of oxa-ring fourth-3-alcohol (1.0g, 13.50mmol).After stirring at room temperature 10min, add (E)-diazene-1,2-dioctyl phthalate diisopropyl ester (3.28g, 16.20mmol).Stir at 30 DEG C and spend the night, by reaction mixture NH ₄cl (aq) cancellation, with EtOAc extraction, uses NH ₄cl (aq) washs, and uses Na ₂sO ₄dry, filter also reduced under vacuum and obtain crude product, it, by silica gel column chromatography purifying (gradient hexane: EtOAc), obtains colorless oil 2-(oxa-ring fourth-3-base oxygen base) isoindoline-1,3-diketone (400mg, 6%).LCMS (method B): [MH] ⁺=220, t _r=1.67min.

O-(oxa-ring fourth-3-base) azanol (intermediate U)

Hydrazine hydrate (50.4mg, 1.0mmol) is added in MeOH (5mL) solution of 2-(oxa-ring fourth-3-base oxygen base) isoindoline-1,3-diketone (220mg, 1.0mmol).Reaction is stirred 1h at 65 DEG C.Solvent removed in vacate and will obtain residue EtOAc (5mL) dilution.After mixture is stirred 20min, the throw out formed is filtered.Product is obtained by concentrated under vacuo for filtrate.

intermediate V

2-(1,3-dioxo isoindoline-2-base oxygen base) ethanamide

By 2-hydroxyisoindolin-1,3-diketone (2.4g, 14.71mmol), 2-chlor(o)acetamide (1.65g, 17.65mmol) and K ₂cO ₃the 40mLDMF solution of (2.44g, 17.65mmol) stirs and spends the night at 90 DEG C.Solution also under reduced pressure concentrates by solids removed by filtration.Residue is adopted EtOAc/ methanol elution gradient purifying by flashchromatography on silica gel, obtains title compound. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 7.89 (dd, 1H), 7.68-7.64 (m, 2H), 7.45-7.43 (m, 2H), 7.35 (s, 1H), 4.23 (s, 2H) .LCMS (method A): [MH] ⁺=221, t _r=2.665min.

intermediate W

1-(3-(quinoline-6-ylmethyl) imidazo [1,2-a] pyrimidine-6-base) ethyl ketone (W)

6-((6-bromine imidazo [1,2-a] pyrimidin-3-yl) methyl) quinoline (i)

2-methyl-Ding-2-alcohol (10mL) solution of chloro-for 2-3-(quinoline-6-base) propionic aldehyde (1.0g, 2.54mmol) and 5-bromo pyrimi piperidine-2-amine (0.53g, 3.05mmol) is stirred 12h at 135 DEG C.After cooling, residue is also adopted CH by flashchromatography on silica gel by solvent removed in vacuo ₂cl ₂/ MeOH gradient elution purifying, obtaining the mixture (250mg, 29%) of title compound and 6-(the bromo-imidazo of 6-[1,2-a] pyrimidine-2-base methyl) quinoline, is brown solid.LCMS (method E): [MH] ⁺=339/341, t _r=3.51min.

1-(3-(quinoline-6-ylmethyl) imidazo [1,2-a] pyrimidine-6-base) ethyl ketone (W)

At N ₂under, by 6-((6-bromine imidazo [1,2-a] pyrimidin-3-yl) methyl) quinoline and 6-(the bromo-imidazo of 6-[1,2-a] pyrimidine-2-base methyl) quinoline (mixture, 250mg, 0.737mmol), PdCl ₂(PPh ₃) ₂the 5mL Isosorbide-5-Nitrae-two of (51.7mg, 0.074mmol) and tributyl (1-vinyl ethyl ether base) stannane (399mg, 1.106mmol) alkane solution heats 12h at 80 DEG C.Reaction mixture EtOAc is diluted, washes with water.By organic layer Na ₂sO ₄drying, filters and reduced under vacuum.Residue is dissolved in HOAc and 3N HCl and also at room temperature stirs 3 hours.Under reduced pressure remove desolventizing and residue is dissolved in CH ₂cl ₂in, with saturated NaHCO ₃the aqueous solution and salt water washing.By organic layer Na ₂sO ₄drying, filters and reduced under vacuum.Residue is adopted EtOAc/MeOH gradient elution purifying by flashchromatography on silica gel, and obtaining title compound, is yellow solid. ¹H-NMR(400MHz，CDCl ₃)δppm 8.97(d，1H)，8.84(d，1H)，8.67(d，1H)，8.04-7.99(m，2H)，7.74(s，1H)，7.53-7.51(m，1H)，7.34(dd，1H)，7.19(s，1H)，4.44(s，2H)，2.49(s，3H).

embodiment 1

(E)-1-(3-((7-fluorine quinoline-6-base) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-ethyl oxime

The chloro-imidazo of 6-[1,2-b] pyridazine-3-base)-(the fluoro-quinoline of 7--6-base)-methyl alcohol (1.1)

At room temperature, in the 160mL THF solution of the chloro-imidazo of the bromo-6-of 3-[1,2-b] pyridazine (13.27g, 57.1mmol), add EtMgBr solution (1M in THF, 68.5mL, 68.5mmol).Reaction mixture is stirred 30min and adds the 40mL THF suspension of the fluoro-quinoline of 7--6-formaldehyde (10g, 57.1mmol).The mixture obtained at room temperature is stirred 3h, then goes out with 400mL shrend and stir 1h again.Collected by filtration thing, washs with EtOAc and uses vacuum drying oven dried overnight, obtains the title compound of 13g (69%). ¹H-NMR(400MHz，DMSO-d ₆)δppm 8.91(dd，1H)，8.49(d，1H)，8.28(d，1H)，8.24(d，1H)，7.74(d，1H)，7.54(q，1H)，7.51(s，1H)，7.40(d，1H)，6.54(m，2H).

6-(the chloro-imidazo of 6-[1,2-b] pyridazine-3-ylmethyl) the fluoro-quinoline of-7-(1.2)

To the chloro-imidazo [1 of 6-, 2-b] pyridazine-3-base)-(the fluoro-quinoline of 7--6-base)-methyl alcohol (9.48g, phospho acid (the aqueous solution of 50% is added in acetic acid (80mL) solution 28.8mmol), 15.73mL, 144mmol) with iodine (18.3g, 72.1mmol).By the solution heated overnight at 110 DEG C obtained.Under reduced pressure except desolventizing.Residue diluted with water is also regulated pH to 8 ~ 10 of mixture by 6N NaOH solution.Then mixture DCM is extracted.By the organic layer washed with brine merged, use anhydrous Na ₂sO ₄dry also reduced under vacuum.By residue by column chromatography eluting (the DCM solution of 5% to 10%MeOH), obtain the title compound of 5.8g (64.3%). ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.91 (dd, 1H), 8.14 (d, 1H), 7.93 (d, 1H), 7.85 (d, 1H), 7.75 (d, 1H), 7.66 (s, 1H), 7.41 (q, 1H), 7.09 (d, 1H), 4.56 (s, 2H) .LCMS (method B): [MH] ⁺=313, t _r=2.48min.

1-[3-(the fluoro-quinoline of 7--6-ylmethyl)-imidazo [1,2-b] pyridazine-6-base]-ethyl ketone (1.3)

Under a nitrogen, to being mounted with four-(triphenylphosphine)-palladium (1.7g, 6-(the chloro-imidazo [1 of 6-is added in flask 1.48mmol), 2-b] pyridazine-3-ylmethyl) DMF (150mL) solution of the fluoro-quinoline (5.8g, 18.55mmol) of-7-.This system nitrogen wash three times is added tributyl-(1-oxyethyl group-vinyl)-stannane (6.59mL, 19.47mmol).Temperature is risen to 100 DEG C and stir and spend the night.After cooling, add the 3N HCl of 20mL and mixture is stirred 2h again.Add water, then by product extracted with EtOAc.By the organic layer Na of merging ₂sO ₄drying also under reduced pressure concentrates.By residue by column chromatography eluting, obtaining the title compound of 4.8g (79%), is dark yellow solid. ¹h-NMR (400MHz, MeOH-d ₄) δ ppm 8.82 (dd, 1H), 8.31 (d, 1H), 8.10 (d, 1H), 7.98 (d, 1H), 7.85 (s, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.50 (q, 1H), 4.72 (s, 2H), 2.68 (S, 3H) .LCMS (method A): [MH] ⁺=321, t _r=5.07min.

(E)-1-(3-((7-fluorine quinoline-6-base) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-ethyl oxime (embodiment 1)

To 1-[3-(the fluoro-quinoline of 7--6-ylmethyl)-imidazo [1,2-b] pyridazine-6-base]-ethyl ketone (50mg, O-ethylhydroxyl amine hydrochloride (46mg, 0.47mmol) is added in methyl alcohol (10mL) solution 0.16mmol).Drip triethylamine and regulate pH to 5 ~ 6.Reaction mixture is at room temperature stirred and spends the night.Under reduced pressure concentrated by solution and residue is passed through preparative HPLC purifying, obtaining the title compound of 30mg (53%), is white solid. ¹h-NMR (400MHz, MeOH-d ₄) δ ppm 8.82 (dd, 1H), 8.30 (d, 1H), 7.93 (m, 2H), 7.85 (d, 1H), 7.70 (d, 1H), 7.66 (s, 1H), 7.49 (q, 1H), 4.62 (s, 2H), 4.31 (q, 2H), 2.27 (s, 3H), 1.36 (t, 3H) .LCMS (method C): [MH] ⁺=364, t _r=4.71min.

embodiment 2

(E)-1-(3-((7-fluorine quinoline-6-base) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-methyloxime

Prepared by the title compound method similar with the synthesis of embodiment 1. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.88 (d, 1H), 8.03 (d, 1H), 7.87 (d, 1H), 7.76 (m, 2H), 7.68 (d, 1H), 7.67 (s, 1H), 7.35 (q, 1H), 4.58 (s, 2H), 4.06 (s, 3H), 2.31 (s, 3H) .LCMS (method C): [MH] ⁺=350, t _r=4.40min.

embodiment 3

(E)-1-(3-((7-fluorine quinoline-6-base) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

Prepared by the title compound method similar with the synthesis of embodiment 1. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.88 (d, 1H), 8.03 (d, 1H), 7.88 (d, 1H), 7.77 (d, 1H), 7.69 (m, 3H), 7.35 (q, 1H), 4.58 (s, 2H), 4.39 (t, 2H), 3.96 (m, 2H), 2.36 (s, 3H) .LCMS (method A): [MH] ⁺=380, t _r=5.15min.

embodiment 4

(E)-1-(3-(quinoline-6-ylmethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-ethyl oxime

Prepared by the title compound method similar with the synthesis of embodiment 1. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.86 (dd, 1H), 8.04 (m, 2H), 7.82 (d, 1H), 7.70 (m, 3H), 7.59 (s, 1H), 7.35 (q, 1H), 4.51 (s, 2H), 4.28 (q, 2H), 2.28 (s, 3H), 1.35 (t, 3H) .LCMS (method C): [MH] ⁺=346, t _r=4.54min.

embodiment 5

(E)-1-(3-(quinoline-6-ylmethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-methyloxime

Prepared by the title compound method similar with the synthesis of embodiment 1. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.86 (dd, 1H), 8.04 (m, 2H), 7.83 (d, 1H), 7.71 (m, 3H), 7.60 (s, 1H), 7.35 (q, 1H), 4.51 (s, 2H), 4.04 (s, 3H), 2.28 (s, 3H) .LCMS (method C): [MH] ⁺=332, t _r=3.96min.

embodiment 6

(E)-1-(3-(quinoline-6-ylmethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

Prepared by the title compound method similar with the synthesis of embodiment 1. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.87 (dd, 1H), 8.06 (m, 2H), 7.85 (d, 1H), 7.69 (m, 4H), 7.37 (q, 1H), 4.52 (s, 2H), 4.38 (m, 2H), 3.97 (t, 2H), 2.31 (s, 3H) .LCMS (method A): [MH] ⁺=362, t _r=4.80min.

embodiment 7A and 7B

(E)-1-(3-(quinoline-6-ylmethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-1,3-dihydroxyl third-2-base oxime and

(E)-1-(3-(quinoline-6-ylmethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-2,3-dihydroxypropyl oxime

To 2-(2,3-dihydroxyl propoxy-) isoindoline-1, a hydrazine hydrate is added in the MeOH mixture of 3-diketone and 2-(1,3-dihydroxyl third-2-base oxygen base) isoindoline-1,3-diketone (1: 1 mixture) (intermediate B).2h is stirred, then under reduced pressure except desolventizing by under reaction mixture refluxed.Residue EtOAc is washed and filters.By filtrate collection, evaporation is also dissolved in MeOH again.Then add 1-(3-(quinoline-6-ylmethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone (be similar to compound 1.3 prepare like that) and reaction mixture is stirred 5h at 30 DEG C.After HPLC purifying, being separated and obtaining title compound, is white solid.The data of embodiment 7A: ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.85 (d, 1H), 8.05 (m, 2H), 7.82 (d, 1H), 7.65 (m, 4H), 7.36 (q, 1H), 4.49 (m, 3H), 3.98 (d, 4H), 2.26 (s, 3H) .LCMS (method A): [MH] ⁺=392, t _rthe data of=3.98min. embodiment 7B: ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.89 (dd, 1H), 8.08 (m, 2H), 7.88 (d, 1H), 7.69 (m, 4H), 7.39 (q, 1H), 4.55 (s, 2H), 4.36 (d, 2H), 4.13 (m, 1H), 3.81 (dd, 1H), 3.69 (dd, 1H), 2.34 (s, 3H) .LCMS (method A): [MH] ⁺=392, t _r=4.42min.

embodiment 8

(E)-1-(3-((5,7-difluoro-quinoline-6-base) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-methyloxime

Prepared by the title compound method similar with the synthesis of embodiment 1. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.96 (dd, 1H), 8.47 (d, 1H), 8.05 (d, 1H), 7.68 (m, 2H), 7.59 (m, 2H), 4.58 (s, 2H), 3.99 (s, 3H), 2.23 (s, 3H) .LCMS (method A): [MH] ⁺=368, t _r=5.58min.

embodiment 9

(E)-1-(3-((5,7-difluoro-quinoline-6-base) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

Prepared by the title compound method that the synthesis of the compound with embodiment 1 is similar. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.96 (dd, 1H), 8.47 (d, 1H), 8.04 (d, 1H), 7.69 (m, 4H), 4.58 (s, 2H), 4.22 (t, 2H), 3.67 (t, 2H), 2.24 (s, 3H) .LCMS (method A): [MH] ⁺=398, t _r=5.52min.

embodiment 10

(E)-1-(3-((5,7-difluoro-quinoline-6-base) (hydroxyl) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-methyloxime

(6-chlorine imidazo [1,2-b] pyridazine-3-base) (5,7-difluoro-quinoline-6-base) methyl alcohol (10.1)

At room temperature, in the 30mL THF solution of the chloro-imidazo of the bromo-6-of 3-[1,2-b] pyridazine (2.40g, 10.35mmol), add EtMgBr (1M in THF, 12.43mL, 12.42mmol) solution.Solution stirring 30min is added the 10mLTHF solution of 5,7-difluoro-quinoline-6-formaldehyde (2.0g, 10.35mmol).The mixture obtained at room temperature is stirred 2h again, then uses the NH of 50mL ₄the cancellation of Cl solution.By solution extracted with EtOAc and by merge organic layers with water, salt water washing, use Na ₂sO ₄drying also concentrates under vacuo, obtains the title compound of 3.48g (97%).LCMS (method B): [MH] ⁺=347, t _r=1.23min.

1-(3-((5,7-difluoro-quinoline-6-base) (hydroxyl) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone (10.2)

Under a nitrogen, to Pd (PPh is housed ₃) ₄dMF (10mL) solution of (6-chlorine imidazo [1,2-b] pyridazine-3-base) (5,7-difluoro-quinoline-6-base) methyl alcohol (200mg, 0.56mmol) is added in the flask of (67mg, 0.058mmol).This system nitrogen wash three times is added tributyl-(1-oxyethyl group-vinyl)-stannane (0.21mL, 0.61mmol).Temperature to 100 DEG C is also stirred and spends the night.Then reaction mixture is cooled to room temperature, adds 3N HCl and mixture is stirred 4h again.Add water and by product extracted with EtOAc.Organic layer is merged, uses Na ₂sO ₄drying also under reduced pressure concentrates.By residue by column chromatography eluting (the DCM solution of 3% to 10%MeOH), obtain the title compound of 132mg (55%). ¹h-NMR (400MHz, CDCl ₃) ppm 8.98 (dd, 1H), 8.42 (d, 1H), 8.05 (dd, 1H), 8.00 (s, 1H), 7.77 (dd, 1H), 7.68 (d, 1H), 7.48 (q, 1H), 7.03 (s, 1H), 2.72 (s, 3H) .LCMS (method B): [MH] ⁺=355, t _r=2.08min.

(E)-1-(3-((5,7-difluoro-quinoline-6-base) (hydroxyl) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-methyloxime (embodiment 10)

Prepared by the title compound method similar with the synthesis of embodiment 1. ¹h-NMR (400MHz, MeOH-d ₄) ppm 8.89 (d, 1H), 8.52 (d, 1H), 7.90 (m, 2H), 7.65 (m, 3H), 6.89 (s, 1H), 3.98 (s, 3H), 2.09 (s, 3H) .LCMS (method A): [MH] ⁺=384, t _r=5.34min.

embodiment 11 (embodiment 11-R, embodiment 11-S)

(E)-1-(3-(1-(7-fluorine quinoline-6-base) ethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

(6-chlorine imidazo [1,2-b] pyridazine-3-base) (7-fluorine quinoline-6-base) ketone (11.1)

To (the chloro-imidazo [1 of 6-, 2-b] pyridazine-3-base)-(the fluoro-quinoline of 7--6-base)-methyl alcohol (1.8g, IBX (8.52g, 45%, 13.69mmol) is added in acetone (200mL) suspension 5.48mmol).Stir under reaction mixture refluxed 1 day.Then under reduced pressure remove desolventizing and residue is dissolved in the water of 200mL.By solution 3N NaOH solution alkalization, and collecting precipitation thing, wash with water and use vacuum drying oven dry, obtaining the title compound of 1.7g (95%), is gray solid. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 9.04 (dd, 1H), 8.56 (d, 1H), 8.47 (m, 2H), 8.41 (s, 1H), 7.92 (d, 1H), 7.75 (d, 1H), 7.64 (q, 1H) .LCMS (method B): [MH] ⁺=327, t _r=2.03min.

1-(6-chlorine imidazo [1,2-b] pyridazine-3-base)-1-(7-fluorine quinoline-6-base) ethanol (11.2)

To (6-chlorine imidazo [1,2-b] pyridazine-3-base) (7-fluorine quinoline-6-base) ketone (2.93g, MeMgI solution (the THF solution of 3M is added in THF (80mL) solution 6.73mmol), 4.48mL, 13.45mmol) and the solution stirring backflow 5h that will obtain.Then reaction mixture is cooled to room temperature, goes out with shrend, use NH ₄cl solution washing also extracts with DCM.By the organic layer Na of merging ₂sO ₄drying also under reduced pressure concentrates, and obtain the title compound of 2.2g (95%), it is for next step.

6-(1-(6-chlorine imidazo [1,2-b] pyridazine-3-base) ethyl)-7-fluorine quinoline (11.3)

To 1-(6-chlorine imidazo [1,2-b] pyridazine-3-base)-1-(7-fluorine quinoline-6-base) ethanol (420mg, phospho acid (50% aqueous solution is added in acetic acid (20mL) solution 1.10mmol), 0.60mL, 5.51mmol) with iodine (700mg, 2.76mmol).By the solution heated overnight at 110 DEG C obtained.Then except desolventizing.Residue diluted with water is also regulated pH to 8 ~ 10 by 6N NaOH solution.By product extracted with DCM and will merge organic layer washed with brine, use anhydrous Na ₂sO ₄dry also reduced under vacuum.Residue is obtained the title compound of 260mg (72%) by column chromatography eluting (the DCM solution of 3% to 10%MeOH).LCMS (method B): [MH] ⁺=327, t _r=2.52min.

1-(3-(1-(7-fluorine quinoline-6-base) ethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone (11.4)

Under a nitrogen, to Pd (PPh is housed ₃) ₄dMF (5mL) solution of 6-(1-(6-chlorine imidazo [1,2-b] pyridazine-3-base) ethyl)-7-fluorine quinoline (130mg, 0.40mmol) is added in the flask of (46mg, 0.040mmol).By this system nitrogen wash three times, then add tributyl-(1-oxyethyl group-vinyl)-stannane (0.14mL, 0.42mmol).Temperature to 100 DEG C is stirred 2h.Then reaction mixture is cooled to room temperature, adds 3N HCl and mixture is stirred 4h again.Add water, then by product extracted with EtOAc.Organic layer is merged, uses Na ₂sO ₄drying also under reduced pressure concentrates.By residue by column chromatography eluting (the DCM solution of 3% to 10%MeOH), obtain the title compound of 120mg (90%).LCMS (method B): [MH] ⁺=335, t _r=2.41min.

(E)-1-(3-(1-(7-fluorine quinoline-6-base) ethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime (embodiment 11, embodiment 11-R, embodiment 11-S)

Prepared by the title compound method similar with the synthesis of embodiment 1. ¹h-NMR (400MHz, MeOH-d ₄) δ ppm 8.79 (d, 1H), 8.22 (d, 1H), 7.89 (dd, 1H), 7.80 (s, 1H), 7.74 (m, 3H), 7.44 (q, 1H), 5.12 (q, 1H), 4.28 (t, 2H), 3.80 (t, 2H), 2.12 (s, 3H), 1.91 (d, 3H) .LCMS (method A): [MH] ⁺=394, t _r=5.37min. chiral separation (method F) provides COMPOUNDS EXAMPLE 11-R and the embodiment 11-S of enantiomeric pure.

embodiment 12 (embodiment 12-R, embodiment 12-S)

(E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

Title compound as racemic mixture is prepared by the method similar with the synthesis of embodiment 11. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.90 (dd, 1H), 8.32 (d, 1H), 7.87 (s, 1H), 7.84 (d, 1H), 7.61 (d, 1H), 7.55 (d, 1H), 7.40 (q, 1H), 5.23 (q, 1H), 4.34 (m, 2H), 3.93 (m, 2H), 2.19 (s, 3H), 2.01 (d, 3H) .LCMS (method A): [MH] ⁺=412, t _r=5.77min. chiral separation (method G) provides COMPOUNDS EXAMPLE 12-R and 12-S of enantiomeric pure.

embodiment 13

(E)-1-[3-(1-methyl isophthalic acid H-indazole-5-ylmethyl)-imidazo [1,2-b] pyridazine-6-base]-ethyl ketone O-(2-hydroxy-ethyl)-oxime

(6-chlorine imidazo [1,2-b] pyridazine-3-base) (1-methyl isophthalic acid H-indazole-5-base) methyl alcohol (13.1)

At-10 DEG C, in THF (5mL) solution of 3-bromo-6-chlorine imidazo [1,2-b] pyridazine (232.0mg, 1.00mmol), add EtMaBr (1M in THF, 1.50mL, 1.50mmol).Stir 1h at-10 DEG C after, add 1-methyl isophthalic acid H-indazole-5-formaldehyde (240.0mg, 1.50mmol).Mixture is warming up to room temperature lentamente and stirs 2h.By the saturated NH of reaction ₄the cancellation of Cl solution also under reduced pressure concentrates.Residue diluted with water is also used EtOAc extracting twice.Organic layer is merged, uses Na ₂sO ₄drying is also concentrated.Crude product DCM washing is obtained title compound, is white solid (230mg, 70%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.21 (d, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.59 (d, 1H), 7.56 (s, 1H), 7.49 (d, 1H), 7.35 (d, 1H), 6.29 (d, 1H), 6.21 (d, 1H), 4.02 (s, 3H) .LCMS (method A): [MH] ⁺=314, t _r=4.44min.

The chloro-3-of 6-((1-methyl isophthalic acid H-indazole-5-base) methyl) imidazo [1,2-b] pyridazine (13.2)

By (6-chlorine imidazo [1,2-b] pyridazine-3-base) (1-methyl isophthalic acid H-indazole-5-base) methyl alcohol (156.8mg, 0.50mmol), I ₂(381mg, 1.50mmol) and H ₃pO ₂acOH (4mL) solution of (0.273mL, 2.50mmol) heats 7h at 110 DEG C.Under reduced pressure except desolventizing.Residue diluted with water is also used DCM extracting twice.Organic layer is merged, uses Na ₂sO ₄drying is also concentrated.By crude product by purified by flash chromatography (DCM: MeOH=20: 1), obtain the title compound containing some iodine, and it does not need to be further purified for next step (180.0mg, 36% purity, 44%).LCMS (method A): [MH] ⁺=298, t _r=5.37min.

6-(1-oxyethyl group-vinyl)-3-(1-methyl isophthalic acid H-indazole-5-ylmethyl)-imidazo [1,2-b] pyridazine (13.3)

By chloro-for 6-3-((1-methyl isophthalic acid H-indazole-5-base) methyl) imidazo [1,2-b] pyridazine (180.0mg, 36% purity, 0.22mmol), tributyl (1-vinyl ethyl ether base) stannane (94mg, 0.26mmol) and Pd (PPh ₃) ₄the 10mL DMF suspension nitrogen wash of (25.1mg, 0.02mmol), then heats and stirs and spend the night at 110 DEG C.Under reduced pressure except desolventizing; Residue DCM is diluted, uses the KF aqueous solution and water washing continuously.By organic layer Na ₂sO ₄drying, filters and reduced under vacuum.By crude product by purified by flash chromatography (DCM: MeOH=20: 1), obtain the title compound containing some triphenylphosphine oxide impurity, but it does not need to be further purified for next step (49mg, 47%, 70% purity).LCMS (method A): [MH] ⁺=334, t _r=5.71min.

1-(3-((1-methyl isophthalic acid H-indazole-5-base) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone (13.4)

By 6-(1-oxyethyl group-vinyl)-3-(1-methyl isophthalic acid H-indazole-5-ylmethyl)-imidazo [1,2-b] pyridazine (50mg, 0.15mmol) at 50 DEG C, heat 3h with AcOH (10mL) solution of HCl (0.15mL, 0.15mmol).Under reduced pressure except desolventizing.By residue diluted with water and with saturated NaHCO ₃the pH of solution regulator solution, to being about 8, then extracts three times with DCM.Organic layer is merged, uses Na ₂sO ₄drying is also concentrated.Crude product does not need purifying for next step (45mg, 75%, 76% purity).LCMS (method A): [MH] ⁺=306, t _r=5.03min.

(E)-1-[3-(1-methyl isophthalic acid H-indazole-5-ylmethyl)-imidazo [1,2-b] pyridazine-6-base]-ethyl ketone O-(2-hydroxy-ethyl)-oxime (embodiment 13)

By 1-(3-((1-methyl isophthalic acid H-indazole-5-base) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone (20.0mg, 0.07mmol) and the 10mLTHF solution of 2-(amino oxygen base) ethylate hydrochlorate (14.87mg, 0.13mmol) stir at 40 DEG C and spend the night.Solvent removed in vacuo.By crude product by purified by flash chromatography (DCM: MeOH=50: 1), obtain title compound, be yellow solid (15.0mg, 57%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.04 (d, 1H), 7.94 (s, 1H), 7.68 ~ 7.61 (m, 3H), 7.54 (d, 1H), 7.39 (d, 1H), 4.41 (s, 2H), 4.23 (s, 2H), 3.98 (s, 3H), 3.68 (s, 2H), 2.29 (s, 3H) .LCMS (method A): [MH] ⁺=365, t _r=4.70min.

embodiment 14

(E)-1-{3-[1-(1-methyl isophthalic acid H-indazole-5-base)-ethyl]-imidazo [1,2-b] pyridazine-6-base }-ethyl ketone O-(2-hydroxy-ethyl)-oxime

(6-chlorine imidazo [1,2-b] pyridazine-3-base) (1-methyl isophthalic acid H-indazole-5-base) ketone (14.1)

By (6-chlorine imidazo [1; 2-b] pyridazine-3-base) (1-methyl isophthalic acid H-indazole-5-base) methyl alcohol (13.1) (500.0mg; 1.60mmol) and the 10mL acetone suspension reflux 3h of 2-iodosobenzoic acid (45%) (1488.0mg, 2.39mmol).Under reduced pressure except desolventizing.By residue diluted with water; Regulate pH to being about 10 with the 10%NaOH aqueous solution.Three times are washed with water by collected by filtration thing.By dissolution of solid in DCM, use Na ₂sO ₄drying, filters and concentrates and obtain title compound, is white solid (410.0mg, 78%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm8.46 (s, 1H), 8.42 (m, 1H), 8.32 (m, 1H), 8.27 (d, 1H), 7.95 (dd, 1H), 7.815 (d, 1H), 7.66 (d, 1H), 4.12 (s, 2H) .LCMS (method A): [MH] ⁺=312, t _r=4.64min.

1-(the chloro-imidazo of 6-[1,2-b] pyridazine-3-base)-1-(1-methyl isophthalic acid H-indazole-5-base)-ethanol (14.2)

At 0 DEG C, to (6-chlorine imidazo [1,2-b] pyridazine-3-base) (1-methyl isophthalic acid H-indazole-5-base) ketone (410mg, 1.32mmol) 10mL THF solution in add methylpyridinium iodide magnesium (0.88mL, 2.63mmol).Stir 3h at 0 DEG C after, by the saturated NH of reaction ₄cl cancellation also under reduced pressure concentrates.Residue DCM is extracted three times.Organic layer is merged, uses Na ₂sO ₄dry and concentratedly obtain title compound, be white solid (430.0mg, 95%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.17 (d, 1H), 7.99 (s, 1H), 7.50 (m, 1H), 7.40 (d, 1H), 7.25 (d, 1H), 5.98 (s, 1H), 3.99 (s, 3H), 2.05 (s, 3H) .LCMS (method A): [MH] ⁺=328, t _r=4.55min.

The chloro-3-of 6-[1-(1-methyl isophthalic acid H-indazole-5-base)-ethyl]-imidazo [1,2-b] pyridazine (14.3)

Title compound (390.0mg, 91%) is by 1-(the chloro-imidazo of 6-[1,2-b] pyridazine-3-base)-1-(1-methyl isophthalic acid H-indazole-5-base)-ethanol (430.0mg, 1.31mmol), I ₂(832.0mg, 3.28mmol) and H ₃pO ₂(0.72mL, 6.56mmol) adopts the same procedure synthesis as described in the synthesis of compound 13.2. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.18 (d, 1H), 7.95 (s, 1H), 7.83 (s, 1H), 7.55 (m, 2H), 7.36 (d, 1H), 7.28 (d, 1H), 4.70 (q, 1H), 3.99 (s, 3H), 1.74 (d, 3H) .LCMS (method A): [MH] ⁺=312, t _r=5.49min.

6-(1-oxyethyl group-vinyl)-3-[1-(1-methyl isophthalic acid H-indazole-5-base)-ethyl]-imidazo [1,2-b] pyridazine (14.4)

Title compound (415.0mg, 86%, 90% purity) by the chloro-3-of 6-[1-(1-methyl isophthalic acid H-indazole-5-base)-ethyl]-imidazo [1,2-b] pyridazine (390.0mg, 1.25mmol), tributyl (1-vinyl ethyl ether base) stannane (497.0mg, 1.38mmol) and Pd (PPh ₃) ₄(145mg, 0.13mmol) adopts the same procedure synthesis as described in the synthesis of compound 13.3.LCMS (method A): [MH] ⁺=348, t _r=5.86min.

1-(3-(1-(1-methyl isophthalic acid H-indazole-5-base) ethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone (14.5)

Title compound (325.0mg, 75%, 88% purity) by 6-(1-oxyethyl group-vinyl)-3-[1-(1-methyl isophthalic acid H-indazole-5-base)-ethyl]-imidazo [1,2-b] pyridazine (415.0mg, the same procedure synthesis as described in the synthesis of compound 13.4 1.20mmol) is adopted with HCl (1.20mL, 1.20mmol).LCMS (method A): [MH] ⁺=320, t _r=5.21min.

(E)-1-{3-[1-(1-methyl isophthalic acid H-indazole-5-base)-ethyl]-imidazo [1,2-b] pyridazine-6-base }-ethyl ketone O-(2-hydroxy-ethyl)-oxime (embodiment 14)

Title compound (9.0mg, 17%, 88% purity) by 1-(3-(1-(1-methyl isophthalic acid H-indazole-5-base) ethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone (40.0mg, the same procedure synthesis as described in the synthesis of implementation column 13 0.13mmol) is adopted with 2-(amino oxygen base) ethylate hydrochlorate (19.31mg, 0.25mmol). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 7.94 (d, 1H), 7.85 (s, 1H), 7.79 (s, 1H), 7.66 (s, 1H), 7.85 (d, 1H), 7.52 (d, 1H), 7.37 (dd, 1H), 4.72 (t, 2H), 4.21 (t, 2H), 3.97 (s, 3H), 3.66 (q, 1H), 2.20 (s, 3H), 1.78 (d, 3H) .LCMS (method A): [MH] ⁺=379, t _r=5.25min.

embodiment 15

(E)-1-[3-(the fluoro-quinoline of 7--6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-base]-ethyl ketone O-(2-hydroxy-ethyl)-oxime

The bromo-N of 5- ^*3 ^*-(the fluoro-quinoline of 7--6-ylmethyl)-pyrazine-2,3-diamines (15.1)

By C-(the fluoro-quinoline of 7--6-base)-methylamine (1.69g, 9.63mmol), 3, the mixture of 5-bis-bromo-pyrazine-2-amine (2.43g, 9.63mmol) and DIPEA (2.96g, 22.90mmol) uses microwave radiation to heat 10h at 120 DEG C.By reaction mixture DCM and water dilution.Organic layer to be separated and with saturated NH ₄cl solution washing, uses Na ₂sO ₄drying, filters and reduced under vacuum.By crude product by Silica gel chromatography (DCM: MeOH), obtaining title compound, is yellow solid (2.60g, 69%) .LCMS (method E): [MH] ⁺=348/350, t _r=5.21min.

6-(6-bromo-[1,2,3] triazolo [4,5-b] pyrazine-1-ylmethyl) the fluoro-quinoline of-7-(15.2)

To the bromo-N of 5- ^*3 ^*water (1mL) solution of Sodium Nitrite (11.4mg, 0.26mmol) is added in the solution of the acetic acid (4mL) of-(the fluoro-quinoline of 7--6-ylmethyl)-pyrazine-2,3-diamines (90mg, 0.26mmol).After at room temperature stirring 3h, solvent removed in vacuo.By residue NaHCO ₃(aq.) dilute, extract with DCM.Organic layer be separated and wash with water, using Na ₂sO ₄drying, filters and reduced under vacuum.By crude product by silica gel chromatography DCM: MeOH=50: 1 purifying, obtain title compound, be yellow solid (57.0mg, 61%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm9.03 (s, 1H), 8.94 (d, 1H), 8.40 (d, 1H), 8.08 (d, 1H), 7.84 (d, 1H), 7.55 (dd, 1H), 7.53 (dd, 1H), 6.21 (s, 2H) .LCMS (method A): [MH] ⁺=359/361, t _r=2.23min.

6-[6-(1-oxyethyl group-vinyl)-[1,2,3] triazolo [4,5-b] pyrazine-1-ylmethyl] the fluoro-quinoline of-7-(15.3)

By 6-(6-bromo-[1,2,3] triazolo [4,5-b] pyrazine-1-ylmethyl) the fluoro-quinoline (2.0g, 5.57mmol) of-7-, Pd (Ph ₃p) ₄dMF (50mL) the mixture nitrogen wash of (0.64g, 0.56mmol) and tributyl (1-vinyl ethyl ether base) stannane (4.02g, 11.14mmol), then heats 7h at 100 DEG C.Under reduced pressure except after desolventizing, residue DCM is diluted, uses the KF aqueous solution and water washing continuously, use Na ₂sO ₄dry also reduced under vacuum.Crude product being adopted gradient (DCM: MeOH=50: 1) purifying by silica gel column chromatography, obtains title compound, is white solid. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 9.11 (s, 1H), 8.93 (d, 1H), 8.40 (d, 1H), 8.15 (d, 1H), 7.83 (d, 1H), 7.54 (m, 1H), 6.22 (s, 2H), 5.50 (d, 1H), 4.73 (d, 1H), 4.02 (q, 2H), 1.40 (t, 3H) .LCMS (method E): [MH] ⁺=351, t _r=5.42min.

1-[3-(the fluoro-quinoline of 7--6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-base]-ethyl ketone (15.4)

By 6-[6-(1-oxyethyl group-vinyl)-[1,2,3] triazolo [4,5-b] pyrazine-1-ylmethyl] acetic acid solution of the fluoro-quinoline (600.0mg, 0.89mmol) of-7-and 3N HCl (0.1mL) stirs 2h at 50 DEG C.Under reduced pressure except desolventizing.By residue diluted with water; Use NaHCO ₃aqueous solution regulator solution pH is to being about 8; Use DCM extracting twice.The organic layer of merging is used continuously water and salt water washing, use Na ₂sO ₄drying, filters and reduced under vacuum obtains title compound, is white solid (630mg, 96%). ¹h-NMR (400MHz, CDCl ₃) δ ppm 9.46 (s, 1H), 8.94 (d, 1H), 8.11 (d, 2H), 7.85 (dd, 1H), 7.41 (dd, 1H), 6.23 (s, 2H), 2.79 (s, 3H) .LCMS (method A): [MH] ⁺=323, t _r=2.23min.

1-[3-(the fluoro-quinoline of 7--6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-base]-ethyl ketone O-(2-hydroxy-ethyl)-oxime (embodiment 15)

To 1-[3-(the fluoro-quinoline of 7--6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-base]-ethyl ketone (190.0mg, 2-(amino oxygen base) ethylate hydrochlorate (134.0mg, 1.18mol) is added in MeOH (40mL) solution 0.59mmol).By mixture heated overnight at 45 DEG C.Under reduced pressure except desolventizing.Residue is adopted gradient (DCM: MeOH=10: 1) purifying by column chromatography, obtains title compound, be white solid (168.0mg, 71%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm9.30 (s, 1H), 8.93 (d, 1H), 8.41 (d, 1H), 8.19 (d, 1H), 7.83 (d, 1H), 7.54 (dd, 1H), 6.24 (s, 2H), 4.78 (t, 1H), 4.31 (t, 2H), 3.72 (m, 2H), 2.29 (s, 3H) .LCMS (method A): [MH] ⁺=382, t _r=4.99min.

embodiment 16

(E)-1-[3-(the fluoro-quinoline of 7--6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-base]-ethyl ketone O-methyl-oxime

Title compound (22.2mg, 64%) by 1-[3-(the fluoro-quinoline of 7--6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-base]-ethyl ketone (15.4) (30.0mg, the same procedure synthesis as described in the synthesis of implementation column 15 0.09mmol) is adopted with O-methyl-hydroxylamine hydrochloride (78.0mg, 0.93mmol). ¹h-NMR (400MHz, CDCl ₃) δ ppm 9.45 (s, 1H), 8.92 (d, 1H), 8.08 (d, 1H), 7.81 (d, 1H), 7.78 (s, 1H), 7.39 (dd, 1H), 6.16 (s, 2H), 4.13 (s, 3H), 2.33 (s, 3H) .LCMS (method E): [MH] ⁺=352, t _r=5.43min.

embodiment 17

(E)-1-[3-(the fluoro-quinoline of 7--6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-base]-ethyl ketone O-(2-hydroxyl-1,1-dimethyl-ethyI)-oxime

Title compound (12.0mg, 89%) by 1-[3-(the fluoro-quinoline of 7--6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-base]-ethyl ketone (15.4) (10.0mg, the same procedure synthesis as described in the synthesis of implementation column 15 0.03mmol) is adopted with 2-amino oxygen base-2-methyl-propyl-1-alcohol hydrochloride (8.8mg, 0.06mmol). ¹h-NMR (400MHz, CDCl ₃) δ ppm 9.41 (s, 1H), 8.94 (d, 1H), 8.18 (d, 1H), 7.94 (d, 1H), 7.83 (s, 1H), 7.46 (dd, 1H), 6.17 (s, 2H), 3.75 (d, 2H), 2.36 (s, 3H), 1.95 (t, 1H), 1.41 (s, 6H) .LCMS (method A): [MH] ⁺410, t _r=5.39min.

embodiment 18

(E)-1-[3-(the fluoro-quinoline of 7--6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-base]-ethyl ketone O-(2-hydroxy-2-methyl-propyl group)-oxime

Title compound (12.0mg, 89%) by 1-[3-(the fluoro-quinoline of 7--6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-base]-ethyl ketone (15.4) (10.0mg, the same procedure synthesis as described in the synthesis of implementation column 15 0.03mmol) is adopted with 1-amino oxygen base-2-methyl-propyl-2-alcohol (6.5mg, 0.06mmol). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 9.29 (s, 1H), 8.93 (dd, 1H), 8.41 (dd, 1H), 8.19 (d, 1H), 7.83 (d, 1H), 7.54 (dd, 1H), 6.23 (s, 2H), 4.60 (s, 1H), 4.12 (d, 2H), 2.30 (s, 3H), 1.17 (s, 6H) .LCMS (method A): [MH] ⁺=410, t _r=5.40min.

embodiment 19

(S, E)-1-(1-((7-fluorine quinoline-6-base) methyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-pyrrolidin-3-yl oxime

Title compound (37.0mg, 70%) by 1-[3-(the fluoro-quinoline of 7--6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-base]-ethyl ketone (15.4) (40.0mg, the same procedure synthesis as described in the synthesis of implementation column 15 0.12mmol) is adopted with (S)-O-pyrrolidin-3-yl-hydroxylamine hydrochloride (30.0mg, 0.17mmol). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 9.30 (s, 1H), 8.92 (dd, 1H), 8.41 (dd, 1H), 8.18 (d, 1H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.23 (s, 2H), 4.95 (m, 1H), 3.16 ~ 2.87 (m, 3H), 2.77 ~ 2.71 (m, 1H), 2.25 (s, 3H), 2.01 ~ 1.87 (m, 2H) .LCMS (method A): [MH] ⁺=407, t _r=3.09min.

embodiment 20

(R, E)-1-(1-((7-fluorine quinoline-6-base) methyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-pyrrolidin-3-yl oxime

Title compound (7.0mg, 50%) by 1-[3-(the fluoro-quinoline of 7--6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-base]-ethyl ketone (15.4) (10.0mg, the same procedure synthesis as described in the synthesis of implementation column 15 0.03mmol) is adopted with (R)-O-pyrrolidin-3-yl-hydroxylamine hydrochloride (10.8mg, 0.06mmol). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 9.31 (s, 1H), 8.93 (d, 1H), 8.40 (d, 1H), 8.16 (d, 1H), 7.83 (d, 1H), 7.54 (dd, 1H), 6.24 (s, 2H), 4.95 (m, 1H), 3.01 ~ 2.87 (m, 3H), 2.74 ~ 2.67 (m, 1H), 2.27 (s, 3H), 2.15 ~ 1.90 (m, 2H) .LCMS (method A): [MH] ⁺=407, t _r=3.98min.

embodiment 21

(S, E)-3-(1-(1-((7-fluorine quinoline-6-base) methyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) second yldeneamino oxygen base) tetramethyleneimine-1-methane amide

To (S, E)-1-(1-((7-fluorine quinoline-6-base) methyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-pyrrolidin-3-yl oxime (embodiment 19) (20.0mg, in EtOH (5mL) solution 0.05mmol), add isocyanato trimethyl silane (7.9mg, 0.07mmol).Mixture is stirred and spends the night.Under reduced pressure except desolventizing.Residue MeOH (3mL) is diluted and filters.Filtrate (is used 0.05%NH with HPLC ₄oH alkalize) purifying, obtain title compound, be white solid (15.0mg, 64%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 9.31 (s, 1H), 8.92 (dd, 1H), 8.40 (d, 1H), 8.17 (d, 1H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.23 (s, 2H), 5.77 (s, 2H), 4.99 (m, 1H), 3.59 (d, 1H), 3.51 ~ 3.47 (m, 1H), 3.44 ~ 3.38 (m, 1H), 3.28 ~ 3.23 (m, 1H), 2.26 (s, 3H), 2.18 ~ 2.17 (m, 2H) .LCMS (method A): [MH] ⁺=450, t _r=4.38min.

embodiment 22

(E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-methyloxime

The bromo-N2-of 6-(quinoline-6-ylmethyl) pyrazine-2,3-diamines (22.1)

Microwave irradiation is used to heat 5h at 130 DEG C in the mixture of quinoline-6-base methylamine (3.6g, 22.76mmol), 3,5-bis-bromo-pyrazine-2-amine (5.75g, 22.76mmol) and triethylamine (4.61g, 45.5mmol).By reaction mixture CH ₂cl ₂with water dilution, and organic layer is separated, uses NH ₄cl solution washing, uses Na ₂sO ₄drying, filters and reduced under vacuum.By residue by adopting EtOAc: hexane column chromatography eluting, obtains the title compound of 6.93g (92%).LCMS (method A): [MH] ⁺=330, t _r=4.89min.

6-((the bromo-1H-of 6-[1,2,3] triazolo [4,5-b] pyrazine-1-base) methyl) quinoline (22.2)

To the bromo-N2-of 6-(quinoline-6-ylmethyl) pyrazine-2,3-diamines (6.55g, in acetic acid (15mL) solution 19.84mmol), add water (3mL) solution of Sodium Nitrite (2.74g, 39.7mmol).Stir 3h under rt after, solution is concentrated.By residue NaHCO ₃(aq) moltenly get and extract with DCM.By organic layer NH ₄cl (aq) washs, and uses Na ₂sO ₄drying, filters, concentrates under vacuo, and by using EtOAc: hexane column chromatography eluting, obtains the title compound of 3.35g (47%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 9.05 (s, 1H), 8.89 (d, 1H), 8.34 (d, 1H), 8.02 (d, 1H), 7.93 (s, 1H), 7.76 (dd, 1H), 7.53 (dd, 1H), 6.19 (s, 2H) .LCMS (method B): [MH] ⁺=343, t _r=2.11min.

6-((6-(1-vinyl ethyl ether base)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-base) methyl) quinoline (22.3)

To in DMF (20mL) de-gassed solution of 6-((the bromo-1H-of 6-[1,2,3] triazolo [4,5-b] pyrazine-1-base) methyl) quinoline (2.50g, 5.86mmol), add Pd (Ph ₃p) ₄(0.542g, 0.469mmol).Solution is stirred 20min at rt, then adds tributyl (1-vinyl ethyl ether base) stannane (2.117g, 5.86mmol).Mixture is heated at 100 DEG C until LC-MS display reaction completes.By reaction mixture by diatomite filtration, and filtrate water is washed, use Na ₂sO ₄drying, and concentrated.By the crude product that obtains by adopting hexane: EtOAc gradient column chromatography eluting, obtain the title compound of 1.2g (62%). ¹h-NMR (400MHz, CDCl ₃) δ ppm 9.19 (s, 1H), 8.94 (m, 1H), 8.20 (m, 1H), 7.99 (s, 1H), 7.89 (d, 1H), 7.55 (m, 1H), 6.12 (s, 2H), 5.61 (d, 1H), 4.61 (d, 1H), 4.05 (q, 2H), 1.51 (t, 3H) .LCMS (method B): [MH] ⁺=360, t _r=2.40min.

1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (22.4)

To 6-((6-(1-vinyl ethyl ether base)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-base) methyl) quinoline (150mg, in acetic acid solution 0.451mmol), add 3N HCl (0.1mL).Stir 2h under rt after, under reduced pressure except desolventizing.By residue diluted with water.And use NaHCO ₃its pH is adjusted to alkalescence by the aqueous solution, and extracts with DCM.By the organic layer NaHCO of merging ₃(aq) and salt water washing, Na is used ₂sO ₄drying, filters and reduced under vacuum.By residue by column chromatography eluting, obtaining the title compound of 131mg (91%), is yellow solid. ¹h-NMR (400MHz, CDCl ₃) δ ppm 9.45 (s, 1H), 8.95 (d, 1H), 8.14 (m, 2H), 7.95 (s, 1H), 7.84 (d, 1H), 7.45 (m, 1H), 6.19 (s, 2H), 2.75 (s, 3H) .LCMS (method B): [MH] ⁺=305, t _r=2.95min.

(E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-methyloxime (embodiment 22)

To 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (6.3mg, in methyl alcohol (3mL) solution 0.021mmol), add O-methyl hydroxylamine hydrochloride (16.7mg, 0.20mmol), add triethylamine subsequently to regulate pH to 5 ~ 6.Reaction mixture is stirred 3h at 30 DEG C.Under reduced pressure remove desolventizing and residue is dissolved in DCM.By the solution NaHCO obtained ₃solution, water and salt water washing, use Na ₂sO ₄dry also reduced under vacuum.By crude product by preparative HPLC purifying, obtain the title compound of 5.3mg (69%). ¹h-NMR (400MHz, CD ₃cl) δ ppm 9.67 (s, 1H), 8.94 (m, 1H), 8.16 (t, 2H), 7.93 (d, 1H), 7.86 (dd, 1H), 7.53 (dd, 1H), 6.11 (s, 2H), 4.14 (s, 3H), 2.38 (s, 3H) .LCMS (method A): [MH] ⁺=334, t _r=5.02min.

embodiment 23

(E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

Title compound is by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (22.4) and 2-(amino oxygen base) ethanol adopts the same procedure as described in the synthesis of implementation column 22 to prepare with 21% productive rate. ¹h-NMR (400MHz, CD ₂cl ₂) δ ppm 9.40 (s, 1H), 8.91 (m, 1H), 8.18 (d, 2H), 7.95 (d, 1H), 7.85 (dd, 1H), 7.45 (dd, 1H), 6.13 (s, 2H), 4.46 (t, 2H), 3.97 (t, 2H), 2.39 (s, 3H) .LCMS (method A): [MH] ⁺=364, t _r=4.28min.

embodiment 24

1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) acetophenone oxime

Title compound is by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (22.4) and hydroxylamine hydrochloride adopt the same procedure as described in the synthesis of implementation column 22 to prepare with 72% productive rate. ¹H-NMR(400MHz，DMSO-d ₆)，δppm 9.31(s，1H)，8.89(d，1H)，8.35(d，1H)，8.01(m，2H)，7.82(d，1H)，7.53(dd，1H)，6.20(s，2H)，2.27(s，3H).

embodiment 25

(E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-ethyl oxime

Title compound is by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (22.4) and O-ethylhydroxyl amine hydrochloride adopt the same procedure as described in the synthesis of implementation column 22 to prepare with 61% productive rate. ¹h-NMR (400MHz, DMSO-d ₆), δ ppm 9.31 (s, 1H), 8.89 (m, 1H), 8.35 (d, 1H), 8.01 (m, 2H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H), 4.34 (q, 2H), 2.32 (s, 3H), 1.24 (t, 3H) .LCMS (method B): [MH] ⁺=348, t _r=2.59min.

embodiment 26A

(E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-1,3-dihydroxyl third-2-base oxime

Title compound is by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (22.4) and 2-(amino oxygen base) propane-1,3-glycol (intermediate B) adopt the same procedure as described in the synthesis of implementation column 22 and embodiment 7A to prepare with 54% productive rate. ¹h-NMR (400MHz, CD ₃oD), δ ppm 9.40 (s, 1H), 8.86 (dd, 1H), 8.38 (d, 1H), 8.05 (m, 2H), 7.90 (dd, 1H), 7.56 (dd, 1H), 6.22 (s, 2H), 4.46 (t, 1H), 3.87 (d, 4H), 2.42 (s, 3H) .LCMS (method B): [MH] ⁺=394, t _r=1.86min.

embodiment 26B

(E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-2,3-dihydroxypropyl oxime

Title compound is by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (22.4) and (3-(amino oxygen base) propane-1,2-glycol) (intermediate B) adopt the same procedure as described in the synthesis of implementation column 22 and embodiment 7B to prepare with 40% productive rate. ¹h-NMR (400MHz, CD ₃oD) δ ppm 9.40 (s, 1H), 8.86 (m, 1H), 8.38 (d, 1H), 8.05 (m, 2H), 7.90 (dd, 1H), 7.57 (dd, 1H), 6.23 (s, 2H), 4.45 (m, 1H), 4.34 (m, 1H), 4.01 (m, 1H), 3.63 (m, 2H), 2.41 (s, 3H) .LCMS (method B): [MH] ⁺=394, t _r=1.96min.

embodiment 27

(E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-benzyl oxime

Title compound is by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (22.4) and O-benzyl hydroxylamine (intermediate H) adopt the same procedure as described in the synthesis of implementation column 22 to prepare with 43% productive rate. ¹h-NMR (400MHz, CDCl ₃), δ ppm 9.43 (s, 1H), 8.93 (d, 1H), 8.13 (m, 2H), 7.91 (s, 1H), 7.83 (d, 1H), 7.42 (m, 6H), 6.10 (s, 2H), 5.36 (s, 2H), 2.40 (s, 3H) .LCMS (method A): [MH] ⁺=410, t _r=5.94min.

embodiment 28

(E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-4-methoxy-benzyl oxime

Title compound is by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (22.4) and O-(4-methoxy-benzyl) azanol (intermediate G) adopt the same procedure as described in the synthesis of implementation column 22 to prepare with 37% productive rate. ¹h-NMR (400MHz, CDCl ₃), δ ppm 9.44 (s, 1H), 8.93 (s, 1H), 8.13 (m, 2H), 7.91 (s, 1H), 7.84 (d, 1H), 7.47 (dd, 1H), 7.44 (d, 2H), 6.92 (d, 2H), 6.10 (s, 2H), 5.28 (s, 2H), 3.82 (s, 3H), 2.37 (s, 3H) .LCMS (method A): [MH] ⁺=440, t _r=5.94min.

embodiment 29

(E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-piperidin-4-yl oxime

To 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (22.4) (40mg, in methyl alcohol (10mL) solution 0.131mmol), add 4-(aminooxymethyl) piperidines-1-t-butyl formate (intermediate compound I) (19.7mg, 0.329mmol).Drip acetic acid to regulate pH to 5 ~ 6.Reaction mixture is stirred 20h at 30 DEG C.Residue is also dissolved in DCM (5mL) by solvent removed in vacuo, adds TFA (0.2mL) subsequently.Reaction mixture is at room temperature stirred 2h, then concentrates under vacuo, obtain crude product, passed through column chromatography eluting, obtain the title compound of 11mg (16%). ¹h-NMR (400MHz, CDCl ₃), δ ppm 9.45 (s, 1H), 8.93 (m, 1H), 8.15 (d, 1H), 8.10 (d, 1H), 7.93 (d, 1H), 7.84 (d, 1H), 7.44 (dd, 1H), 6.11 (s, 2H), 4.46 (m, 1H), 3.15 (m, 2H), 2.81 (m, 2H), 2.49 (s, 3H), 2.12 (m, 2H), 1.72 (m, 2H) .LCMS (method B): [MH] ⁺=403, t _r=1.59min.

embodiment 30

(E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-piperidin-4-ylmethyl oxime

Title compound is by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (22.4) and 4-(aminooxymethyl) piperidines-1-t-butyl formate (intermediate J) adopt the same procedure as described in the synthesis of implementation column 29 to prepare with 15% productive rate. ¹h-NMR (400MHz, CDCl ₃), δ ppm 9.43 (s, 1H), 8.93 (m, 1H), 8.13 (m, 2H), 7.92 (s, 1H), 7.83 (dd, 1H), 7.43 (dd, 1H), 6.10 (s, 2H), 4.20 (d, 2H), 3.18 (d, 2H), 2.68 (t, 2H), 2.37 (s, 3H), 1.98 (br s, 1H), 1.80 (d, 2H), 1.37 (q, 2H) .LCMS (method A): [MH] ⁺=417, t _r=1.66min.

embodiment 31

(E)-2-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) second yldeneamino oxygen base) methyl acetate

Title compound is by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (22.4) and 2-(amino oxygen base) methyl acetate (intermediate K) adopt the same procedure as described in the synthesis of implementation column 22 to prepare with 31% productive rate. ¹h-NMR (400MHz, CD ₃oD), δ ppm 9.32 (s, 1H), 8.86 (m, 1H), 8.38 (d, 1H), 8.06 (m, 2H), 7.90 (dd, 1H), 7.56 (dd, 1H), 6.24 (s, 2H), 4.87 (s, 2H), 3.79 (s, 3H), 2.45 (s, 3H) .LCMS (method B): [MH] ⁺=392, t _r=2.16min.

embodiment 32

(E)-2-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) second yldeneamino oxygen base) ethanamide

To (E)-2-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) second yldeneamino oxygen base) methyl acetate (embodiment 31) (70mg, in solution 0.179mmol), add ammonia (2N, 0.268mL, 0.537mmol).Reflux 12h will be reacted.Reaction mixture is concentrated under vacuo, obtains crude product, passed through preparative HPLC purifying, obtain the title compound of 9mg (16%). ¹h-NMR (400MHz, DMSO-d ₆+ D ₂o) δ ppm 9.32 (s, 1H), 8.88 (d, 1H), 8.34 (d, 1H), 8.01 (m, 2H), 7.81 (d, 1H), 7.52 (dd, 1H), 7.33 (br, 2H), 6.20 (s, 2H), 4.67 (s, 2H), 2.27 (s, 3H) .LCMS (method B): [MH] ⁺=377, t _r=1.06min.

embodiment 33

(E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-2-hydroxy-2-methyl propyl group oxime

Title compound is by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (22.4) and 1-(amino oxygen base)-2-methyl propan-2-ol adopt the same procedure as described in the synthesis of implementation column 22 to prepare with 85% productive rate. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 9.29 (s, 1H), 8.89 (d, 1H), 8.35 (d, 1H), 8.01 (m, 2H), 7.82 (dd, 1H), 7.53 (dd, 1H), 6.21 (s, 2H), 4.60 (s, 1H), 4.13 (s, 2H), 2.34 (s, 3H), 1.17 (s, 6H) .LCMS (method B): [MH] ⁺=392, t _r=2.38min.

embodiment 34

(E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-2-amino-ethyl oxime

(E)-2-(2-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) second subunit-amino oxygen base) ethyl) isoindoline-1,3-diketone (34.1)

To (E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-2-hydroxyethyl oxime (embodiment 23) (200mg, in THF (10mL) solution 0.55mmol), add triphenylphosphine (144mg continuously, 0.55mmol), isoindoline-1,3-diketone (81mg, 0.55mmol) with (E)-diazene-1,2-dioctyl phthalate diisopropyl ester (111mg, 0.55mmol).Mixture is at room temperature stirred 48h and reduced under vacuum.By residue by column chromatography eluting, obtain the title compound of 120mg (42%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.90 (s, 1H), 8.89 (m, 1H), 8.35 (d, 1H), 8.02 (m, 2H), 7.81 (d, 1H), 7.71 (m, 2H), 7.63 (m, 2H), 7.52 (dd, 1H), 6.19 (s, 2H), 4.53 (t, 2H), 3.97 (t, 2H), 2.20 (s, 3H) .LCMS (method B): [MH] ⁺=493, t _r=2.52min.

(E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-2-amino-ethyl oxime (embodiment 34)

To (E)-2-(2-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) second yldeneamino oxygen base) ethyl) isoindoline-1,3-diketone (70mg, in MeOH (10mL) solution 0.142mmol), add a hydrazine hydrate (35.6mg, 0.711mmol).By vlil 30h and reduced under vacuum.By crude product by column chromatography eluting, obtain the title compound of 19mg (37%). ¹h-NMR (400MHz, DMSO-d ₆+ D ₂o) δ ppm 9.35 (s, 1H), 8.98 (s, 1H), 8.35 (d, 1H), 8.02 (s, 1H), 8.01 (d, 1H), 7.81 (d, 1H), 7.53 (m, 1H), 6.20 (s, 2H), 4.47 (s, 2H), 3.22 (s, 2H), 2.34 (s, 3H) .LCMS (method B): [MH] ₊=363, t _r=1.57min.

embodiment 35

(R, E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-pyrrolidin-3-yl oxime

Title compound is by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (22.4) (25mg, 0.082mmol) and (R)-O-(pyrrolidin-3-yl) hydroxylamine dihydrochloride adopt the same procedure as described in the synthesis of implementation column 22 to prepare with 60% productive rate. ¹h-NMR (400MHz, CDCl ₃) δ ppm 9.41 (s, 1H), 8.92 (d, 1H), 8.13 (d, 1H), 8.09 (d, 1H), 7.91 (s, 1H), 7.82 (d, 1H), 7.41 (dd, 1H), 6.10 (s, 2H), 5.30 (s, 1H), 5.09 (s, 1H), 3.31 (m, 3H), 2.38 (s, 3H), 2.25 (m, 2H) .LCMS (method B): [MH] ⁺=389, t _r=1.17min.

embodiment 36

(E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-1-hydroxyl third-2-base oxime

Title compound is by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (22.4) and 2-(amino oxygen base) third-1-alcohol hydrochloride (intermediate Q) adopt the same procedure as described in the synthesis of implementation column 22 to prepare with 90% productive rate. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm9.41 (s, 1H), 8.93 (m, 1H), 8.15 (m, 2H), 7.92 (s, 1H), 7.84 (dd, 1H), 7.43 (dd, 1H), 6.12 (s, 2H), 4.61 (m, 1H), 3.85 (m, 2H), 2.41 (s, 3H), 2.00 (s, 1H), 1.38 (d, 3H) .LCMS (method B): [MH] ⁺=378, t _r=1.96min.

embodiment 37A

(E)-2-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) second yldeneamino oxygen base) ethylidene dicarbamate

To (E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-2-amino-ethyl oxime (embodiment 34) (6mg, in DCM (5mL) solution 0.017mmol), add methyl-chloroformate (2.66mg, 0.028mmol) and triethylamine (3.35mg, 0.033mmol).Mixture is at room temperature stirred 10h.After concentrated, by crude product by Silica gel chromatography, obtain the title compound of 3.4mg (46%). ¹h-NMR (400MHz, CDCl ₃) δ ppm 9.41 (s, 1H), 8.93 (s, 1H), 8.14 (dd, 2H), 7.92 (s, 1H), 7.84 (dd, 1H), 7.44 (m, 1H), 6.12 (s, 2H), 4.42 (t, 2H), 3.69 (s, 3H), 3.60 (m, 2H), 2.39 (s, 3H) .LCMS (method B): [MH] ⁺=421, t _r=1.95min.

embodiment 37B

(E)-1-(2-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) second yldeneamino oxygen base) ethyl) urea

To (E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-2-amino-ethyl oxime (embodiment 34) (15mg, in DCM (5mL) solution 0.041mmol), add trimethylsilylisocyanate (19.07mg, 0.166mmol).Mixture is stirred 24h.After concentrated, by crude product by Silica gel chromatography, obtain the title compound of 11.6mg (69%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 9.32 (s, 1H), 8.89 (dd, 1H), 8.35 (d, 1H), 8.01 (m, 2H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.21 (s, 2H), 6.05 (t, 1H), 5.50 (s, 2H), 4.27 (t, 2H), 3.35 (m, 2H), 2.32 (s, 3H) .LCMS (method B): [MH] ⁺=406, t _r=1.91min.

embodiment 38

(E)-1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-formaldehyde O-2-hydroxyethyl oxime

6-((6-vinyl-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-base) methyl) quinoline (38.1)

To 6-((the bromo-1H-[1 of 6-, 2,3] triazolo [4,5-b] pyrazine-1-base) methyl) quinoline (22.2) (1.2g, in DMF (10mL) de-gassed solution 3.52mmol), add Pd (PPh ₃) ₄(610mg, 0.528mmol).By solution stirring 20min, then add tributyl (vinyl) stannane (1.227g, 3.87mmol).Reaction mixture is heated 5h at 120 DEG C.Add NH ₄the cancellation of the Cl aqueous solution is reacted, and adds EtOAc subsequently.By mixture by diatomite filtration and by filtrate with saturated NaHCO ₃and NH ₄cl solution washing.Organic layer is separated, uses Na ₂sO ₄drying is also concentrated, obtains crude product, is used Analogix system at purified over silica gel (hexane: EtOAc), obtain the title compound of 210mg (20%).LCMS (method B): [MH] ⁺=288, t _r=2.05min.

1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-formaldehyde (38.2)

To 6-((6-vinyl-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-base) methyl) quinoline (100mg, 0.347mmol) He 2, in the mixture of 6-lutidine (74.3mg, 0.694mmol), add osmium oxide (VIII) (297mg, water (1.333mL) solution 1.387mmol), add the Isosorbide-5-Nitrae-two of sodium periodate (88mg, 6.94 μm of ol) subsequently alkane (4mL) solution.Reaction mixture is at room temperature stirred 10h.Solvent removed in vacuo, adds DCM to dilute residue.By the saturated NaHCO of solution obtained ₃solution, NH ₄cl and salt water washing.Organic layer is separated, uses Na ₂sO ₄drying, and concentrated, obtain crude product, used Analogix system at purified over silica gel (hexane: EtOAc), obtain the title compound of 45mg (43%).LCMS (method B): [MH] ⁺=291, t _r=1.00min.

(E)-1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-formaldehyde O-2-hydroxyethyl oxime (embodiment 38)

Title compound is by 1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-formaldehyde and 2-(amino oxygen base) ethylate hydrochlorate adopt the same procedure as described in the synthesis of implementation column 22 to prepare with 45% productive rate. ¹h-NMR (400MHz, CD ₃oD), δ ppm 9.27 (s, 1H), 8.84 (m, 1H), 8.36 (s, 1H), 8.34 (d, 1H), 8.01 (d, 1H), 8.00 (s, 1H), 7.85 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H), 4.39 (t, 2H), 3.87 (t, 2H) .LCMS (method B): [MH] ⁺=350, t _r=1.94min.

embodiment 39 (embodiment 39-R, embodiment 39-S)

(E)-1-(3-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-base) ethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

1-(6-chlorine imidazo [1,2-b] pyridazine-3-base)-1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-base) ethanol (39.1)

At-100 DEG C, in THF (79mL) solution of the bromo-6-of 5-fluoro-1-methyl isophthalic acid H-indazole (intermediate L) (1.800g, 7.86mmol), drip n-BuLi (5.40mL, 8.64mmol).After stirring 1h at-100 DEG C, drip THF (20mL) solution of 1-(6-chlorine imidazo [1,2-b] pyridazine-3-base) ethyl ketone (intermediate M) (1.691g, 8.64mmol).Reaction soln is stirred 2h again, and uses NH ₄cl (aq) cancellation.The mixture EtOAc obtained is extracted.By the organic layer NH of merging ₄cl (aq) washs, and uses Na ₂sO ₄dry also concentrating under vacuo obtains crude product, is passed through column chromatography eluting (hexane: EtOAc), obtains title compound with 34% productive rate.LCMS (method B): [MH] ⁺=346, t _r=2.14min.

The chloro-3-of 6-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-base) ethyl) imidazo [1,2-b] pyridazine (39.2)

By 1-(6-chlorine imidazo [1,2-b] pyridazine-3-base)-1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-base) ethanol (1.1g, 3.18mmol), I ₂acetic acid (10mL) mixture of (2.019g, 7.95mmol) and phospho acid (0.840g, 12.73mmol) heats 5h at 120 DEG C.After cooling, reaction mixture is concentrated under vacuo.Residue is got with water-soluble, and is adjusted to pH 8 with the NaOH aqueous solution.Then mixture DCM is extracted, use Na ₂sO ₄drying is also concentrated.By residue with column chromatography eluting (MeOH: EtOAc), obtain the title compound of 900mg (60%).LCMS (method B): [MH] ⁺=330, t _r=2.59min.

6-(1-vinyl ethyl ether base)-3-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-base) ethyl) imidazo [1,2-b] pyridazine (39.3)

To in DMF (8mL) solution of the chloro-3-of 6-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-base) ethyl) imidazo [1,2-b] pyridazine (900mg, 1.910mmol), add Pd (Ph ₃p) ₄(221mg, 0.191mmol).Mixture is stirred 20min, adds tributyl (1-vinyl ethyl ether base) stannane (784mg, 2.102mmol).The mixture obtained is heated at 100 DEG C until LC-MS display reaction completes.By reaction mixture by diatomite filtration, and by solid washed with ether.By the filtrate water washing merged, use Na ₂sO ₄drying, and concentrated.By residue by adopting hexane: EtOAc gradient column chromatography eluting, obtains the title compound of 450mg (52%).

1-(3-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-base) ethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone (39.4)

To 6-(1-vinyl ethyl ether base)-3-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-base) ethyl)-imidazo [1,2-b] pyridazine (450mg, in acetic acid (8mL) solution 0.985mmol), add 3N HCl (0.5mL).Solution at room temperature stirred 2h and under reduced pressure remove desolventizing.By residue diluted with water, and use NaHCO ₃its pH is adjusted to alkalescence by the aqueous solution, extracts with DCM.By organic layer NaHCO ₃(aq) and salt water washing, Na is used ₂sO ₄drying, and reduced under vacuum.By residue by column chromatography eluting, obtaining the title compound of 300mg (81%), is yellow solid.LCMS (method B): [MH] ⁺=338, t _r=2.49min.

(E)-1-(3-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-base) ethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime (embodiment 39, embodiment 39-R, embodiment 39-S)

To 1-(3-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-base) ethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone (100mg, in methyl alcohol (10mL) solution 0.267mmol), add 2-(amino oxygen base) ethylate hydrochlorate (30.3mg, 0.267mmol).Drip triethylamine to regulate pH to 5 ~ 6.Reaction mixture is stirred 20h at 30 DEG C.Residue is also dissolved in DCM by solvent removed in vacuo, uses NaHCO ₃and salt water washing (aq).By organic layer Na ₂sO ₄dry also concentrating under vacuo obtains crude product, is passed through Silica gel chromatography, obtains the title compound of 19mg (17%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.01 (d, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.58 (d, 1H), 7.50 (s, 1H), 7.49 (d, 1H), 4.91 (q, 1H), 4.76 (t, 1H), 4.20 (t, 2H), 3.95 (s, 3H), 3.65 (m, 2H), 2.13 (s, 3H), 1.76 (d, 3H) .LCMS (method B): [MH] ⁺=397, t _r=2.50min. chiral separation (method K) provides COMPOUNDS EXAMPLE 39-R and the embodiment 39-S of enantiomeric pure.

embodiment 40

(E)-1-(3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-base) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

6-chlorine imidazo [1,2-b] pyridazine-3-base) (6-fluoro-1-methyl isophthalic acid H-indazole-5-base) methyl alcohol (40.1)

Be similar to the synthesis of compound 39.1, preparing title compound by 6-chlorine imidazo [1,2-b] pyridazine-3-formaldehyde, is yellow solid.LCMS (method B): [MH] ⁺=332, t _r=2.09min.

The chloro-3-of 6-((6-fluoro-1-methyl isophthalic acid H-indazole-5-base) methyl) imidazo [1,2-b] pyridazine (40.2)

Being similar to the synthesis of compound 39.2, by (6-chlorine imidazo [1,2-b] pyridazine-3-base) (6-fluoro-1-methyl isophthalic acid H-indazole-5-base) Methanol for title compound, is yellow solid.LCMS (method B): [MH] ⁺=316, t _r=2.56min.

6-(1-vinyl ethyl ether base)-3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-base) methyl) imidazo [1,2-b] pyridazine (40.3)

Be similar to the synthesis of compound 39.3, prepare title compound by the chloro-3-of 6-((6-fluoro-1-methyl isophthalic acid H-indazole-5-base) methyl) imidazo [1,2-b] pyridazine.

1-(3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-base) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone (40.4)

Be similar to the synthesis of compound 39.4, by 6-(1-vinyl ethyl ether base)-3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-base) methyl), imidazo [1,2-b] pyridazine prepares title compound, is white solid.LCMS (method B): [MH] ⁺=324, t _r=2.41min.

(E)-1-(3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-base) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime (embodiment 40)

To 1-(3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-base) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone (50mg, in methyl alcohol (7mL) solution 0.155mmol), add 2-(amino oxygen base) ethylate hydrochlorate (17.6mg, 0.155mmol).Drip triethylamine to regulate pH to 5 ~ 6.Reaction mixture is stirred 20h at 30 DEG C.Residue is also dissolved in DCM by solvent removed in vacuo, uses NaHCO ₃and salt water washing (aq).By organic layer Na ₂sO ₄dry also concentrating under vacuo obtains crude product, and it, by column chromatography eluting, obtains the title compound of 43mg (70%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.05 (d, 1H), 7.97 (s, 1H), 7.70 (d, 1H), 7.63 (d, 1H), 7.62 (s, 1H), 7.53 (d, 1H), 4.75 (t, 1H), 4.43 (s, 1H), 4.23 (t, 2H), 3.97 (s, 3H), 3.68 (q, 2H), 2.28 (s, 3H) .LCMS (method B): [MH] ⁺=383, t _r=2.45min.

embodiment 41

(E)-1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-methyloxime

6-((6-(1-vinyl ethyl ether base)-[1,2,4] triazolo [4,3-b] pyridazine-3-base) methyl) quinoline (41.1)

By 6-((6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-base) methyl) quinoline (intermediate O) (50mg, 0.169mmol) and DMF (6mL) the solution N of tributyl (1-vinyl ethyl ether base) stannane (0.06mL, 0.178mmol) ₂rinse 30min, then add Pd (PPh ₃) ₄(9.77mg, 0.0085mmol).The solution obtained is heated 3h at 100 DEG C.Reaction mixture shrend is gone out, extracts three times with EtOAc.Organic layer is merged, with KF solution and salt water washing, uses Na ₂sO ₄dry.After concentrated, be not further purified and crude product is directly used in next step.LCMS (method A): [MH] ⁺=332.1, t _r=4.969min.

1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone (41.2)

To in MeOH (30mL) solution of 6-((6-(1-vinyl ethyl ether base)-[1,2,4] triazolo [4,3-b] pyridazine-3-base) methyl) quinoline, add excessive 3N HCl solution.Solution is at room temperature stirred and spends the night, and with saturated NaHCO ₃solution neutralizes.Evaporation of organic solvent, and residue EtOAc is extracted three times.Organic layer is merged, uses Na with salt water washing ₂sO ₄dry.Evaporating solvent, and by crude product with column chromatography eluting (DCM: MeOH=95: 5), obtain title compound, be yellow solid (51.3%).LCMS (method B): [MH] ⁺=304.1, t _r=1.708min.

(E)-1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-methyloxime (embodiment 41)

By 1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone (60mg, 0.198mmol) and MeOH (10mL) solution of O-methyl hydroxylamine (49.6mg, 0.593mmol) at room temperature stir and spend the night.Crude product is also passed through HPLC purifying (become acid with 0.05%TFA, then neutralization is free alkali) by evaporating solvent, and obtaining the title compound of 40mg (60.8%), is white solid. ¹h-NMR (400MHz, MeOH- δ ppm 8.82 (s, 1H), 8.32 (d, 1H), 8.12 (d, 1H), 7.98 (m, 3H), 7.84 (d, 1H), 7.54 (m, 1H), 4.83 (s, 2H), 4.09 (s, 3H), 2.28 (s, 3H) .LC-MS (method B): [MH] ⁺=333.1, t _r=2.34min.

embodiment 42

(E)-1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-ethyl oxime

By 1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone (41.2) (30mg, 0.099mmol) and the 5mL MeOH solution of O-ethylhydroxyl amine (18.12mg, 0.297mmol) at room temperature stir and spend the night.Crude product by HPLC (becoming acid with 0.05%TFA) purifying, is obtained the title compound for white tfa salt of 15.8mg (46.1%) by evaporating solvent. ¹h-NMR (400MHz, MeOH-d ₄δ ppm 9.05 (s, 1H), 8.85 (d, 1H), 8.23 (s, 1H), 8.12 (m, 3H), 7.98 (d, 1H), 7.89 (m, 1H), 4.91 (s, 2H), 4.36 (q, 2H), 2.30 (s, 3H), 1.36 (t, 3H) .LC-MS (method B): [MH] ⁺=347.1.1, t _r=2.50min.

embodiment 43

(E)-1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-1-hydroxyl third-2-base oxime

By 1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone (41.2) (40mg, 0.132mmol) and the solution of 15mL MeOH of 2-(amino oxygen base) third-1-alcohol (intermediate Q) (33.6mg, 0.264mmol) at room temperature stir and spend the night.Evaporating solvent, and crude product (is used 0.05%NH by HPLC ₄oH alkalize) purifying, obtaining the title compound of 22mg (44%), is white solid. ¹h-NMR (400MHz, MeOH- δ ppm 8.82 (s, 1H), 8.33 (d, 1H), 8.12 (d, 1H), 7.98 (t, 3H), 7.84 (d, 1H), 7.55 (m, 1H), 4.84 (s, 2H), 4.50 (m, 1H), 3.72 (d, 2H), 2.32 (s, 3H), 1.33 (d, 3H) .LC-MS (method B): [MH] ⁺=377.0, t _r=1.867min.

embodiment 44

(E)-1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

By a hydrazine hydrate (3.96mg, 0.124mmol) join 2-(2-hydroxyl-oxethyl) isoindoline-1, in the 5mLMeOH solution of 3-diketone (preparing by the method for similar intermediate B) (25.6mg, 0.124mmol).By vlil 2h, be then cooled to room temperature.White depositions is filtered, and adds 1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone (41.2) (15mg, 0.049mmol).With 1N HCl solution, the pH value of solution is adjusted to 5-6.Then reaction soln is at room temperature stirred 2h.Crude product is also passed through HPLC purifying (using 0.05%TFA acidifying) by evaporating solvent, and obtaining the title compound of 8mg (44.5%), is the tfa salt of white. ¹h-NMR (400MHz, MeOH-d _4.) δ ppm 9.09 (s, 1H), 8.93 (d, 1H), 8.27 (s, 1H), 8.16 (m, 3H), 7.98 (d, 1H), 7.93 (m, 1H), 4.92 (s, 2H), 4.38 (t, 2H), 3.86 (t, 2H), 2.34 (s, 3H) .LC-MS (method B): [MH] ⁺=363.1, t _r=2.31min.

embodiment 45

(E)-1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-1,3-dihydroxyl third-2-base oxime

Title compound (12mg, 28.6%) by 2-(1,3-dihydroxyl third-2-base oxygen base) isoindoline-1,3-diketone (intermediate B) (152mg, 0.643mmol, isomer mixture), a hydrazine hydrate (14mg, 0.27mmol) with 1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) the same procedure synthesis of ethyl ketone (41.2) (30mg, 0.11mmol) employing as described in the synthesis of implementation column 44.By (using 0.05%TFA acidifying, being then neutralized to alkalescence) after HPLC purifying, obtaining title compound, is white solid. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.89 (d, 1H), 8.12 (d, 1H), 8.08 (d, 1H), 7.97 (d, 1H), 7.86 (s, 1H), 7.82 (d, 1H), 7.73 (d, 1H), 7.42 (m, 1H), 4.77 (s, 2H), 4.49 (m, 1H), 4.00 (dd, 4H), 2.33 (s, 3H) .LC-MS (method B): [MH] ⁺=393.2, t _r=1.708min.

embodiment 46

(E)-1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2,3-dihydroxypropyl oxime

Title compound (6mg, 14.3%) by 2-(2,3-dihydroxyl propoxy-) isoindoline-1,3-diketone (intermediate B) (152mg, 0.643mmol, isomer mixture), a hydrazine hydrate (14mg, 0.27mmol) with 1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) the same procedure synthesis of ethyl ketone (41.2) (30mg, 0.11mmol) employing as described in the synthesis of implementation column 44.By (using 0.05%TFA acidifying, being then neutralized to alkalescence) after HPLC purifying, obtaining title compound, is white solid. ¹h-NMR (400MHz, CDCl _3.) δ ppm 8.89 (d, 1H), 8.12 (d, 1H), 8.08 (d, 1H), 7.98 (d, 1H), 7.86 (s, 1H), 7.83 (d, 1H), 7.74 (d, 1H), 7.42 (m, 1H), 4.78 (s, 2H), 4.37 (d, 2H), 4.15 (m, 1H), 3.75 (m, 2H), 2.32 (s, 3H) .LC-MS (method B): [MH] ⁺=393.2, t _r=1.841min.

embodiment 47

(E)-1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-3-(trifluoromethyl) phenyl oxime

By a hydrazine hydrate (2.6mg, 0.052mmol) join 2-(3-(trifluoromethyl) phenoxy group) isoindoline-1,3-diketone (Organic Lett., 2001,31,139) in the MeOH solution of the 5mL of (19.75mg, 0.064mmol).By vlil 2h, be then cooled to room temperature.White depositions is filtered, and adds 1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone (41.2) (15mg, 0.049mmol).With 1N HCl solution, the pH value of solution is adjusted to 5-6.Reaction soln is at room temperature stirred and spends the night.Crude product is also obtained title compound by HPLC purifying (using 0.05%TFA acidifying) by evaporating solvent, is white solid (tfa salt, 15mg, 65.6%). ¹h-NMR (400MHz, MeOH-d _4.) δ ppm 9.07 (s, 1H), 8.90 (d, 1H), 8.26 (m, 2H), 8.16 (m, 3H), 7.91 (m, 1H), 7.60 (m, 3H), 7.43 (d, 1H), 4.96 (s, 2H), 2.59 (s, 3H) .LC-MS (method E): [MH] ⁺=463.1, t _r=6.03min.

embodiment 48

(E)-1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-phenyl oxime

One hydrazine hydrate (5.45mg, 0.109mmol) is joined in the 10mL MeOH solution of 2-phenoxy group isoindoline-1,3-diketone (Organic Lett., 2001,31,139) (30.8mg, 0.129mmol).By vlil 2h, be then cooled to room temperature.White depositions is filtered, and adds 1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone (41.2) (30mg, 0.1mmol).With 1N HCl solution, the pH value of solution is adjusted to 5-6.Then reaction soln is at room temperature stirred and spend the night.Evaporating solvent also by crude product by HPLC purifying (using 0.05%TFA acidifying), obtains the title compound of 23mg (59%), is white solid (tfa salt). ¹h-NMR (400MHz, CDCl ₃) δ ppm 9.23 (d, 1H), 8.68 (d, 1H), 8.53 (d, 1H), 8.15 (m, 3H), 8.04d, 1H), 7.83 (m, 1H), 7.40 (t, 2H), 7.29 (m, 2H), 7.15 (t, 1H), 4.92 (s, 2H), 2.56 (s, 3H) .LC-MS (method H): [MH] ⁺=395.2, t _r=2.42min.

embodiment 49

(E)-1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-benzyl oxime

Title compound is by 1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone (41.2) and O-benzyl hydroxylamine (intermediate H) adopt the same procedure as described in the synthesis of embodiment 41 to prepare. ¹h-NMR (400MHz, CHCl ₃-d _1.) δ ppm 8.87 (d, 1H), 8.06 (m, 2H), 7.95 (d, 1H), 7.84 (s, 1H), 7.80 (m, 2H), 7.38 (m, 6H), 5.30 (s, 2H), 4.77 (s, 2H), 2.32 (s, 3H) .LC-MS (method J): [MH] ⁺=409.1, t _r=2.42min.

embodiment 50

(E)-1-(3-(difluoro (quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

1-(3-(difluoro (quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone (50.1)

Title compound, for pale yellow oil (180mg, 30%, 80% purity), it is by 6-((6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-base) difluoromethyl) quinoline (intermediate R) (500mg, 1.507mmol), tributyl (1-vinyl ethyl ether base) stannane (2.55mL, 7.54mmol) and PdCl ₂(PPh ₃) ₂the Isosorbide-5-Nitrae-two of (106mg, 0.151mmol) alkane adopts the similarity method synthesis as described in the synthesis of compound 41.2. ¹h-NMR (400MHz, MeOH-d ₄) δ ppm 9.17 (s, 1H), 8.91 (d, 1H), 8.65 (s, 1H), 8.43 (d, 1H), 8.28 (q, 2H), 7.96 (d, 1H), 7.92 (m, 1H), 2.61 (s, 3H) .LCMS (method B): [MH] ⁺=340.1, t _r=2.16min.

(E)-1-(3-(difluoro (quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime (embodiment 50)

By 1-(3-(difluoro (quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone (54mg, 0.159mmol) and the 8mL MeOH solution of 2-(amino oxygen base) ethanol (intermediate S) (36.1mg, 0.318mmol) at room temperature stir and spend the night.Residue also distributes by evaporating solvent between water and EtOAc.By aqueous extracted with EtOAc twice.Organic layer is merged, uses Na with salt water washing ₂sO ₄dry.Crude product also (is used 0.05%NH by HPLC purifying by evaporating solvent ₄oH alkalizes), obtaining the title compound of 35mg (55%), is white solid. ¹h-NMR (400MHz, MeOH-d ₄) δ ppm 8.98 (d, 1H), 8.52 (d, 1H), 8.43 (s, 1H), 8.23 (d, 1H), 8.19 (d, 1H), 8.06 (d, 1H), 8.04 (d, 1H), 7.66 (m, 1H), 4.36 (m, 2H), 3.84 (m, 2H), 2.18 (s, 3H) .LCMS (method B): [MH] ⁺=398.9, t _r=2.29min.

embodiment 51 (embodiment 51-R, embodiment 51-S)

(E)-1-(3-(1-(4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base) ethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

1-(the chloro-imidazo of 6-[1,2-b] pyridazine-3-base)-1-(4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base)-ethanol (51.1)

At-78 DEG C, n-BuLi (the hexane solution of 1.6M is added in anhydrous THF (20mL) solution of 4,6-bis-fluoro-1-methyl isophthalic acid H-indazole (intermediate P) (600mg, 3.57mmol), 2.56mL, 4.1mmol).Solution is stirred 1h at such a temperature, then drips anhydrous THF (10mL) solution of 1-(the chloro-imidazo of 6-[1,2-b] pyridazine-3-base)-ethyl ketone (intermediate M) (698mg, 3.57mmol).The solution obtained stirred at such a temperature 3h and be warming up to rt while stirring overnight lentamente.Reaction mixture shrend is gone out, extracts three times with EtOAc.Organic layer merged and uses salt water washing, using Na ₂sO ₄dry.By crude product by purified by flash chromatography (DCM: MeOH=95: 5), obtaining the title compound of 530mg (41%), is yellow oil. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.05 (d, 1H), 8.0 (s, 1H), 7.85 (s, 1H), 7.1 (d, 1H), 6.85 (d, 1H), 4.0 (s, 3H), 2.3 (s, 3H) .LCMS (method B): [MH] ⁺=363.9, t _r=2.15min.

The chloro-3-of 6-[1-(4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base)-ethyl]-imidazo [1,2-b] pyridazine (51.2)

By 1-(the chloro-imidazo [1 of 6-, 2-b] pyridazine-3-base)-1-(4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base)-ethanol (530mg, 1.457mmol), iodine (925mg, 3.64mmol) at 110 DEG C, heat 2h with the 20mL acetic acid solution of phospho acid (50%, 0.556mL).Residue is also dissolved in water by evaporating solvent, with saturated NaHCO ₃solution neutralization also extracts three times with DCM.Organic layer merged and uses salt water washing, using Na ₂sO ₄dry.Then evaporating solvent (hexane: EtOAc=1: 2) obtain title compound is faint yellow solid (320mg, 63.2%) by purified by flash chromatography by crude product. ¹h-NMR (400MHz, MeOH-d ₄) δ ppm 8.03 (s, 1H), 8.0 (d, 1H), 7.8 (s, 1H), 7.23 (d, 1H), 7.19 (d, 1H), 5.1 (q, 1H), 4.0 (s, 3H), 1.92 (d, 3H) .LCMS (method B): [MH] ⁺=347.9, t _r=2.69min.

3-[1-(4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base)-ethyl]-6-(1-oxyethyl group-vinyl)-imidazo [1,2-b] pyridazine (51.3)

By chloro-for 6-3-[1-(4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base)-ethyl]-imidazo [1,2-b] pyridazine (80mg, 0.23mmol) and the 15mL DMF solution N of tributyl (1-vinyl ethyl ether base) stannane (0.234mL, 0.69mmol) ₂rinse 30min, then add Pd (PPh ₃) ₄(80mg, 0.069mmol) by solution heated overnight at 95 DEG C.After having reacted, by this solution with water cancellation, extract three times with EtOAc.Organic layer is merged, then uses salt water washing with KF solution washing, use Na ₂sO ₄dry.Evaporating solvent and crude product (80mg, 90%) do not need to be further purified for next step.LCMS (method C): [MH] ⁺=384.0, t _r=4.67min

1-(3-(1-(4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base) ethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone (51.4)

The 3N HCl solution of 2mL is joined in the 10mL MeOH solution of 3-[1-(4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base)-ethyl]-6-(1-oxyethyl group-vinyl)-imidazo [1,2-b] pyridazine.Reaction soln is at room temperature stirred 3h, then with saturated NaHCO ₃solution neutralizes.Residue is also obtained title compound by chromatography purification (DCM: MeOH=10: 1) by evaporating solvent, is yellow solid (30mg, 41%).LCMS (method C): [MH] ⁺=355.9, t _r=3.75min

(E)-1-(3-(1-(4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base) ethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime (embodiment 51, embodiment 51-R, embodiment 51-S)

By 1-(3-(1-(4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base) ethyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone (110mg, 0.31mmol) and the 10mL MeOH solution of 2-(amino oxygen base) ethanol (intermediate S) (35.1mg, 0.31mmol) at room temperature stir and spend the night.Residue also distributes by evaporating solvent between water and EtOAc.By aqueous extracted with EtOAc twice.Organic layer is merged, uses Na with salt water washing ₂sO ₄dry.Crude product also (is used 0.05%NH by HPLC purifying by evaporating solvent ₄oH alkalizes), obtaining the title compound of 55mg (43%), is white solid. ¹h-NMR (400MHz, MeOH-d ₄) δ ppm 8.01 (s, 1H), 7.88 (d, 1H), 7.78 (s, 1H), 7.76 (s, 1H), 7.16 (d, 1H), 5.16 (m, 1H), 4.29 (m, 2H), 3.99 (s, 3H), 3.82 (m, 2H), 2.17 (s, 3H), 1.95 (d, 3H) .LCMS (method B): [MH] ⁺=415.0, t _r=2.64min. chiral separation (method G) provides COMPOUNDS EXAMPLE 51-R and the embodiment 51-S of enantiomeric pure.

embodiment 52

(E)-1-(3-((4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

(6-chlorine imidazo [1,2-b] pyridazine-3-base) (4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base) methyl alcohol (52.1)

For the title compound (60mg of yellow solid, 41%) by (intermediate P) (70mg, 0.416mmol) with 6-chlorine imidazo [1,2-b] the same procedure synthesis of pyridazine-3-formaldehyde (intermediate N) (76mg, 0.416mmol) employing as described in the synthesis of compound 51.1. ¹h-NMR (400MHz, MeOH-d ₄) δ ppm 8.08 (s, 1H), 8.03 (d, 1H), 7.85 (s, 1H), 7.26 (q, 2H), 6.76 (s, 1H), 4.03 (s, 3H) .LCMS (method B): [MH] ⁺=349.9, t _r=2.12min.

The chloro-3-of 6-((4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base) methyl) imidazo [1,2-b] pyridazine (52.2)

For the title compound (370mg of faint yellow solid, 78%) by (6-chlorine imidazo [1,2-b] pyridazine-3-base) (4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base) methyl alcohol (500mg, 1.43mmol), iodine (907mg, the same procedure synthesis as described in the synthesis of compound 51.2 3.57mmol) is adopted with phospho acid (50%, 0.55mL). ¹h-NMR (400MHz, MeOH-d ₄) δ ppm 8.07 (s, 1H), 8.01 (d, 1H), 7.44 (s, 1H), 7.29 (d, 1H), 7.27 (d, 1H), 4.46 (s, 2H), 4.04 (s, 3H) .LCMS (method B): [MH] ⁺=333.9, t _r=2.68min.

1-(3-((4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone (52.3)

For the title compound (350mg of faint yellow solid, 71.3%) by the chloro-3-((4 of 6-, 6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base) methyl) imidazo [1,2-b] pyridazine (360mg, 1.079mmol), tributyl (1-vinyl ethyl ether base) stannane (1.095mL, 3.24mmol) and Pd (PPh ₃) ₄(374mg, 0.324mmol) adopts the same procedure synthesis as described in the synthesis of compound 51.3 and 51.4. ¹h-NMR (400MHz, MeOH-d ₄) δ ppm 8.09 (s, 1H), 8.07 (s, 1H), 7.78 (d, 1H), 7.71 (s, 1H), 7.26 (d, 1H), 4.59 (s, 2H), 4.02 (s, 3H), 2.74 (s, 3H) .LCMS (method B): [MH] ⁺=342.0, t _r=2.39min.

(E)-1-(3-((4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime (embodiment 52)

By 1-(3-((4,6-bis-fluoro-1-methyl isophthalic acid H-indazole-5-base) methyl) imidazo [1,2-b] pyridazine-6-base) ethyl ketone (62mg, 0.136mmol) at room temperature stir 2 days with the 3mL MeOH of 2-(amino oxygen base) ethanol (intermediate S) (77mg, 0.681mmol) and the solution of 2mL DCM.Evaporating solvent obtains residue, and its crystallization by chromatography purification (DCM: MeOH 10: 1) and from MeOH obtains title compound, is white solid (32mg, 59%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.16 (s, 1H), 8.04 (d, 1H), 7.62 (t, 2H), 7.48 (d, 1H), 4.44 (s, 2H), 4.24 (t, 2H), 4.00 (s, 3H), 3.68 (m, 2H), 2.29 (s, 3H) .LCMS (method E): [MH] ⁺=401.1, t _r=5.591min.

embodiment 53 (embodiment 53-S and embodiment 53-R)

(E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

2-(5,7-difluoro-quinolin-6-base)-methyl propionate (53.1)

At-78 DEG C to LDA (the THF solution of 1.2M, 9.5mL, THF (20mL) solution of (5,7-difluoro-quinoline-6-base)-methyl acetate (2.12g, 9.5mmol) is dripped in THF (30mL) solution of drying 11.4mmol).After 30min, drip MeI (0.9mL, 14.2mmol), and reaction mixture is warming up to 0 DEG C naturally.After 1h, by the saturated NaHCO of reaction ₃aqueous solution cancellation, extracts with EtOAc.By organic layer washed with brine, use anhydrous Na ₂sO ₄drying, filters, concentrated, and by column chromatography eluting, obtaining the title compound of 2.272g (95%), is light yellow solid. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.93 (d, 1H), 8.39 (dd, 1H), 7.61 (dd, 1H), 7.41-7.46 (m, 1H), 4.29 (q, 1H), 3.73 (s, 3H), 1.62 (d, 3H) .LCMS (method A): [MH] ⁺=252, t _r=5.09min. (5,7-difluoro-quinoline-6-base)-methyl acetate adopts the method described in WO2008/144767p108 (intermediate 2), then adopts the method synthesis described in WO2008/144767p114 intermediate 12 step 1.

2-(5,7-difluoro-quinolin-6-base)-propionyl hydrazine (53.2)

To 2-(5,7-difluoro-quinolin-6-base)-methyl propionate (2.270g, 9.57mmol) ethanol (25mL) solution in, add a hydrazine hydrate (3mL, 96mmol), and by reaction mixture stir at 25 DEG C and spend the night.Under reduced pressure except desolventizing, and residue does not need to be further purified namely to use. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 9.06 (s, 1H), 8.97 (dd, 1H), 8.45 (d, 1H), 7.58-7.67 (m, 2H), 4.23 (br s, 2H), 4.08 (q, 1H), 1.51 (d, 3H) .LCMS (method A): [MH] ⁺=252, t _r=3.82min.

6-[1-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-base)-ethyl]-5,7-difluoro-quinolin (53.3)

By 2-(5,7-difluoro-quinolin-6-base)-propionyl hydrazine (2.404g, 9.404mmol) and fourth-1-alcohol (60mL) solution of 3,6-dichloro-pyridazines (2.138g, 14.35mmol) stir in sealed tube at 135 DEG C and spend the night.Under reduced pressure except desolventizing, and by residue by the column chromatography eluting title compound obtaining 1.476g (45%, two steps), be light yellow solid. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm8.93 (dd, 1H), 8.36 (dd, 1H), 8.07 (d, 1H), 7.62 (dd, 1H), 7.43 (dd, 1H), 7.05 (d, 1H), 5.26 (q, 1H), 2,13 (d, 1H) .LCMS (method A): [MH] ⁺=346, t _r=5.00min.

6-{1-[6-(1-oxyethyl group-vinyl)-[1,2,4] triazolo [4,3-b] pyridazine-3-base]-ethyl }-5,7-difluoro-quinolin (53.4)

By two of 6-[1-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-base)-ethyl]-5,7-difluoro-quinolin (1.500g, 4.34mmol) alkane (60mL) solution argon cleaning 3min, adds tributyl-(1-oxyethyl group-vinyl)-stannane (2.2mL, 6.51mmol) and PdCl subsequently continuously ₂(PPh ₃) ₂(150mg, 0.21mmol).Mixture argon gas is rinsed half a minute again.By reaction mixture 80-85 DEG C, under argon gas under stir 6h.LC/MS display reacts completely.Reaction mixture EtOAc is diluted, continuously with the KF aqueous solution (2x25mL), water and salt water washing.By organic phase anhydrous Na ₂sO ₄drying, concentrate and obtain thick title compound, it does not need to be further purified namely to use.LCMS (method A): [MH] ⁺=382, t _r=5.05min.

1-{3-[1-(5,7-difluoro-quinolin-6-base)-ethyl]-[1,2,4] triazolo [4,3-b] pyridazine-6-base }-ethyl ketone (53.5)

By the thick 6-{1-[6-(1-oxyethyl group-vinyl)-[1 obtained by previous step, 2,4] triazolo [4,3-b] pyridazine-3-base]-ethyl }-5,7-difluoro-quinolin is dissolved in HOAc (50mL), adds the 3N HCl aqueous solution (5mL).Reaction mixture is at room temperature stirred and spends the night.LC/MS display reacts completely.Under reduced pressure except desolventizing.Add EtOAc, and the cold 1N NaOH aqueous solution is added lentamente until pH 8-9.Mixture EtOAc is extracted, and the organic over anhydrous Na that will merge ₂sO ₄drying, filters, concentrated, and by the column chromatography eluting title compound obtaining 1.0g (65%, two steps), is white solid. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.92 (dd, 1H), 8.32 (d, 1H), 8.14 (d, 1H), 7.68 (d, 1H), 7.61 (d, 1H), 7.42 (dd, 1H), 5.32 (q, 1H), 2.43 (s, 3H), 2.21 (d, 3H) .LCMS (method A): [MH] ⁺=354, t _r=4.42min.

(E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime (embodiment 53)

To 1-{3-[1-(5,7-difluoro-quinolin-6-base)-ethyl]-[1,2,4] triazolo [4,3-b] pyridazine-6-base }-ethyl ketone (4.2g, 2-(amino oxygen base) ethylate hydrochlorate (intermediate S) (2.70g, 23.8mmol) is added in methyl alcohol (250mL) suspension 11.9mmol).Mixture is at room temperature stirred and spends the night.LC-MS display reacts completely.The 1N NaOH aqueous solution is added lentamente until pH 8-9.Mixture is concentrated, with EtOAc extraction, with water and salt water washing.By organic over anhydrous Na ₂sO ₄drying, filters, concentrated, and by gradient column chromatography (EtOAc: hexane=2: 1, then 100%EtOAc, then MeOH: EtOAc=1: 12 as elutriant) purifying, obtaining the title compound of 4.8g (98%), is white solid. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.97 (dd, 1H), 8.44 (m, 1H), 8.25 (d, 1H), 7.64-7.70 (m, 2H), 7.59 (dd, 1H), 5.25 (q, 1H), 4.70 (t, 1H), 4.19 (t, 2H), 3.62 (dd, 2H), 2.02 (d, 3H), 1.88 (s, 3H) .LCMS (method A): [MH] ⁺=413, t _r=5.09min.

(E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime (embodiment 53-S and embodiment 53-R)

Using method I is by separation of racemic mixture (E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime (4.2g) obtains title compound.The data of embodiment 53-S (1.5g): ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.96 (d, 1H), 8.44 (d, 1H), 8.25 (d, 1H), 7.64-7.71 (m, 2H), 7.59 (dd, 1H), 5.25 (q, 1H), 4.70 (t, 1H), 4.19 (t, 2H), 3.62 (dd, 2H), 2.02 (d, 3H), 1.88 (s, 3H) .LCMS (method A): [MH] ⁺=413, t _rthe data of=5.09min. embodiment 53-R (1.6g): ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.96 (d, 1H), 8.44 (d, 1H), 8.25 (d, 1H), 7.64-7.71 (m, 2H), 7.59 (dd, 1H), 5.25 (q, 1H), 4.70 (t, 1H), 4.19 (t, 2H), 3.62 (dd, 2H), 2.02 (d, 3H), 1.88 (s, 3H) .LCMS (method A): [MH] ⁺=413, t _r=5.09min.

embodiment 54

(E)-1-(3-((5,7-difluoro-quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

Title compound adopts the same procedure preparation as described in the synthesis of implementation column 53. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 9.00 (d, 1H), 8.50 (d, 1H), 8.27 (d, 1H), 7.72-7.76 (m, 2H), 7.63 (dd, 1H), 4.78 (s, 3H), 4.27 (t, 2H), 3.69 (t, 2H), 2.20 (s, 3H) .LCMS (method A): [MH] ⁺=399, t _r=4.86min.

embodiment 55

(E)-1-(3-((5,7-difluoro-quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-fluoro ethyl oxime

At 0 DEG C, to (E)-1-(3-((5,7-difluoro-quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime (embodiment 54) (20mg, 0.05mmol) drying DCM (4mL) solution in add two-(2-methoxy ethyl) amino sulfur trifluoride (toluene solution of 3.2M, 0.13mL, 0.4mmol).Reaction mixture is stirred 1h at 0 DEG C, then stirs at 35 DEG C and spend the night.LC-MS display reacts completely, and adds the saturated NaHCO of 5mL ₃solution.Mixture DCM is extracted; By organic phase Na ₂sO ₄drying, filters, concentrated, and by the column chromatography eluting title compound obtaining 6.8mg (34%), is white solid. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.95 (dd, 1H), 8.41 (dd, 1H), 8.00 (d, 1H), 7.81 (d, 1H), 7.66 (d, 1H), 7.46 (dd, 1H), 4.83 (s, 2H), 4.78 (dd, 1H), 4.67 (dd, 1H), 4.56 (dd, 1H), 4.49 (dd, 1H), 2.33 (s, 3H) .LCMS (method A): [MH] ⁺=401, t _r=5.44min.

embodiment 56

(E)-1-(3-((5,7-difluoro-quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-3-hydroxypropyl oxime

Title compound adopts the same procedure preparation as described in the synthesis of implementation column 53. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.99 (dd, 1H), 8.49 (dd, 1H), 8.26 (d, 1H), 7.72-7.75 (m, 2H), 7.62 (dd, 1H), 4.76 (s, 2H), 4.52 (t, 1H), 4.32 (t, 2H), 3.48-3.53 (m, 2H), 2.18 (s, 3H), 1.80-1.88 (m, 2H) .LCMS (method A): [MH] ⁺=413, t _r=5.21min.

embodiment 57

(E)-1-(3-((7-fluorine quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

Title compound adopts the same procedure preparation as described in the synthesis of implementation column 53. ¹h-NMR (400MHz, DMSO-d6) δ ppm 8.89 (d, 1H), 8.36 (d, 1H), 8.29 (d, 1H), 8.06 (d, 1H), 7.74-7.81 (m, 2H), 7.51 (dd, 1H), 4.77 (s, 3H), 3.68-3.70 (m, 2H), 2.23 (s, 3H) .LCMS (method A): [MH] ⁺=381, t _r=4.66min.

embodiment 58

(E)-1-(3-((5-fluorine quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

Title compound adopts the same procedure preparation as described in the synthesis of implementation column 53. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.95 (d, 1H), 8.50 (d, 1H), 8.27 (d, 1H), 7.85 (d, 1H), 7.70-7.81 (m, 2H), 7.63 (dd, 1H), 4.78 (s, 2H), 4.26 (t, 2H), 4.09 (s br, 1H), 3.68-3.69 (m, 2H), 2.23 (s, 3H) .LCMS (method A): [MH] ⁺=381, t _r=5.05min.

embodiment 59

(E)-1-(3-(1-(quinoline-6-base) cyclopropyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-ethyl oxime

1-(quinoline-6-base) cyclopropanecarboxylate (59.1)

At nitrogen, at-78 DEG C, LDA (1.8M toluene solution, 14.8mL, 26.6mmol) is added drop-wise in dry THF (40mL) solution of quinoline-6-base-methyl acetate (2.14g, 10.64mmol).After 30min, go through 3min and drip glycol dibromide (2.40g, 12.76mmol).The mixture obtained at room temperature is stirred 1h, then with saturated NH ₄the cancellation of the Cl aqueous solution, with DCM extraction, uses salt water washing, uses Na ₂sO ₄drying, and vapourisation under reduced pressure.Residue is adopted EtOAc/ hexanes gradient elution purifying by flash chromatography on silica gel, obtains the title compound (463mg, 20%) into yellow solid. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.91 (dd, 1H), 8.12 (d, 1H), 8.07 (d, 1H), 7.77-7.74 (m, 2H), 7.40 (dd, 1H), 3.65 (s, 3H), 1.73-1.71 (m, 2H), 1.33-1.30 (m, 2H) .LCMS (method A): [MH] ⁺=228, t _r=4.37min.

1-(quinoline-6-base) cyclopropanecarbonyl hydrazine (59.2)

By 1-(quinoline-6-base) cyclopropanecarboxylate (513mg, 2.26mmol) and a hydrazine hydrate (3.39

G, 67.7mmol) 5mL methanol solution heated overnight at reflux.After cooling, solvent removed in vacuo obtains title compound (513mg, 100%).LCMS (method A): [MH] ⁺=228, t _r=2.88min.

6-(1-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-base) cyclopropyl) quinoline (59.3)

1-(quinoline-6-base) cyclopropanecarbonyl hydrazine (513mg, 2.26mmol), 3,6-bis-chloro-pyridazine (437mg, 2.93mmol) and 5mL propyl carbinols will be loaded in sealed tube.Mixture is heated 12h at 140 DEG C.After cooling, residue is also adopted EtOAc/ methanol elution gradient purifying by flash chromatography by solvent removed in vacate on silica gel, obtains title compound (196mg, 41%).LCMS (method A): [MH] ⁺=322, t _r=4.38min.

1-(3-(1-(quinoline-6-base) cyclopropyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone (59.4)

Under a nitrogen, by 6-[1-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-base)-cyclopropyl]-quinoline (30mg, 0.093mmol), PdCl ₂(PPh ₃) ₂the 3mL Isosorbide-5-Nitrae-two of (6.5mg, 0.0093mmol) and tributyl (1-vinyl ethyl ether base) stannane (67mg, 0.186mmol) alkylating mixture heats 3h at 90 DEG C.Reaction mixture EtOAc is diluted, uses KF solution washing.By organic layer Na ₂sO ₄drying, filters and reduced under vacuum.Residue is dissolved in HOAc and 3N HCl, and solution is at room temperature stirred 3h.Under reduced pressure remove desolventizing and residue is dissolved in DCM.With saturated NaHCO ₃the aqueous solution and salt water washing.By organic layer Na ₂sO ₄drying, filters and reduced under vacuum.Residue is adopted EtOAc/MeOH gradient elution purifying by flash chromatography on silica gel, obtains the title compound into yellow solid. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.89 (dd, 1H), 8.13-8.04 (m, 3H), 7.93 (d, 1H), 7.87 (dd, 1H), 7.70 (d, 1H), 7.40 (dd, 1H), 2.51 (s, 3H), 1.92-1.89 (m, 2H), 1.73-1.69 (m, 2H) .LCMS (method A): [MH] ⁺=330, t _r=4.18min.

(E)-1-(3-(1-(quinoline-6-base) cyclopropyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-ethyl oxime (embodiment 59)

By 1-(3-(1-(quinoline-6-base) cyclopropyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone (30mg, 0.09mmol) and the 2mL DCM solution of O-ethyl-hydroxylamine hydrochloride (18mg, 0.18mmol) stir at 40 DEG C and spend the night.Under reduced pressure remove desolventizing and residue is adopted EtOAc/ methanol elution gradient purifying by flash chromatography on silica gel, obtaining title compound. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.84 (d, 1H), 8.29 (d, 1H), 8.25 (d, 1H), 7.92-7.91 (m, 2H), 7.72-7.68 (m, 2H), 7.49 (dd, 1H), 4.26 (q, 2H), 2.01 (s, 3H), 1.76 (s, 2H), 1.66 (s, 2H), 1.27 (t, 3H) .LCMS (method A): [MH] ⁺=373, t _r=5.56min.

embodiment 60

(E)-1-(3-(1-(quinoline-6-base) cyclopropyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

By 1-(3-(1-(quinoline-6-base) cyclopropyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone (30mg, 0.09mmol) the 4mL DCM of (59.4) and 2-amino oxygen base-ethylate hydrochlorate (intermediate S) (14mg, 0.18mmol) and 0.5mL acetic acid solution stir and spend the night at 40 DEG C.Under reduced pressure remove desolventizing and residue is adopted EtOAc/ methanol elution gradient purifying by flash chromatography on silica gel, obtaining title compound. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.84 (t, 1H), 8.30 (d, 1H), 8.25 (d, 1H), 7.93-7.91 (m, 2H), 7.71-7.68 (m, 2H), 7.51 (dd, 1H), 4.73 (t, 1H), 4.23 (t, 2H), 3.65 (q, 2H), 2.02 (s, 3H), 1.78-1.75 (m, 2H), 1.68-1.64 (m, 2H) .LCMS (method A): [MH] ⁺=389, t _r=4.55min.

embodiment 61

(E)-2-(1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) second subunit-amino oxygen base) ethanamide

Microwave tube is loaded the methyl alcohol of 2-(1,3-dioxo isoindoline-2-base oxygen base) ethanamide (intermediate V) (166mg, 0.76mmol), a hydrazine hydrate (34.4mg, 0.69mmol) and 2mL.By this pipe 95 DEG C, heat 12h under microwave radiation.After cooling, by solids removed by filtration solution under reduced pressure concentrated.

By residue methanol dilution, then 1-(3-(quinoline-6-ylmethyl)-[1 is added, 2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone (41.2) (32mg, 0.105mmol) and the acetic acid of 0.3mL, and mixture is stirred at 40 DEG C spend the night.After concentrated, residue is obtained title compound by preparative HPLC purifying. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.86 (dd, 1H), 8.33-8.27 (m, 2H), 7.98-7.95 (m, 2H), 7.78 (dd, 1H), 7.69 (d, 1H), 7.50 (dd, 1H), 7.31 (d, 2H), 4.77 (s, 2H), 4.63 (s, 2H), 2.32 (s, 3H) .LCMS (method A): [MH] ⁺=376, t _r=4.02min.

embodiment 62 (embodiment 62-S and embodiment 62-R)

(E)-1-(3-(1-(7-fluorine quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

2-(7-fluorine quinoline-6-base) propane hydrazides (62.1)

By methyl alcohol (5mL) solution heated overnight at 50 DEG C of 2-(7-fluorine quinoline-6-base) methyl propionate (756mg, 3.24mmol) and a hydrazine hydrate (1.5mL).After cooling, solvent removed in vacuo obtains title compound (756mg, 100%), and it does not need to be further purified use.LCMS (method A): [MH] ⁺=234, t _r=3.14min.

6-(1-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-base) ethyl)-7-fluorine quinoline (62.2)

2-(7-fluorine quinoline-6-base) propane hydrazides (11.4g, 48.9mmol), 3,6-bis-chloro-pyridazine (8.01g, 53.8mmol) and 190mL propyl carbinols will be loaded in sealed tube.Mixture is heated 12h at 140 DEG C.After cooling, residue is also adopted EtOAc/ methanol elution gradient purifying by flash chromatography by solvent removed in vacuo on silica gel, obtains title compound (7.1g, 44%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.95 (d, 1H), 8.49-8.46 (m, 2H), 7.96 (d, 1H), 7.84 (d, 1H), 7.58 (dd, 1H), 7.48 (dd, 1H), 5.17 (q, 1H), 1.88 (d, 3H) .LCMS (method A): [MH] ⁺=328, t _r=5.00min.

1-(3-(1-(7-fluorine quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone (62.3)

Under a nitrogen, by 6-(1-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-base) ethyl)-7-fluorine quinoline (100mg, 0.305mmol), PdCl ₂(PPh ₃) ₂the 5mL Isosorbide-5-Nitrae-two of (21.4mg, 0.031mmol) and tributyl (1-vinyl ethyl ether base) stannane (220mg, 0.61mmol) alkylating mixture heats 5h at 90 DEG C.Reaction mixture EtOAc is diluted and washes with water.By organic layer Na ₂sO ₄drying, filters and reduced under vacuum.Residue is dissolved in HOAc and 3N HCl, and at room temperature stirs 3h.Under reduced pressure remove desolventizing and residue be dissolved in DCM, with saturated NaHCO ₃the aqueous solution and salt water washing.By organic layer Na ₂sO ₄drying, filters and reduced under vacuum.Residue is adopted EtOAc/MeOH gradient elution purifying by flash chromatography on silica gel, obtains the title compound into yellow solid. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.87 (d, 1H), 8.16 (d, 1H), 8.03 (d, 1H), 7.80 (d, 1H), 7.73 (d, 2H), 34 (dd, 1H), 5.39 (q, 1H), 2.62 (s, 3H), 2.09 (d, 3H) .LCMS (method A): [MH] ⁺=336, t _r=4.95min.

(E)-1-(3-(1-(7-fluorine quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime (embodiment 63, embodiment 62-S, embodiment 62-R)

Title compound as racemic mixture adopts the same procedure preparation as described in the synthesis of implementation column 53.The data of racemic mixture embodiment 63: ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.88 (d, 1H), 8.11 (d, 1H), 8.00 (d, 1H), 7.86 (d, 1H), 7.75 (d, 2H), 7.38 (dd, 1H), 5.36 (q, 1H), 4.38 (t, 2H), 3.93 (s, 3H), 2.24 (s, 3H), 2.06 (d, 3H) .LCMS (method A): [MH] ⁺=395, t _r=4.89min.

The enantiotopic component of this racemic mixture is separated: embodiment 62-S, t with method H _r=9.293min and embodiment 62-R, t _r=11.519min.

embodiment 63

(E)-1-(3-((3-(4-methylpiperazine-1-yl) quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

2-(3-(4-methylpiperazine-1-yl) quinoline-6-base) methyl acetate (63.1)

By 2-(3-bromoquinoline-6-base) methyl acetate (1.0g, 3.57mmol), 1-methylpiperazine (0.429g, 4.28mmol), Pd ₂(dba) ₃(65mg, 0.071mmol), BINAP (133mg, 0.214mmol) and Cs ₂cO ₃the 10mL toluene solution of (1.628g, 5.00mmol) heats 18h at 100 DEG C.After cooling, filtrate also under reduced pressure concentrates by solids removed by filtration.Adopt EtOAC/ hexanes gradient elution at purified over silica gel by flash chromatography residue, obtain the title compound for yellow solid of 599mg (56%). ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.77 (s, 1H), 7.94 (d, 1H), 7.57 (s, 1H), 7.42 (d, 1H), 7.30 (s, 1H), 3.78 (s, 2H), 3.72 (s, 3H), 3.41-3.33 (m, 4H), 2.65-2.63 (m, 4H), 2.39 (s, 3H) .LCMS (method A): [MH] ⁺=300, t _r=2.06min.

2-(3-(4-methylpiperazine-1-yl) quinoline-6-base) acethydrazide (63.2)

Title compound adopts the same procedure described in synthesis as 53.2 to prepare .LCMS (method A): [MH] ⁺=300, t _r=1.30min.

6-((6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-base) methyl)-3-(4-methylpiperazine-1-yl) quinoline (63.3)

Title compound adopts the preparation of the same procedure described in synthesis as 53.3. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.75 (d, 1H), 8.05 (d, 1H), 7.92 (d, 1H), 7.68 (d, 1H), 7.56 (dd, 1H), 7.28 (s, 1H), 7.10 (d, 1H), 4.70 (s, 2H), 3.33-3.30 (m, 4H), 2.65-2.63 (m, 4H), 2.39 (s, 3H) .LCMS (method A): [MH] ⁺=394, t _r=2.679min.

1-(3-((3-(4-methylpiperazine-1-yl) quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone (63.4)

Title compound adopts the preparation of the same procedure described in synthesis as 53.4 and 53.5.LCMS (method A): [MH] ⁺=402, t _r=2.506min.

(E)-1-(3-((3-(4-methylpiperazine-1-yl) quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime (embodiment 63)

Title compound adopts the same procedure preparation as described in the synthesis of implementation column 53. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.74 (d, 1H), 7.96 (d, 1H), 7.90 (d, 1H), 7.74 (d, 1H), 7.66 (s, 1H), 7.56 (dd, 1H), 7.23 (d, 1H), 4.72 (s, 2H), 4.40 (t, 2H), 3.95 (t, 2H), 3.30 (t, 4H), 2.63 (t, 4H), 2.38 (s, 3H), 2.32 (s, 3H) .LCMS (method A): [MH] ⁺=461, t _r=2.965min.

embodiment 64

(E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-methoxy ethyl oxime

By (E)-1-(3-((5,7-difluoro-quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime (31.0mg, 0.078mmol) the 5mL THF of (embodiment 54), sodium hydride (6.85mg, 0171mmol) and methyl iodide (221mg, 1.556mmol) and 0.5mL DMF solution at room temperature stir 3h.By the methyl alcohol cancellation of reaction by adding 3mL lentamente.Under reduced pressure remove desolventizing and residue is adopted EtOAc/ methanol elution gradient purifying by flash chromatography on silica gel, obtaining title compound. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.97 (dd, 1H), 8.45 (dd, 1H), 8.26 (d, 1H), 7.70-7.65 (m, 2H), 7.60 (dd, 1H), 5.26 (q, 1H), 4.30 (dd, 2H), 3.58 (dd, 2H), 3.23 (s, 3H), 2.02 (d, 3H), 1.88 (s, 3H) .LCMS (method A): [MH] ⁺=427, t _r=5.50min.

embodiment 65

(E)-1-(3-((5,7-difluoro-quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-4-hydroxybutyl oxime

Title compound adopts the same procedure preparation as described in the synthesis of implementation column 53. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.93 (dd, 1H), 8.39-8.36 (m, 1H), 7.98 (d, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.43 (dd, 1H), 4.81 (s, 2H), 4.32 (t, 2H), 3.73-3.69 (m, 2H), 2.26 (s, 3H), 1.88-1.81 (m, 2H), 1.73-1.66 (m, 2H) .LCMS (method A): [MH] ⁺=427, t _r=4.839min.

embodiment 66

(E)-1-(3-((5,7-difluoro-quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-4-fluorine butyl oxime

At-78 DEG C, to (E)-1-(3-((5,7-difluoro-quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-4-hydroxybutyl oxime (30mg, 0.070mmol) (embodiment 65) 4mLDCM solution in add two (2-methoxy ethyl) amino sulfur trifluoride (180mg, 0.813mmol).Mixture is stirred 1h at such a temperature, and at room temperature stirring is spent the night.By NaHCO saturated for mixture impouring ₃the aqueous solution, with DCM extraction, uses Na ₂sO ₄drying, filters and reduced under vacuum.On silica gel, DCM/ methanol-eluted fractions is adopted to obtain title compound by flash chromatography. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.94 (s, 1H), 8.37 (d, 1H), 7.98 (d, 1H), 7.81 (d, 1H), 7.63 (d, 1H), 7.44 (dd, 1H), 4.81 (s, 2H), 4.58-4.57 (m, 1H), 4.45 (t, 1H), 4.32 (t, 2H), 2.26 (s, 3H), 1.90-1.78 (m, 4H) .LCMS (method A): [MH] ⁺=429, t _r=5.239min.

embodiment 67

(E)-1-(6-((6-((E)-1-(2-hydroxyl-oxethyl imino-) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-base) methyl) quinoline-3-base) ethyl ketone O-2-hydroxyethyl oxime

(the bromo-quinoline of 3--6-base)-methyl alcohol (67.1)

At 0 DEG C, THF (50mL) solution to the bromo-quinoline of 3--6-methyl-formiate (1.09g, 4mmol) stirred adds LiAlH with dividing small portion ₄(0.155g, 4mmol).The mixture obtained is stirred 0.5h at 0 DEG C.Drip water (0.2mL), then add the water of 10%aq.NaOH and 0.2mL of 0.2mL.Solvent also concentrates by removing solid under vacuo.Residue is adopted EtOAc/ hexanes gradient elution purifying by flash chromatography on silica gel, obtains title compound (413mg, 42%) .LCMS (method A): [MH] ⁺=238/240, t _r=4.453min.

2-(the bromo-quinoline of 3--6-ylmethyl)-isoindole-1,3-diketone (67.2)

At 0 DEG C, to phthalic imidine (281mg, drip DIAD (386mg, 1.9mmol) in the 10mL THF solution of 1.9mmol), triphenylphosphine (500mg, 1.9mmol) and mixture is stirred 10min at such a temperature.By (the bromo-quinoline of 3--6-base) ,-methyl alcohol (413mg, 1.7mmol) is disposable joins in above-mentioned solution, and the solution obtained at room temperature is stirred 30min, then at 40 DEG C, heats 5h.After cooling, get molten for reaction mixture EtOAc, wash with water, extract with EtOAc.By organic layer Na ₂sO ₄drying, filters, concentrates under vacuo.Residue is adopted EtOAc/ hexanes gradient elution by flash chromatography on silica gel, obtains title compound. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.89 (d, 1H), 8.31 (d, 1H), 8.06 (d, 1H), 7.90-7.86 (m, 3H), 7.82-7.73 (m, 3H), 5.04 (s, 2H) .LCMS (method A): [MH] ⁺=368/370, t _r=5.54min.

(3-bromoquinoline-6-base) methylamine (67.3)

2-(the bromo-quinoline of 3--6-ylmethyl) the 15mL methyl alcohol of-isoindole-1,3-diketone (635g, 1.73mmol) and the solution of 1mL mono-hydrazine hydrate are heated 2h at 80 DEG C.After cooling, residue is also adopted EtOAc/ methanol elution gradient purifying by flash chromatography by solvent removed in vacuo on silica gel, obtains title compound.LCMS (method A): [MH] ⁺=237/239, t _r=2.795min.

The bromo-N2-of 6-((3-bromoquinoline-6-base) methyl) pyrazine-2,3-diamines (67.4)

Microwave tube is loaded the ethanol of (3-bromoquinoline-6-base) methylamine (237mg, 1.0mmol), 3,5-bis-bromo-pyrazine-2-amine (253mg, 1.0mmol), DIPEA (0.6mL) and 5mL.This pipe is heated 15h under 120 DEG C of microwave radiations.After cooling, under reduced pressure remove desolventizing and residue is adopted DCM/ methanol elution gradient purifying by flash chromatography on silica gel, obtaining title compound.LCMS (method E): [MH] ⁺=406/408/410, t _r=5.803min.

The bromo-6-of 3-((the bromo-1H-of 6-[1,2,3] triazolo [4,5-b] pyrazine-1-base) methyl) quinoline (67.5)

At 20 DEG C, in the 5mL acetic acid solution of the bromo-N2-of 6-((3-bromoquinoline-6-base) methyl) pyrazine-2,3-diamines (300mg, 0.73mmol), drip NaNO ₂the 0.5mL aqueous solution of (150mg, 2.17mmol).Mixture is at room temperature stirred and spends the night.Under reduced pressure remove desolventizing and residue is adopted DCM/ methanol elution gradient purifying by flash chromatography on silica gel, obtaining title compound (130mg, 42%). ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.84 (s, 1H), 8.71 (s, 1H), 8.24 (s, 1H), 8.01 (d, 1H), 7.74 (s, 2H), 5.99 (s, 2H) .LCMS (method E): [MH] ⁺=421, t _r=5.50min.

1-(6-((6-ethanoyl-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-base) methyl) quinoline-3-base) ethyl ketone (67.6)

Under a nitrogen, by bromo-for 3-6-((the bromo-1H-of 6-[1,2,3] triazolo [4,5-b] pyrazine-1-base) methyl) quinoline (128mg, 0.305mmol), Pd (PPh ₃) ₄the 5mL DMF solution of (51.5mg, 0.045mmol) and tributyl (1-vinyl ethyl ether base) stannane (253mg, 0.701mmol) heats 1h at 95 DEG C.Reaction mixture EtOAc is diluted, washes with water.Organic layer is separated, uses Na ₂sO ₄drying, filters and reduced under vacuum.Residue is dissolved in HOAc and 3NHCl, and at room temperature stirs 3h.Under reduced pressure remove desolventizing and residue be dissolved in DCM, with saturated NaHCO ₃the aqueous solution and salt water washing.By organic layer Na ₂sO ₄drying, filters and reduced under vacuum.Residue is adopted DCM/MeOH gradient elution purifying by flash chromatography on silica gel, and obtaining title compound (74mg, 45%), is yellow solid. ¹h-NMR (400MHz, CDCl ₃) δ ppm9.47-9.45 (m, 2H), 8.70 (d, 1H), 8.19 (d, 1H), 8.05 (d, 1H), 7.97 (dd, 1H), 6.21 (s, 2H), 2.82 (s, 3H), 2.74 (s, 3H) .LCMS (method E): [MH] ⁺=347, t _r=4.503min.

(E)-1-(6-((6-((E)-1-(2-hydroxyl-oxethyl imino-) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-base) methyl) quinoline-3-base) ethyl ketone O-2-hydroxyethyl oxime (embodiment 67)

By 1-(6-((6-ethanoyl-1H-[1; 2; 3] triazolo [4; 5-b] pyrazine-1-base) methyl) quinoline-3-base) ethyl ketone (74mg; 0.213mmol) and the methyl alcohol of 5mL of 2-amino oxygen base-ethanol (35mg, 0.45mmol) and the solution of the acetic acid of 0.1mL stir at 40 DEG C and spend the night.Under reduced pressure except desolventizing and by residue DCM and methanol dilution.Collecting precipitation thing, with DCM washing, dry, obtaining title compound (16mg, 15%), is white solid. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 9.31 (s, 1H), 9.23 (d, 1H), 8.52 (d, 1H), 8.03 (d, 1H), 7.98 (s, 1H), 7.86 (dd, 1H), 6.22 (s, 2H), 4.76 (d, 2H), 4.31 (t, 2H), 4.22 (t, 2H), 3.72-3.69 (m, 4H), 2.32 (s, 3H), 2.29 (s, 3H) .LCMS (method E): [MH] ⁺=465, t _r=4.85min.

embodiment 68 (embodiment 68-R, embodiment 68-S)

(E)-2-(1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) second yldeneamino oxygen base) acetic acid

2-(1,3-dioxo isoindoline-2-base oxygen base) methyl acetate (237mg, 1.01mmol) and a hydrazine hydrate (50mg, 1.0mmol) are dissolved in methyl alcohol (3mL), and heat 2h at 70 DEG C.After filtration, by solid washed with EtOAc.The solution of merging is concentrated and by residue methanol dilution.Add NaOH solution (6N, 3mL) and mixture is stirred 2h at 70 DEG C.Solution is concentrated, is acidified to pH 1 with 3NHCl and filters.By solids washed with water, and the solution of merging is concentrated.Diluted by residue DCM, (4NHCl is two then to add ketone 53.5 (40mg, 0.113mmol) and HCl in alkane, 0.7mL).It is at room temperature stirred 24h.After concentrated, by residue by preparative HPLC purifying, obtaining the title compound of 21mg (34%), is white solid. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 12.90 (s, 1H), 8.97 (d, 1H), 8.45 (d, 1H), 8.26 (d, 1H), 7.70 (d, 1H), 7.60 (d, 1H), 5.27 (q, 1H), 4.76 (s, 2H), 2.03 (d, 3H), 1.94 (s, 3H) .LCMS (method B): [MH] ⁺=427, t _r=2.259min. chiral separation (method L) provides the COMPOUNDS EXAMPLE 68-R (t of enantiomeric pure _r=7.71min) and embodiment 68-S (t _r=9.99min).

embodiment 69

(E)-1-(1-((5,7-difluoro-quinoline-6-base) methyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

(5,7-difluoro-quinoline-6-base) methyl alcohol (69.1)

In MeOH (120mL) solution of 5,7-difluoro-quinoline-6-formaldehyde (4.00g, 20.71mmol), gradation adds NaBH ₄(0.79g, 20.71mmol).After stirring 15min, add saturated NH ₄the Cl aqueous solution.By aqueous phase CH ₂cl ₂(4x25mL) extract.Organic layer is merged and uses NaSO ₄dry.Product is adopted hexane by silica gel: EtOAc purifying, obtain (5,7-difluoro-quinoline-6-base) methyl alcohol (3.80g, 94%). ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.97 (m, 1H), 8.42 (m, 1H), 7.63 (d, 1H), 7.46 (m, 1H), 4.99 (d, 2H), 2.07 (t, 1H) .LCMS (method B): [MH] ⁺=196.0, t _r=1.67min

2-(5,7-difluoro-quinoline-6-ylmethyl) isoindoline-1,3-diketone (69.2)

By (E)-diazene-1,2-dioctyl phthalate diisopropyl ester (4.72g, 23.36mmol) with triphenylphosphine (6.13g, THF (100mL) mixture 23.36mmol) stirs 15min, and drip (5,7-difluoro-quinoline-6-base) methyl alcohol (3.80g, 19.47mmol) and isoindoline-1, THF (200mL) solution of 3-diketone (3.15g, 21.42mmol).Reaction mixture is heated 24h at 40 DEG C.Cool and after evaporation, residue is adopted hexane by silica gel: EtOAc purifying, obtain 2-(5,7-difluoro-quinoline-6-ylmethyl) isoindoline-1,3-diketone (5.10g, 81%). ¹H-NMR(400MHz，CDCl ₃)δppm 8.93(m，1H)，8.39(m，1H)，7.85(m，2H)，7.72(m，2H)，7.59(d，1H)，7.43(m，1H)，5.15(s，2H).

(5,7-difluoro-quinoline-6-base) methylamine (69.3)

To the CH of 2-(5,7-difluoro-quinoline-6-ylmethyl) isoindoline-1,3-diketone (5.10g, 15.73mmol) ₃a hydrazine hydrate (0.50g, 15.73mmol) is added in OH (150mL) solution.By vlil 3h.After cooling, mixture is passed through diatomite filtration.Filtrate is concentrated under vacuo.Add EtOAc to dilute residue, filter and concentrate under vacuo, obtaining (5,7-difluoro-quinoline-6-base) methylamine (2.70g, 88%). ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.93 (d, 1H), 8.38 (d, 1H), 7.59 (d, 1H), 7.43 (m, 1H), 4.12 (s, 2H) .LCMS (method B): [MH] ⁺=195.0, t _r=0.17min.

The bromo-N2-of 6-(5,7-difluoro-quinoline-6-ylmethyl) pyrazine-2,3-diamines (69.4)

By the CH of (5,7-difluoro-quinoline-6-base) methylamine (2.7g, 13.9mmol), 3,5-bis-bromo-pyrazine-2-amine (2.4mg, 9.49mmol) and triethylamine (4.8g, 47.5mmol) ₃cN (6mL) mixture heats 40min in microwave radiation, at 180 DEG C.Reaction mixture concentrated under vacuo and passes through column chromatography eluting (hexane: EtOAc), obtaining the bromo-N2-of 6-(5,7-difluoro-quinoline-6-ylmethyl) pyrazine-2,3-diamines (1.50g, 43%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 9.00 (d, 1H), 8.52 (d, 1H), 7.73 (d, 1H), 7.64 (m, 1H), 7.21 (s, 1H), 7.00 (s, 1H), 6.21 (s, 2H), 4.69 (d, 2H) .LCMS (method B): [MH] ⁺=367.9, t _r=2.36min

6-((the bromo-1H-of 6-[1,2,3] triazolo [4,5-b] pyrazine-1-base) methyl)-5,7-difluoro-quinolines (69.5)

To the bromo-N2-(5 of 6-, 7-difluoro-quinoline-6-ylmethyl) pyrazine-2,3-diamines (1.5g, water (3mL) solution of Sodium Nitrite (283mg, 4.10mmol) is added in acetic acid (50mL) 4.10mmol) and water (10mL) solution.After at room temperature stirring 3h, solvent removed in vacuo, by residue NaHCO ₃(aq.) dissolve, use CH ₂cl ₂extraction.By organic layer NH ₄cl (aq.) washs, and uses Na ₂sO ₄drying, filters and reduced under vacuum, and adopts hexane by silica gel chromatography: EtOAc purifying, obtain 6-((the bromo-1H-of 6-[1,2,3] triazolo [4,5-b] pyrazine-1-base) methyl)-5,7-difluoro-quinolines (1.02g, 65%). ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.99 (d, 1H), 8.79 (s, 1H), 8.43 (d, 1H), 7.65 (d, 1H), 7.49 (m, 1H), 6.13 (s, 2H) .LCMS (method B): [MH] ⁺=376.8, t _r=2.23min.

6-((6-(1-vinyl ethyl ether base)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-base) methyl)-5,7-difluoro-quinolines (69.6)

Pd (Ph is added in DMF (1mL) de-gassed solution of 6-((the bromo-1H-of 6-[1,2,3] triazolo [4,5-b] pyrazine-1-base) methyl)-5,7-difluoro-quinolines (10mg, 0.03mmol) ₃p) ₄(3.1mg, 2.65 μm of ol).After stirring 20min, add tributyl (1-vinyl ethyl ether base) stannane (14.4mg, 0.04mmol).Reaction is heated at 100 DEG C until LC-MS display reacts completely.Reaction mixture is used washed with diethylether by diatomite filtration.Filtrate water is washed, uses Na ₂sO ₄drying, and concentrated.Crude product is adopted hexane by column chromatography: EtOAc purifying, obtain 6-((6-(1-vinyl ethyl ether base)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-base) methyl)-5,7-difluoro-quinolines (6.0mg, 61%). ¹h-NMR (400MHz, CDCl ₃) δ ppm 9.16 (s, 1H), 8.98 (d, 1H), 8.43 (d, 1H), 7.65 (d, 1H), 7.48 (m, 1H), 6.17 (s, 2H), 5.60 (s, 1H), 4.57 (s, 1H), 4.04 (q, 2H), 1.49 (t, 3H) .LCMS (method B): [MH] ⁺=369.0, t _r=2.45min.

1-(1-((5,7-difluoro-quinoline-6-base) methyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (69.7)

To 6-((6-(1-vinyl ethyl ether base)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-base) methyl)-5, in the acetic acid solution of 7-difluoro-quinoline (6.0mg, 0.45mmol), add 3N HCl (0.1mL).This solution is at room temperature stirred 2h.Under reduced pressure except desolventizing.By residue diluted with water, use NaHCO ₃aqueous solution process, extracts with DCM.Organic layer is used NaHCO continuously ₃(aq.) and salt water washing, Na is used ₂sO ₄drying, filters and reduced under vacuum.By residue by silica gel column chromatography hexane: ethyl acetate purifying, obtain yellow solid 1-(1-((5,7-difluoro-quinoline-6-base) methyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (3.5mg), productive rate 63%.LCMS (method B): [MH] ⁺=340.9, t _r=2.09min.

(E)-1-(1-((5,7-difluoro-quinoline-6-base) methyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-2-hydroxyethyl oxime (embodiment 69)

To 1-(1-((5,7-difluoro-quinoline-6-base) methyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (3.5mg, add 2-(amino oxygen base) ethylate hydrochlorate (intermediate S) (1.6mg, 0.02mmol) in MeOH (1mL) solution 0.01mmol), solution is heated to 50 DEG C and spends the night.Solvent removed in vacuo.By residue diluted with water, use NaHCO ₃aqueous solution process, extracts with DCM.By organic layer Na ₂sO ₄drying, filters and reduced under vacuum.By crude product by preparative HPLC purifying, obtain white solid (E)-1-(1-((5,7-difluoro-quinoline-6-base) methyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-2-hydroxyethyl oxime (2.4mg, 56%). ¹h-NMR (400MHz, CDCl ₃) δ ppm 9.38 (s, 1H), 8.98 (d, 1H), 8.42 (d, 1H), 7.64 (d, 1H), 7.48 (m, 1H), 6.18 (s, 2H), 4.45 (m, 2H), 3.98 (m, 2H), 2.36 (s, 3H), 1.96 (m, 1H) .LCMS (method B): [MH] ⁺=399.9, t _r=2.19min.

embodiment 70

(E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-1-hydroxy-2-methyl third-2-base oxime

Title compound is by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (22.4) and 2-(amino oxygen base)-2-methyl-prop-1-alcohol hydrochloride adopt the same procedure as described in the synthesis of implementation column 22 to prepare with 94% productive rate. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm9.35 (s, 1H), 8.89 (m, 1H), 8.35 (dd, 1H), 8.01 (m, 2H), 7.82 (m, 1H), 7.52 (dd, 1H), 6.20 (s, 2H), 4.73 (t, 1H), 3.51 (d, 2H), 2.29 (s, 3H), 1.13 (s, 6H) .LCMS (method B): [MH] ⁺=392, t _r=2.40min.

embodiment 71

(E)-1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-oxa-ring fourth-3-base oxime

Title compound is by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (22.4) and O-(oxa-ring fourth-3-base) azanol (intermediate U) adopt the same procedure as described in the synthesis of implementation column 22 to prepare with 23% productive rate. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm9.27 (s, 1H), 8.89 (m, 1H), 8.35 (d, 1H), 8.01 (m, 2H), 7.82 (m, 1H), 7.52 (dd, 1H), 6.22 (s, 2H), 5.45 (t, 1H), 4.86 (t, 2H), 4.66 (m, 2H), 2.40 (s, 3H) .LCMS (method B): [MH] ⁺=376, t _r=2.26min.

embodiment 72

(E)-1-(1-((7-fluorine quinoline-6-base) methyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) acetophenone oxime

Title compound (68.0mg, 62%) by 1-[3-(the fluoro-quinoline of 7--6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-base]-ethyl ketone (15.4) (100.0mg, the same procedure synthesis as described in the synthesis of implementation column 15 0.31mmol) is adopted with hydroxylamine hydrochloride (43.1mg, 0.62mmol). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 12.49 (bs, 1H), 9.31 (s, 1H), 8.92 (d, 1H), 8.40 (d, 1H), 8.18 (d, 1H), 7.82 (d, 1H), 7.54 (d, 1H), 6.22 (s, 2H), 2.23 (s, 3H) .LCMS (method A): [MH] ⁺=338, t _r=5.15min.

embodiment 73

(E)-1-(1-(1-(5,7-difluoro-quinoline-6-base) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-2-hydroxyethyl oxime

1-(5,7-difluoro-quinoline-6-base) ethanol (73.1)

At-78 DEG C, in THF (80mL) solution of 5,7-difluoro-quinoline-6-formaldehyde (5.0g, 25.9mmol), add ethyl phosphonium iodide magnesium (3M, 9.5mL, 28.5mmol).Stir at-78 DEG C after 1 hour, by the saturated NH of reaction ₄cl cancellation also under reduced pressure concentrates.By residue diluted with water, extract three times with DCM.Organic layer is merged, uses Na ₂sO ₄drying, filters and under reduced pressure concentrates.Crude product is obtained title compound by chromatography purification (hexane/EtOAc), is white solid (3.3g, 58%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.97 (dd, 1H), 8.47 (d, 1H), 7.66 ~ 7.58 (m, 2H), 5.54 (d, 1H), 5.29 (m, 1H), 1.56 (d, 3H) .LCMS (method A): [MH] ⁺=210, t _r=4.71min.

2-(1-(5,7-difluoro-quinoline-6-base) ethyl) isoindoline-1,3-diketone (73.2)

By (E)-diazene-1,2-dioctyl phthalate diisopropyl ester (3.8g, 18.9mmol) with triphenylphosphine (5.4g, THF (50mL) mixture 20.5mmol) stirs 30min, and drip 1-(5,7-difluoro-quinoline-6-base) ethanol (3.3g, 15.8mmol) and isoindoline-1, THF (50mL) solution of 3-diketone (2.7g, 17.4mmol).By reaction mixture heated overnight at 50 DEG C.To cool and after evaporating, residue silica gel purification is obtained title compound with hexane/EtOAc wash-out, is white solid (2.6g, 49%).LCMS (method A): [MH] ⁺=339, t _r=5.81min.

1-(5,7-difluoro-quinoline-6-base) ethamine (73.3)

To the CH of 2-(1-(5,7-difluoro-quinoline-6-base) ethyl) isoindoline-1,3-diketone (2.6g, 7.7mmol) ₃a hydrazine hydrate (0.38g, 7.7mmol) is added in OH (50mL) solution.Solution is heated and stirs at 50 DEG C and spends the night.To cool and after evaporating, residue is obtained title compound (1.0g, 60%) by silica gel purification with hexane/EtOAc wash-out. ¹H-NMR(400MHz，DMSO-d ₆)δppm 8.95(d，1H)，8.45(d，1H)，7.65(d，1H)，7.60(dd，1H)，4.49(q，1H)，2.20(bs，2H)，1.48(d，3H).

The bromo-N2-of 6-(1-(5,7-difluoro-quinoline-6-base) ethyl) pyrazine-2,3-diamines (73.4)

By 1-(5,7-difluoro-quinoline-6-base) ethamine (800mg, 3.8mmol), 3,5-bis-bromo-pyrazine-2-amine (972.0mg, 3.8mmol) microwave irradiation is used to heat 45min at 180 DEG C with acetonitrile (50mL) mixture of DIPEA (2.0g, 15.4mmol).Reaction mixture is under reduced pressure concentrated, dilute with water, extract three times with DCM.The organic layer merged is separated and uses salt water washing, uses Na ₂sO ₄drying, filters and reduced under vacuum.By the title compound (508mg, 35%) that crude product obtains as yellow solid by Silica gel chromatography (DCM/MeOH). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.95 (d, 1H), 8.46 (dd, 1H), 7.63 (d, 1H), 7.60 (dd, 1H), 7.11 (s, 1H), 7.08 (dd, 1H), 6.36 (bs, 2H), 5.45 (m, 1H), 1.70 (d, 3H) .LCMS (method A): [MH] ⁺=380/382, t _r=5.03min.

6-(1-(the bromo-1H-of 6-[1,2,3] triazolo [4,5-b] pyrazine-1-base) ethyl)-5,7-difluoro-quinolines (73.5)

To the bromo-N2-of 6-(1-(5,7-difluoro-quinoline-6-base) ethyl) pyrazine-2,3-diamines (450mg, water (2mL) solution of Sodium Nitrite (82.0mg, 1.2mmol) is added in acetic acid (12mL) solution 1.2mmol).At room temperature stir after 2 hours, solvent removed in vacuo.By residue NaHCO ₃(aq.) dilute, extract with DCM.Organic layer be separated and wash with water, using Na ₂sO ₄drying, filters also reduced under vacuum and obtains the title compound (423mg, 91%) into yellow solid. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 9.01 (dd, 1H), 8.95 (s, 1H), 8.52 (d, 1H), 7.75 (d, 1H), 7.64 (dd, 1H), 6.77 (q, 1H), 2.30 (d, 3H) .LCMS (method A): [MH] ⁺=391/393, t _r=5.59min.

6-(1-(6-(1-vinyl ethyl ether base)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-base) ethyl)-5,7-difluoro-quinolines (73.6)

By 6-(1-(the bromo-1H-of 6-[1,2,3] triazolo [4,5-b] pyrazine-1-base) ethyl)-5,7-difluoro-quinolines (423.0mg, 1.2mmol), Pd (Ph ₃p) ₄dMF (5mL) the mixture nitrogen wash of (125.0mg, 0.12mmol) and tributyl (1-vinyl ethyl ether base) stannane (781.0mg, 2.2mmol), then heats 12 hours at 100 DEG C.Under reduced pressure except after desolventizing, residue DCM is diluted, uses the KF aqueous solution and water washing continuously, use Na ₂sO ₄dry also reduced under vacuum.Crude product is adopted gradient (DCM/MeOH=50: 1) purifying by column chromatography on silica gel, obtains the title compound (370mg, 91%) into yellow solid.LCMS (method E): [MH] ⁺=383, t _r=4.24min.

1-(1-(1-(5,7-difluoro-quinoline-6-base) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (73.7)

By 6-(1-(6-(1-vinyl ethyl ether base)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-base) ethyl)-5, the CH of 7-difluoro-quinoline (100.0mg, 0.24mmol) and 3N HCl (0.1mL) ₃oH (10mL) solution stirs 2 hours at 50 DEG C.Under reduced pressure except desolventizing.Reaction mixture is concentrated under vacuo, obtains the title compound (80.0mg, 96%) into yellow solid. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 9.23 (s, 1H), 9.01 (dd, 1H), 8.53 (d, 2H), 7.76 (d, 1H), 7.64 (dd, 1H), 6.87 (q, 1H), 2.49 (s, 3H), 2.40 (d, 3H) .LCMS (method A): [MH] ⁺=355, t _r=5.36min.

(E)-1-(1-(1-(5,7-difluoro-quinoline-6-base) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone O-2-hydroxyethyl oxime (embodiment 73)

To 1-(1-(1-(5,7-difluoro-quinoline-6-base) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (76.5mg, 2-(amino oxygen base) ethylate hydrochlorate (49.0mg, 0.43mol) is added in MeOH (50mL) solution 0.22mmol).By mixture heated overnight at 45 DEG C.Under reduced pressure except desolventizing.By residue by column chromatography gradient (DCM/MeOH=10: 1) purifying, obtain title compound, be white solid (58.0mg, 62%). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm9.23 (s, 1H), 9.01 (dd, 1H), 8.52 (d, 1H), 7.74 (d, 1H), 7.63 (dd, 1H), 6.80 (q, 1H), 4.74 (t, 1H), 4.27 (t, 2H), 3.68 (m, 2H), 2.36 (d, 3H), 2.10 (s, 3H) .LCMS (method A): [MH] ⁺=414, t _r=5.44min.

embodiment 74

(E)-1-(1-(1-(5,7-difluoro-quinoline-6-base) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) acetophenone oxime

Title compound (26.4mg, 63%) by 1-(1-(1-(5,7-difluoro-quinoline-6-base) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-base) ethyl ketone (73.7) (40.0mg, 0.11mmol) and hydroxylamine hydrochloride (15.7mg, 0.23mmol) adopt the same procedure as described in the synthesis of implementation column 73 to synthesize. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 12.28 (bs, 1H), 9.23 (s, 1H), 9.01 (d, 1H), 8.52 (d, 1H), 7.73 (d, 1H), 7.63 (dd, 1H), 6.80 (q, 1H), 2.36 (d, 3H), 2.05 (s, 3H) .LCMS (method A): [MH] ⁺=370, t _r=5.53min.

embodiment 75-S and 75-R

(S, E)-and (R, E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) acetophenone oxime

(E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) acetophenone oxime (embodiment 75)

By 1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) methyl alcohol (30mL) solution of ethyl ketone (53.5,491mg, 1.390mmol) joins hydroxylamine hydrochloride (140mg, 2.015mmol), then drip hydrochloric acid and obtain light yellow settled solution.Reaction mixture is at room temperature stirred and spends the night.LCMS display reacts completely.At 0 DEG C, add the NaOH aqueous solution (1N) until pH 8-9.Evaporating solvent, and by residue by column chromatography eluting, obtaining the title compound of 410mg (88% productive rate), is white solid. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm12.21 (s, 1H), 8.97 (dd, 1H), 8.45 (d, 1H), 8.22 (d, 1H), 7.57-7.71 (m, 3H), 5.25 (q, 1H), 2.01 (d, 3H), 1.84 (s, 3H) .LCMS (method A): [MH] ⁺=369, t _r=5.45min.

(S, E)-and (R, E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) acetophenone oxime (embodiment 75-S and 75-R)

By adopting SFC (method L) separation of racemic mixture (E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) acetophenone oxime (75,12.0g), title compound is obtained.The data of embodiment 75-S (4.98g): ¹h-NMR (400MHz, DMSO-d ₆) δ ppm12.20 (s, 1H), 8.96 (d, 1H), 8.44 (d, 1H), 8.22 (d, 1H), 7.56-7.70 (m, 3H), 5.25 (q, 1H), 2.01 (d, 3H), 1.84 (s, 3H) .LCMS (method B): [MH] ⁺=369, t _rthe data of=2.35min. embodiment 75-R (5.08g): ¹h-NMR (400MHz, DMSO-d ₆) δ ppm12.20 (s, 1H), 8.96 (d, 1H), 8.44 (d, 1H), 8.22 (d, 1H), 7.56-7.70 (m, 3H), 5.25 (q, 1H), 2.01 (d, 3H), 1.84 (s, 3H) .LCMS (method B): [MH] ⁺=369, t _r=2.35min.

embodiment 76-S and 76-R

(S, E)-and (R, E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-Cvclopropvlmethvl oxime

(E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-Cvclopropvlmethvl oxime (embodiment 76)

Methyl alcohol (5mL) solution of 2-(cyclo propyl methoxy) isoindoline-1,3-diketone (300mg, 1.42mmol) and a hydrazine hydrate (35 μ L, 0.71mmol) is heated 3hr at 75 DEG C.Reaction mixture is cooled, and throw out is filtered, and by the methanol wash twice of minimum.1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2 is added in the methanol solution merged, 4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone (53.6,100mg, 0.28mmol), (1N is two then to drip hydrochloric acid in alkane) obtain settled solution.At room temperature stirred by reaction mixture and spend the night, LCMS display reacts completely.Add the 1N NaOH aqueous solution until pH 8-9.Mixture is concentrated, and by the column chromatography eluting title compound obtaining 109mg (91% productive rate), is white solid. ¹h-NMR (400MHz, CDCl ₃) δ ppm 8.93 (dd, 1H), 8.33 (d, 1H), 7.96 (d, 1H), 7.75 (d, 1H), 7.59 (d, 1H), 7.41 (dd, 1H), 5.28 (q, 1H), 4.03 (d, 2H), 2.19 (d, 3H), 2.02 (s, 3H), 1.13-1.22 (m, 1H), 0.52-0.62 (m, 2H), 0.22-0.31 (m, 2H) .LCMS (method A): [MH] ⁺=423, t _r=5.49min.

(S, E)-and (R, E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-Cvclopropvlmethvl oxime (embodiment 76-S and 76-R)

Adopt SFC (method I) separation of racemic mixture (E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-Cvclopropvlmethvl oxime (76,102mg) obtains title compound.The data of embodiment 76-S (32mg): ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.96 (dd, 1H), 8.44 (d, 1H), 8.24 (d, 1H), 7.66 (dd, 2H), 7.9 (dd, 1H), 5.25 (q, 1H), 4.01 (d, 2H), 2.02 (d, 3H), 1.89 (s, 3H), 1.04-1.18 (m, 1H), 0.45-0.56 (m, 2H), 0.26-0.31 (m, 2H). the data of embodiment 76-R (42mg): ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.96 (dd, 1H), 8.44 (d, 1H), 8.24 (d, 1H), 7.66 (dd, 2H), 7.9 (dd, 1H), 5.25 (q, 1H), 4.01 (d, 2H), 2.02 (d, 3H), 1.89 (s, 3H), 1.04-1.18 (m, 1H), 0.45-0.56 (m, 2H), 0.26-0.31 (m, 2H).

embodiment 77-R

(R, E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-formamyl oxime

At 0 DEG C, to (E)-1-(3-(1-(5 of previously preparation, 7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) acetophenone oxime (75-R, 100mg, drip trichloromethylchloroformate (0.1mL, 0.829mmol) in anhydrous THF (8mL) solution 0.271mmol), and reaction mixture is heated 4hr at 50 DEG C.Removing oil bath, and reaction mixture is cooled in ice-water-bath.(0.5N is two to drip ammonia solution in alkane, 8.0mL, 4.0mmol).Temperature is risen to room temperature naturally, and reaction mixture is at room temperature stirred spends the night.Evaporating solvent, and using residue by column chromatography eluting (ethyl acetate solution of 8% methyl alcohol is as elutriant), obtain the title compound of 64mg (45.8% productive rate), for white solid, it is as unstable in methyl alcohol for nucleophile, and is easy to be degraded into initial feed 75-R. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.96 (d, 1H), 8.44 (d, 1H), 8.34 (d, 1H), 8.10 (d, 1H), 7.56-7.74 (m, 2H), 7.34 (s br, 2H), 5.27 (q, 1H), 2.02 (d, 3H), 2.03 (s, 3H) .LCMS (method B): [MH] ⁺=412, t _r=2.25min.

embodiment 77-S

(S, E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-formamyl oxime

Title compound is by (E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) acetophenone oxime (75-S) adopts the acquisition of as similar in embodiment 77-R method. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.96 (d, 1H), 8.44 (d, 1H), 8.34 (d, 1H), 8.10 (d, 1H), 7.56-7.74 (m, 2H), 7.34 (s br, 2H), 5.27 (q, 1H), 2.02 (d, 3H), 2.03 (s, 3H) .LCMS (method B): [MH] ⁺=412, t _r=2.20min.

embodiment 78

(E)-1-(3-((5,7-difluoro-quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) acetophenone oxime

(5,7-difluoro-quinolin-6-base)-acethydrazide (78.1)

In ethanol (15mL) solution of (5,7-difluoro-quinolin-6-base)-methyl acetate (1.023g, 4.32mmol), add a hydrazine hydrate (2mL) and mixture is stirred 24h at 30 DEG C.Solvent removed in vacuo obtains the title compound of 1.024g, is white solid, and it does not need to be further purified namely to use. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 9.33 (s, 1H), 8.97 (d, 1H), 8.46 (d, 1H), 7.67 (d, 1H), 7.61 (dd, 1H), 4.27 (s, 2H) .LCMS (method A): [MH] ⁺=238, t _r=3.24min.Adopt the method that WO2008/144767p108 (intermediate 2) describes, apply WO2008/144767p114 subsequently to intermediate 12, method synthesis (5,7-difluoro-quinoline-6-base)-methyl acetate that step 1 describes.

6-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-5,7-difluoro-quinolin (78.2)

By the 60mL fourth-1-alcoholic solution of (5,7-difluoro-quinolin-6-base)-acethydrazide (1.024g, 4.32mmol) and 3,6-dichloro-pyridazines (0.772g, 5.18mmol) 135 DEG C, heat 16h in sealed tube.Solvent removed in vacuo, and by residue by purified by flash chromatography, obtaining the title compound of 842mg, is gray solid. ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 8.96 (dd, 1H), 8.26 (d, 1H), 7.60-7.66 (m, 2H), 7.45 (d, 1H), 4.81 (s, 2H) .LCMS (method A): [MH] ⁺=332, t _r=4.88min.

6-[6-(1-oxyethyl group-vinyl)-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl]-5,7-difluoro-quinolin (78.3)

By two of 6-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-5,7-difluoro-quinolin (58mg, 0.175mmol) alkane (5mL) solution argon cleaning 1min.Then add tributyl-(1-oxyethyl group-vinyl) stannane (0.2mL, 0.53mmol), add PdCl subsequently ₂(PPh ₃) ₂(14.4mg, 0.021mmol).Reaction mixture argon gas is rinsed half a minute again.Reaction mixture is stirred 4h at 80-85 DEG C; LC/MS display reacts completely.Reaction mixture EtOAc is diluted, and adds the KF aqueous solution of 15mL.Mixture EtOAc is extracted, uses anhydrous Na ₂sO ₄drying, concentrate and obtain thick title compound, it does not need to be further purified namely to use.LCMS (method A): [MH] ⁺=368, t _r=5.39min.

1-[3-(5,7-difluoro-quinolin-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base] ethyl ketone (78.4)

By the 3N HCl aqueous solution (0.2mL, 0.6mmol) join 6-[6-(1-oxyethyl group-vinyl)-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl]-5, in HOAc (2mL) solution of 7-difluoro-quinolin (87mg, 0.237mmol).Reaction mixture is stirred 6h at 40 DEG C.LC/MS display reacts completely.Solvent removed in vacuo, and the residue neutralization that will be dissolved in EtOAc, and extract with EtOAc.Organic layer is dry, and concentrating and pass through purified by flash chromatography, obtaining the title compound of 40mg, is light yellow solid. ¹h-NMR (400MHz, MeOH-d ₄) δ ppm 8.95 (dd, 1H), 8.56 (d, 1H), 8.29 (d, 1H), 7.85 (d, 1H), 7.60-7.67 (m, 2H), 4.94 (s, 2H), 2.67 (s, 3H) .LCMS (method A): [MH] ⁺=339, t _r=4.88min.

(E)-1-(3-((5,7-difluoro-quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) acetophenone oxime (embodiment 78)

By 1-[3-(5,7-difluoro-quinolin-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base] ethyl ketone (78.4,320mg, 0.943mmol) and the methyl alcohol (30mL) of hydroxylamine hydrochloride (131mg, 1.886mmol) at room temperature stir and spend the night.LCMS display reacts completely.The reaction soln 1N NaOH aqueous solution is regulated until pH 8-9, evaporating solvent, and by residue by column chromatography eluting, obtain the title compound for yellow solid of 310mg (93% productive rate). ¹h-NMR (400MHz, DMSO-d ₆) δ ppm 12.29 (s, 1H), 8.99 (dd, 1H), 8.49 (d, 1H), 8.24 (d, 1H), 7.74 (d, 2H), 7.63 (dd, 1H), 4.76 (s, 2H), 2.15 (s, 3H) .LCMS (method A): [MH] ⁺=355, t _r=5.32min.

embodiment 79

(E)-1-(7-(quinoline-6-ylmethyl) imidazo [1,2-b] [1,2,4] triazine-2-base) ethyl ketone O-2-hydroxyethyl oxime

Bromo-1,2, the 4-triazine-3-amine (79.1) of 6-

Water (6000mL) mixture of amino for 3--1,2,4-triazine (50.0g, 521mmol) is cooled to 0-5 DEG C.Go through 1h bromine (70mL, 1.30mmol) is added drop-wise in reaction mixture.Then mixture is stirred at 0-10 DEG C and spend the night.By saturated Na ₂sO ₃the aqueous solution is added in reaction, and the mixture 6NNaOH aqueous solution is neutralized to pH=12.By mixture dichloromethane extraction, use Na ₂sO ₄dry.Solvent removed in vacuo obtains the title compound for yellow solid of 50.0g (54%). ¹h-NMR (400MHz, d ₆-DMSO) δ ppm 8.40 (s, 1H), 7.47 (s, 2H) .LCMS (method B): [MH] ⁺=175/177, t _r=0.328min.

6-(1-vinyl ethyl ether base)-1,2,4-triazine-3-amine (79.2)

By bromo-for 6-1,2, DMF (50mL) solution tetrakis triphenylphosphine palladium (the 0) (258mg of 4-triazine-3-amine (780mg, 4.46mmol), 0.22mmol), N, N-diisopropylethylamine (2284mg, 11.14mmol), lithium chloride (661mg, 15.6mmol) and vinyl three-normal-butyl tin (2093mg, 5.79mmol) process, and reaction is heated 2h at 120 DEG C.Reaction mixture is cooled to room temperature and concentrated solvent under vacuo.Residue dchloromethane is also used KF solution washing.On silica gel, adopt wash-out ethyl acetate/hexane gradient-purified by flash chromatography crude product, obtain the title compound for yellow solid of 380mg (51%). ¹H-NMR(400MHz，CDCl ₃)δppm 8.48(s，1H)，5.41-5.39(m，3H)，4.36(s，1H)，3.98(q，2H)，1.43(t，2H).

6-((2-(2-methyl isophthalic acid, 3-dioxolane-2-base) imidazo [1,2-b] [1,2,4] triazine-7-base) methyl) quinoline (79.3)

By 6-(1-vinyl ethyl ether base)-1,2, ethylene glycol (8mL) solution of the chloro-3-of 4-triazine-3-amine (120mg, 0.72mmol), 2-(quinoline-3-base) propionic aldehyde (317mg, 1.44mmol) stirs 2h at 140 DEG C.Reaction mixture is cooled to room temperature, with saturated Na ₂cO ₃aqueous solution neutralization also dilute with water, is extracted with ethyl acetate, uses Na ₂sO ₄dry.Residue is also adopted ethyl acetate/hexane gradient elution purifying by flash chromatography by solvent removed in vacuo on silica gel, obtains the title compound for yellow solid of 135mg (54%).LCMS (method B): [MH] ⁺=348, t _r=2.03min.

1-(7-(quinoline-6-ylmethyl) imidazo [1,2-b] [1,2,4] triazine-2-base) ethyl ketone (79.4)

By 6-((2-(2-methyl isophthalic acid, 3-dioxolane-2-base) imidazo [1,2-b] [1,2,4] triazine-7-base) methyl) 3NHCl (5mL) solution of quinoline (130mg, 0.37mmol) stirs 0.5h at 90 DEG C.Reaction mixture is cooled to room temperature, with saturated Na ₂cO ₃the aqueous solution neutralizes, and is extracted with ethyl acetate, uses Na ₂sO ₄dry.Solvent removed in vacuo, obtains the title compound for yellow solid of 85mg (75%). ¹h-NMR (400MHz, CDCl ₃) δ ppm 9.06 (s, 1H), 8.91 (d, 1H), 8.12 (t, 2H), 8.04 (s, 1H), 7.74-7.71 (m, 2H), 7.48-7.39 (m, 1H), 4.60 (s, 2H), 2.70 (s, 3H) .LCMS (method B): [MH] ⁺=304, t _r=1.81min.

(E)-1-(7-(quinoline-6-ylmethyl) imidazo [1,2-b] [1,2,4] triazine-2-base) ethyl ketone O-2-hydroxyethyl oxime (embodiment 79)

By 1-(7-(quinoline-6-ylmethyl) imidazo [1,2-b] [1,2,4] triazine-2-base) ethyl ketone (40mg, 0.13mmol), 2-(amino oxygen base) ethylate hydrochlorate (30mg, 0.26mmol) (4N is at Isosorbide-5-Nitrae-two with HCl in alkane, 0.1mL) methyl alcohol (5mL) solution at room temperature stir 48h.By the saturated NaHCO of reaction mixture ₃aqueous solution neutralization also dilute with water, with dichloromethane extraction, uses Na ₂sO ₄dry.Except desolventizing residue adopted ethyl acetate/methanol gradient elution purifying by flashchromatography on silica gel in vacuum, to 35mg (74%) is the title compound of yellow solid. ¹h-NMR (400MHz, d ₆-DMSO) δ ppm 8.94 (s, 1H), 8.84 (d, 1H), 8.28 (d, 1H), 7.97-7.91 (m, 3H), 7.77 (d, 1H), 7.49 (dd, 1H), 4.77 (t, 1H), 4.56 (s, 2H), 4.30-4.27 (m, 2H), 3.71-3.70 (m, 2H), 2.25 (s, 3H) .LCMS (method B): [MH] ⁺=363, t _r=2.08min.

embodiment 80

(E)-1-(7-(quinoline-6-ylmethyl) imidazo [1,2-b] [1,2,4] triazine-2-base) acetophenone oxime

Title compound adopts the same procedure preparation as described in the synthesis of implementation column 79. ¹h-NMR (400MHz, d ₆-DMSO) δ ppm 12.27 (s, 1H), 8.93 (s, 1H), 8.85 (s, 1H), 8.29 (d, 1H), 7.95 (d, 1H), 7.90 (d, 2H), 7.77 (d, 1H), 7.50 (s, 1H), 4.56 (s, 2H), 2.21 (s, 3H) .LCMS (method B): [MH] ⁺=319, t _r=2.065min.

embodiment 81

1-(3-quinoline-6-ylmethyl-imidazo [1,2-a] pyrimidine-6-base)-acetophenone oxime

1-(3-quinoline-6-ylmethyl-imidazo [1,2-a] pyrimidine-6-base)-acetophenone oxime can be generated by 1-(3-quinoline-6-ylmethyl-imidazo [1,2-a] pyrimidine-6-base)-ethyl ketone (intermediate W) and azanol.

embodiment 82

1-(3-quinoline-6-ylmethyl-imidazo [1,2-a] pyrimidine-6-base)-ethyl ketone O-(2-hydroxy-ethyl)-oxime can by 1-(3-quinoline-6-ylmethyl-imidazo [1,2-a] pyrimidine-6-base)-ethyl ketone (intermediate W) and 2-amino oxygen base-ethanol generation.

In another embodiment of the present invention, the crystalline form of embodiment 53S compound is provided.Compared with amorphous form, described crystalline form provides significant improvement in working properties, and provides improvement in thermostability and water absorbability.In addition, crystallization method contributes to removing impurity.

embodiment 1: the amorphous form of embodiment 53S compound

The amorphous form of embodiment 53S adopts method below to obtain:

1A. room temperature slow evaporation crystallization method

Solvent: acetone, primary isoamyl alcohol, methylene dichloride, methyl ethyl ketone, n-propyl alcohol, tetrahydrofuran (THF), amylalcohol, EtOH/ water 1: 1.

Step:

(1) by about 2mg medicine dissolution in 0.2ml solvent.

(2) at room temperature slow evaporation solvent

(3) solid product is analyzed with XRPD 40 DEG C of dried overnight in vacuum drying oven.

IB. solvent resistant method:

(1) by about 2mg medicine dissolution in 0.2ml solvent.

(2) solvent resistant is added to make compound precipitation.

(3) by bottle freeze overnight.

(4) solvent slow evaporation is made.

(5) solid product is analyzed with XRPD 40 DEG C of dried overnight in vacuum drying oven.

IC. slurry method:

Solvent: ethyl acetate

(1) about 2mg medicine is suspended in 0.2ml solvent.

(2) at room temperature slow evaporation solvent

embodiment 2: the crystalline form I of embodiment 53S compound

Different crystallization method is adopted to obtain the crystalline form I of embodiment 53S compound:

2A. room temperature slow evaporation crystallization method

Solvent: acetonitrile, ethanol, ether, ethyl acetate, methyl alcohol, methyl tertiary butyl ether, butylacetate, 2-methyl isophthalic acid-propyl alcohol, toluene, water, 95%EtOH.

(1) by about 2mg medicine dissolution in 0.2ml solvent.

(2) at room temperature slow evaporation solvent

(3) solid product is analyzed with XRPD 40 DEG C of dried overnight in vacuum drying oven.To the sample of production be scaled up further with XRPD, DSC and TGA qualification.

Obtain Ex 53S crystalline form I.

2B. solvent resistant method:

(1) by about 2mg medicine dissolution in 0.2ml solvent

(2) solvent resistant is added to make compound precipitation

(3) by bottle freeze overnight

(4) slow evaporation solvent

(5) solid product is analyzed with XRPD 40 DEG C of dried overnight in vacuum drying oven.Sample XRPD, DSC and TGA qualification of production will be scaled up.

Solvent	Solvent resistant
		Acetonitrile	Water
Methyl alcohol	Hexane
		Ethanol	Water
THF	Hexane
		Acetone	Ether

Obtain embodiment 53S crystalline form I.

2C. slurry method

Solvent: ether, hexane, methyl tertiary butyl ether, butylacetate, toluene, water, pentane.

(1) about 2mg medicine to be suspended in 0.2ml solvent and to balance 24 hours.

(2) at room temperature slow evaporation solvent

(3) solid product is studied with XRPD 40 DEG C of dried overnight in vacuum drying oven.To the sample of production be scaled up further with XRPD, DSC and TGA qualification.

Obtain embodiment 53S crystalline form I.

Table 1: the XRPD data of embodiment 53S crystalline form I

In of the present invention one special embodiment, provide the crystalline form of embodiment 53S compound, it comprises following peak:

embodiment 3: the Form II of embodiment 53S compound

Different crystallization method is adopted to obtain the Form II of embodiment 53S compound

3A. room temperature slow evaporation crystallization method:

Solvent: hexanaphthene, hexane, methyl alcohol, propyl carbinol, pentane.

(1) by about 2mg medicine dissolution in 0.2ml solvent.

(2) at room temperature slow evaporation solvent

Obtain embodiment 53S Form II.

3B. solvent resistant method:

(1) by about 2mg medicine dissolution in 0.2ml methylene dichloride.

(2) solvent resistant hexane is added to make compound precipitation.

(3) by bottle freeze overnight

(4) slow evaporation solvent

(5) solid product is analyzed with XRPD 40 DEG C of dried overnight in vacuum drying oven.To the sample of production be scaled up further with XRPD, DSC and TGA qualification.

Obtain embodiment 53S Form II.

3C. slurry method

Solvent: hexanaphthene

(1) about 2mg medicine is suspended in 0.2ml solvent.

(2) at room temperature slow evaporation solvent

Obtain Ex 53S Form II.

The XRPD data of table 2. embodiment 53S Form II

In of the present invention one special embodiment, provide the crystalline form of the compound of embodiment 53S, it comprises following peak:

Instrument title: X-ray diffractometer

Model: D8Discover

Manufacturer: Bruker AXS GMBH

Wavelength:

Producer is arranged: 40.00KV, 40.00mA

Monochromator

Detector: HI-STAR

Frame size (Frame Size): 1024 pixels, 107.79mm

Experimental technique: 2-θ

2-θ starts: 5.0 degree

2-θ terminates: 45.0 degree

Pixel is overlapping: 20%

Integration step: 0.02 degree

Sweep time: 120 seconds

Temperature: room temperature

c-Met enzyme is analyzed

Many compounds of the present invention are with analyzing based on the kinases phosphorylated analysis of antibody as follows.

EPK cMET composes (profiling) and analyzes:

Application comprises the restructuring GST-fusion rotein of the purifying of the cytoplasm domain of enzyme, establishes the EPK kinase assays of cMET receptor tyrosine kinase.GST-cMET (969-1390) is by affinity chromatography purifying.

Kinase assays is based on LanthaScreen ^tMtechnology.LanthaScreen ^tMbe the detection of temporal resolution-FRET (fluorescence resonance energy transfer) (TR-FRET), its application lanthanide chelate measures the interaction between multiple binding partner.In TR-FRET kinase assays, by conjugated for the long lifetime lanthanon donor substance antibody using the Phosphorylated products of the kinase reaction of the acceptor fluorophore mark be applicable to specific binding.This antibody-mediated interaction make lanthanon donor and acceptor close, thus occur Resonance energy transfer, cause detectable FRET signal to raise.

Kinase reaction carries out in 384 hole microtiter plates, and total reaction volume is 10.05 μ L.The test compound of the applicable experimental concentration of every hole 0.05 μ L is formulated in analysis plates, as what describe under " preparation of diluted chemical compound liquid ".Start by the enzyme substrates mixture (comprising kinases and substrate) of the ATP solution of 5 μ L and 5 μ L is merged and react.Final concentration in kinase reaction is 25mMTris/HCl, 1mM DTT, 0.025% polysorbas20,10 μMs of sodium orthovanadates, 0.25%BSA, 0.5%DMSO, 10mM MgCl ₂, 3mM MnCl ₂, 2 μMs of ATP, 50nM fluorescein-PolyEAY and 0.3nM enzymes.

At room temperature incubation 60 minutes will be reacted, and carry out termination reaction by adding 5 μ L stop buffers (50mMEDTA, 0.04%NP40,20mM Tris/HCl).

Subsequently the detection mixture (50mM Tris/HCl, 2mM DTT, 0.05% polysorbas20,20 μMs of sodium orthovanadates, 1%BSA, 1nM Tb-PY20 antibody) of 5 μ L is added in the reaction of termination.Under room temperature dark condition, incubation is after 45 minutes, and Perkinelmer Envision fluorescence reader measures plate.In all analyses the effect of compound to enzymic activity be obtained by development of linear curve and (the terminal measurement) of being measured by single-point reading.

The results listed in the following table." activity " of the present invention compound has and is less than 5000nM, is preferably less than 1000nM, is more preferably less than 200nM and is most preferably less than the IC50 of 10nM in this enzyme analysis.

gTL16 cells survival is analyzed:

GTL16 clone is available from patients with gastric cancer.Due to gene amplification, GTL16 expresses high-caliber cMet receptor Tyrosylprotein kinase.The growing height of GTL16 depends on cMet kinase activity; Therefore it is used as the analysis based on cell of the cytoactive of monitoring cMet kinase inhibitor.

GTL16 cell is seeded in having in the DMEM substratum of 10%FBS and 1%Pene. & Strep. in 96 orifice plates with 5000 cells/well/90 μ L, and 37 DEG C, at 5%CO ₂be incubated overnight in incubator to make attachment.The compound of 10 times of serial dilutions is added to cell with 10 μ L/ holes.Final analysis volume is 100 μ L/ holes.By analysis plates at 37 DEG C, 5%CO ₂incubation 24 hours in incubator.CellTiter Glo (catalogue #G7573Promega) is adopted to measure the viability of cell according to the scheme of retailer's suggestion.In brief, plate is cooled 10 minutes in room temperature, in each hole, add 100 μ lCellTiter Glo reagent.By plate jolting 10 minutes.Chemoluminescence light unit is read in the Envision of Perkin Elmer.All tests are carried out in triplicate.Adopt Spotfire computed in software IC ₅₀.

The inhibit activities of table 1 compound

Claims

1. be selected from following compound or its pharmacy acceptable salt:

(E)-1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-methyloxime,

(E)-1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-1-hydroxyl third-2-base oxime,

(E)-1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime,

(E)-1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-1,3-dihydroxyl third-2-base oxime,

(E)-1-(3-((5,7-difluoro-quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-fluoro ethyl oxime,

(E)-1-(3-((7-fluorine quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime,

(E)-1-(3-((5-fluorine quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime,

(S, E)-1-(3-(1-(7-fluorine quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime,

(E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-methoxy ethyl oxime,

(E)-1-(3-((5,7-difluoro-quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-4-hydroxybutyl oxime,

(S, E)-2-(1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) second yldeneamino oxygen base) acetic acid,

(E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) acetophenone oxime,

(R, E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) acetophenone oxime,

(S, E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-Cvclopropvlmethvl oxime,

(E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-formamyl oxime, and

(R, E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-formamyl oxime.

2. (E)-1-(3-((5,7-difluoro-quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-3-hydroxypropyl oxime,

Or its pharmacy acceptable salt.

3. (S, E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime,

Or its pharmacy acceptable salt.

4. (E)-1-(3-((5,7-difluoro-quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime,

Or its pharmacy acceptable salt.

5. (E)-1-(3-(difluoro (quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime,

Or its pharmacy acceptable salt.

6. (S, E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) acetophenone oxime,

Or its pharmacy acceptable salt.

7. (S, E)-1-(3-(1-(5,7-difluoro-quinoline-6-base) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-formamyl oxime,

Or its pharmacy acceptable salt.

8. (E)-1-(3-((5,7-difluoro-quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) acetophenone oxime,

Or its pharmacy acceptable salt.

9. (E)-1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-ethyl oxime,

Or its pharmacy acceptable salt.

10. (E)-1-(3-((3-(4-methylpiperazine-1-yl) quinoline-6-base) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-base) ethyl ketone O-2-hydroxyethyl oxime,

Or its pharmacy acceptable salt.

11. compounds as required for protection in any one in claim 1 to 10 or the purposes of its pharmacy acceptable salt in the medicine for the preparation for the treatment of proliferative disease or inflammatory diseases.

12. compounds as required for protection in any one in claim 1 to 10 or its pharmacy acceptable salt treat the purposes in the medicine of the tyrosine kinase mediated disease of one or more c-Met in preparation.

13. pharmaceutical compositions, it comprises compound as required for protection in any one in claim 1 to 10 or its pharmacy acceptable salt, and the pharmaceutically acceptable carrier of at least one, and one or more optional other therapeutical agents.

The combined prod of 14. compounds as required for protection in any one in claim 1 to 10 or its pharmacy acceptable salt and one or more other therapeutic activity agent.