CN101641336A - 3 - cinnolinecarboxamide derivatives and their use for treating cancer - Google Patents
3 - cinnolinecarboxamide derivatives and their use for treating cancer Download PDFInfo
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- CN101641336A CN101641336A CN200880009821A CN200880009821A CN101641336A CN 101641336 A CN101641336 A CN 101641336A CN 200880009821 A CN200880009821 A CN 200880009821A CN 200880009821 A CN200880009821 A CN 200880009821A CN 101641336 A CN101641336 A CN 101641336A
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- formamyl
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Abstract
The invention relates to chemical compounds of formula (I): Formula (I), or pharmaceutically acceptable salts thereof which possess CSF 1R kinase inhibitory activity and are accordingly useful for their anti cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti cancer effect in a warm blooded animal such as man.
Description
The present invention relates to compound or its pharmacy acceptable salt, it has colony-stimulating factor 1 acceptor (CSF-1R) kinase inhibiting activity, therefore is useful on its antitumour activity, thereby is useful in the methods of treatment of human body or animal body.The invention still further relates to the preparation method of described compound, comprise their composition, and they are used for producing purposes in the medicine of anticancer effect warm-blooded animal such as people in preparation.
Receptor tyrosine kinase (RTK ' s) is the subfamily of the protein kinase that plays a crucial role in cell signalling, and involves various cancer correlated processes, comprises cell proliferation, survival, vasculogenesis, invasion and attack and transfer.Believe and comprise that CSF-1R has 96 kinds of different RTK ' s at least.
CSF-1R or c-fms are accredited as the oncogene v-fms that is derived from cat sarcoma virus at first.CSF-1R is the member of III type RTK ' s together with the relevant Tyrosylprotein kinase 3 (Flt3) of c-Kit, fms-and platelet derived growth factor receptor α and β (PDGFR α and PDGFR β).All these kinases all involve the tumour generating process.CSF-1R is typically expressed as jejune 130kDa transmembrane protein, finally forms the glycosylated protein that sophisticated 145-160kDa cell surface N-connects.The part of CSF-1R, macrophage colony stimulating factor (M-CSF or CSF-1) and receptors bind cause two polymerizations and the autophosphorylation of acceptor, and the activation (C.J.Sherr of downstream signal transductory cascade subsequently, Biochim Biophys Acta, 1988,948:225-243).
CSF-1R expresses in the epithelial cell of the conduit in the mammary tissue (but improper stationary phase (normal resting)) of the myelocyte of mononuclear macrophage system and myeloid progenitor and lactation and acinus usually.It is propagation, survival, migration and the differentiation of cell that the activation of CSF-1R stimulates monocyte/macrophage.Sophisticated scavenger cell healthy tissues grow and immune defense in play an important role (F.L.Pixley and E.R.Stanley, Trends in Cell Biology, 2004,14 (11): 628-638).For example, scleroblast secretion CSF-1 also activates acceptor on the broken osteoprogenitor cells, make its be divided into mature osteoclast (S.L.Teitelbaum, Science, 2000,289:1504-1508).The CSF-1R axle placenta growth, embryo transfer, breast duct and LA is grown and lactation in play an important role (E.Sapi, Exp Biol Med, 2004,229:1-11).
The conversion and the in-vivo tumour that use or do not use CSF-1 transfection CSF-1R to bring out NIH3T3, Rat2 and granulosa cell of ovary take place.Autocrine and/the paracrine signal transduction mechanism involves the activation of CSF-1R in tumour epithelial cell and tumor-associated macrophages.The unconventionality expression and the activation of CSF-1R and/or its part in people's myelocyte derived leukocythemia, prostate cancer, mammary cancer, ovarian cancer, carcinoma of endometrium and various other cancer, have been found.The poor prognosis of several in numerous studies show that, the overexpression of CSF-1R and these cancers is relevant.In addition, the CSF-1/CSF-1R axle plays a significant role in the adjusting of tumor-associated macrophages, and the scavenger cell that tumour is relevant is assumed in have vital role in tumor-blood-vessel growth, invasion and attack and the process (E.Sapi, Exp Biol Med, 2004,229:1-11).
In WO 2006/124996, Supergen Inc discloses some inhibitor of Polo sample kinases 1 (Polo-LikeKinase-1); Aston etc. and Glaxo Group Limited disclose some inhibitor of IV type PDE in WO/2007045861, Astrazeneca AB (AstraZeneca) discloses some inhibitor of CSF-1R in WO2006/067445.The inventor has found that the new cinnolines of a class is the inhibitor of CSF-1R, and this has constituted basis of the present invention.
Therefore, the invention provides compound or its pharmacy acceptable salt of formula (I):
Wherein:
R
1And R
2Be independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkanoyloxy, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, N-(C
1-6Alkyl)-N-(C
1-6Alkoxyl group) amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, wherein a is the C of 0-2
1-6Alkyl S (O) a, C
1-6Alkoxy carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical or heterocyclic radical; R wherein
1And R
2Can choose wantonly independently of one another on carbon by one or more R
5Replace; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
6Group replace;
R
3It is hydrogen or halogen;
M is 0 or 1;
R
4Be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, phenyl, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl;
If perhaps two R wherein
4Group is on adjacent carbon, and then they can randomly form carbocyclic ring or heterocycle; Wherein said carbocyclic ring or heterocycle can be chosen wantonly on carbon by one or more R
7Replace; If wherein described heterocycle contains-the NH-part, then nitrogen can randomly be selected from R
8Group replace;
N is 0-5; R wherein
4Implication (value) identical or different;
R
5Be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkanoyloxy, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, N-(C
1-6Alkyl)-N-(C
1-6Alkoxyl group) amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, wherein a is the C of 0-2
1-6Alkyl S (O)
a, C
1-6Alkoxy carbonyl, C
1-6Alkoxycarbonyl amino, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical-R
9-or heterocyclic radical-R
10-; R wherein
5Can choose wantonly on carbon by one or more R
11Replace; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
12Group replace;
R
6And R
12Be independently selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl; R wherein
6And R
12Can choose wantonly independently of one another on carbon by one or more R
13Replace;
R
13Be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkanoyloxy, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl) 2 amino, N-(C
1-6Alkyl)-N-(C
1-6Alkoxyl group) amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, wherein a is the C of 0-2
1-6Alkyl S (O)
a, C
1-6Alkoxy carbonyl, C
1-6Alkoxycarbonyl amino, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical-R
14-or heterocyclic radical-R
15-; R wherein
13Can be randomly on carbon by one or more R
16Replace; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
17Group replace;
R
9, R
10, R
14And R
15Be independently selected from direct key ,-O-,-N (R
18)-,-C (O)-,-N (R
19) C (O)-,-C (O) N (R
20)-,-S (O)
s-,-SO
2N (R
21)-or-N (R
22) SO
2-; R wherein
18, R
19, R
20, R
21And R
22Be independently selected from hydrogen or C
1-6Alkyl, s are 0-2;
R
8And R
17Be independently selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl;
R
7, R
11And R
16Be independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl; methoxyl group; oxyethyl group; ethanoyl; acetoxyl group; methylamino; ethylamino; dimethylamino; diethylamino; N-methyl-N-ethylamino; acetylamino; N-methylamino formyl radical; N-ethylamino formyl radical; N; the N-formyl-dimethylamino; N; N-diethylamino formyl radical; N-methyl-N-ethylamino formyl radical; phenyl; methylthio group; ethylmercapto group; methylsulfinyl; the ethyl sulfinyl; methylsulfonyl; ethylsulfonyl; methoxycarbonyl; ethoxy carbonyl; N-methyl sulfamyl; N-ethyl sulfamyl; N; N-dimethylamino alkylsulfonyl; N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl.
In some embodiments, the present invention relates to compound or its pharmacy acceptable salt of formula (I):
Wherein:
R
1And R
2Be independently selected from hydrogen, halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkanoyloxy, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, N-(C
1-6Alkyl)-N-(C
1-6Alkoxyl group) amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, C
1-6Alkoxy carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical or heterocyclic radical; R wherein
1And R
2Can on carbon, choose wantonly independently of one another by one or more R
5Replace; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
6Group replace;
R
3It is hydrogen or halogen;
M is 0 or 1;
R
4Be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, phenyl, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl;
If perhaps two R wherein
4Group is on adjacent carbon, and then they can randomly form carbocyclic ring or heterocycle; Wherein said carbocyclic ring or heterocycle can be chosen wantonly on carbon by one or more R
7Replace; And if wherein described heterocycle contains-the NH-part, then nitrogen can randomly be selected from R
8Group replace;
N is 0-5; R wherein
4Implication identical or different;
R
5Be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkanoyloxy, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, N-(C
1-6Alkyl)-N-(C
1-6Alkoxyl group) amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, wherein a is the C of 0-2
1-6Alkyl S (O)
a, C
1-6Alkoxy carbonyl, C
1-6Alkoxycarbonyl amino, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical-R
9-or heterocyclic radical-R
10-; R wherein
5Can choose wantonly on carbon by one or more R
11Replace; And if wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
12Group replace;
R
6And R
12Be independently selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl; R wherein
6And R
12Can choose wantonly independently of one another on carbon by one or more R
13Replace;
R
13Be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkanoyloxy, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, N-(C
1-6Alkyl)-N-(C
1-6Alkoxyl group) amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, wherein a is the C of 0-2
1-6Alkyl S (O)
a, C
1-6Alkoxy carbonyl, C
1-6Alkoxycarbonyl amino, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl) 2 sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical-R
14-or heterocyclic radical-R
15-; R wherein
13Can be randomly on carbon by one or more R
16Replace; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can be chosen wantonly and is selected from R
17Group replace;
R
9, R
10, R
14And R
15Be independently selected from direct key ,-O-,-N (R
18)-,-C (O)-,-N (R
19) C (O)-,-C (O) N (R
20)-,-S (O)
s-,-SO
2N (R
21)-or-N (R
22) SO
2-; R wherein
18, R
19, R
20, R
21And R
22Be independently selected from hydrogen or C
1-6Alkyl, s are 0-2;
R
8And R
17Be independently selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl;
R
7, R
11And R
16Be independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl; methoxyl group; oxyethyl group; ethanoyl; acetoxyl group; methylamino; ethylamino; dimethylamino; diethylamino; N-methyl-N-ethylamino; acetylamino; N-methylamino formyl radical; N-ethylamino formyl radical; N; the N-formyl-dimethylamino; N; N-diethylamino formyl radical; N-methyl-N-ethylamino formyl radical; phenyl; methylthio group; ethylmercapto group; methylsulfinyl; the ethyl sulfinyl; methylsulfonyl; ethylsulfonyl; methoxycarbonyl; ethoxy carbonyl; N-methyl sulfamyl; N-ethyl sulfamyl; N; N-dimethylamino alkylsulfonyl; N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl.
In some embodiments, the present invention relates to have formula formula (I) compound or its pharmacy acceptable salt of (IA):
Formula (IA)
Wherein:
---be selected from singly-bound or two key;
If---be singly-bound, then X is selected from CR
24And N;
If the two keys of---be, then X is C;
Y is selected from O and S;
A is selected from O, S, NR
25And CR
28R
29
P is 0-2;
M is 0 or 1;
R
4Be independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, phenyl, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl;
If perhaps two R wherein
4Group is on adjacent carbon, and then they can randomly form carbocyclic ring or heterocycle; Wherein said carbocyclic ring or heterocycle can be randomly on carbon by one or more R
7Replace; And if wherein described heterocycle contains-the NH-part, then nitrogen can randomly be selected from R
8Group replace;
N is 0-5; R wherein
4Implication identical or inequality;
R
7Can be independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, phenyl, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl;
R
8Can be selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl;
R
23Be selected from H and C
1-6Alkyl, wherein C
1-6Alkyl is randomly by C
1-6Alkoxyl group replaces;
R
24, R
26, R
27, R
28Be selected from hydrogen and C independently of one another
1-6Alkyl;
R
25Can be selected from hydrogen, C
1-6Alkyl and C
1-6Alkyloyl, wherein C
1-6Alkyl and C
1-6Alkyloyl can be randomly on carbon by one or more R
30Replace;
Perhaps R
25And R
27Randomly form heterocycle with the atom that they connected; Wherein said heterocycle can be randomly on carbon by one or more R
35Replace; And if described heterocycle contains-the NH-part, then nitrogen can randomly be selected from R
36Group replace;
R
29Can be selected from hydrogen and amino, wherein amino can be randomly by one or more C
1-6Alkyl replaces;
R
30Can be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, phenyl, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl and N-methyl-N-ethyl sulfamyl;
R
35Can be independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, phenyl, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl; And
R
36Can be selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl.
In some embodiments, the present invention relates to have formula formula (I) compound or its pharmacy acceptable salt of (IB):
Formula (IB)
Wherein:
R
1And R
2Be independently selected from hydrogen, halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkanoyloxy, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, N-(C
1-6Alkyl)-N-(C
1-6Alkoxyl group) amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, C
1-6Alkoxy carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical or heterocyclic radical; R wherein
1And R
2Can choose wantonly independently of one another on carbon by one or more R
5Replace; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
6Group replace;
R
5Be independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkanoyloxy, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, N-(C
1-6Alkyl)-N-(C
1-6Alkoxyl group) amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, wherein a is the C of 0-2
1-6Alkyl S (O)
a, C
1-6Alkoxy carbonyl, C
1-6Alkoxycarbonyl amino, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical-R
9-or heterocyclic radical-R
10-; R wherein
5Can be randomly on carbon by one or more R
11Replace; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
12Group replace;
R
6And R
12Be independently selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl; R wherein
6And R
12Can choose wantonly independently of one another on carbon by one or more R
13Replace;
R
13Be independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkanoyloxy, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, N-(C
1-6Alkyl)-N-(C
1-6Alkoxyl group) amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, wherein a is the C of 0-2
1-6Alkyl S (O)
a, C
1-6Alkoxy carbonyl, C
1-6Alkoxycarbonyl amino, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical-R
14-or heterocyclic radical-R
15-; R wherein
13Can be randomly on carbon by one or more R
16Replace; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
17Group replace;
R
9, R
10, R
14And R
15Be independently selected from direct key ,-O-,-N (R
18)-,-C (O)-,-N (R
19) C (O)-,-C (O) N (R
20)-,-S (O)
s-,-SO
2N (R
21)-or-N (R
22) SO
2-; R wherein
18, R
19, R
20, R
21And R
22Be independently selected from hydrogen or C
1-6Alkyl, s are 0-2;
R
17Be independently selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl;
R
11And R
16Be independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, phenyl, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl; And
R
31, R
32, R
33And R
34Be selected from hydrogen, halogen and C independently of one another
1-4Alkyl.
In some embodiments, the present invention relates to have formula formula (I) compound or its pharmacy acceptable salt of (IC):
Formula (IC)
Wherein:
---be selected from singly-bound or two key;
If---be singly-bound, then X is selected from CR
24And N;
If the two keys of---be, then X is C;
Y is selected from O and S;
A is selected from O, S, NR
25And CR
28R
29
P is 0-2;
R
23Be C
1-6Alkyl;
R
24, R
26, R
27, R
28Be selected from hydrogen and C independently of one another
1-6Alkyl;
R
25Can be selected from hydrogen, C
1-6Alkyl and C
1-6Alkyloyl, wherein C
1-6Alkyl and C
1-6Alkyloyl can be randomly on carbon by one or more R
30Replace;
R
29Can be selected from hydrogen and optional by one or more C
1-6The amino that alkyl replaces;
R
30Can be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, phenyl, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl and N-methyl-N-ethyl sulfamyl;
R
31Be selected from hydrogen and C
1-4Alkyl;
R
32Be selected from hydrogen, halogen and C
1-4Alkyl;
R
33Be selected from hydrogen and halogen; And
R
34Be selected from halogen.
In some embodiments, the present invention relates to have formula formula (I) compound or its pharmacy acceptable salt of (ID):
Formula (ID)
Wherein:
---be selected from singly-bound or two key;
If---be singly-bound, then X is selected from CH and N;
If the two keys of---be, then X is C;
A is selected from O, NR
25And CHR
29
P is 0-2;
R
23Be selected from methyl and ethyl;
R
25Be selected from hydrogen, methyl, ethyl, sec.-propyl, the tertiary butyl, 1-methoxyl group-2-ethyl, 1-hydroxyl-2-ethyl, 1,1,1-three fluoro-2-ethyls, 2-hydroxyl-1-propionyl and methylsulfonyl;
R
26And R
27Be selected from hydrogen and methyl independently of one another;
R
29It can be dimethylamino;
R
31Be selected from hydrogen and methyl;
R
32Be selected from hydrogen, fluorine and methyl;
R
33Be selected from hydrogen and chlorine; And
R
34Be selected from fluorine and chlorine.
In some embodiments, the present invention relates to have formula formula (I) compound or its pharmacy acceptable salt of (IE):
Formula (IE)
Wherein:
---be selected from singly-bound and two key;
A is selected from N and CH;
D is selected from N, NH, CH and CH
2
E is selected from N, NH, CH and CH
2
P is 0-1;
R
23Be selected from C
1-6Alkyl;
R
31Be selected from hydrogen and C
1-4Alkyl;
R
32Be selected from hydrogen, halogen and C
1-4Alkyl;
R
33Be selected from hydrogen and halogen;
R
34It is halogen; And
R
37Be selected from H and OH.
In this manual, term " alkyl " comprise the straight or branched alkyl both.Mentioning of independent alkyl such as " propyl group " specifically is used for only censuring (version) straight chained alkyl, the mentioning of independent alkyl such as " sec.-propyl " specifically is used for only censuring branched-chain alkyl." C for example
1-6Alkyl " comprise C
1-4Alkyl, C
1-3Alkyl, propyl group, sec.-propyl and the tertiary butyl.Similar rule application is in other group, for example " phenyl C
1-6Alkyl " comprise phenyl C
1-4Alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.Term " halogen " refers to fluorine, chlorine, bromine and iodine.
When optional substituting group is selected from " one or more " group, should be appreciated that this definition comprises and be selected from all substituting groups of specifying one of group, or be selected from two or more the substituting group of specifying in the group.
" heterocyclic radical " is the monocycle or the dicyclo of saturated, fractional saturation or the undersaturated 4-12 of containing carbon atom, and at least one atom wherein is selected from nitrogen, sulphur or oxygen, and unless otherwise, it can be that carbon or nitrogen connect, wherein-and CH
2-group can be randomly by-C (O)-displacement, and the epithio atom can be randomly oxidized, to form the S-oxide compound.The example of the suitable implication (value) of term " heterocyclic radical " is a morpholino, piperidyl, pyridyl, pyranyl, pyrryl, pyrazolyl, isothiazolyl, indyl, quinolyl, thienyl, 1,3-benzo dioxolyl, thiadiazolyl group, piperazinyl, thiazolidyl, pyrrolidyl, thiomorpholine generation, pyrrolinyl, high piperazinyl, 3,5-two oxa-piperidyls, THP trtrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl isoxazolyl, N-methylpyrrole base, the 4-pyridone, the 1-isoquinolone, 2-Pyrrolidone, the 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide compound.The special example of term " heterocyclic radical " is a pyrazolyl.In one aspect of the invention, " heterocyclic radical " is saturated, fractional saturation or the undersaturated monocycle that contains 5 or 6 atoms, and at least one atom wherein is selected from nitrogen, sulphur or oxygen, and unless otherwise, it can be that carbon or nitrogen connect-CH
2-group can be randomly by-C (O)-displacement, and the epithio atom can be randomly oxidized, to form the S-oxide compound.
" carbocylic radical " is the monocycle or the bicyclic carbocyclic of saturated, fractional saturation or the undersaturated 3-12 of containing atom; Wherein ,-CH
2-group can be randomly by-C (O)-displacement.Especially, " carbocylic radical " is the dicyclo that contains the monocycle of 5 or 6 atoms or contain 9 or 10 atoms.The suitable implication of " carbocylic radical " comprises cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetrahydro naphthyl, indanyl or 1-oxo-dihydro indenyl.The special example of " carbocylic radical " is a phenyl.
" if two R4 groups are on adjacent carbon, and then they can randomly form carbocyclic ring or heterocycle ".Therefore, described " carbocyclic ring " or " heterocycle " condense in the phenyl ring of formula (I).
" carbocyclic ring " is fractional saturation or whole monocycles of the undersaturated 3-8 of a containing carbon atom, and wherein two carbon atoms and the phenyl ring in the formula (I) are shared; Wherein-CH
2-group can be randomly by-C (O)-displacement.The suitable example that condenses " carbocyclic ring " of the phenyl ring in formula (I) comprises indanyl (carbocyclic ring is 5 yuan of rings of fractional saturation) and naphthyl (carbocyclic ring is complete undersaturated 6 yuan of rings).
" heterocycle " be fractional saturation or the complete monocycle of the undersaturated 4-8 of a containing atom, at least one atom wherein is selected from nitrogen, sulphur or oxygen, and two atoms be with formula (I) in the shared carbon atom of phenyl ring; Wherein-CH
2-group can be randomly by-C (O)-displacement, and the epithio atom can be randomly oxidized, to form the S-oxide compound.The suitable example that condenses " heterocycle " of the phenyl ring in formula (I) comprises indolinyl (heterocycle is 5 yuan of rings that contain a nitrogen-atoms of fractional saturation) and quinoxalinyl (heterocycle is complete undersaturated 6 yuan of rings that contain two nitrogen-atoms).
" C
1-6Alkanoyloxy " example be acetoxyl group." C
1-6Alkoxy carbonyl " example comprise methoxycarbonyl, ethoxycarbonyl, positive butoxy carbonyl and tertbutyloxycarbonyl." C
1-6Alkoxyl group " example comprise methoxyl group, oxyethyl group and propoxy-." C
1-6Alkanoylamino " example comprise formamido group, kharophen and propionamido." wherein a is the C of 0-2
1-6Alkyl S (O)
a" example comprise methylthio group, ethylmercapto group, methylsulfinyl, ethyl sulfinyl, methylsulfonyl and ethylsulfonyl." C
1-6Alkyloyl " example comprise propionyl and ethanoyl." N-(C
1-6Alkyl) amino " example comprise methylamino and ethylamino." N, N-(C
1-6Alkyl)
2Amino " example comprise the amino and N-ethyl-N-methylamino of two-N-methylamino, two-(N-ethyl)." C
2-6Thiazolinyl " example be vinyl, allyl group and 1-propenyl." C
2-6Alkynyl " example be ethynyl, 1-proyl and 2-propynyl." N-(C
1-6Alkyl) sulfamyl " example be N-(methyl) sulfamyl and N-(ethyl) sulfamyl." N-(C
1-6Alkyl)
2Sulfamyl " example be N, N-(dimethyl) sulfamyl and N-(methyl)-N-(ethyl) sulfamyl." N-(C
1-6Alkyl) formamyl " example be N-(C
1-4Alkyl) formamyl, methylamino carbonyl and ethylamino carbonyl." N, N-(C
1-6Alkyl)
2Formamyl " example be N, N-(C
1-4Alkyl)
2Formamyl, dimethylamino carbonyl and methylethyl aminocarboxyl." C
1-6Alkyl sulphonyl " example be methylsulfonyl, ethylsulfonyl and sec.-propyl alkylsulfonyl." C
1-6Alkyl sulfonyl-amino " example be methylsulfonyl amino, ethylsulfonylamino and sec.-propyl sulfuryl amino." C
1-6Alkoxycarbonyl amino " example be methoxycarbonyl amino and t-butoxycarbonyl amino." C
1-6Alkoxycarbonyl amino " example comprise methoxycarbonyl amino and t-butoxycarbonyl amino.
The suitable pharmacy acceptable salt of The compounds of this invention for example is, the acid salt of the The compounds of this invention of abundant alkalescence, for example with mineral acid or organic acid acid salt, described mineral acid or organic acid for example are: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid or toxilic acid.In addition, fully the suitable pharmacy acceptable salt of tart The compounds of this invention be an alkali metal salt (for example sodium salt or sylvite), alkaline earth salt (for example calcium salt or magnesium salts), ammonium salt or with the salt of organic bases, described organic bases provides physiologically acceptable positively charged ion, for example with the salt of methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or trans-(2-hydroxyethyl) amine.
Some compounds of formula (I) can have chiral centre and/or rotamerism center (E-and Z-isomer), should be appreciated that, present invention includes all the such optically active isomer with CSF-1R kinase inhibiting activity, diastereomer and geometrical isomers.The invention further relates to any and whole tautomeric form with CSF-1R kinase inhibiting activity of formula (I) compound.
Some compound that should also be understood that formula (I) can solvation form and the existence of non-solvent form, for example hydrated form.Should be appreciated that, present invention includes all such solvation forms with CSF-1R kinase inhibiting activity.
The concrete implication of variable group is as described below.This type of implication can be used at the appropriate location of any definition, claim or the embodiment of definition above or hereinafter.
R
1And R
2Be independently selected from C
1-6Alkoxyl group or heterocyclic radical; R wherein
1And R
2Can choose wantonly independently of one another on carbon by one or more R
5Replace; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
6Group replace; Wherein
R
5Be C
1-6Alkoxyl group; And
R
6Be C
1-6Alkyl.
R
1And R
2Be independently selected from C
1-6Alkoxyl group or heterocyclic radical; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
6Group replace; R wherein
6Be selected from C
1-6Alkyl.
R
1And R
2Be independently selected from C
1-6Alkoxyl group or piperazinyl; R wherein
1And R
2Can choose wantonly independently of one another on carbon by one or more R
5Replace; If described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
6Group replace; Wherein
R
5Be C
1-6Alkoxyl group; And
R
6Be C
1-6Alkyl.
R
1And R
2Be independently selected from C
1-6Alkoxyl group or piperazinyl; Wherein said piperazinyl can be chosen wantonly and be selected from R on nitrogen
6Group replace; R wherein
6Be selected from C
1-6Alkyl.
R
1And R
2Be independently selected from methoxyl group, oxyethyl group or piperazine-1-base; R wherein
1And R
2Can choose wantonly independently of one another and on carbon, be selected from one or more R
5Replace; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
6Group replace; Wherein
R
5It is methoxyl group; And
R
6Be methyl, ethyl, sec.-propyl or the tertiary butyl.
R
1And R
2Be independently selected from methoxyl group, oxyethyl group or piperazinyl; Wherein said piperazinyl can be chosen wantonly and be selected from R on nitrogen
6Group replace; R wherein
6Be selected from methyl, ethyl or sec.-propyl.
R
1And R
2Be independently selected from 2-methoxy ethoxy, oxyethyl group, methoxyl group, 4-ethyl piperazidine-1-base, 4-sec.-propyl piperazine-1-base, 4-methylpiperazine-1-base or 4-tertiary butyl piperazine-1-base.
R
1And R
2Independent of being selected from methoxyl group, oxyethyl group, 1-methylpiperazine-4-base, 1-ethyl piperazidine-4-base or 1-sec.-propyl piperazine-4-base.
R
1And R
2All be methoxyl group, perhaps R
1Be oxyethyl group and R
2Be selected from 1-methylpiperazine-4-base, 1-ethyl piperazidine-4-base or 1-sec.-propyl piperazine-4-base.
R
1And R
2It all is methoxyl group.
R
1Be oxyethyl group, and R
2Be selected from 1-methylpiperazine-4-base, 1-ethyl piperazidine-4-base or 1-sec.-propyl piperazine-4-base.
R
1Be 2-methoxy ethoxy, oxyethyl group or methoxyl group.
R
2Be 4-ethyl piperazidine-1-base, 4-sec.-propyl piperazine-1-base, 4-methylpiperazine-1-base, 4-tertiary butyl piperazine-1-base or methoxyl group.
R
1Be 2-methoxy ethoxy, oxyethyl group or methoxyl group, and R
2Be 4-ethyl piperazidine-1-base, 4-sec.-propyl piperazine-1-base, 4-methylpiperazine-1-base, 4-tertiary butyl piperazine-1-base or methoxyl group.
R
3Be hydrogen.
M is 0.
M is 1.
R
4Be selected from halogen or methyl.
R
4Be selected from fluorine, chlorine or methyl.
N is 2; R wherein
4Implication identical or different.
R
4, the phenyl that is connected with them of n forms 2,3-dichlorophenyl, 2,4 difluorobenzene base, 2-fluoro-4-methyl-phenyl, 2-fluoro-5-methyl-phenyl or 3-chloro-2-fluoro-phenyl.
Therefore, in another aspect of this invention, provide compound or its pharmacy acceptable salt of formula (I) (as mentioned above), wherein:
R
1And R
2Be independently selected from C
1-6Alkoxyl group or heterocyclic radical; R wherein
1And R
2Can choose wantonly independently of one another on carbon by one or more R
5Replace; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
6Group replace;
R
3Be hydrogen;
M is 0;
R
4Be selected from halogen or methyl;
N is 2; R wherein
4Implication identical or different;
R
5Be C
1-6Alkoxyl group; And
R
6Be C
1-6Alkyl.
Therefore, in another aspect of this invention, provide compound or its pharmacy acceptable salt of formula (I) (as mentioned above), wherein:
R
1And R
2Be independently selected from C
1-6Alkoxyl group or heterocyclic radical; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
6Group replace; R wherein
6Be selected from C
1-6Alkyl;
R
3Be hydrogen;
M is 0;
R
4Be selected from halogen or methyl; And
N is 2; R wherein
4Implication identical or different.
Therefore, in another aspect of this invention, provide compound or its pharmacy acceptable salt of formula (I) (as mentioned above), wherein:
R
1And R
2Be independently selected from 2-methoxy ethoxy, oxyethyl group, methoxyl group, 4-ethyl piperazidine-1-base 4-sec.-propyl piperazine-1-base, 4-methylpiperazine-1-base or 4-tertiary butyl piperazine-1-base;
R
3Be hydrogen;
M is 0;
R
4Be selected from fluorine, chlorine or methyl; And
N is 2; R wherein
4Implication identical or different.
Therefore, in another aspect of this invention, provide compound or its pharmacy acceptable salt of formula (I) (as mentioned above), wherein:
R
1And R
2Be independently selected from methoxyl group, oxyethyl group, 1-methylpiperazine-1-base, 1-ethyl piperazidine-1-base or 1-sec.-propyl piperazine-1-base;
R
3Be hydrogen;
M is 0;
R
4Be selected from fluorine, chlorine or methyl; And
N is 2; R wherein
4Implication identical or different.
In another aspect of this invention, preferred compounds of the invention are any one or its pharmacy acceptable salt among the embodiment.
Another aspect of the present invention provides the preparation method of formula (I) compound or its pharmacy acceptable salt, and this method (wherein unless otherwise, variable group is suc as formula defining in (I)) comprising:
Method a) makes formula (II) compound
Wherein L is replaceable atom or group; React with formula (III) compound;
Perhaps, method b) make formula (IV) compound or its activated derivatives and ammonia react;
Method c) make formula V compound and methane amide and alkali reaction,
Wherein R is C
1-6Alkyl, especially methyl and ethyl;
Perhaps, hydrolyzing type (VI) compound method d);
Perhaps, method e), work as R for formula (I) compound
1And R
2One of when being the carbon linking group, make formula (VIIa) or compound (VIIb):
Wherein L is replaceable group; With formula (VIIIa) or the reaction of compound (VIIIb),
R
1-B(R
a)
2????????R
2-B(R
a)
2
(VIIIa)??????????(VIIIb)
Wherein-B (R
a)
2Be boric acid derivatives or trialkylborane; Perhaps
Method f) for formula (I) compound, works as R
1And R
2One of when being the nitrogen linking group; Make formula (IXa) and compound (IXb):
Wherein L is replaceable group; With formula (Xa) or the reaction of compound (Xb);
R
1-H?????????????R
2-H
(Xa)?????????????(Xb)
And after this if necessary:
I) formula (I) compound is changed into another kind of formula (I) compound;
Ii) remove any protecting group;
Iii) form pharmacy acceptable salt.
L is replaceable group, and the suitable implication of L comprises chlorine, bromine, tosyl group and trifluoromethyl sulfonyloxy.
-B (R
a)
2Be boric acid derivatives, the suitable example of boric acid derivatives comprises dihydroxyl boryl, 4,4,5,5-tetramethyl--1,3,2-two assorted oxygen pentaborane bases (dioxaborolanyl); The suitable example of trialkylborane is assorted dicyclo [3.3.1] nonyl of 9-boron (9-borabicyclo[3.3.1] nonyl).
The concrete reaction conditions of above-mentioned reaction is as follows:
Method a) usually under heating condition (common 70 ℃-100 ℃), can make formula (II) compound and formula (III) compound react in solvent (for example ethanol or dimethyl formamide), in some cases, carries out catalysis by adding acetate.
Perhaps, utilize the coupling chemistry, (difference is Pd for example to use suitable catalyzer and ligand
2(dba)
3And BINAP) and suitable alkali (as sodium tert-butoxide or cesium carbonate), can make the reaction of formula (II) compound and formula (III) compound.This reaction needs heating condition usually, carries out under 80 ℃-100 ℃ usually.
Can be by scheme 1 or scheme 2 (as follows) preparation formula (II) compound of revising.
Formula (III) compound is that commercial compound or they are that documentation compound or they can prepare by method known to those skilled in the art.
Method b) in the presence of suitable coupling reagent, the acid and the ammonia of formula (IV) are coupled together.Can use standard peptide coupling reagent known in the art as coupling reagent, for example carbonyl dimidazoles and dicyclohexyl-carbodiimide, choose wantonly in the presence of catalyzer (for example dimethyl aminopyridine or 4-pyrrolidyl pyridine), choose wantonly at alkali (for example triethylamine, pyridine or 2,6-dialkyl group-pyridine is as 2,6-lutidine or 2,6-two-tert .-butylpyridine) under the existence.Suitable solvent comprises N,N-DIMETHYLACETAMIDE, methylene dichloride, benzene, tetrahydrofuran (THF) and dimethyl formamide.Coupled reaction can be expediently carried out under-40-40 ℃ temperature.
Suitable activated acid derivatives comprises acyl halide (as acyl chlorides) and active ester (as the pentafluorophenyl group ester).The compound of these types and the reaction of amine are well known in the art, and for example, they can be in the presence of alkali (for example described above those), reaction in suitable solvent (for example described above those).This reaction can be expediently carried out under-40-40 ℃ temperature.
Can be by scheme 1 or scheme 2 (as follows) preparation formula (IV) compound of revising.
Method c) ester of formula V can react with methane amide and alkali one.Preferably should reaction take place successively, at first add methane amide, add alkali then.Suitable alkali is alkoxide base, and for example methyl alcohol is saline and alkaline and ethanol is saline and alkaline, as sodium methylate.Generally under 100 ℃ of temperature, (in DMF) carries out at suitable solvent in reaction.
Can be according to scheme 1 preparation formula V compound.
Scheme 1
Formula (Va) and compound (Vb) are that commercial compound or they are that documentation compound or they easily prepare by method known to those skilled in the art.
Method d) can be with formula (VI) compound hydrolysis under standard acidic or alkaline condition.
Can be by scheme 1 or scheme 2 preparation formulas (VI) compound of revising.
Method e) can use under palladium catalyst and the alkali condition, make the reaction of formula (VIIa) and compound (VIIb) and formula (VIIIa) and boric acid derivatives (VIIIb).Appropriate catalyst is Pd (PPh
3)
4, suitable alkali is salt of wormwood.Generally under 100 ℃ of temperature, or under microwave condition, at suitable solvent systems (such as diox/water) in react.
Formula (VIIa) and compound (VIIb) can react under standard Suzuki (Suzuki) condition with formula (VIIIa) and trialkylborane (VIIIb), for example use palladium catalyst, in the presence of alkali, in suitable solvent (DMF), react in 50 ℃ usually.
Can be by scheme 1 or scheme 2 preparation formulas (VIIa) and the compound of revising (VIIb).
Formula (VIIIa) and compound (VIIIb) are that commercial compound or they are that documentation compound or they easily prepare by method known to those skilled in the art.
Method f) use under the condition of palladium catalyst, ligand and alkali, formula (IXa) and compound (IXb) can react with formula (Xa) and amine (Xb).Appropriate catalyst is Pd
2(dba)
3, suitable ligand is BINAP, suitable alkali is cesium carbonate.Usually 100 ℃ of temperature or under microwave condition, in suitable solvent systems (as toluene or N,N-DIMETHYLACETAMIDE), react.
Can be by scheme 1 or scheme 2 preparation formulas (IXa) and the compound of revising (IXb).
Formula (Xa) and compound (Xb) are that commercial compound or they are that documentation compound or they easily prepare by method known to those skilled in the art.
The alternative arrangement that is used for some compound of preparation formula (I) is shown in scheme 2, can revise described scheme, to prepare some intermediate mentioned above.
Scheme 2
In some embodiments, the present invention relates to prepare the method for formula disclosed herein (I) compound, it comprises makes formula V compound and methane amide and alkali reaction
Wherein R is C
1-6Alkyl, so that form formula (I) compound; And optional thereafter:
I) formula (I) compound is converted into another kind of formula (I) compound;
Ii) remove any protecting group; Perhaps
Iii) form pharmacy acceptable salt.
In other embodiments, R is selected from methyl and ethyl.
In some embodiments, the present invention relates to prepare the method for formula disclosed herein (I) compound, it comprises hydrolyzing type (VI) compound:
So that form formula (I) compound; And optional thereafter:
I) formula (I) compound is converted into another kind of formula (I) compound;
Ii) remove any protecting group; Perhaps
Iii) form pharmacy acceptable salt.
In other embodiments, by being mixed with metal hydroxides and branched alkyl alcohol, formula (VI) compound is hydrolyzed.
In other embodiments, described metal hydroxides is a potassium hydroxide.
In other embodiments, described branched alkyl alcohol is the tertiary alcohol, as the trimethyl carbinol.
Should be understood that before above-mentioned method or following closely, can introduce or produce some in the various ring substituents in the The compounds of this invention that these are included among the method for the present invention aspect by the substitution reaction of standard aromatics by conventional modified with functional group.This type of reaction and modification for example comprise introduces substituting group by the aromatics substitution reaction, reduction substituting group, alkylation substituting group and oxidation substituting group.Be used for this class method reagent and and reaction conditions be well-known at chemical field.The object lesson of aromatics substitution reaction comprises use concentrated nitric acid introducing nitro; Under Friedel Crafts condition, use such as acyl halide and Lewis acid (as aluminum chloride) and introduce acyl group; Under Friedel Crafts condition, use such as alkylogen and Lewis acid (as aluminum chloride) and introduce alkyl; And introducing halogen group.The object lesson of modifying comprises by for example with the iron heat treated nitroreduction being become amino with the catalytic hydrogenation of nickel catalyzator or in the presence of hydrochloric acid; Alkylthio is oxidized to alkyl sulphinyl or alkyl sulphonyl.
Should also be understood that in reactions more mentioned in this article, may essential/hope protect any sensitive group in the compound.Wherein must or wish the situation of protection and protect suitable method known to those skilled in the art.Can adopt GPF (General Protection False group (specifically consulting T.W.Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991) according to standard practices.Therefore, if reactant comprises the group such as amino, carboxyl or hydroxyl, can wish the described group of protection in reactions more mentioned in this article.
The appropriate protection group of amino or alkylamino is for example acyl group, for example alkyloyl (as ethanoyl), alkoxy carbonyl (as methoxycarbonyl, ethoxycarbonyl or tertbutyloxycarbonyl), aryl methoxy carbonyl (as benzyloxycarbonyl) or aroyl (as benzoyl).The protective condition that goes of above-mentioned blocking group must change along with selected blocking group.Therefore, for example can remove acyl group (as alkyloyl) or alkoxy carbonyl or aroyl by using suitable alkali (for example alkali metal hydroxide, as lithium hydroxide or sodium hydroxide) hydrolysis.Perhaps, can for example remove acyl group (as tertbutyloxycarbonyl) by using suitable acid (example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid) to handle; For example can remove the aryl methoxycarbonyl, as carbobenzoxy-(Cbz) by through catalyzer (palladium/carbon) hydrogenation or by handling with Lewis acid (as (trifluoroacetyl oxygen base) boron).The suitable alternative blocking group of primary amino is a phthaloyl for example, and it can remove by handling such as the alkylamine of dimethylamino propylamine or handling with hydrazine.
The appropriate protection group of hydroxyl is for example acyl group (for example alkyloyl, as ethanoyl), aroyl (as benzoyl) or arylmethyl (as benzyl).The protective condition that goes of above-mentioned blocking group must change along with selected blocking group.Therefore, for example can remove acyl group (as alkyloyl) or aroyl by using suitable alkali (for example alkali metal hydroxide, as lithium hydroxide or sodium hydroxide) hydrolysis.Perhaps, for example can be by removing arylmethyl (as benzyl) through catalyzer (as palladium/carbon) hydrogenation.
The appropriate protection group of carboxyl is an esterified group for example, and as methyl or ethyl, it for example can be by removing with alkali (as sodium hydroxide) hydrolysis; The perhaps tertiary butyl for example, it can remove by handling with acid (for example organic acid, as trifluoroacetic acid); Perhaps benzyl for example, it can be by removing through catalyzer (as palladium/carbon) hydrogenation.
How easily the well-known routine techniques of available chemical field synthesis phase in office removes blocking group.
Some intermediate described herein is new, provides these as other feature of the present invention.
As mentioned before, the compound of the present invention's definition has antitumour activity, it is believed that it comes from the CSF-1R kinase inhibiting activity of compound.For example can use follow procedure to estimate these character.
In some embodiments, the present invention relates to treat method for cancer, it comprises providing to be in to diagnose to suffer from or show the object of the risk of cancer symptoms, and gives the pharmaceutical composition that described object comprises formula disclosed herein (I) compound.
In some embodiments, the present invention relates to suppress the kinase whose method of CSF-1R, it comprises provides CSF-1R kinases and formula disclosed herein (I) compound, and is consequently suppressing to mix under CSF-1R kinases and the condition.
Biologic activity
The external α screening of test 1:CSF-1R (AlphaScreen) test
As described below, use the activity of Amplified Luminescent Proximity Homogeneous Assay (ALPHA) (Perkin Elmer) external test purifying CSF-1R, its phosphorylation, biotinylation of measuring the CSF-1R substrate gathers-glutamine-tyrosine peptide (pEY-HTRF CisBio 61GT0BLD).The kinases territory of the His-mark of CSF-1R (that is, amino acid 568-912, GeneBank IDNM_005211; (sequence table sees that the 25th page of 13-19 of WO 2006/067445 is capable)) insect cell (purifying of 1.4x106 cell/ml) of expressing from the SF+ of baculovirus infection, with French press crushing (French pressed) cell, according to the order of sequence by Qiagen Ni-NTA post, Superflow Mono Q HR10/10 post and Superdex 200SEC column chromatography.General productive rate is 245 μ g/l cell precipitation things, purity＞95%.
In the compound of interest existence and not, measure the phosphorylation of CSF-1R substrate.In brief, under 25 ℃, with 0.57nM purifying CSF-1R, 5nM pEY substrate and compound preincubate 30 minutes in the 1x damping fluid.Come initiation reaction and under 25 ℃, hatched 60 minutes by being added in 90 μ M Triphosadens (ATP) in the 1x damping fluid, detect mixtures (forming) and make reaction terminating by 136mMNaCl, 102mM ethylenediamine tetraacetic acid (EDTA), 1.65mg/ml BSA, 40 μ g/ml Streptavidin donor bead (Perkin Elmer 6760002), 40 μ g/ml pTyr, 100 acceptor bead (Perkin Elmer 6760620) by adding 5 μ l.In the dark plate was hatched under 25 ℃ 18 hours.Read plate device (Perkin Elmer) by EnVision and under 680nm excitation wavelength, 520-620nm emission wavelength, detect phosphorylated substrate.Use Excel Fit (Microsoft) with data mapping and calculating IC50.
The external Alpha shaker test of test 2:CSF1R
As described below, use Amplified Luminescent Proximity Homogeneous Assay (ALPHA) (Perkin Elmer, MA) activity of external test purifying CSF-1R, its phosphorylation, biotinylation of measuring the CSF-1R substrate gathers-glutamine-tyrosine peptide (pEY-HTRF CisBio61GT0BLD).The kinases territory of the His-mark of CSF-1R (promptly, amino acid 568-912, GeneBank IDNM_005211) insect cell of the expressing (purifying of 1.4x106 cell/ml) from the SF+ of baculovirus infection, use the French press crush cell, carry out chromatography by Qiagen Ni-NTA post, Superflow MonoQ HR 10/10 post and Superdex 200SEC post according to the order of sequence.General productive rate is 322 μ g/l cell precipitation things, purity＞95%.
In the compound of interest existence and not, measure the phosphorylation of CSF-1R substrate.In brief, under 25 ℃, 5 μ l enzyme/substrates/Triphosaden (ATP) mixture that will form by 0.46nM purifying CSF-1R, 12nM pEY substrate and the 12mM ATP in the 1x damping fluid and 2 μ l compound preincubates 20 minutes.With 5 μ l metal mixtures (by the 24mM MgCl in the 1.2x damping fluid
2Form) come initiation reaction and under 25 ℃, hatched 90 minutes, detect mixture (by 102mM HEPES, 102mM ethylenediamine tetraacetic acid (EDTA), 1.65mg/ml BSA, 136mM NaCl, 40 μ g/ml Streptavidin donor bead (Perkin Elmer by adding 5 μ l, MA, catalog number (Cat.No.) 6760002) and 40 μ g/ml apply phosphoric acid tyrosine-specific antibody receptor pearl (Perkin Elmer, MA, catalog number (Cat.No.) 6760620) form) make reaction terminating.In the dark plate was hatched under 25 ℃ 18 hours.Read plate device (Perkin Elmer) by EnVision and under 680nm excitation wavelength, 520-620nm emission wavelength, detect phosphorylated substrate.Use Excel Fit (Microsoft) with data mapping and calculating IC
50
When testing in above-mentioned one or another in vitro tests, The compounds of this invention generally shows the activity that is lower than 30 μ M.For example, below be with the test of above-described one or another test substantially similarity in the result that obtains:
| The embodiment numbering | Test 1 IC 50 | Test 2 IC 50 | |
| ??1 | ??＜3nM | ||
| ??2 | ??8nM | ||
| ??3 | ??＜3nM | ||
| ??4 | ??5nM | ||
| ??5 | ??＜3nM | ||
| ??6 | ??＜3nM | ||
| ??7 | ??＜4nM | ||
| ??8 | ??3nM | ||
| ??9 | ??＜15nM | ||
| ??10 | ??＜3nM | ||
| ??11 | ??8nM |
| The embodiment numbering | Test 1 IC 50 | Test 2 IC 50 | |
| ??12 | ??5nM | ||
| ??13 | ??＜3nM | ||
| ??14 | ??＜3nM | ||
| ??15 | ??＜4nM | ||
| ??16 | ??9nM | ||
| ??17 | ??＜3nM | ||
| ??18 | ??＜3nM | ||
| ??19 | ??＜3nM | ||
| ??20 | ??＜3nM | ||
| ??21 | ??＜3nM | ||
| ??22 | ??＜3nM |
| The embodiment numbering | Test 1 IC 50 | Test 2 IC 50 | |
| ??23 | ??＜5nM | ||
| ??24 | ??＜3nM | ||
| ??25 | ??＜3nM | ||
| ??26 | ??51nM | ||
| ??27 | ??＜3nM | ||
| ??28 | ??＜3nM | ||
| ??29 | ??7nM | ||
| ??30 | ??10nM | ||
| ??31 | ??13nM | ||
| ??32 | ??8nM | ||
| ??33 | ??12nM | ||
| ??34 | ??5nM | ||
| ??35 | ??＜9nM | ||
| ??36 | ??＜3nM | ||
| ??37 | ??71nM | ||
| ??38 | ??＜3nM | ||
| ??39 | ??＜3nM | ||
| ??40 | ??＜3nM | ||
| ??41 | ??＜3nM | ||
| ??42 | ??7nM | ||
| ??43 | ??3nM | ||
| ??44 | ??16nM | ||
| ??45 | ??6nM | ||
| ??46 | |||
| ??47 | ??6nM | ||
| ??48 | ??＜3nM | ||
| ??49 | ??20nM | ||
| ??50 | ??33nM |
| The embodiment numbering | Test 1 IC 50 | Test 2 IC 50 | |
| ??51 | |||
| ??52 | |||
| ??53 | |||
| ??54 |
According to other aspects of the invention, provide pharmaceutical composition, it comprises above defined formula (I) compound or its pharmacy acceptable salt and pharmaceutically acceptable diluent or carrier.
Said composition can be the form that is suitable for oral administration, for example is tablet or capsule; Be suitable for parenteral injection form such as sterile solution, suspensoid or the emulsion of (comprising in intravenously, subcutaneous, intramuscular, the blood vessel or infusion); Be suitable for form such as the ointment or the emulsifiable paste of topical or be suitable for the form such as the suppository of rectal administration.
On the whole, above-mentioned composition can use the conventional excipients preparation in a usual manner.
Formula (I) compound gives warm-blooded animal with the unitary dose of 1-1000mg/kg scope usually, and this provides the treatment effective dose usually.The preferred per daily dose that adopts the 10-100mg/kg scope.But per daily dose is necessary to change according to the host who is treated, concrete route of administration and the severity of disease for the treatment of.Therefore, optimal dose can be decided by any concrete patient's of treatment practitioner.
According to other aspects of the invention, provide above defined formula (I) compound or its pharmacy acceptable salt, it is used for the treatment of in the method for human body or animal body.
We find that compound or its pharmacy acceptable salt that the present invention defines are effective anticarcinogens, it is believed that this character is derived from their CSF-1R kinase inhibition character.Therefore, The compounds of this invention expection be useful on treatment separately or part by CSF-1R kinase mediated disease or medical condition (medicalconditions), promptly described compound is used in and produces CSF-1R kinase inhibition effect in the warm-blooded animal that needs this treatment.
Therefore, The compounds of this invention provides the treatment method for cancer, and this method is characterized by and suppresses the CSF-1R kinases, that is, this compound can be used for producing separately or part by suppressing the kinase mediated anticancer effect of CSF-1R.
Expect that this compounds of the present invention has the anticancer character of wide region, because in various human cancer and derived cell system, find the unconventionality expression of CSF1R and/or CSF1, include but not limited to the tumour of mammary gland, ovary, uterine endometrium, prostate gland, lung, kidney and pancreas; And malignant hematologic disease (haematologicalmalignancies) includes but not limited to myelodysplastic syndrome, acute myeloid derived leukocythemia, chronic myelocytic derived leukocythemia, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma and lymphocytic leukemia.Be reported in addition in hematopoiesis and Lymphoid tissue and the lung cancer and have activated mutant.In addition, in the kinds of tumors type, tumor-associated macrophages is followed poor prognosis, and described tumor type includes but not limited to mammary gland, uterine endometrium, kidney, lung, bladder and cervical cancer; Glioma; Esophageal squamous cell carcinoma; Uveal tract malignant melanoma and follicular lymphoma.The expection The compounds of this invention is by acting directly on tumour and/or indirect action will have anti-these cancers in tumor-associated macrophages antitumour activity.
In others of the present invention, formula (I) compound also can have value in some other indication of treatment.These indications include but not limited to the osteolysis relevant with tumour, osteoporosis; Orthopedic graft failure; Autoimmune disease comprises systemic lupus erythematosus; Sacroiliitis comprises rheumatoid arthritis, osteoarthritis; Ephritis and glomerulonephritis; Inflammatory bowel; Transplant rejection comprises kidney and marrow allograft and skin heterograft; Atherosclerosis; Obesity; Alzheimer and langerhans cell histiocytosis.Therefore others of the present invention comprise one or more in these diseases of treatment, and particularly sacroiliitis comprises rheumatoid arthritis and osteoarthritis.These indications also include but not limited to chronic obstructive pulmonary disease, diabetes and chronic dermatosis (comprising psoriatic).
Therefore, according to this aspect of the invention, provide above defined formula (I) compound or its pharmacy acceptable salt, it is as medicine.
According to other aspects of the invention, provide above defined formula (I) compound or its pharmacy acceptable salt to be used for producing purposes in the medicine of CSF-1R kinase inhibition effect warm-blooded animal (as the people) in preparation.
According to this aspect of the invention, provide above defined formula (I) compound or its pharmacy acceptable salt to be used for producing purposes in the medicine of anticancer effect warm-blooded animal (as the people) in preparation.
According to another feature of the present invention, provide above defined formula (I) compound or its pharmacy acceptable salt to be used for the treatment of purposes in the medicine of following disease: the tumour of mammary gland, ovary, bladder, uterine cervix, uterine endometrium, prostate gland, lung, kidney and pancreas in preparation; Malignant hematologic disease, it includes but not limited to myelodysplastic syndrome, acute myeloid derived leukocythemia, chronic myelocytic derived leukocythemia, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma and lymphocytic leukemia; And glioma; Esophageal squamous cell carcinoma; Uveal tract malignant melanoma and follicular lymphoma.
The further feature according to the present invention provides above defined formula (I) compound or its pharmacy acceptable salt to be used for the treatment of purposes in the medicine in the following disease in preparation: the osteolysis relevant with tumour, osteoporosis (comprising the bone forfeiture that oophorectomize causes), orthopedic graft failure, autoimmune disease (comprising systemic lupus erythematosus), sacroiliitis (comprising rheumatoid arthritis, osteoarthritis), ephritis and glomerulonephritis; Inflammatory bowel; Transplant rejection (comprising kidney and marrow allograft and skin heterograft); Atherosclerosis; Obesity; Alzheimer; Chronic obstructive pulmonary disease; Diabetes and chronic dermatosis (comprising psoriatic) and langerhans cell histiocytosis.
Further feature according to this aspect of the invention, be provided at the method that produces CSF-1R kinase inhibition effect in the warm-blooded animal (as the people) that needs this treatment, it comprises above defined formula (I) compound or its pharmacy acceptable salt that gives described animal effective dose.
Further feature according to this aspect of the invention is provided at the method that produces anticancer effect in the warm-blooded animal (as the people) that needs this treatment, and it comprises above defined formula (I) compound or its pharmacy acceptable salt that gives described animal effective dose.
Further feature according to this aspect of the invention is provided at the method for the treatment of following disease in the warm-blooded animal (as the people) that needs this treatment: the tumour of mammary gland, ovary, bladder, uterine cervix, uterine endometrium, prostate gland, lung, kidney and pancreas; Malignant hematologic disease, it comprises myelodysplastic syndrome, acute myeloid derived leukocythemia, chronic myelocytic derived leukocythemia, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma and lymphocytic leukemia; And glioma; Esophageal squamous cell carcinoma; Uveal tract malignant melanoma and follicular lymphoma, this method comprise above defined formula (I) compound or its pharmacy acceptable salt that gives described animal effective dose.
Further feature according to this aspect of the invention is provided at the method for the treatment of following disease in the warm-blooded animal (as the people) that needs this treatment: the osteolysis relevant with tumour, osteoporosis (comprising the bone forfeiture that oophorectomize causes), orthopedic graft failure, autoimmune disease (comprising systemic lupus erythematosus), sacroiliitis (comprising rheumatoid arthritis, osteoarthritis), ephritis and glomerulonephritis; Inflammatory bowel; Transplant rejection (comprising kidney and marrow allograft and skin heterograft); Atherosclerosis; Obesity; Alzheimer; Chronic obstructive pulmonary disease; Diabetes and chronic dermatosis (comprising psoriatic) and langerhans cell histiocytosis, this method comprises above defined formula (I) compound or its pharmacy acceptable salt that gives described animal effective dose.
In others of the present invention, pharmaceutical composition is provided, it comprises above defined formula (I) compound or its pharmacy acceptable salt, and pharmaceutically acceptable diluent or carrier, and it is used for producing CSF-1R kinase inhibition effect warm-blooded animal (as the people).
In others of the present invention, pharmaceutical composition is provided, it comprises above defined formula (I) compound or its pharmacy acceptable salt, and pharmaceutically acceptable diluent or carrier, and it is used for producing anticancer effect warm-blooded animal (as the people).
In others of the present invention, pharmaceutical composition is provided, it comprises above defined formula (I) compound or its pharmacy acceptable salt, and pharmaceutically acceptable diluent or carrier, it is used in the following disease of warm-blooded animal (as the people) treatment: the tumour of mammary gland, ovary, bladder, uterine cervix, uterine endometrium, prostate gland, lung, kidney and pancreas; Malignant hematologic disease, it comprises myelodysplastic syndrome, acute myeloid derived leukocythemia, chronic myelocytic derived leukocythemia, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma and lymphocytic leukemia; And glioma; Esophageal squamous cell carcinoma; Uveal tract malignant melanoma and follicular lymphoma.
In others of the present invention, pharmaceutical composition is provided, it comprises above defined formula (I) compound or its pharmacy acceptable salt, and pharmaceutically acceptable diluent or carrier, it is used in the following disease of warm-blooded animal (as the people) treatment: the osteolysis relevant with tumour, osteoporosis (comprising the bone forfeiture that oophorectomize causes), orthopedic graft failure, autoimmune disease (comprising systemic lupus erythematosus), sacroiliitis (comprising rheumatoid arthritis, osteoarthritis), ephritis and glomerulonephritis; Inflammatory bowel; Transplant rejection (comprising kidney and marrow allograft and skin heterograft); Atherosclerosis; Obesity; Alzheimer; Chronic obstructive pulmonary disease; Diabetes and chronic dermatosis (comprising psoriatic) and langerhans cell histiocytosis.
According to other aspects of the invention, provide above defined formula (I) compound or its pharmacy acceptable salt in warm-blooded animal (as the people), to produce the purposes of CSF-1R kinase inhibition effect.
According to other aspects of the invention, provide above defined formula (I) compound or its pharmacy acceptable salt in warm-blooded animal (as the people), to produce the purposes of anticancer effect.
According to another feature of the present invention, provide above defined formula (I) compound or its pharmacy acceptable salt purposes in the following disease of treatment: the tumour of mammary gland, ovary, bladder, uterine cervix, uterine endometrium, prostate gland, lung, kidney and pancreas; Malignant hematologic disease, it comprises myelodysplastic syndrome, acute myeloid derived leukocythemia, chronic myelocytic derived leukocythemia, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma and lymphocytic leukemia; And glioma; Esophageal squamous cell carcinoma; Uveal tract malignant melanoma and follicular lymphoma.
According to another feature of the present invention, provide above defined formula (I) compound or its pharmacy acceptable salt purposes in the following disease of treatment: the osteolysis relevant, osteoporosis (comprising the bone forfeiture that oophorectomize causes), orthopedic graft failure, autoimmune disease (comprising systemic lupus erythematosus), sacroiliitis (comprising rheumatoid arthritis, osteoarthritis), ephritis and glomerulonephritis with tumour; Inflammatory bowel; Transplant rejection (comprising kidney and marrow allograft and skin heterograft); Atherosclerosis; Obesity; Alzheimer; Chronic obstructive pulmonary disease; Diabetes and chronic dermatosis (comprising psoriatic) and langerhans cell histiocytosis.
Above defined CSF-1R kinase inhibition treatment can be used as independent therapy or except The compounds of this invention, can comprise conventional operation or radiotherapy or chemotherapy.This based chemotherapy can comprise the antitumour drug of one or more following kinds:
(i) be used for the antiproliferative/antitumour drug and the combination thereof of Internal Medicine-Oncology, for example alkylating agent (as cis-platinum, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan and nitrosourea); Antimetabolite (as antifol, for example fluorine pyrimidine such as 5 FU 5 fluorouracil and Tegafur (tegafur), Raltitrexed (raltitrexed), methotrexate, cytosine arabinoside and hydroxyurea; Antitumor antibiotics (for example anthracene nucleus class, as Zorubicin, bleomycin (bleomycin), Dx (doxorubicin), daunomycin (daunomycin), epirubicin (epirubicin), idarubicin (idarubicin), Mitomycin-C (mitomycin-C), gengshengmeisu (dactinomycin) and Plicamycin (mithramycin)); Antimitotic agent (for example vinca alkaloids (vinca alkaloids), as vincristine(VCR) (vincristine), vinealeucoblastine(VLB) (vinblastine), vindesine (vindesine) and vinorelbine (vinorelbine) and yew alkanes such as taxol and Docetaxel); And topoisomerase enzyme inhibitor (for example epipodophyllotoxin (epipodophyllotoxins) is as Etoposide (etoposide) and teniposide (teniposide), amsacrine (amsacrine), Hycamtin (topotecan) and camptothecine (camptothecin));
(ii) cytostatic agent, for example antiestrogen is (as tamoxifen (tamoxifen), toremifene (toremifene), raloxifene (raloxifene), droloxifene (droloxifene) and iodoxyfene), adjust under the estrogen receptor (as fulvestrant (fulvestrant)), antiandrogen is (as bicalutamide (bicalutamide), flutamide (flutamide), Nilutamide (nilutamide) and cyproterone acetate (cyproterone acetate)), lhrh antagonist or LHRH agonist are (as goserelin (goserelin), Leuprolide (leuprorelin) and buserelin (buserelin)), progestogens (for example Magace), aromatase inhibitor (Anastrozole (anastrozole) for example, letrozole (letrozole), vorozole (vorazole) and close smooth (exemestane) according to the west) and 5 inhibitor such as finasteride (finasteride);
The (iii) medicament (for example inhibitor of inhibitors of metalloproteinase such as Marimastat (marimastat) and upar function) of anticancer invasion;
(iv) somatomedin depressant of functions, for example this type of inhibitor comprises growth factor antibodies, growth factor receptor antibody (anti--erbb2 antibody trastuzumab (trastuzumab) [Herceptin for example
TM] and anti--erbb1 antibody Cetuximab (cetuximab) [C225]), farnesyl transferase inhibitor, mek inhibitor, tyrosine kinase inhibitor and serine/threonine kinase inhibitor, as the inhibitor of epidermal growth factor family (EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (Gefitinib (gefitinib) for example, AZD1839), N-(3-ethynyl phenyl)-6, two (2-methoxy ethoxy) quinazolines of 7--4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033)), for example Thr6 PDGF BB man group inhibitor and for example pHGF man group inhibitor;
(v) anti-angiogenic agent, those anti-angiogenic agents that for example suppress the vascular endothelial growth factor effect are (as anti-vascular endothelial cell growth factor antibody rhuMAb-VEGF (bevacizumab) [Avastin
TM], disclosed compound in International Patent Application WO 97/22596, WO 97/30035, WO 97/32856 and WO98/13354 for example) and the compound (for example linomide (linomide), beta 2 integrin alpha v β 3 depressant of functions and angiostatin) that works by other mechanism;
(vi) vascular lesion agent is as disclosed compound among combretastatin (Combretastatin) A4 and International Patent Application WO 99/02166, WO00/40529, WO 00/41669, WO01/92224, WO02/04434 and the WO02/08213;
(vii) antisense therapy is as those therapies at above target of enumerating such as ISIS 2503 (anti--the ras antisense);
(viii) gene therapy comprises the method that for example substitutes distortion gene (distortion p53 or distortion BRCA1 or BRCA2); GDEPT (gene targeting enzyme prodrug therapy) is as using those methods of Isocytosine deaminase, thymidine kinase or bacterium nitroreductase; And the raising patient is to the method such as the multiple medicines thing drug resistant gene therapy of chemotherapy or radiotherapeutic tolerance;
(ix) immunotherapy, comprise therapy and the interior therapy of body in the elder generation that for example the increases the patient tumors cell immunogenicity external back body, as using cytokine (as interleukin-22, interleukin 4 or granulocyte-macrophage colony stimutaing factor) transfection, reduce the method for T-cell anergy, use the method for transfection immunocyte (as the dendritic cell of cytokine transfection), use the method for cytokine transfection tumor cell line and the method for use antiidiotypic antibody;
(x) cell cycle inhibitor comprises for example CDK inhibitor (as flavones pyrrole many (flavopiridol)) and other cell cycle restriction point inhibitor (as the restriction point kinases); Aurora kinases and involve mitotic division and other kinase whose inhibitor (as mitotic kinesins) that division of cytoplasm is regulated; And histone deacetylase inhibitors; And
(xi) endothelin antagonist comprises endothelin A antagonist, endothelin B antagonist and Endothelin A and B antagonist; For example ZD4054 and ZD1611 (WO 9640681), atrasentan (atrasentan) and YM598.
Can be by simultaneously, according to the order of sequence or individually dosedly give various therapeutic components and realize this type of combination therapy.The compounds of this invention in this type of combined prod application of aforementioned dosage range and through other forms of pharmacologically active agents of approval dosage range.
Except its purposes in medicine, formula (I) compound and pharmacy acceptable salt thereof are also as pharmacological tool, be used for exploitation and standardization body endosome automatic checkout system, described system is used for estimating at laboratory animal (as cat, dog, rabbit, monkey, rat and mouse) effect of CSF-1R kinase inhibitor, as the part of research novel treatment.
In above-mentioned other medicinal compositions, technology, method, purposes and medication preparation feature, the alternative of The compounds of this invention described herein and preferred embodiment also are suitable for.
Embodiment
To set forth the present invention by following non-limiting example now, wherein except as otherwise noted, otherwise:
(i) temperature that provides be degree centigrade (℃); Except as otherwise noted, under room temperature or envrionment temperature, operate, that is, under 18-25 ℃ temperature, carry out;
(ii) with anhydrous sodium sulphate or dried over mgso organic solution; Under 60 ℃ bath temperature at the most with Rotary Evaporators decompression (600-4000 pascal; 4.5-30mmHg) evaporating solvent;
(iii) common, reaction process is monitored by TLC, and the reaction times that provides only is used to illustrate;
(iv) end product has satisfied proton magnetic resonance (PMR) (NMR) spectrum and/or mass-spectrometric data;
(productive rate that v) provides only is used to illustrate, the available productive rate of not necessarily diligent process exploitation; More if desired materials then repeat preparation;
Unless (vii) indicate in addition, the δ value form of NMR The data principal character character that provides, as counting (ppm) very much with respect to hundred of internal standard substance tetramethyl-silicomethane (TMS), (DMSO-d6) measures at 400MHz as solvent with full deuterated dimethyl sulfoxide;
(vii) chemical symbol has its implication commonly used; Use SI units and symbol;
(solvent ratio that viii) provides is a volume: volume (v/v) ratio; With
(ix) using directly, exposure probe electronic energy with 70 electron-volts in chemi-ionization (CI) pattern moves mass spectrum; Wherein use electronic impact (EI), fast atom bombardment(FAB) (FAB) or electron spray(ES) (ESP) to finish specified ionization; Provide the m/z value; Usually, only report the ion of expression parent quality; Except as otherwise noted, the mass ion of quoting is (MH)
+
(x) when being similar to the described description of last embodiment when synthetic, used amount is to be equal to the mmole ratio that last embodiment uses;
(xi) " H-Cube " refers to the H-Cube continuous hydrogenation equipment by Thales Nanotechnology manufacturing.And
(xii) use following abbreviation:
The DMA N,N-dimethylacetamide;
DMF N, dinethylformamide;
The EtOAc ethyl acetate;
MeOH methyl alcohol;
The THF tetrahydrofuran (THF);
The TFA trifluoroacetic acid;
The DMSO dimethyl sulfoxide (DMSO); And
The DCM methylene dichloride.
Embodiment 1
4-[(2, the 4-difluorophenyl) amino]-6,7-dimethoxy cinnolines-3-methane amide
In having the 25mL round-bottomed flask of magnetic stirring bar, add 4-[(2, the 4-difluorophenyl) amino]-6,7-dimethoxy cinnolines-3-carboxylic acid, ethyl ester (0.195g, 0.50mmol) (method 27), dry DMF (3mL), methane amide (0.135g, 3mmol) and the methanol solution of the sodium methylate of 3mL 0.5M.Reactant is warming to 100 ℃, and continues 2 hours, make it cool to room temperature then.Reactant is poured in the water (about 50mL), and crude product is settled out from solution.Use B to collect solid, use EtOAc/MeOH (4: 1), obtain the title compound of 0.174g (96%), be white solid as elutriant purifying on 40g silicon-dioxide by vacuum filtration.
1H?NMR：11.35(s，1H)，8.86(s，1H)，8.05(s，1H)，7.71(s，1H)，7.48(m，1H)，7.38(m，1H)，7.18(m，1H)，6.69(s，1H)，4.06(s，3H)，3.50(s，3H)；m/z?361。
Embodiment 2-12
According to the program among the embodiment 1, use the following embodiment of suitable feedstock production, and by silica gel chromatography or half preparation type reversed-phase HPLC purifying.
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??2 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-6,7-dimethoxy cinnolines-3-methane amide | ??11.26(s，1H)，8.80(s，??1H)，7.95(s，1H)，7.65??(s，1H)，7.15(m，2H)，??7.05(d，1H)，6.62(s，??1H)，4.00(s，3H)，??3.37(s，3H)，2.30(s，??3H) | ??357 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-6,7-dimethoxy cinnolines-3-carboxylic acid, ethyl ester (method 29) |
| ??3 | 4-[(3-chloro-2-fluorophenyl) amino]-6,7-dimethoxy cinnolines-3-methane amide | ??11.35(s，1H)，8.85(s，??1H)，8.05(s，1H)，7.70??(s，1H)，7.35(t，1H)，??7.17(t，1H)，7.05(t，??1H)，6.70(s，1H)，4.05??(s，3H)，3.48(s，3H) | ??378 | 4-[(3-chloro-2-fluorophenyl) amino]-6,7-dimethoxy cinnolines-3-carboxylic acid, ethyl ester (method 30) |
| ??4 | 4-[(2-fluoro-5-aminomethyl phenyl) amino]-6,7-dimethoxy cinnolines-3-methane amide | ??11.30(s，1H)，8.80(s，??1H)，7.98(s，1H)，??7.65(s，1H)，7.20(m，??1H)，7.039m，2H)，??6.65(s，1H)，4.00(s，3??H)，3.40(s，3H)，2.22??(s，3H) | ??357 | 4-[(2-fluoro-5-aminomethyl phenyl) amino]-6,7-dimethoxy cinnolines-3-carboxylic acid, ethyl ester (method 31) |
| ??5 | 4-[(2, the 3-dichlorophenyl) amino]-6,7-dimethoxy cinnolines-3-methane amide | ??11.50(s，1H)，8.89(s，??1H)，8.05(s，1H)，??7.71(s，1H)，7.40(d，??1H)，7.25(t，1H)，??6.90(d，1H)，6.55(s，??1H)，4.00(s，3H)，??3.50(s，3H) | ??394 | 4-[(2, the 3-dichlorophenyl) amino]-6,7-dimethoxy cinnolines-3-carboxylic acid, ethyl ester (method 32) |
| ??6 | 7-oxyethyl group-4-[(2-fluoro-5-aminomethyl phenyl) amino]-6-(4-methylpiperazine-1-base cinnolines-3-methane amide | ??8.78(s，1H)，7.85(s，??1H)，7.56(s，1H)，??7.31-7.15(m，2H)，??7.03(d，2H)，6.64(s，??1H)，4.26(q，2H)，2.76??(s，4H)，2.33(s，4H)，??2.27(s，3H)，2.12(s，??3H)，1.42(t，3H) | ??440 | 7-oxyethyl group-4-[(2-fluoro-5-aminomethyl phenyl) amino]-6-(4-methylpiperazine-1-yl) cinnolines-3 carboxylic acid, ethyl ester (method 47) |
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??7 | 4-[(2, the 4-difluorophenyl) amino]-7-oxyethyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-methane amide | ??11.90(s，br，1H)，8.62??(s，1H)，8.07(s，1H)，??7.60(s，1H)，7.50(m，??2H)，7.20(m，1H)，??7.00(s，br，1H)，4.30??(q，2H)，3.50(m，4??H)，3.13(m，2H)，2.90??(m，2H)，3.80(d，3??H)，1.50(t，3H) | ??443 | 4-[(2, the 4-difluorophenyl) amino]-7-oxyethyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-carboxylic acid, ethyl ester (method 48) |
| ??8 | 4-[(2, the 3-dichlorophenyl) amino]-7-oxyethyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-methane amide | ??11.48(s，1H)，8.84(s，??1H)，8.01(s，1H)，??7.61(s，1H)，7.41(s，1??H)，7.26(t，1H)，6.94??(s，1H)，6.45(s，1H)，??4.28(d，2H)，2.81(s，??4H)，2.33(s，4H)，??2.15(s，3H)，1.42(t，3??H) | ??476 | 4-[(2, the 3-dichlorophenyl) amino]-7-oxyethyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-carboxylic acid, ethyl ester (method 49) |
| ??9 | 4-[(3-chloro-2-fluoro-phenyl) amino]-7-oxyethyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-methane amide | ??11.36(s，1H)，8.83(s，??1H)，8.00(s，1H)，??7.60(s，1H)，7.38(t，1??H)，7.17(d，2H)，6.58??(s，1H)，4.28(q，2H)，??2.80(s，4H)，2.32(s，4??H)，2.15(s，3H)，1.42??(t，3H) | ??460 | 4-[(3-chloro-2-fluoro-phenyl) amino]-7-oxyethyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-carboxylic acid, ethyl ester (method 50) |
| ??10 | 7-oxyethyl group-4-[(2-fluoro-4-methyl-phenyl) amino]-6-(4-methylpiperazine-1-yl) cinnolines-3-methane amide | ??11.27(s，1H)，8.75(s，??1H)，7.91(s，1H)，??7.53(s，1H)，7.18(d，??2H)，7.05(s，1H)，??6.59(s，1H)，4.25(d，??2H)，2.74(s，4H)，??2.32(s，7H)，2.17(s，3??H)，1.41(t，3H) | ??439 | 7-oxyethyl group-4-[(2-fluoro-4-methyl-phenyl) amino]-6-(4-methylpiperazine-1-yl) cinnolines-3-carboxylic acid, ethyl ester (method 51) |
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??11 | 4-[(2, the 4-difluorophenyl) amino]-7-oxyethyl group-6-(4-third-2-base piperazine-1-yl) cinnolines-3-methane amide | ??11.25(s，1H)，8.78(s，??1H)，7.94(s，1H)，??7.56(s，1H)，7.38-??7.50(m，1H)，7.24-??7.38(m，1H)，7.02-??7.17(m，1H)，6.55(s，??1H)，4.26(q，2H)，??2.78(s，4H)，2.60-2.64??(m，1H)，2.47(s，4H)，??1.42(t，3H)，0.96(d，6??H) | ??472 | 4-[(2, the 4-difluorophenyl) amino]-7-oxyethyl group-6-(4-third-2-base piperazine-1-yl) cinnolines-3-carboxylic acid, ethyl ester (method 52) |
| ??12 | 4-[(2, the 4-difluorophenyl) amino]-7-oxyethyl group-6-(4-ethyl piperazidine-1-yl) cinnolines-3-methane amide | ??11.20(s，1H)，7.90(s，??1H)，7.50(s，1H)，??7.39(t，1H)，7.25(t，1??H)，7.06(t，1H)，6.51??(s，1H)，4.25(q，2H)，??3.30(q，2H)，2.70(s，??4H)，2.30(s，4H)，??1.37(t，3H)，0.90(t，3??H) | ??457 | 4-[(2, the 4-difluorophenyl) amino]-7-oxyethyl group-6-(4-ethyl piperazidine-1-yl) cinnolines-3-carboxylic acid, ethyl ester (method 53) |
In some cases, also according to the program that is similar to for embodiment 13 and method 47,27 and 24 described those programs, from suitable intermediate preparation embodiment 6-12.
Embodiment 13
4-(2-fluoro-4-aminomethyl phenyl amino)-7-methoxyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-methane amide
In the 100mL round-bottomed flask, be equipped with 4-(2-fluoro-4-aminomethyl phenyl amino)-7-methoxyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-nitrile (method 60) (360mg, 0.89mmol) and potassium hydroxide (4.9g, 88.6mmol).Add anhydrous tertiary butanol (30ml), with reactant heating 1 hour, make it cool to room temperature then under the vigorous reflux.Then reaction mixture is poured in the separating funnel of be filled with water (about 100mL), and extracted with EtOAc (2X200mL).The organic layer that merges washs with saturated nacl aqueous solution, through MgSO
4Drying is filtered, and vacuum concentration obtains crude product, uses EtOAc/MeOH (1: 1) to pass through silica gel chromatography purifying crude product as elutriant, obtains title compound, is yellow solid.With solid recrystallization from 5mlMeOH, obtain pure title compound (184mg, 48.9%) then, be light yellow solid.
1HNMR：11.60(s，1H)，8.55(s，1H)，7.85(s，1H)，7.16(s，1H)，7.37(m，2H)，7.10(m，1H)，6.21(s，1H)，4.05(s，3H)，2.46(s，br，4H)，2.70-2.60(m，7H)，2.35(s，3H)；m/z?425。
Embodiment 14-46
According to the program of embodiment 13, use the following embodiment of suitable feedstock production, and carry out purifying by silica gel chromatography or half preparation type reversed-phase HPLC.In case of necessity, subsequently with gained material recrystallization.
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??14 | 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-methane amide | ??11.38(s，1H)，8.84??(s，1H)，8.00(s，1??H)，7.64(s，1H)，??7.39(s，1H)，7.09-??7.24(m，2H)，6.60??(s，1H)，4.02(s，3??H)，2.79(s，4H)，??2.35(s，4H)，2.17(s，??3H) | ??446 | 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-nitrile method 54 |
| ??15 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-(4-sec.-propyl piperazine-1-yl)-7-methoxyl group cinnolines-3-methane amide | ??11.29(s，1H)，8.77??(s，1H)，7.91(s，1??H)，7.56(s，1H)，??7.17(t，2H)，7.04(d，??1H)，6.60(s，1H)，??3.99(s，3H)，2.69(s，??4H)，2.55-2.66(m，??1H)，2.42(s，4H)，??2.32(s，3H)，0.94(d，??6H) | ??453 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-(4-sec.-propyl piperazine-1-yl)-7-methoxyl group cinnolines-3-nitrile method 55 |
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??16 | 6-(4-tertiary butyl piperazine-1-yl)-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-methane amide | ??11.31(s，1H)，8.76??(s，1H)，7.90(s，1??H)，7.56(s，1H)，??7.13-7.24(m，2H)，??7.06(s，1H)，6.59(s，??1H)，3.99(s，3H)，??2.69(s，4H)，2.50(s，??4H)，2.32(s，3H)，??0.99(s，9H) | ??467 | 6-(4-tertiary butyl piperazine-1-yl)-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 56 |
| ??17 | 4-[(2, the 4-difluorophenyl) amino]-7-(2-methoxy ethoxy)-6-(4-methylpiperazine-1-yl) cinnolines-3-methane amide | ??10.65(s，br，1H)，??8.60(s，1H)，7.95(s，??1H)，7.68(s，1H)，??7.39(m，2H)，7.10??(t，1H)，6.82(s，br，1??H)，4.30(s，2H)，??3.75(s，2H)，3.65(m，??2H)，3.40(m，2H)，??3.30(s，3H)，3.05??(m，2H)，2.80(m，??2H)，2.72(s，3H) | ??473 | 4-[(2, the 4-difluorophenyl) amino]-7-(2-methoxy ethoxy)-6-(4-methylpiperazine-1-yl) cinnolines-3-nitrile method 61 |
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??18 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-(2-methoxy ethoxy)-6-(4-methylpiperazine-1-yl) cinnolines-3-methane amide | ??10.90(s，br，1H)，??8.64(s，1H)，8.03(s，??1H)，7.58(s，1H)，??7.28(m，1H)，7.20??(d，1H)，7.05(d，1??H)，6.75(s，br，1H)，??4.30(m，2H)，3.70??(m，2H)，3.35(m，4??H)，3.30(s，3H)，3.01??(m，2H)，2.75(m，5??H)，2.35(s，3H) | ??469 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-(2-methoxy ethoxy)-6-(4-methylpiperazine-1-yl) cinnolines-3-nitrile method 62 |
| ??19 | 4-[(2-fluoro-5-aminomethyl phenyl) amino]-7-(2-methoxy ethoxy)-6-(4-methylpiperazine-1-yl) cinnolines-3-methane amide | ??11.05(s，br，1H)，??8.65(s，1H)，8.05(s，??1H)，7.60(s，1H)，??7.25-7.10(m，3H)，??6.81(s，br，1H)，4.30??(m，2H)，3.73(m，2??H)，3.31(m，4H)，??3.30(s，3H)，3.01??(m，2H)，2.80(m，2??H)，2.70(s，3H)，??2.20(s，3H)， | ??469 | 4-[(2-fluoro-5-aminomethyl phenyl) amino]-7-(2-methoxy ethoxy)-6-(4-methylpiperazine-1-yl) cinnolines-3-nitrile method 63 |
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??20 | 4-[(2, the 4-difluorophenyl) amino]-7-methoxyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-methane amide | ??11.30(s，1H)，8.85??(s，1H)，7.97(s，1??H)，7.65(s，1H)，??7.47(m，1H)，7.36??(m，1H)，7.16(m，1??H)，6.62(s，1H)，??4.08(s，3H)，2.82(s，??4H)，2.35(s，4H)，??2.20(s，3H) | ??429 | 4-[(2, the 4-difluorophenyl) amino]-7-methoxyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-nitrile method 57 |
| ??21 | 4-[(3-chloro-2-fluorophenyl) amino]-7-(2-methoxy ethoxy)-6-(4-methylpiperazine-1-yl) cinnolines-3-methane amide | ??11.30(s，1H)，8.85??(s，1H)，7.90(s，1??H)，7.57(s，1H)，??7.30(m，1H)，7.12??(m，1H)，7.08(m，1??H)，6.52(s，1H)，??4.26(m，2H)，3.70??(m，2H)，3.25(s，3??H)，2.80(m，4H)，??2.29(m，4H)，2.12??(s，3H) | ??490 | 4-[(3-chloro-2-fluorophenyl) amino]-7-(2-methoxy ethoxy)-6-(4-methylpiperazine-1-yl) cinnolines-3-nitrile method 64 |
| ??22 | 4-[(2-fluoro-5-aminomethyl phenyl) amino]-7-methoxyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-methane amide | ??11.35(s，1H)，8.80??(s，1H)，7.95(s，1??H)，7.60(s，1H)，??7.22(m，1H)，7.05??(m，2H)，6.69(s，1??H)，4.01(s，3H)，??2.76(s，4H)，2.30(s，??4H)，2.25(s，3H)，??2.16(s，3H) | ??425 | 4-[(2-fluoro-5-aminomethyl phenyl) amino]-7-methoxyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-nitrile method 58 |
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??23 | 4-[(2-fluoro-5-aminomethyl phenyl) amino]-6-(4-sec.-propyl piperazine-1-yl)-7-methoxyl group cinnolines-3-methane amide | ??11.38(s，1H)，8.85??(s，1H)，8.01(s，1??H)，7.69(s，1H)，??7.30(m，1H)，7.10??(m，2H)，6.72(s，1??H)，4.10(s，3H)，??2.81(s，4H)，2.70??(m，1H)，2.50(s，??4H)，2.30(s，3H)，??1.02(d，6H) | ??453 | 4-[(2-fluoro-5-aminomethyl phenyl) amino]-6-(4-sec.-propyl piperazine-1-yl)-7-methoxyl group cinnolines-3-nitrile method 59 |
| ??24 | 4-[(2, the 4-difluorophenyl) amino]-6-(4-sec.-propyl piperazine-1-yl)-7-(2-methoxy ethoxy) cinnolines-3-methane amide | ??11.00(s，br，1H)，??8.50(s，1H)，7.99(s，??1H)，7.60(s，1H)，??7.40(m，2H)，7.10??(m，2H)，4.30(s，2??H)，3.75(s，2H)，??3.60-3.40(m，8H)，??3.00(m，4H)，1.21??(d，6H) | ??501 | 4-[(2, the 4-difluorophenyl) amino]-6-(4-sec.-propyl piperazine-1-yl)-7-(2-methoxy ethoxy) cinnolines-3-nitrile method 65 |
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??25 | 7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-(4-sec.-propyl piperazine-1-yl) cinnolines-3-methane amide | ??11.02(s，br，1H)，??8.59(s，1H)，8.05(s，??1H)，7.55(s，1H)，??7.29(m，1H)，7.20??(d，1H)，7.08(d，1??H)，6.80(s，br，1H)，??4.25(q，2H)，3.60??(m，1H)，3.30(m，4??H)，2.92(m，4H)，??2.30(s，3H)，1.40(t，??3H)，1.25(d，6H) | ??467 | 7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-(4-sec.-propyl piperazine-1-yl) cinnolines-3-nitrile method 66 |
| ??26 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-pyridine-4-base cinnolines-3-methane amide | ??11.64(s，1H)，8.84??(s，1H)，8.54(d，2??H)，8.00(s，1H)，??7.78(s，1H)，7.58??(m，3H)，7.29(m，2??H)，7.15(m，1H)，??4.01(s，3H)，2.37(s，??3H) | ??404 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-pyridin-4-yl cinnolines-3-nitrile method 84 |
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??27 | 7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) cinnolines-3-methane amide | ??11.14(s，1H)，8.70(s，??1H)，7.86(s，1H)，??7.48(s，1H)，7.17(m，??1H)，7.09(m，1H)，??7.01(m，1H)，6.46(s，??1H)，4.24(q，2H)，??3.17(m，2H)，2.96??(m，2H)，2.41(m，??2H)，2.31(s，3H)，??2.20(m，2H)，1.69??(m，2H)，1.42(t，3H) | ??453 | 7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) cinnolines-3-nitrile method 67 |
| ??28 | 6-[(3R, 5S)-3,5-lupetazin-1-yl]-7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino] cinnolines-3-methane amide | ??11.30(s，1H)，8.73(s，??1H)，7.89(s，1H)，??7.51(s，1H)，7.19??(m，2H)，7.06(m，??1H)，6.58(s，1H)，??4.25(q，2H)，3.06(d，??2H)，2.75(m，2H)，??2.32(s，3H)，1.79??(m，2H)，1.40(t，3H)，??0.85(d，6H) | ??453 | 6-[(3R, 5S)-3,5-lupetazin-1-yl]-7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino] cinnolines-3-nitrile method 68 |
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??29 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-(1-sec.-propyl-1,2,3,6-tetrahydropyridine-4-yl)-7-methoxyl group cinnolines-3-methane amide | 12.37 (s, 1H), 10.34 (s, 1H), 8.77 (s, 1H), 8.19 (s, 1H), 7.64 (s, 1H), 7.30 (m, 3H), 7.11 (m, 1H), 5.74 (s, 1H), 4.01 (s, 3H), 3.71 (m, 2H), 3.47 (m, 2H), 2.99 (m, 1H), 2.71 (m, 1H), 2.40 (s, 3H), 2.31 (m, 1H), 1.28 (d 6H) is separated into hydrochloride | ??450 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-(1-sec.-propyl-1,2,3,6-tetrahydropyridine-4-yl)-7-methoxyl group cinnolines-3-nitrile method 86 |
| ??30 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-[4-(2-methoxy ethyl) piperazine-1-yl] cinnolines-3-methane amide | ??11.29(s，1H)，8.76??(s，1H)，7.91(s，1??H)，7.57(s，1H)，??7.19(m，2H)，7.04??(m，1H)，6.60(s，1??H)，3.99(s，3H)，??3.41(m，2H)，3.22??(s，3H)，2.71(m，4??H)，2.39(m，6H)，??2.32(s，3H) | ??469 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-[4-(2-methoxy ethyl) piperazine-1-yl] cinnolines-3-nitrile method 69 |
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??31 | 6-(5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazines-7 (8H)-yl)-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-methane amide | ??11.34(s，1H)，8.79??(s，1H)，8.46(s，1??H)，7.95(s，1H)，??7.66(s，1H)，7.23??(m，2H)，7.17(m，1??H)，6.75(s，1H)，??4.06(m，5H)，3.97??(s，2H)，3.17(s，2??H)，2.41(s，3H) | ??449 | 6-(5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazines-7 (8H)-yl)-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 70 |
| ??32 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-(3-hydroxyl-2,5,6,8-tetrahydrochysene [1,2,4] triazolo [4,3-a] pyrazines-7 (3H)-yl)-7-methoxyl group cinnolines-3-methane amide | 11.18 (s, 1H), 8.76 (s, 1H), 7.91 (s, 1H), 7.59 (s, 1H), 7.20 (s, 1H), 7.11 (m, 1H), 7.04 (m, 2H), 7.00 (m, 1H), 6.86 (s, 1H), 6.63 (s, 1H), 3.99 (s, 3H), 3.62 (s, 2H), 3.07 (m, 2H), 2.87 (m, 2H), 2.34 (s, 3H) by product synthesizing from embodiment 31 | ??467 | 6-(5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazines-7 (8H)-yl)-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 70 |
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??33 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl)-7-methoxyl group cinnolines-3-methane amide also for 6- | ??451 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl)-7-methoxyl group cinnolines-3-nitrile method 71 also for 6- | |
| ??34 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridine-4-yl]-7-methoxyl group cinnolines-3-methane amide | ??MeOD?7.49(s，1H)，??7.41(s，2H)，7.28??(m，2H)，5.73(s，1??H)，4.12(s，3H)，??4.04(m，1H)，3.95??(t，2H)，3.84(m，1??H)，3.70(m，1H)，??3.37(m，3H)，2.75??(m，1H)，2.54(m，1??H)，2.51(s，3H) | ??452 | 6-[1-(the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl)-1,2,3,6-tetrahydropyridine-4-yl]-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 87 |
| ??35 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-morpholine-4-base cinnolines-3-methane amide | ??11.33(s，1H)，8.77??(s，1H)，7.92(s，1??H)，7.59(s，1H)，??7.18(m，2H)，7.04??(m，1H)，6.62(s，1??H)，4.00(s，3H)，3.60??(m，4H)，2.68(m，??4H)，2.31(s，3H) | ??412 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-morpholine-4-base cinnolines-3-nitrile method 72 |
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??36 | 6-[(3R, 5S)-3,5-lupetazin-1-yl]-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-methane amide | ??11.33(s，1H)，8.76??(s，1H)，7.90(s，1??H)，7.55(s，1H)，??7.21(m，2H)，7.06??(m，1H)，6.61(s，1??H)，4.07(br?s，1H)，??4.00(s，3H)，3.00(d，??2H)，2.71(m，2H)，??2.32(s，3H)，1.75(m，??2H)，0.85(d，6H) | ??439 | 6-[(3R, 5S)-3,5-lupetazin-1-yl]-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 73 |
| ??37 | 6-[(2R, 6S)-2,6-thebaine-4-yl]-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-methane amide | ??11.36(s，1H)，8.77??(s，1H)，7.91(s，1??H)，7.58(s，1H)，??7.23(m，2H)，7.08??(m，1H)，6.63(s，1??H)，4.00(s，3H)，??3.59(m，2H)，3.04??(d，2H)，2.32(s，3??H)，1.90(m，2H)，??0.99(d，6H) | ??440 | 6-[(2R, 6S)-2,6-thebaine-4-yl]-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 74 |
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??38 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-[4-(2-hydroxyethyl) piperazine-1-yl]-7-methoxyl group cinnolines-3-methane amide | ??11.30(s，1H)，8.77??(s，1H)，7.92(s，1??H)，7.58(s，1H)，??7.19(m，2H)，7.06??(m，1H)，6.62(s，1??H)，4.40(t，1H)，??4.01(s，3H)，3.50??(m，2H)，2.73(m，4??H)，2.42(m，6H)，??2.33(s，3H) | ??455 | 6-[4-(the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl) piperazine-1-yl]-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 75 |
| ??39 | 6-[4-(dimethylamino) piperidines-1-yl]-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-methane amide | ??11.28(s，1H)，8.76??(s，1H)，7.91(s，1??H)，7.57(s，1H)，7.18??(m，2H)，7.05(m，1??H)，6.63(s，1H)，??4.01(s，3H)，3.22??(m，2H)，2.34(s，3??H)，2.28(m，2H)，??2.15(s，6H)，2.10??(m，1H)，1.63(m，2??H)，1.38(m，2H) | ??453 | 6-[4-(dimethylamino) piperidines-1-yl]-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 76 |
| ??40 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) cinnolines-3-methane amide | ??MeOD?7.33(s，1H)，??6.94(m，3H)，6.43??(s，1H)，3.93(s，3H)，??3.12(m，2H)，2.85??(m，2H)，2.58(m，2??H)，2.49(m，2H)，??2.26(s，3H)，2.23(s，??3H)，1.75(m，2H) | ??439 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) cinnolines-3-nitrile method 77 |
| Embodiment | Compound | 1H NMR (300MHz) | M/z | Raw material |
| 41 | 6-[(3S)-3-(dimethylamino) tetramethyleneimine-1-yl]-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-methane amide | 11.12 (s, 1H), 8.71 (s, 1H), 7.85 (s, 1 H), 7.48 (s, 1H), 7.13 (m, 2H), 7.02 (m, 1H), 6.17 (s, 1 H), 3.96 (s, 3H), 2.97 (m, 1H), 2.79 (m, 1H), (2.62 m, 1 H), 2.28 (s, 3H), 2.13 (s, 6H), 1.98 (m, 1H), 1.60 (m, 1 H).Two protons are sheltered by solvent | 439 | 6-[(3S)-3-(dimethylamino) tetramethyleneimine-1-yl]-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 78 |
| 42 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] cinnolines-3-methane amide | 11.30 (s, 1H), 8.75 (s, 1H), 7.90 (s, 1 H), 7.57 (s, 1H), 7.19 (m, 2H), 7.06 (m, 1H), 6.61 (s, 1 H) 3.99 (s, 3H), 3.18 (q, 2H), 2.70 (m, 4 H), 2.62 (m, 4H), 2.31 (s, 3H) | 493 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] cinnolines-3-nitrile method 79 |
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??43 | 7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-[4-(2-hydroxyethyl) piperazine-1-yl] cinnolines-3-methane amide | ??CDCl3?11.00(s，1??H)，8.38(br?s，1H)，??7.55(s，1H)，7.07??(m，1H)，6.93(m，2??H)，6.75(m，1H)，??5.59(br?s，1H)，4.26??(q，2H)，3.66(m，2??H)，2.88(m，4H)，??2.62(m，6H)，2.35??(s，3H)，1.53(t，3H) | ??469 | 6-[4-(the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl) piperazine-1-yl]-7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino] cinnolines-3-nitrile method 80 |
| ??44 | 4-[(2, the 4-difluorophenyl) amino]-6-[(3R, 5S)-3,5-lupetazin-1-yl]-7-methoxyl group cinnolines-3-methane amide | ??11.38(s，1H)，8.81??(s，1H)，7.97(s，1??H)，7.62(s，1H)，??7.43(m，1H)，7.21??(m，2H)，6.52(s，1??H)，4.00(s，3H)，??3.06(d，2H)，2.76??(m，2H)，1.86(m，2??H)，0.86(d，6H) | ??443 | 4-[(2, the 4-difluorophenyl) amino]-6-[(3R, 5S)-3,5-lupetazin-1-yl]-7-methoxyl group cinnolines-3-nitrile method 81 |
| ??45 | 4-[(3-chloro-2-fluorophenyl) nitrogen base]-6-[(3R, 5S)-3,5-lupetazin-1-yl]-7-methoxyl group cinnolines-3-methane amide | ??11.34(s，1H)，8.79??(s，1H)，7.94(s，1H)，??7.59(s，1H)，7.45(m，??2H)，7.17(m，1H)，??6.55(s，1H)，4.01(s，??3H)，3.04(d，2H)，??2.77(m，2H)，1.80??(m，2H)，0.88(d，6H) | ??459 | 4-[(3-chloro-2-fluorophenyl) amino]-6-[(3R, 5S)-3,5-lupetazin-1-yl]-7-methoxyl group cinnolines-3-nitrile method 82 |
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??46 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-piperazine-1-base cinnolines-3-methane amide | ??411 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-piperazine-1-base cinnolines-3-nitrile method 83 |
Embodiment 47
4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-(1-sec.-propyl piperidin-4-yl)-7-methoxyl group cinnolines-3-carboxamide hydrochloride
Under 10 crust, make 4-(2-fluoro-4-aminomethyl phenyl amino)-6-(the 1-sec.-propyl-1 that contains several concentrated hydrochloric acids, 2,3,6-tetrahydropyridine-4-yl)-(embodiment 29 for 7-methoxyl group cinnolines-3-methane amide, 0.250g MeOH 0.56mmol) (20ml) solution uses 20wt%Pd (OH) with 1mL/min by (run through)
2The H-Cube device of/carbon tube (carbon catridge).When judging that by LCMS reduction is finished, decompression concentrated solution obtains 0.234g (86%) product.
1H?NMR：12.51(s，1H)，10.51(s，1H)，8.76(s，1H)，8.21(s，1H)，7.65(s，1H)，7.36(m，3H)，7.18(m，1H)，4.03(s，3H)，3.38(m，1H)，3.26(m，2H)，3.05(m，3H)，2.41(s，3H)，1.72(m，2H)，1.61(m，2H)，1.26(d，6H)；m/z?452。
Embodiment 48
According to the program of embodiment 47, use the following embodiment of suitable feedstock production, carry out purifying by reversed-phase HPLC in addition.
| Embodiment | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??48 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-[1-(2-hydroxyethyl) piperidines-4-yl]-7-methoxyl group cinnolines-3-methane amide | ??MeOD?7.48(s，1H)，??7.28(s，1H)，7.16??(m，1H)，7.05(m，??2H)，4.02(s，3H)，??3.67(t，2H)，2.96??(m，2H)，2.85(m，??1H)，2.54(t，2H)，??2.38(s，3H)，2.17??(m，2H)，1.60(m，??2H)，1.18(m，2H) | ??454 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-[1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridine-4-yl]-7-methoxyl group cinnolines-3-methane amide embodiment 34 |
Embodiment 49
4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-{4-[(2R)-and 2-hydroxyl propionyl] piperazine-1-yl }-7-methoxyl group cinnolines-3-methane amide
In that 4-(2-fluoro-4-aminomethyl phenyl amino)-(embodiment 46, and 0.395g is 0.96mmol) at CH for 7-methoxyl group-6-(piperazine-1-yl) cinnolines-3-methane amide
2Cl
2(20mL) and add benzotriazole-1-base oxygen base tripyrrole alkyl-Phosphonium hexafluorophosphate (0.551g in the solution in the methyl alcohol (5mL), 1.06mmol), (R)-2 hydroxy propanoic acid (0.079mL, 1.06mmol) and the N-ethyl diisopropyl amine (0.181mL, 1.06mmol).After 1 hour, and the benzotriazole of the other part of adding-1-base oxygen base tripyrrole alkyl-Phosphonium hexafluorophosphates (1.10g, 2.12mmol).After 2 hours, add entry (100mL), mixture CH
2Cl
2Extraction.The concentrating under reduced pressure organic extract, (Hex/EtOAc uses CH to resistates then through the silicon-dioxide chromatogram purification
2Cl
2/ MeOH).Crude product CH
3The CN development is also filtered, and obtains 173mg (37%) yellow solid.
1H?NMR：11.33(s，1H)，8.77(s，1H)，7.91(s，1H)，7.60(s，1H)，7.17(m，2H)，7.06(m，1H)，6.62(s，1H)，4.98(d，1H)，4.39(m，1H)，4.01(s，3H)，3.54(m，4H)，2.72(m，4H)，2.32(s，3H)，1.16(d，3H)；m/z?484。
Embodiment 50
4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-[1-(methyl sulphonyl) piperidin-4-yl] cinnolines-3-methane amide
(2-fluoro-4-aminomethyl phenyl amino)-(embodiment 51, and 0.1g is 0.24mmol) at CH for 7-methoxyl group-6-(piperidin-4-yl) cinnolines-3-methane amide at 4-
2Cl
2Add (2.5ml) and in the solution among the DMF (2.5ml) the N-ethyl diisopropyl amine (0.127ml, 0.73mmol) and methylsulfonyl chloride (0.021ml, 0.27mmol).Stirred reaction mixture 1 hour is used CH
2Cl
2Dilution also washes with water.The concentrating under reduced pressure organic layer, resistates obtains 28mg (24%) pale solid through reverse-phase chromatography (using 0.1% aqueous formic acid and methyl alcohol (50-70%)) purifying.
1H?NMR：11.56(s，1H)，8.78(s，1H)，7.94(s，1H)，7.61(s，1H)，7.29(m，1H)，7.21(m，1H)，7.11(m，2H)，4.01(s，3H)，3.51(m，2H)，2.91(m，1H)，2.84(s，3H)，2.74(m，2H)，2.35(s，3H)，1.63(m，2H)，0.97(m，2H)；m/z?488。
Embodiment 51
4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-piperidin-4-yl cinnolines-3-methane amide
Under 10 crust, make 4-(2-fluoro-4-aminomethyl phenyl the amino)-7-methoxyl group-6-(1,2 that contains several concentrated hydrochloric acids, 3,6-tetrahydropyridine-4-yl) (embodiment 52, and 0.9g, methyl alcohol 2.21mmol) (44.2ml) solution pass through to use 20wt%Pd (OH) for cinnolines-3-methane amide
2The H Cube device of/carbon tube.Solvent is removed in decompression, and resistates is through silicon-dioxide chromatogram CH
2Cl
2/ 10%MeOH (1%NH
4OH) purifying obtains 692mg (77%) light yellow solid.
1H?NMR：MeOD?7.61(s，1H)，7.37(m，1H)，7.23(m，1H)，7.12(m，2H)，4.09(s，3H)，3.38(m，2H)，3.22(m，1H)，3.12(m，2H)，2.43(s，3H)，1.90(m，2H)，1.36(m，2H)；m/z?410。
Embodiment 52
4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-(1,2,3,6-tetrahydropyridine-4-yl) cinnolines-3-methane amide
With 4-(3-formamyl-4-(2-fluoro-4-aminomethyl phenyl amino)-7-methoxyl group cinnolines-6-yl)-5, (implement 53,1.5g is 2.96mmol) at CH for 6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
2Cl
2(11.84mL) and trifluoroacetic acid (11.84mL, 153.68mmol) solution stirring in is 16 hours, concentrating under reduced pressure, resistates is through silicon-dioxide chromatogram CH
2Cl
2/ 5%MeOH (1%NH
4OH) purifying obtains 960mg (80%) product.m/z?408。
Embodiment 53
4-{3-(aminocarboxyl)-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-6-yl }-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
Under 100 ℃, (2-fluoro-4-aminomethyl phenyl amino)-(embodiment 54 for 7-methoxyl group cinnolines-3-carboxamide hydrochloride with 6-bromo-4-, 1.40g, 3.169mmol), 4-(4,4,5,5-tetramethyl--1,3,2-two assorted oxygen pentaborane-2-yls)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (1.47g, 4.75mmol), Tripotassium phosphate (2.018g, 9.51mmol), dicyclohexyl (2 ', 6 '-dimethoxy-biphenyl-2-yl) phosphine (0.260g, 0.63mmol) and three (dibenzalacetones), two palladiums (0) (0.29g, 0.32mmol) mixture in propyl carbinol (4.53ml) and water (1.81ml) is in N
2(g) stirring is spent the night down.Reaction mixture, concentrating under reduced pressure, resistates is through silicon-dioxide chromatogram (CH
2Cl
2/ MeOH) purifying obtains the light brown solid of 1.54g (96%).
1H?NMR：11.54(s，1H)，8.79(s，1H)，7.94(s，1H)，7.62(s，1H)，7.25(m，2H)，7.08(m，2H)，5.56(s，1H)，3.97(s，3H)，3.82(m，2H)，3.37(m，2H)，2.35(s，3H)，2.14(m，2H)，1.41(s，6H)，1.06(s，9H)；m/z?508。
Embodiment 54
6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-carboxamide hydrochloride
6-bromo-4-chloro-7-methoxyl group cinnolines-3-methane amide (method 21,8.89g, add in ethanol 28.09mmol) (70ml) suspension 2-fluoro-4-monomethylaniline (3.49ml, 30.89mmol) and acetate (0.016ml, 0.28mmol).Under 80 ℃, stirred reaction mixture 1 hour, cooling is also filtered.Solid matter obtains 9.16g (74%) brown solid with washing with alcohol and dry, supposes it is hydrochloride.
1H?NMR：12.15(s，1H)，8.79(s，1H)，8.13(s，1H)，7.73(s，1H)，7.66(s，1H)，7.33(m，2H)，7.12(m，1H)，4.07(s，3H)，2.38(s，3H)；m/z?406。
The preparation of raw material
Method 1
1-{4, the 5-dimethoxy-2-[(E)-and tetramethyleneimine-1-base diazenyl] phenyl } ethyl ketone
(1.23g adds entry (4mL) in the round-bottomed flask of 100mL carrying magnetic stirring rod 6.29mmol) in that 1-(2-amino-4,5-Dimethoxyphenyl) ethyl ketone is housed.With ice bath mixture is cooled to 0 ℃, in reaction mixture, adds concentrated hydrochloric acid aqueous solution (1.95mL).Under fully stirring, (0.434g, water 6.9mmol) (3mL) solution joins in the reaction mixture with Sodium Nitrite via pasteur transfer pipet (Pasteur pipette).Reaction stirred is 5 minutes under this temperature, then slowly adds tetramethyleneimine (0.447g, 6.30mmol) solution in 50mL 0.4N potassium hydroxide aqueous solution.Reaction stirred is 0.5 hour under this temperature, pours into afterwards in the separating funnel also with DCM (2 * 100mL) extractions.The organic extract that merges is through MgSO
4Drying is filtered, and vacuum concentration obtains crude product, and it uses normal hexane/EtOAc (1: 1) to carry out purifying as elutriant on 80g silicon-dioxide, obtains the title compound of 1.49g (85%), is brown solid.
1H?NMR：7.12(s，1H)，7.01(s，1H)，3.92(m，2H)，3.80(s，3H)，3.75(s，3H)，3.58(m，2H)，2.60(s，3H)，2.00(M，4H)；m/z：278。
Method 2
According to the program in the method 1, use the suitable following intermediate of feedstock production.
| Method | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??2 | 1-{5-bromo-4-oxyethyl group-2-[(E)-tetramethyleneimine-1-base diazenyl] phenyl } ethyl ketone | ??7.79(s，1H)，7.11(s，1??H)，4.20(q，2H)，4.05??(m，2H)，3.69(m，2H)，??2.62(s，3H)，2.07(m，4??H)，1.45(t，3H) | ??341 | 1-(2-amino-5-bromo-4-ethoxyl phenenyl) ethyl ketone (method 46) |
Method 3
3-{4, the 5-dimethoxy-2-[(E)-and tetramethyleneimine-1-base diazenyl] phenyl }-3-oxo ethyl propionate sodium salt
In 250ml is equipped with the three-necked flask of magnetic stirring bar and anhydrous THF (55ml), add sodium hydride (1.73g, 43.3mmol) and new distillatory diethyl carbonate (1.28g, 10.83mmol).Make reaction mixture reach backflow, and dropwise add 1-{4 via the application of sample funnel, the 5-dimethoxy-2-[(E)-and tetramethyleneimine-1-base diazenyl] phenyl } ethyl ketone (3.0g, 10.83mmol) anhydrous THF (25mL) solution of (method 1).Mixture was refluxed other 8 hours, make it cool to room temperature then.Use B to separate lurid throw out by vacuum filtration, (about 2 * 100mL) washings are collected and vacuum-drying, obtain the title compound of 4.03g (99%), are its sodium salt, and it uses without being further purified with diethyl ether.
1H?NMR：7.10(s，1H)，6.71(s，1H)，4.75(s，1H)，3.85(m，2H)，3.71(s，3H)，3.70(s，3H)，3.62(m，2H)，3.44(m，2H)，1.96(M，4H)，1.05(m，3H)；m/z：350。
Method 4
According to the program in the method 3, use the suitable following intermediate of feedstock production.
| Method | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??4 | 3-{5-bromo-4-oxyethyl group-2-[(E)-tetramethyleneimine-1-base diazenyl] phenyl }-3-oxo ethyl propionate | ??7.66(s，1H)，6.75(s，??1H)，4.80(s，1H)，??4.05-3.30(m，8H)，??1.32(t，2H)，1.02(m，??8H) | ??413 | 1-{5-bromo-4-oxyethyl group-2-[(E)-tetramethyleneimine-1-base diazenyl] phenyl } ethyl ketone (method 2) |
Method 5
6,7-dimethoxy-4 '-oxo-1,4-dihydro cinnolines-3-carboxylic acid, ethyl ester
In the 100mL of carrying magnetic stirring rod round-bottomed flask, add TFA (30mL).In ice bath, flask is cooled to 0 ℃, through 10 minutes, in batches with 3-{4, the 5-dimethoxy-2-[(E)-and tetramethyleneimine-1-base diazenyl] phenyl }-(4.03g, 10.83mmol) (method 3) joins in the reaction mixture 3-oxo ethyl propionate sodium salt.Under this temperature, reaction stirred 2 hours is poured on (about 300mL) on 0 ℃ of frozen water then.Required product precipitates from mixture, uses B to collect by vacuum filtration.The solid water (1 * 100mL) and diethyl ether (1 * 100mL) flushing, obtain 1.55g (51%) title compound, be pale solid, it uses without being further purified.
1H?NMR：13.70(s，NH，1H)，7.39(s，1H)，7.00(s，1H)，4.30(q，2H)，3.95(s，3H)，3.89(s，3H)，1.30(t，3H)；m/z?279。
Method 6
According to the program in the method 5, use the suitable following intermediate of feedstock production.
Method 7
4-chloro-6,7-dimethoxy cinnolines-3-carboxylic acid, ethyl ester
Be equipped with 6,7-dimethoxy-4 '-oxo-1, (1.00g 3.6mmol) adds phosphoryl chloride (15mL) in the 50mL round-bottomed flask of the carrying magnetic stirring rod of (method 5) to 4-dihydro cinnolines-3-carboxylic acid, ethyl ester.Reaction flask is furnished with reflux exchanger, and is heated to backflow, keeps 2 hours, allows cool to room temperature then.The vacuum concentration crude product mixture, resistates NaHCO
3The aqueous solution (about 25mL) is handled.Crude product precipitates from solution, and uses B to collect by vacuum filtration, water (1 * 100mL) and diethyl ether (1 * 100mL) washs solid, obtains 0.941g (88%) title compound, is light brown solid, and it uses without being further purified.
1H?NMR：7.98(s，1H)，7.50(s，1H)，4.55(q，2H)，4.13(s，6H)，1.45(t，3H)；m/z?298。
Method 8
According to the program in the method 7, use the suitable following intermediate of feedstock production.
| Method | Compound | ??m/z | Raw material |
| ??8 | 6-bromo-4-chloro-7-oxyethyl group cinnolines-3-carboxylic acid, ethyl ester | ??361 | 6-bromo-7-oxyethyl group-4-oxo-1,4-dihydro cinnolines-3-carboxylic acid, ethyl ester (method 6) |
Method 9
2-bromo-5-nitrophenols
(11.0g adds the anhydrous DCM of 100mL in 500mL round-bottomed flask 47mmol) in that 2-bromo-5-Nitroanisole is housed.In reaction mixture, add then aluminum chloride (25g, 150mmol).Under 50 ℃, heat gained suspension down in nitrogen and spend the night.Make the reactant cool to room temperature, be poured on ice, add 10% aqueous hydrochloric acid and be acidified to pH 4.The gained mixture is filtered by bed of diatomaceous earth, filtrate is transferred to separating funnel.Water extracts with methylene dichloride (about 2x200mL).The organic phase that merges is through Na
2SO
4Drying, and vacuum concentration obtain rough title compound, and it obtains title compound (8.0g, 78%) m/z:217 through silica gel chromatography (330g) (using EtOAc/ hexane (1: 1) to be elutriant) purifying.
Method 10
1-bromo-2-(2-methoxy ethoxy)-4-oil of mirbane
2-bromo-5-nitrophenols (7.24g, 33.2mmol) add in the anhydrous DMF solution of (method 9) 2-methoxyl group-1-monobromethane (6.92g, 49.8mmol) and the potassiumiodide (about 100mg) of catalytic amount.70 ℃ of reacting by heating things 4 hours, allow cool to room temperature then.Then reactant is poured in the separating funnel, between EtOAc (about 250mL) and water (about 250mL), distributed.Organic phase is through Na
2SO
4Dry also vacuum concentration obtains rough title compound, and it is dissolved among the warm EtOAc of minimum volume.Gained solution is cooled off in ice bath, and slowly add hexane to impel crystallization.Come separating obtained throw out, the air-dry pure title compound (8.3g, 91%) that obtains via vacuum filtration by sinter funnel (fritted funnel).
1H?NMR：(300MHz)7.87-7.92(m，2H)，7.76(dd，1H)，4.35(t，2H)，3.73(t，2H)，3.35(s，3H)。
Method 11
4-bromo-3-(2-methoxy ethoxy) aniline
In the 250mL round-bottomed flask that opens wide, pack into 1-bromo-2-(2-methoxy ethoxy)-4-oil of mirbane (method 10) (5g, 18.11mmol), (17.6g 5.43mmol) carries 5wt%FeCl3, activated carbon (10g) and 100mL methyl alcohol to SiO2.Stir down gained mixture heating up to 80 ℃.In reaction mixture, add carefully then a hydrazine hydrate (10.6mL, 217mmol).After adding a hydrazine hydrate and finishing, other 40 minutes of 80 ℃ of following stirred reaction mixtures.Allow then the reactant cool to room temperature, and filter and pass through bed of diatomaceous earth.Filter cake washs with MeOH (about 150mL) and EtOAc (about 150mL).Vacuum concentration gained filtrate obtains title compound, and it uses (3.16g, 71%) m/z:247 without being further purified.
Method 12
2-[(4-bromo-3-p-methoxy-phenyl) diazenyl]-the 2-malonamide nitrile
(8.54g, (25g, 123.7mmol) (46ml is 1514mmol) and in the ice-cold suspension in the water (100ml) at concentrated hydrochloric acid 123.7mmol) to join 4-bromo-3-anisidine with the Sodium Nitrite in water-soluble (100ml).After stirring 10 minutes, (10.40g 123.7mmol) and sodium acetate trihydrate, stirs reactant and spends the night to be added in 2-malonamide nitrile in the water (1.8L).Filter and collect the gained solid, wash with water, drying obtains orange solids, and it refluxed 30 minutes in 1.4L ethanol.With the mixture cool to room temperature, solid collected by filtration, with ethanol (100mlx3) washing, drying obtains title compound, is yellow solid (34.4g, 94%).
1H?NMR：11.70(s，1H)，7.90(s，1H)，7.50(m，2H)，7.35(s，1H)，7.20(d，1H)，3.90(s，3H)；m/z：296。
Method 13-14
According to the program in the method 12, use the suitable following intermediate of feedstock production.
| Method | Compound | ??m/z | Raw material |
| ??13 | 2-[(E)-(4-bromo-3-ethoxyl phenenyl) diazenyl]-the 2-malonamide nitrile | ??312 | 4-bromo-3-phenetidine |
| ??14 | 2-{ (E)-[4-bromo-3-(2-methoxy ethoxy) phenyl] diazenyl }-the 2-malonamide nitrile | ??342 | 4-bromo-3-(2-methoxy ethoxy) aniline method 11 |
Method 15
4-amino-6-bromo-7-methoxyl group cinnolines-3-methane amide:
At N
2Down, (34.4g 115.8mmol) adds TiCl in the mixture in toluene (250ml) to 2-((4-bromo-3-p-methoxy-phenyl) diazenyl)-2-malonamide nitrile (method 12)
4(51.1ml, 463mmol).Behind the backflow stirred reaction mixture 4 hours, allow cool to room temperature.Reaction mixture is poured on the ice-cold solution of 3N HCl (about 600ml) carefully, makes reaction mixture be warming to room temperature then, stirred 10 minutes down at 90 ℃ subsequently.Collect the throw out that forms by vacuum filtration, water (about 200mL), ethanol (about 200mL), ether (about 200mL) washing, vacuum-drying obtains title compound, is brown solid, and it uses (30.0g, 87%) without being further purified.
1H?NMR：10.30(s，br，1H)，9.95(s，br，1H)，9.15(s，1H)，8.55(s，1H)，8.09(s，1H)，7.68(s，1H)，4.15(s，3H)；m/z?298。
Method 16-17
According to the program in the method 15, use the suitable following intermediate of feedstock production.
| Method | Compound | ??m/z | Raw material |
| ??16 | 4-amino-6-bromo-7-oxyethyl group cinnolines-3-methane amide | ??312 | 2-[(E)-(4-bromo-3-ethoxyl phenenyl) diazenyl]-2-malonamide nitrile method 13 |
| ??17 | 4-amino-6-bromo-7-(2-methoxy ethoxy) cinnolines-3-methane amide | ??342 | 2-{ (E)-[4-bromo-3-(2-methoxy ethoxy) phenyl] diazenyl }-2-malonamide nitrile method 14 |
Method 18
6-bromo-4-hydroxyl-7-methoxyl group cinnolines-3-carboxylic acid
In the 1L flask, pack into 4-amino-6-bromo-7-methoxyl group cinnolines-3-methane amide (method 15) (30g, 101mmol) and ethanol (650ml).(100g, water 1782mmol) (350ml) suspension stirred the mixture 9 days under refluxing to add potassium hydroxide in reactant.Cool off reactant then and filter the Celite pad that washs by through water (about 250mL).Vacuum concentration gained filtrate to remove ethanol, is acidified to pH about 3 with concentrated hydrochloric acid with obtained aqueous solution.The throw out that forms is collected in vacuum filtration.The gained solid suspension in 1.4L ethanol, is heated to 75 ℃, kept 15 minutes, and cool to room temperature, obtaining first lees, it is collected by vacuum filtration.Filter cake obtains title compound with ethanol (about 200mL) and diethyl ether (about 200mL) washing, is brown solid, and it uses (26.0g, 86%) without being further purified.
1H?NMR：14.60(m，br，2H)，8.35(s，1H)，7.23(s，1H)，4.08(s，3H)；m/z：310。
Method 19-20
According to the program in the method 18, use the suitable following intermediate of feedstock production.
| Method | Compound | ??m/z | Raw material |
| ??19 | 6-bromo-7-oxyethyl group-4-hydroxyl cinnolines-3-carboxylic acid | ??314 | 4-amino-6-bromo-7-oxyethyl group cinnolines-3-methane amide method 16 |
| ??20 | 6-bromo-4-hydroxyl-7-(2-methoxy ethoxy) cinnolines-3-carboxylic acid | ??342(M-H)- | 4-amino-6-bromo-7-(2-methoxy ethoxy) cinnolines-3-methane amide method 17 |
Method 21
6-bromo-4-chloro-7-methoxyl group cinnolines-3-methane amide
With SOCl
2(342ml) and DMF (1ml) join and 6-bromo-4-hydroxyl-7-methoxyl group cinnolines-3-carboxylic acid (method 18) be housed (14g is in 1L round-bottomed flask 46.8mmol).The gained mixture heating up to refluxing, was kept 4 hours, then cool to room temperature.The vacuum concentration reaction mixture obtains resistates, and it is suspended in the acetone (about 400ml).Suspension is cooled to 0 ℃ in ice bath, (50ml 1284mmol), makes the gained mixture stir other 15 minutes down at 0 ℃ dropwise to add strong aqua via the application of sample funnel.Form throw out, it is collected by vacuum filtration.Filter cake water (3x100mL), acetone (3x50mL) washing are collected and vacuum-drying, obtain title compound (14.00g, 94%), are pale solid, and it uses without being further purified.
1H?NMR：8.55(s，1H)，8.40(s，1H)，8.05(m，2H)，4.10(s，3H)；m/z：317。
Method 22-23
According to the program in the method 21, use the suitable following intermediate of feedstock production.
| Method | Compound | ??m/z | Raw material |
| ??22 | 6-bromo-4-chloro-7-oxyethyl group cinnolines-3-methane amide | ??331 | 6-bromo-7-oxyethyl group-4-hydroxyl cinnolines-3-carboxylic acid method 19 |
| ??23 | 6-bromo-4-chloro-7-(2-methoxy ethoxy) cinnolines-3-methane amide | ??361 | 6-bromo-4-hydroxyl-7-(2-methoxy ethoxy) cinnolines-3-carboxylic acid method 20 |
Method 24
6-bromo-4-chloro-7-methoxyl group cinnolines-3-nitrile
With POCl
3(200ml) join that 6-bromo-4-chloro-7-methoxyl group cinnolines-(12g is in DCM 37.9mmol) (400ml) suspension for 3-methane amide (method 21).In mixture, add triethylamine (15ml) then carefully, reflux and stirred 7 hours.Make the reactant cool to room temperature subsequently, and vacuum concentration.Under 0 ℃, use saturated NaHCO then
3The aqueous solution is handled rough resistates carefully.Form throw out, it is collected by vacuum filtration.Filter cake water (about 100mL) washing is collected and vacuum-drying, obtains title compound (9.80g, 87%), is gray solid, and it uses without being further purified.
1H?NMR：8.71(s，1H)，8.29(s，1H)，4.30(s，3H)；m/z：299。
Method 25-26
According to the program in the method 24, use the suitable following intermediate of feedstock production.
| Method | Compound | ??m/z | Raw material |
| ??25 | 6-bromo-4-chloro-7-oxyethyl group cinnolines-3-nitrile | ??313 | 6-bromo-4-chloro-7-oxyethyl group cinnolines-3-methane amide method 22 |
| ??26 | 6-bromo-4-chloro-7-(2-methoxy ethoxy) cinnolines-3-nitrile | ??343 | 6-bromo-4-chloro-7-(2-methoxy ethoxy) cinnolines-3-methane amide method 23 |
Method 27
4-[(2, the 4-difluorophenyl) amino]-6,7-dimethoxy cinnolines-3-carboxylic acid, ethyl ester
With dehydrated alcohol (10mL), 2,4-difluoroaniline (0.087g, 0.675mmol) and Glacial acetic acid (about 100 μ L) join 4-chloro-6 be housed, (0.200g is 0.675mmol) in the 50mL round-bottomed flask of the carrying magnetic stirring rod of (method 7) for 7-dimethoxy cinnolines-3-carboxylic acid, ethyl ester.Reacting by heating mixture to 75 ℃ continues 1 hour then, and cool to room temperature dilutes with strong aqua (about 5mL).Crude product precipitates from this reaction mixture, and collects via vacuum filtration with B.The solid water (1 * 100mL) and diethyl ether (1 * 100mL) washing, obtain crude product, it uses EtOAc to carry out purifying as elutriant on 40g silicon-dioxide, obtains 0.231g (88%) title compound, is yellow solid.
1H?NMR：9.25(s，1H)，7.70(s，1H)，7.50(s，1H)，7.40(m，1H)，7.30(m，1H)，7.10(m，1H)，4.02(s，3H)，3.95(q，2H)，3.85(s，3H)，1.20(t，3H)；m/z?390。
Method 28-45
According to the program in the method 27, use the suitable following intermediate of feedstock production.
| Method | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??28 | 6-bromo-7-oxyethyl group-4-[(2-fluoro-5-aminomethyl phenyl) amino] cinnolines-3-carboxylic acid, ethyl ester | ??10.47(s，1H)，7.72??(s，2H)，7.06(d，2??H)，6.99(s，1H)，??4.57(q，2H)，4.30(q，??2H)，2.29(s，3H)，??1.53(m，6H) | ??449 | 6-bromo-4-chloro-7-oxyethyl group cinnolines-3-carboxylic acid, ethyl ester (method 8) and 2-fluoro-5-monomethylaniline |
| ??29 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-6,7-dimethoxy cinnolines-3-carboxylic acid, ethyl ester | ??9.29(s，1H)，7.70(s，??1H)，7.40(s，1H)，??7.18-7.09(m，2H)，??7.00(d，1H)，4.00(s，??3H)，3.95(q，2H)，??3.75(s，3H)，2.30(s，??3H)，1.20(t，3H) | ??386 | 4-chloro-6,7-dimethoxy cinnolines-3-carboxylic acid, ethyl ester (method 7) and 2-fluoro-4-monomethylaniline |
| ??30 | 4-[(3-chloro-2-fluorophenyl) amino]-6,7-dimethoxy cinnolines-3-carboxylic acid, ethyl ester | ??9.30(s，1H)，7.74(s，??1H)，7.59(s，1H)，??7.35(t，1H)，7.15(t，??1H)，7.10(t，1H)，??4.05(s，3H)，??3.90-3.87(m，5H)，??1.15(t，3H) | ??407 | 4-chloro-6,7-dimethoxy cinnolines-3-carboxylic acid, ethyl ester (method 7) and 2-fluoro-3-chloroaniline |
| ??31 | 4-[(2-fluoro-5-aminomethyl phenyl) amino]-6,7-dimethoxy cinnolines-3-carboxylic acid, ethyl ester | ??9.25(s，1H)，7.70(s，??1H)，7.52(s，1H)，??7.20(t，1H)，7.00??(m，2H)，4.05(s，3??H)，3.90(q，2H)，??3.80(s，3H)，2.22(s，??3H)，1.19(t，3H) | ??386 | 4-chloro-6,7-dimethoxy cinnolines-3-carboxylic acid, ethyl ester (method 7) and 2-fluoro-5-monomethylaniline |
| Method | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??32 | 4-[(2, the 3-dichlorophenyl) amino]-6,7-dimethoxy cinnolines-3-carboxylic acid, ethyl ester | ??9.40(s，1H)，7.78(s，??1H)，7.41(d，1H)，??7.26(m，2H)，7.00??(d，1H)，4.05(m，5??H)，3.79(s，3H)，??1.20(t，3H) | ??423 | 4-chloro-6,7-dimethoxy cinnolines-3-carboxylic acid, ethyl ester (method 7) and 2,3-dichlorphenamide bulk powder |
| ??33 | 6-bromo-4-[(2, the 4-difluorophenyl) amino]-7-oxyethyl group cinnolines-3-carboxylic acid, ethyl ester | ??9.25(s，1H)，7.70(s，??1H)，7.50(s，1H)，??7.40(m，1H)，7.30??(m，1H)，7.10(m，??1H)，4.02(s，3H)，??3.95(q，2H)，3.85??(s，3H)，1.20(t，3H) | ??453 | 6-bromo-4-chloro-7-oxyethyl group cinnolines-3-carboxylic acid, ethyl ester (method 8) and 2,4 difluorobenzene amine |
| ??34 | 6-bromo-4-[(2, the 3-dichlorophenyl) amino]-7-oxyethyl group-cinnolines-3-carboxylic acid, ethyl ester | ??486 | Ethyl 6-bromo-4-chloro-7-oxyethyl group cinnolines-3-carboxylic acid, ethyl ester (method 8) and 2, the 3-dichlorphenamide bulk powder | |
| ??35 | 6-bromo-4-[(3-chloro-2-fluoro-phenyl) amino]-7-oxyethyl group-cinnolines-3-carboxylic acid, ethyl ester | ??470 | 6-bromo-4-chloro-7-oxyethyl group cinnolines-3-carboxylic acid, ethyl ester (method 8) and 2-fluoro-3-chloroaniline |
| Method | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??36 | 6-bromo-7-oxyethyl group-4-[(2-fluoro-4-methyl-phenyl) amino] cinnolines-3-carboxylic acid, ethyl ester | ??9.58(s，1H)，8.56(s，??1H)，7.77(s，1H)，??7.17(d，2H)，7.02??(s，1H)，4.36(q，2??H)，3.88(q，2H)，??2.32(s，3H)，1.45(t，??3H)，1.16(t，3H) | ??449 | 6-bromo-4-chloro-7-oxyethyl group cinnolines-3-carboxylic acid, ethyl ester (method 8) and 2-fluoro-4-monomethylaniline |
| ??37 | 6-bromo-4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group cinnolines-3-nitrile | ??408 | 6-bromo-4-chloro-7-methoxyl group cinnolines-3-nitrile method 24 and 3-chloro-2-fluoroaniline | |
| ??38 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile | ??388 | 6-bromo-4-chloro-7-methoxyl group cinnolines-3-nitrile method 24 and 2-fluoro-4-monomethylaniline | |
| ??39 | 6-bromo-4-[(2, the 4-difluorophenyl) amino]-7-methoxyl group cinnolines-3-nitrile | ??392 | 6-bromo-4-chloro-7-methoxyl group cinnolines-3-nitrile method 24 and 2,4 difluorobenzene amine |
| Method | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??40 | 6-bromo-4-[(2-fluoro-5-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile | ??388 | 6-bromo-4-chloro-7-methoxyl group cinnolines-3-nitrile method 24 and 2-fluoro-5-monomethylaniline | |
| ??41 | 6-bromo-4-[(2, the 4-difluorophenyl) amino]-7-(2-methoxy ethoxy) cinnolines-3-nitrile | ??436 | 6-bromo-4-chloro-7-(2-methoxy ethoxy) cinnolines-3-nitrile method 26 and 2,4 difluorobenzene amine | |
| ??42 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-(2-methoxy ethoxy) cinnolines-3-nitrile | ??432 | 6-bromo-4-chloro-7-(2-methoxy ethoxy) cinnolines-3-nitrile method 26 and 2-fluoro-4-monomethylaniline | |
| ??43 | 6-bromo-4-[(2-fluoro-5-aminomethyl phenyl) amino]-7-(2-methoxy ethoxy) cinnolines-3-nitrile | ??432 | 6-bromo-4-chloro-7-(2-methoxy ethoxy) cinnolines-3-nitrile method 26 and 2-fluoro-5-monomethylaniline | |
| ??44 | 6-bromo-4-[(3-chloro-2-fluorophenyl) amino]-7-(2-methoxy ethoxy) cinnolines-3-nitrile | ??453 | 6-bromo-4-chloro-7-(2-methoxy ethoxy) cinnolines-3-nitrile method 26 and 3-chloro-2-fluoroaniline |
| Method | Compound | ?? 1H?NMR(300MHz) | ??m/z | Raw material |
| ??45 | 6-bromo-7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino] cinnolines-3-nitrile | ??402 | 6-bromo-4-chloro-7-oxyethyl group cinnolines-3-nitrile method 25 and 2-fluoro-4-monomethylaniline |
Intermediate described in the method 37-45 also can with two step preparations, that is, use for embodiment 54 described aniline addition programs from the intermediate of method 21-23, then acid amides is changed into the nitrile described in the method 24.
Method 46
1-(2-amino-5-bromo-4-ethoxyl phenenyl) ethyl ketone
On the 1L three-necked flask that is equipped with reflux exchanger and application of sample funnel, magnetic stirring bar is housed, and the 4-bromo-3-phenetole amine hydrochlorate of packing into (25g, 100mmol) and dry toluene (300mL).Reaction mixture is cooled to 0 ℃, in reactant, dropwise is added in the DCM solution of 100mL 1M boron trichloride via the application of sample funnel.After boron trichloride added, (6.56mL 125mmol), then dropwise added 110mL 1M TiCl to add acetonitrile
4DCM solution.The multi-phase reaction mixture of gained is heated to backflow, kept 16 hours, allow cool to room temperature then.Crude product mixture is poured on the 2M aqueous hydrochloric acid (about 250mL) carefully, and makes reaction mixture be warmed to 80 ℃, kept one hour.After the cool to room temperature, by adding the 2N NaOH aqueous solution carefully, with the pH regulator to 6 of reaction mixture.Cross filter solid, (2 * 1000mL) extract filtrate with EtOAc.The organic extract that merges is through MgSO
4Drying is filtered, and vacuum concentration, obtains dark buttery crude product.In crude product oil, add methyl alcohol (about 100mL), be settled out required product, use B to collect, obtain 10.9g (42%) title compound, be brown solid by vacuum filtration.m/z?259。
Method 47
7-oxyethyl group-4-[(2-fluoro-5-aminomethyl phenyl) amino]-6-(4-methylpiperazine-1-yl) cinnolines-3-carboxylic acid, ethyl ester
6-bromo-7-oxyethyl group-4-[(2-fluoro-5-aminomethyl phenyl is being housed) amino] (0.100g 0.223mmol) adds 2.5mL anhydrous dimethyl yl acetamide to cinnolines-3-carboxylic acid, ethyl ester in the 50mL round-bottomed flask that has magnetic stirring bar of (method 28).In reactant, add Pd
2(dba)
3(50mg, 0.55mmol), racemize BINAP (70mg, 0.11mmol), cesium carbonate (150mg, 0.45mmol) and 1-methylpiperazine (0.334mmol).Mixture heating up to 90 ℃ was kept 4 hours, cool to room temperature then, and filter and pass through Celite pad.Vacuum concentrated filtrate obtains crude product, and it is (use EtOAc/MeOH (4: 1) is as elutriant) purifying on 12g silicon-dioxide, obtains 0.033g (32%) title compound, is yellow solid.m/z?468。
Method 48-83
According to the program in the method 47, use the suitable following intermediate of feedstock production.Use sodium tert-butoxide to replace cesium carbonate, perhaps use 2-two cyclohexyl phosphines-2 ', 4 ', 6 '-three-different-propyl group-1,1 '-(XPHOS replaces BINAP to prepare some intermediates to biphenyl.
| Method | Compound | ??m/z | Raw material |
| ??48 | 4-[(2, the 4-difluorophenyl) amino]-7-oxyethyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-carboxylic acid, ethyl ester | ??472 | 6-bromo-4-[(2, the 4-difluorophenyl) amino]-7-oxyethyl group cinnolines-3-carboxylic acid, ethyl ester (method 33) |
| ??49 | 4-[(2, the 3-dichlorophenyl) amino]-7-oxyethyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-carboxylic acid, ethyl ester | ??505 | 6-bromo-4-[(2, the 3-dichlorophenyl) amino]-7-oxyethyl group-cinnolines-3-carboxylic acid, ethyl ester (method 34) |
| ??50 | 4-[(3-chloro-2-fluoro-phenyl) amino]-7-oxyethyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-carboxylic acid, ethyl ester | ??489 | 6-bromo-4-[(3-chloro-2-fluoro-phenyl) amino]-7-oxyethyl group-cinnolines-3-carboxylic acid, ethyl ester (method 35) |
| ??51 | 7-oxyethyl group-4-[(2-fluoro-4-methyl-phenyl) amino]-6-(4-methylpiperazine-1-yl) cinnolines-3-carboxylic acid, ethyl ester | ??469 | 6-bromo-7-oxyethyl group-4-[(2-fluoro-4-methyl-phenyl) amino] cinnolines-3-carboxylic acid, ethyl ester (method 36) |
| ??52 | 4-[(2, the 4-difluorophenyl) amino]-7-oxyethyl group-6-(4-third-2-base piperazine-1-yl) cinnolines-3-carboxylic acid, ethyl ester | ??501 | 6-bromo-4-[(2, the 4-difluorophenyl) amino]-7-oxyethyl group cinnolines-3-carboxylic acid, ethyl ester (method 33) |
| Method | Compound | ??m/z | Raw material |
| ??53 | 4-[(2, the 4-difluorophenyl) amino]-7-oxyethyl group-6-(4-ethyl piperazidine-1-yl) cinnolines-3-carboxylic acid, ethyl ester | ??486 | 6-bromo-4-[(2, the 4-difluorophenyl) amino]-7-oxyethyl group cinnolines-3-carboxylic acid, ethyl ester (method 33) |
| ??54 | 4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-nitrile | ??428 | 6-bromo-4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 37 |
| ??55 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-(4-sec.-propyl piperazine-1-yl)-7-methoxyl group cinnolines-3-nitrile | ??435 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 38 |
| ??56 | 6-(4-tertiary butyl piperazine-1-yl)-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile | ??449 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 38 |
| ??57 | 4-[(2, the 4-difluorophenyl) amino]-7-methoxyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-nitrile | ??411 | 6-bromo-4-[(2, the 4-difluorophenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 39 |
| ??58 | 4-[(2-fluoro-5-aminomethyl phenyl) amino]-7-methoxyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-nitrile | ??407 | 6-bromo-4-[(2-fluoro-5-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 40 |
| ??59 | 4-[(2-fluoro-5-aminomethyl phenyl) amino]-6-(4-sec.-propyl piperazine-1-yl)-7-methoxyl group cinnolines-3-nitrile | ??435 | 6-bromo-4-[(2-fluoro-5-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 40 |
| ??60 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-nitrile | ??407 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 38 |
| ??61 | 4-[(2, the 4-difluorophenyl) amino]-7-(2-methoxy ethoxy)-6-(4-methylpiperazine-1-yl) cinnolines-3-nitrile | ??456 | 6-bromo-4-[(2, the 4-difluorophenyl) amino]-7-(2-methoxy ethoxy) cinnolines-3-nitrile method 41 |
| Method | Compound | ??m/z | Raw material |
| ??62 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-(2-methoxy ethoxy)-6-(4-methylpiperazine-1-yl) cinnolines-3-nitrile | ??451 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-(2-methoxy ethoxy) cinnolines-3-nitrile method 42 |
| ??63 | 4-[(2-fluoro-5-aminomethyl phenyl) amino]-7-(2-methoxy ethoxy)-6-(4-methylpiperazine-1-yl) cinnolines-3-nitrile | ??451 | 6-bromo-4-[(2-fluoro-5-aminomethyl phenyl) amino]-7-(2-methoxy ethoxy) cinnolines-3-nitrile method 43 |
| ??64 | 4-[(3-chloro-2-fluorophenyl) amino]-7-(2-methoxy ethoxy)-6-(4-methylpiperazine-1-yl) cinnolines-3-nitrile | ??472 | 6-bromo-4-[(3-chloro-2-fluorophenyl) amino]-7-(2-methoxy ethoxy) cinnolines-3-nitrile method 44 |
| ??65 | 4-[(2, the 4-difluorophenyl) amino]-6-(4-sec.-propyl piperazine-1-yl)-7-(2-methoxy ethoxy) cinnolines-3-nitrile | ??483 | 6-bromo-4-[(2, the 4-difluorophenyl) amino]-7-(2-methoxy ethoxy) cinnolines-3-nitrile method 41 |
| ??66 | 7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-(4-sec.-propyl piperazine-1-yl) cinnolines-3-nitrile | ??449 | 6-bromo-7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino] cinnolines-3-nitrile method 45 |
| ??67 | 7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) cinnolines-3-nitrile | ??435 | 6-bromo-7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino] cinnolines-3-nitrile method 45 |
| ??68 | 6-[(3R, 5S)-3,5-lupetazin-1-yl]-7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino] cinnolines-3-nitrile | ??435 | 6-bromo-7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino] cinnolines-3-nitrile method 45 |
| ??69 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-[4-(2-methoxy ethyl) piperazine-1-yl] cinnolines-3-nitrile | ??451 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 38 |
| Method | Compound | ??m/z | Raw material |
| ??70 | 6-(5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazines-7 (8H)-yl)-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile | ??431 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 38 |
| ??71 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-(hexahydropyrrolo is [1,2-a] pyrazine-2 (1H)-yl)-7-methoxyl group cinnolines-3-nitrile also for 6- | ??433 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 38 |
| ??72 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-morpholine-4-base cinnolines-3-nitrile | ??394 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 38 |
| ??73 | 6-[(3R, 5S)-3,5-lupetazin-1-yl]-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile | ??421 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 38 |
| ??74 | 6-[(2R, 6S)-2,6-thebaine-4-yl]-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile | ??422 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 38 |
| ??75 | 6-[4-(the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl) piperazine-1-yl]-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile | ??551 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 38 and 1-(the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl) piperazine method 89 |
| ??76 | 6-[4-(dimethylamino) piperidines-1-yl]-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile | ??435 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 38 |
| Method | Compound | ??m/z | Raw material |
| ??77 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) cinnolines-3-nitrile | ??421 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 38 |
| ??78 | 6-[(3S)-3-(dimethylamino) tetramethyleneimine-1-yl]-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile | ??421 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 38 |
| ??79 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-[4-(2,2, the 2-trifluoroethyl) piperazine-1-yl] cinnolines-3-nitrile | ??475 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 38 |
| ??80 | 6-[4-(the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl) piperazine-1-yl]-7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino] cinnolines-3-nitrile | ??565 | 6-bromo-7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino] and cinnolines-3-nitrile method 45 and 1-(the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl) piperazine method 89 |
| ??81 | 4-[(2, the 4-difluorophenyl) amino]-6-[(3R, 5S)-3,5-lupetazin-1-yl]-7-methoxyl group cinnolines-3-nitrile | ??425 | 6-bromo-4-[(2, the 4-difluorophenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 39 |
| ??82 | 4-[(3-chloro-2-fluorophenyl) amino]-6-[(3R, 5S)-3,5-lupetazin-1-yl]-7-methoxyl group cinnolines-3-nitrile | ??441 | 6-bromo-4-[(3-chloro-2-fluorophenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 37 |
| ??83 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-piperazine-1-base cinnolines-3-nitrile | ??393 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 38 |
Method 84
4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-pyridin-4-yl cinnolines-3-nitrile
To 6-bromo-4-(2-fluoro-4-aminomethyl phenyl amino)-7-methoxyl group cinnolines-3-nitrile (method 38,0.25g, 0.65mmol), pyridin-4-yl boric acid (0.159g, 1.29mmol) and K
2CO
3(0.357g 2.58mmol) adds Pd (Ph in the mixture in DMA (3.0ml) and water (0.30ml)
3P)
4(0.224g, 0.19mmol).Under argon gas, in 90 ℃ of reaction stirred 12 hours, cooling, water (50mL) dilution is with EtOAc (2x50mL) extraction.Dry (MgSO
4) organic extract that merges, filtering, resistates obtains 0.175g (64%) product through silicon-dioxide chromatogram (EtOAc) purifying.m/z?386。
Method 85
According to the program in the method 84, use the following intermediate of suitable feedstock production.
| Method | Compound | ??m/z | Raw material |
| ??85 | 4-{3-cyano group-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-6-yl }-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester | ??490 | 6-bromo-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile method 38 and 4-(4,4,5,5-tetramethyl--1,3,2-two assorted oxygen pentaborane-2-yls)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester |
Method 86
4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-(1-sec.-propyl-1,2,3,6-tetrahydropyridine-4-yl)-7-methoxyl group cinnolines-3-nitrile
4-(2-fluoro-4-aminomethyl phenyl amino)-7-methoxyl group-6-(1,2,3,6-tetrahydropyridine-4-yl) cinnolines-3-nitrile (method 88,200mg is 0.51mmol) at ethylene dichloride (5mL), acetone (0.566mL, 7.70mmol) and acetate (0.147mL, 2.57mmol) in solution in add sodium triacetoxy borohydride (544mg, 2.57mmol), 55 ℃ of following reaction stirred 6 hours.The concentrating under reduced pressure reaction mixture, resistates obtains 120mg (50%) product with silicon-dioxide chromatogram (MeOH/EtOAc (1: 1)) purifying.m/z?432。
Method 87
According to the program in the method 86, use the suitable following intermediate of feedstock production.
| Method | Compound | ??m/z | Raw material |
| ??87 | 6-[1-(the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl)-1,2,3,6-tetrahydropyridine-4-yl]-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-nitrile | ??549 | 4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-(1,2,3,6-tetrahydropyridine-4-yl) cinnolines-3-nitrile method 88 and (t-butyldimethylsilyl oxygen base) acetaldehyde |
Method 88
4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group-6-(1,2,3,6-tetrahydropyridine-4-yl) cinnolines-3-nitrile
With 4-(3-cyano group-4-(2-fluoro-4-aminomethyl phenyl amino)-7-methoxyl group cinnolines-6-yl)-5, (method 85,600mg is 1.23mmol) at CH for 6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
2Cl
2(4.9mL) and trifluoroacetic acid (4.9mL, 63.6mmol) solution stirring in is 2 hours.The concentrating under reduced pressure reaction mixture, with the chloroform azeotropic, to remove trifluoroacetic acid, resistates obtains 302mg (63%) product through reversed-phase HPLC (MeCN/ water) purifying.m/z?390。
Method 89
1-(the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl) piperazine
Under hydrogen, with 4-(2-(t-butyldimethylsilyl oxygen base) ethyl) piperazine-1-benzyl carboxylate (method 90,2.1g, 5.55mmol) and Pd/C (0.059g, 0.55mmol) mixture in methyl alcohol (30mL) stirred 24 hours.Reaction mixture is filtered by Celite pad, and concentrating under reduced pressure obtains 1.20g (88%) yellow oil.
1H?NMR：CD
3Cl?3.74(t，2H)，2.90(m，4H)，2.51(m，6H)，0.88(s，9H)，0.04(s，6H)。
Method 90
4-(the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl) piperazine-1-benzyl carboxylate.
With 1-piperazine carboxylic acid benzyl ester (1.751mL, 9.08mmol) and 2-(t-butyldimethylsilyl oxygen base) acetaldehyde (1.209mL, 9.99mmol) mixture among (5mL) in MeOH (5mL) and ethylene dichloride with
Molecular sieve stirred 20 minutes.Mixture is joined sodium triacetoxy borohydride, and (4.81g in tetrahydrofuran (THF) 22.70mmol) (5mL) solution, and stirs and spends the night.Reaction mixture is joined in the sodium bicarbonate (100mL), use CH
2Cl
2(3x50mL) extraction.The organic extract that concentrating under reduced pressure merges, resistates obtains 2.10g (61% clarified oil through silicon-dioxide chromatogram (EtOAc/MeOH) purifying.
1H?NMR：7.34(m，5H)，5.05(s，2H)，3.67(t，2H)，3.36(m，4H)2.40(m，6H)，0.84(s，9H)，0.02(s，6H)。
Claims (19)
1. the compound of formula (I) or its pharmacy acceptable salt:
Wherein:
R
1And R
2Be independently selected from hydrogen, halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkanoyloxy, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, N-(C
1-6Alkyl)-N-(C
1-6Alkoxyl group) amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, C
1-6Alkoxy carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical or heterocyclic radical; R wherein
1And R
2Can on carbon, choose wantonly independently of one another by one or more R
5Replace; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
6Group replace;
R
3It is hydrogen or halogen;
M is 0 or 1;
R
4Be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, phenyl, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl;
If perhaps two R wherein
4Group is on adjacent carbon, and then they can randomly form carbocyclic ring or heterocycle; Wherein said carbocyclic ring or heterocycle can be chosen wantonly on carbon by one or more R
7Replace; And if wherein described heterocycle contains-the NH-part, then nitrogen can randomly be selected from R
8Group replace;
N is 0-5; R wherein
4Implication identical or different;
R
5Be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkanoyloxy, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, N-(C
1-6Alkyl)-N-(C
1-6Alkoxyl group) amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, wherein a is the C of 0-2
1-6Alkyl S (O)
a, C
1-6Alkoxy carbonyl, C
1-6Alkoxycarbonyl amino, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical-R
9-or heterocyclic radical-R
10-; R wherein
5Can choose wantonly on carbon by one or more R
11Replace; And if wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
12Group replace;
R
6And R
12Be independently selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl; R wherein
6And R
12Can choose wantonly independently of one another on carbon by one or more R
13Replace;
R
13Be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkanoyloxy, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, N-(C
1-6Alkyl)-N-(C
1-6Alkoxyl group) amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, wherein a is the C of 0-2
1-6Alkyl S (O)
a, C
1-6Alkoxy carbonyl, C
1-6Alkoxycarbonyl amino, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical-R
14-or heterocyclic radical-R
15-; R wherein
13Can be randomly on carbon by one or more R
16Replace; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can be chosen wantonly and is selected from R
17Group replace;
R
9, R
10, R
14And R
15Be independently selected from direct key ,-O-,-N (R
18)-,-C (O)-,-N (R
19) C (O)-,-C (O) N (R
20)-,-S (O)
s-,-SO
2N (R
21)-or-N (R
22) SO
2-; R wherein
18, R
19, R
20, R
21And R
22Be independently selected from hydrogen or C
1-6Alkyl, s are 0-2;
R
8And R
17Be independently selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl;
R
7, R
11And R
16Be independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl; methoxyl group; oxyethyl group; ethanoyl; acetoxyl group; methylamino; ethylamino; dimethylamino; diethylamino; N-methyl-N-ethylamino; acetylamino; N-methylamino formyl radical; N-ethylamino formyl radical; N; the N-formyl-dimethylamino; N; N-diethylamino formyl radical; N-methyl-N-ethylamino formyl radical; phenyl; methylthio group; ethylmercapto group; methylsulfinyl; the ethyl sulfinyl; methylsulfonyl; ethylsulfonyl; methoxycarbonyl; ethoxy carbonyl; N-methyl sulfamyl; N-ethyl sulfamyl; N; N-dimethylamino alkylsulfonyl; N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl.
2. the compound of formula (IA) or its pharmacy acceptable salt:
Formula (IA)
Wherein:
---be selected from singly-bound or two key;
If---be singly-bound, then X is selected from CR
24And N;
If the two keys of---be, then X is C;
Y is selected from O and S;
A is selected from O, S, NR
25And CR
28R
29
P is 0-2;
M is 0 or 1;
R
4Be independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, phenyl, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl;
If perhaps two R wherein
4Group is on adjacent carbon, and then they can randomly form carbocyclic ring or heterocycle; Wherein said carbocyclic ring or heterocycle can be randomly on carbon by one or more R
7Replace; And if wherein described heterocycle contains-the NH-part, then nitrogen can randomly be selected from R
8Group replace;
N is 0-5; R wherein
4Implication identical or inequality;
R
7Can be independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, phenyl, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl;
R
8Can be selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl;
R
23Be selected from H and C
1-6Alkyl, wherein C
1-6Alkyl is randomly by C
1-6Alkoxyl group replaces;
R
24, R
26, R
27, R
28Be selected from hydrogen and C independently of one another
1-6Alkyl;
R
25Can be selected from hydrogen, C
1-6Alkyl and C
1-6Alkyloyl, wherein C
1-6Alkyl and C
1-6Alkyloyl can be randomly on carbon by one or more R
30Replace;
Perhaps R
25And R
27Randomly form heterocycle with the atom that they connected; Wherein said heterocycle can be randomly on carbon by one or more R
35Replace; And if described heterocycle contains-the NH-part, then nitrogen can randomly be selected from R
36Group replace;
R
29Can be selected from hydrogen and amino, wherein amino can be randomly by one or more C
1-6Alkyl replaces;
R
30Can be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, phenyl, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl and N-methyl-N-ethyl sulfamyl;
R
35Can be independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, phenyl, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl; And
R
36Can be selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl.
3. the compound of formula (IB) or its pharmacy acceptable salt:
Formula (IB)
Wherein:
R
1And R
2Be independently selected from hydrogen, halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkanoyloxy, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, N-(C
1-6Alkyl)-N-(C
1-6Alkoxyl group) amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, C
1-6Alkoxy carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical or heterocyclic radical; R wherein
1And R
2Can choose wantonly independently of one another on carbon by one or more R
5Replace; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
6Group replace;
R
5Be independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkanoyloxy, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, N-(C
1-6Alkyl)-N-(C
1-6Alkoxyl group) amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, wherein a is the C of 0-2
1-6Alkyl S (O)
a, C
1-6Alkoxy carbonyl, C
1-6Alkoxycarbonyl amino, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical-R
9-or heterocyclic radical-R
10-; R wherein
5Can be randomly on carbon by one or more R
11Replace; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
12Group replace;
R
6And R
12Be independently selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl; R wherein
6And R
12Can choose wantonly independently of one another on carbon by one or more R
13Replace;
R
13Be independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkanoyloxy, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, N-(C
1-6Alkyl)-N-(C
1-6Alkoxyl group) amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, wherein a is the C of 0-2
1-6Alkyl S (O)
a, C
1-6Alkoxy carbonyl, C
1-6Alkoxycarbonyl amino, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical-R
14-or heterocyclic radical-R
15-; R wherein
13Can be randomly on carbon by one or more R
16Replace; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can randomly be selected from R
17Group replace;
R
9, R
10, R
14And R
15Be independently selected from direct key ,-O-,-N (R
18)-,-C (O)-,-N (R
19) C (O)-,-C (O) N (R
20)-,-S (O)
s-,-SO
2N (R
21)-or-N (R
22) SO
2-; R wherein
18, R
19, R
20, R
21And R
22Be independently selected from hydrogen or C
1-6Alkyl, s are 0-2;
R
17Be independently selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl;
R
11And R
16Be independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, phenyl, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl; And
R
31, R
32, R
33And R
34Be selected from hydrogen, halogen and C independently of one another
1-4Alkyl.
4. the compound of formula (IC) or its pharmacy acceptable salt:
Formula (IC)
Wherein:
---be selected from singly-bound or two key;
If---be singly-bound, then X is selected from CR
24And N;
If the two keys of---be, then X is C;
Y is selected from O and S;
A is selected from O, S, NR
25And CR
28R
29
P is 0-2;
R
23Be C
1-6Alkyl;
R
24, R
26, R
27, R
28Be selected from hydrogen and C independently of one another
1-6Alkyl;
R
25Can be selected from hydrogen, C
1-6Alkyl and C
1-6Alkyloyl, wherein C
1-6Alkyl and C
1-6Alkyloyl can be randomly on carbon by one or more R
30Replace;
R
29Can be selected from hydrogen and optional by one or more C
1-6The amino that alkyl replaces;
R
30Can be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, phenyl, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl and N-methyl-N-ethyl sulfamyl;
R
31Be selected from hydrogen and C
1-4Alkyl;
R
32Be selected from hydrogen, halogen and C
1-4Alkyl;
R
33Be selected from hydrogen and halogen; And
R
34Be selected from halogen.
5. the compound of formula (ID) or its pharmacy acceptable salt:
Formula (ID)
Wherein:
---be selected from singly-bound or two key;
If---be singly-bound, then X is selected from CH and N;
If the two keys of---be, then X is C;
A is selected from O, NR
25And CHR
29
P is 0-2;
R
23Be selected from methyl and ethyl;
R
25Be selected from hydrogen, methyl, ethyl, sec.-propyl, the tertiary butyl, 1-methoxyl group-2-ethyl, 1-hydroxyl-2-ethyl, 1,1,1-three fluoro-2-ethyls, 2-hydroxyl-1-propionyl and methylsulfonyl;
R
26And R
27Be selected from hydrogen and methyl independently of one another;
R
29It can be dimethylamino;
R
31Be selected from hydrogen and methyl;
R
32Be selected from hydrogen, fluorine and methyl;
R
32Be selected from hydrogen and chlorine; And
R
34Be selected from fluorine and chlorine.
6. the compound of formula (IE) or its pharmacy acceptable salt:
Formula (IE)
Wherein:
---be selected from singly-bound and two key;
A is selected from N and CH;
D is selected from N, NH, CH and CH
2
E is selected from N, NH, CH and CH
2
P is 0-1;
R
23Be selected from C
1-6Alkyl;
R
31Be selected from hydrogen and C
1-4Alkyl;
R
32Be selected from hydrogen, halogen and C
1-4Alkyl;
R
33Be selected from hydrogen and halogen;
R
34It is halogen; And
R
37Be selected from H and OH.
7. the compound of formula (I) or its pharmacy acceptable salt, it is selected from:
7-oxyethyl group-4-[(2-fluoro-4-methyl-phenyl) amino]-6-(4-methylpiperazine-1-yl) cinnolines-3-methane amide;
4-(2-fluoro-4-aminomethyl phenyl amino)-7-methoxyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-methane amide;
4-[(2, the 4-difluorophenyl) amino]-7-methoxyl group-6-(4-methylpiperazine-1-yl) cinnolines-3-methane amide;
6-[(3R, 5S)-3,5-lupetazin-1-yl]-4-[(2-fluoro-4-aminomethyl phenyl) amino]-7-methoxyl group cinnolines-3-methane amide;
4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-[4-(2-hydroxyethyl) piperazine-1-yl]-7-methoxyl group cinnolines-3-methane amide;
7-oxyethyl group-4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-[4-(2-hydroxyethyl) piperazine-1-yl] cinnolines-3-methane amide;
4-[(3-chloro-2-fluorophenyl) amino]-6-[(3R, 5S)-3,5-lupetazin-1-yl]-7-methoxyl group cinnolines-3-methane amide;
4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-(1-sec.-propyl piperidin-4-yl)-7-methoxyl group cinnolines-3-carboxamide hydrochloride;
4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-[1-(2-hydroxyethyl) piperidin-4-yl]-7-methoxyl group cinnolines-3-methane amide; With
4-[(2-fluoro-4-aminomethyl phenyl) amino]-6-{4-[(2R)-and 2-hydroxyl propionyl] piperazine-1-yl }-7-methoxyl group cinnolines-3-methane amide.
8. (I) compound of the formula described in the claim 1-7 or its pharmacy acceptable salt, it is as medicine.
9. (I) compound of the formula described in the claim 1-7 or its pharmacy acceptable salt are used for producing purposes in the medicine of CSF-1R kinase inhibition effect warm-blooded animal such as people in preparation.
10. (I) compound of the formula described in the claim 1-7 or its pharmacy acceptable salt are used for producing purposes in the medicine of anticancer effect warm-blooded animal such as people in preparation.
11. (I) compound of the formula described in the claim 1-7 or its pharmacy acceptable salt are used for the treatment of purposes in the medicine in the following disease in preparation: the tumour of mammary gland, ovary, bladder, uterine cervix, uterine endometrium, prostate gland, lung, kidney and pancreas; Malignant hematologic disease, it comprises myelodysplastic syndrome, acute myeloid derived leukocythemia, chronic myelocytic derived leukocythemia, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma and lymphocytic leukemia; And glioma; Esophageal squamous cell carcinoma; Uveal tract malignant melanoma and follicular lymphoma.
12. the treatment method for cancer, it comprises providing to be in to diagnose to suffer from or show the object of the risk of cancer symptoms, and gives the pharmaceutical composition that described object comprises the formula described in the claim 1-7 (I) compound.
13. suppress the kinase whose method of CSF-1R, formula (I) compound that provides described in CSF-1R kinases and the claim 1-7 is provided for it, and is consequently suppressing to mix under the kinase whose condition of CSF-1R.
14. the preparation method of (I) compound of the formula described in the claim 1-7 or its pharmacy acceptable salt, it comprises makes formula V compound and methane amide and alkali reaction, forming formula (I) compound,
Wherein R is C
1-6Alkyl; Thereafter optional:
I) formula (I) compound is converted into another kind of formula (I) compound;
Ii) remove any protecting group; Perhaps
Iii) form pharmacy acceptable salt.
15. the described method of claim 14, wherein R is selected from methyl and ethyl.
16. the preparation method of (I) compound of the formula described in the claim 1-7 or its pharmacy acceptable salt, it comprises:
Hydrolyzing type (VI) compound,
To form formula (I) compound; Thereafter randomly:
I) formula (I) compound is converted into another kind of formula (I) compound;
Ii) remove any protecting group; Perhaps
Iii) form pharmacy acceptable salt.
17. the described method of claim 16 is wherein carried out described hydrolysis by formula (VI) compound and metal hydroxides and the tertiary alcohol are reacted.
18. the described method of claim 17, wherein said metal hydroxides is a potassium hydroxide.
19. the described method of claim 17, the wherein said tertiary alcohol is the trimethyl carbinol.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US88658507P | 2007-01-25 | 2007-01-25 | |
| US60/886,585 | 2007-01-25 | ||
| US60/951,576 | 2007-07-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101641336A true CN101641336A (en) | 2010-02-03 |
Family
ID=41615730
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200880009821A Pending CN101641336A (en) | 2007-01-25 | 2008-01-24 | 3 - cinnolinecarboxamide derivatives and their use for treating cancer |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101641336A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103917525A (en) * | 2011-05-23 | 2014-07-09 | 依兰制药公司 | Inhibitors of LRRK2 kinase activity |
| CN104370825A (en) * | 2014-09-29 | 2015-02-25 | 人福医药集团股份公司 | Substituted heterocyclic compound as kinase inhibitor and its preparation method and use |
-
2008
- 2008-01-24 CN CN200880009821A patent/CN101641336A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103917525A (en) * | 2011-05-23 | 2014-07-09 | 依兰制药公司 | Inhibitors of LRRK2 kinase activity |
| CN103917525B (en) * | 2011-05-23 | 2016-08-17 | 依兰制药公司 | The inhibitor of LRRK2 kinase activity |
| US9884828B2 (en) | 2011-05-23 | 2018-02-06 | Imago Pharmaceuticals, Inc. | Substituted cinnolines as inhibitors of LRRK2 kinase activity |
| CN104370825A (en) * | 2014-09-29 | 2015-02-25 | 人福医药集团股份公司 | Substituted heterocyclic compound as kinase inhibitor and its preparation method and use |
| CN104370825B (en) * | 2014-09-29 | 2017-04-19 | 人福医药集团股份公司 | Substituted heterocyclic compound as kinase inhibitor and its preparation method and use |
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