CN101119988B - Chemical compouns - Google Patents
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- CN101119988B CN101119988B CN200680005004.2A CN200680005004A CN101119988B CN 101119988 B CN101119988 B CN 101119988B CN 200680005004 A CN200680005004 A CN 200680005004A CN 101119988 B CN101119988 B CN 101119988B
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Abstract
This invention relates to novel compounds having the formula (I); and to their pharmaceutical compositions and to their methods of use. These novel compounds provide a treatment for cancer.
Description
Invention field
The present invention relates to new pyrazole derivatives, its pharmaceutical composition and using method.In addition, the present invention relates to treat the methods for the treatment of with preventing cancer, and relate to these pyrazole derivatives for the preparation of the application in the medicine for the treatment of and preventing cancer.
Background of invention
Receptor tyrosine kinase (RTK ' s) be the subfamily of protein kinase, it plays keying action in cell signaling, and relevant with the various cancer correlated processes that comprise hyperplasia, survival, vasculogenesis and transfer.At present, have been found that nearly 100 kinds of different RTK ' s, comprised the relevant kinases of tropomyosin (Trk ' s).
Trk ' s is the high affinity acceptor that is known as the solvable somatomedin activation of neurotrophin (NT) by a group.The Trk receptor family has three member-TrkA, TrkB and TrkC.In NT, the nerve growth factor (NGF) of (i) activation TrkA is arranged, (ii) activate brain derived somatomedin (BDNF) and the NT-4/5 of TrkB, and the NT3 that (iii) activates TrkC.Each Trk acceptor contains ectodomain (ligand binding), cross-film district and born of the same parents' intracellular domain (comprising kinase domain).With ligand binding the time, kinase catalytic autophosphorylation also causes the downstream signal transduction pathway.
Trk ' s in its evolution in neuronal tissue wide expression, and Trk ' s for these cells keep and survival is vital.Yet rear embryo's effect of Trk/ neurenergen axle (or approach) remains query.Have the report point out, Trk ' s in neural growth and function, all play an important role (Patapoutian, the people such as A., Current Opinion inNeurobiology, 2001,11,272-280).
In in the past 10 years, delivered a large amount of documents that the conduction of Trk signal and cancer are connected.For example, although the neural system outside of Trk ' s in the adult with low expression level, Trk expresses late to be increased in the prostate cancer.The tumor of prostate of normal prostate tissue and Androgen-dependent is all expressed low-level TrkA and TrkB and C that can not detection level.Yet all isotypes of Trk acceptor and related part thereof raise late with in the irrelevant prostate cancer of male sex hormone.Evidence suggests in addition, these advanced prostate cancer cells become for its existence and depend on Trk ' s/ neurenergen axle.Therefore, the Trk inhibitor can produce the irrelevant prostate cancer of a class pair and male sex hormone have specific inducer of apoptosis (Weeraratna, the people such as A.T., The Prostate, 2000,45,140-148).
And document is recently also pointed out, the overexpression of Trk ' s, activation, amplification and/or sudden change and secretion property mammary cancer (Cancer Cell, 2002,2,367-376), the colorectal carcinoma (people such as Bardelli, Science, 2003,300,949-949) and ovarian cancer (Davidson, B. wait the people, ClinicalCancer Research, 2003,9,2248-2259) relevant.
The report that several pieces of selectivity Trk tyrosine kinase inhibitors are arranged.Cephalon described as the CEP-751 of Trk inhibitor, CEP-701 (George, the people such as D., Cancer Research, 1999,59,2395-2341) and other indolocarbazole analogue (WO0114380).Evidence suggests, compare with single therapy, when eliminating when linked together with the male sex hormone of operation or chemical induction, CEP-701 and/or CEP751 provide better effectiveness.GlaxoSmithKline discloses some oxindole compounds as Trk A inhibitor in WO0220479 and WO0220513.Recently, Japan Tobacco has reported the pyrazolyl fused ring compound (JP2003231687A) as the Trk inhibitor.
Except top described, Vertex Pharmaceuticals has described the pyrazole compound as the GSK3 inhibitor in WO0250065, WO0262789, WO03027111 and the WO200437814 of Aurora etc., and AstraZeneca has reported the pyrazole compound (WO0348133) as the inhibitor of anti-IGF-1 receptor kinase.
Summary of the invention
According to the present invention, the applicant has invented new pyrazole compound or its pharmacologically acceptable salt, described pyrazole compound or its pharmacologically acceptable salt have the Trk kinase inhibiting activity, therefore can be used in the method for its anti-hyperplasia and/or short apoptosis (proapoptotic) (for example anticancer) activity and human or animal body treatment.The invention still further relates to the preparation method of described pyrazole compound or its pharmacologically acceptable salt, relate to the composition that contains described pyrazole compound or its pharmacologically acceptable salt, and relate to described pyrazole compound or its pharmacologically acceptable salt for the preparation of the application in the medicine that for example produces anti-hyperplasia and/or apoptosis-promoting effect warm-blooded animal among the mankind.
According to the present invention, the applicant also provides the method that described pyrazole compound or its pharmacologically acceptable salt is used for the treatment of cancer.
The character of the present invention's compound required for protection is estimated valuable in the treatment of the illness relevant with hyperplasia, and described illness for example is: cancer (noumenal tumour and leukemia), fibroplasia and differentiation illness, psoriasis, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, congee sample spot, atherosclerosis, arterial restenosis, autoimmune disorders, acute and chronic inflammation, osteopathy and have the illness in eye of retinal vessel hyperplasia.
In addition, the compounds of this invention or its pharmacologically acceptable salt are estimated in the treatment that is selected from following cancer or prevention valuable: congenital fibrosarcoma, mesoblastic nephroma, mesothelioma, acute myelocytic leukemia, acute lymphoblastic leukemia, multiple myeloma, melanoma, esophagus cancer, myelomatosis, hepatocellular carcinoma, carcinoma of the pancreas, cervical cancer, Ewing sarcoma, neuroblastoma, Kaposi sarcoma, ovarian cancer, the mammary cancer that comprises secretion property mammary cancer, colorectal carcinoma, the prostate cancer that comprises hormone-refractory prostate cancer, bladder cancer, melanoma, nonsmall-cell lung cancer (NSCLC) and small cell lung cancer (SCLC), cancer of the stomach, head and neck cancer, kidney, lymphoma, the thyroid carcinoma that comprises papillary thyroid carcinoma, mesothelioma and leukemia; Particularly ovarian cancer, mammary cancer, colorectal carcinoma, prostate cancer and lung cancer-NSCLC and SCLC; Prostate cancer more especially; And hormone-refractory prostate cancer more especially.
Detailed Description Of The Invention
Therefore, the invention provides (I) compound:
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, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, wherein a is the C of 0-1
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
8Replace; And wherein heterocyclic radical contains-the NH-part as described, and nitrogen can be chosen wantonly and is selected from R so
9Group replace;
X
1, X
2And X
3Independently=N-or=CR
10-;
R
3And R
10Be 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, 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-R
11-or heterocyclic radical-R
12-; R wherein
3And R
10Can choose wantonly independently of one another on carbon by one or more R
13Replace; And if wherein described heterocyclic radical contains-the NH-part, nitrogen can be chosen wantonly and is selected from R so
14Group replace;
R
4Hydrogen or the optional C that has replaced
1-6Alkyl; Wherein said optional substituting group is selected from one or more R
15
R
5And R
6Be 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, 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
5And R
6Can choose wantonly independently of one another on carbon by one or more R
16Replace; And if wherein described heterocyclic radical contains-the NH-part, nitrogen can be chosen wantonly and is selected from R so
17Group replace;
A is direct key or C
1-2Alkylidene group; Wherein said C
1-2Alkylidene group can be chosen wantonly by one or more R
18Replace;
Ring C is carbocylic radical or heterocyclic radical; And if wherein described heterocyclic radical contains-the NH-part, nitrogen can be chosen wantonly and is selected from R so
19Group replace;
R
7Be 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, 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
7Can choose wantonly on carbon by one or more R
20Replace; And if wherein described heterocyclic radical contains-the NH-part, nitrogen can be chosen wantonly and is selected from R so
21Group replace;
N is 0,1,2 or 3; R wherein
7Value can be identical or different;
R
8, R
13, R
15, R
16, R
18And R
20Be 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, 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-R
22-or heterocyclic radical-R
23-; R wherein
8, R
13, R
15, R
16, R
18And R
20Can choose wantonly independently of one another on carbon by one or more R
24Replace; And if wherein described heterocyclic radical contains-the NH-part, nitrogen can be chosen wantonly and is selected from R so
25Group replace;
R
9, R
14, R
17, R
19, R
21And R
25Be 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
9, R
14, R
17, R
19, R
21And R
25Can choose wantonly independently of one another on carbon by one or more R
26Replace;
R
24And R
26Be 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, 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
24And R
26Can choose wantonly independently of one another on carbon by one or more R
27Replace; And if wherein described heterocyclic radical contains-the NH-part, nitrogen can be chosen wantonly and is selected from R so
28Group replace;
R
11, R
12, R
22And R
23Be independently selected from direct key ,-O-,-N (R
29)-,-C (O)-,-N (R
30) C (O)-,-C (O) N (R
31)-,-S (O)
s-,-SO
2N (R
32)-or-N (R
33) SO
2-; R wherein
29, R
30, R
31, R
32And R
33Be independently selected from hydrogen or C
1-6Alkyl and s are 0-2;
R
27Be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, methyl, ethyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl, 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, 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
28Be 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;
Or its pharmacologically acceptable salt.
The occurrence of the variable group that comprises in the formula (I) is as follows.In appropriate circumstances, such value can be used with preamble or any definition, claim or the embodiment that hereinafter limit.
R
1Be selected from C
1-6Alkyl, C
1-6Alkoxyl group and carbocylic radical.
R
1Be selected from methyl, isopropoxy and cyclopropyl.
R
2Hydrogen.
R
1And R
2Be independently selected from hydrogen, C
1-6Alkyl, C
1-6Alkoxyl group and carbocylic radical.
R
1And R
2Be independently selected from hydrogen, methyl, isopropoxy and cyclopropyl.
X
1Be=CR
10-and X
2And X
3Be independently selected from-N=.
X
1And X
2Be independently selected from=CR
10-and X
3Be-N=.
X
1And X
3Be independently selected from=CR
10-and X
2Be-N=.
X
1, X
2And X
3Be independently selected from=CR
10-.
X
1, X
2And X
3Be selected from-N=.
R
3Be selected from hydrogen, cyano group, formamyl, C
1-6Alkyl and C
1-6Alkoxy carbonyl; R wherein
3Can choose wantonly on carbon by one or more R
13Replace;
R
13It is hydroxyl.
R
3Be selected from hydrogen, cyano group, formamyl, methyl and methoxycarbonyl; R wherein
3Can choose wantonly on carbon by one or more R
13Replace;
R
13It is hydroxyl.
R
3Be selected from hydrogen and C
1-6Alkyl, wherein R
3Can choose wantonly on carbon by one or more R
13Replace; Wherein:
R
13It is hydroxyl.
R
3Be selected from hydrogen, cyano group, formamyl, methyl, hydroxymethyl and methoxycarbonyl.
R
3Be selected from hydrogen, methyl and hydroxymethyl.
R
3And R
10Be independently selected from hydrogen, halogen, cyano group, formamyl, C
1-6Alkyl and C
1-6Alkoxy carbonyl; R wherein
3And R
10Can choose wantonly independently of one another on carbon by one or more R
13Replace;
R
13Be selected from hydroxyl, amino and C
1-6Alkanoylamino.
R
3And R
10Be independently selected from hydrogen, fluorine, chlorine, cyano group, formamyl, methyl and ethoxy carbonyl; R wherein
3And R
10Can choose wantonly independently of one another on carbon by one or more R
13Replace;
R
13Be selected from hydroxyl, amino and acetylamino.
R
3And R
10Be independently selected from hydrogen, halogen, cyano group, formamyl, C
1-6Alkyl and C
1-6Alkoxy carbonyl; R wherein
3And R
10Can choose wantonly independently of one another on carbon by one or more R
13Replace; Wherein:
R
13It is hydroxyl.
R
3And R
10Be independently selected from hydrogen, fluorine, chlorine, cyano group, formamyl, methyl, amino methyl, acetylamino methyl, hydroxymethyl and ethoxy carbonyl.
R
3And R
10Be independently selected from hydrogen, fluorine, chlorine, cyano group, formamyl, methyl, hydroxymethyl and ethoxy carbonyl.
R
10Be selected from hydrogen, halogen, cyano group, formamyl and C
1-6Alkyl; R wherein
10Can choose wantonly on carbon by one or more R
13Replace;
R
13Be selected from amino and C
1-6Alkanoylamino.
R
10Be selected from hydrogen, fluorine, chlorine, cyano group, formamyl and methyl; R wherein
10Can choose wantonly on carbon by one or more R
13Replace;
R
13Be selected from amino and acetylamino.
R
10Be selected from hydrogen, halogen, cyano group, formamyl and C
1-6Alkoxy carbonyl.
R
10Be selected from hydrogen, fluorine, chlorine, cyano group, formamyl, methyl, amino methyl and acetylamino methyl.
R
10Be selected from hydrogen, fluorine, chlorine, cyano group, formamyl and ethoxy carbonyl.
R
4Hydrogen.
R
4The optional C that has replaced
1-6Alkyl; Wherein said optional substituting group is selected from one or more R
15
R
5And R
6Be independently selected from hydrogen or C
1-6Alkyl; R wherein
5And R
6Can choose wantonly independently of one another on carbon by one or more R
16Replace; Wherein:
R
16It is hydroxyl.
R
5And R
6Be independently selected from hydrogen, methyl; Ethyl or hydroxymethyl.
R
5And R
6Be independently selected from hydrogen, methyl or hydroxymethyl.
R
5Be selected from hydrogen, methyl, ethyl or hydroxymethyl.
R
5Be selected from hydrogen, methyl or hydroxymethyl.
R
6Be selected from hydrogen or hydroxymethyl.
R
6Hydrogen.
A is direct key.
A is C
1-2Alkylidene group; Wherein said C
1-2Alkylidene group can be chosen wantonly by one or more R
18Replace.
A is direct key or C
1-2Alkylidene group; Wherein said C
1-2Alkylidene group can be chosen wantonly by one or more R
18Replace; Wherein
R
18It is hydroxyl.
A is direct key or methylene radical; Wherein said C
1-2Alkylidene group can be chosen wantonly by one or more R
18Replace; Wherein
R
18It is hydroxyl.
A is direct key, methylene radical or hydroxy methylene.
Ring C is heterocyclic radical; Wherein if described heterocyclic radical contains-the NH-part, and nitrogen can be chosen wantonly and is selected from R so
19Group replace;
Ring C is carbocylic radical.
Ring C is carbocylic radical or heterocyclic radical.
Ring C is phenyl, pyridyl, pyrimidyl, 1,3-benzodioxole base or 1H-indyl.
Ring C is phenyl, pyridyl, 1,3-benzodioxole base or 1H-indyl.
Ring C is phenyl, pyridine-2-base, pyrimidine-2-base, 1,3-benzodioxole-5-base or 1H-indol-3-yl.
Ring C is phenyl, pyridine-2-base, 1,3-benzodioxole-5-base or 1H-indol-3-yl.
Ring C is phenyl.
Ring C is pyridyl.
Ring C is pyridine-2-base.
Ring C is pyrimidyl.
Ring C is pyrimidine-2-base.
R
7Be selected from halogen and C
1-6Alkyl; R wherein
7Can choose wantonly on carbon by one or more R
20Replace; Wherein
R
20It is halogen.
R
7Be selected from fluorine and methyl; R wherein
7Can choose wantonly on carbon by one or more R
20Replace;
Wherein
R
20It is fluorine.
R
7It is halogen.
R
7Trifluoromethyl and fluorine.
R
7It is fluorine.
N is 0,1 or 2; R wherein
7Value can be identical or different.
N is 0 or 1.
N is 1.
Ring C, R
7With n together 4-fluorophenyl, 5-fluorine pyridine-2-base or 5-FU-2-base.
Ring C, R
7Form together the 4-fluorophenyl with n.
Ring C, R
7Form together 5-fluorine pyridine-2-base with n.
Ring C, R
7Form together 5-FU-2-base with n.
Therefore, in another aspect of this invention, provide formula (I) compound (describing as mentioned), wherein:
R
1And R
2Be independently selected from hydrogen, C
1-6Alkyl, C
1-6Alkoxyl group and carbocylic radical;
X
1, X
2And X
3Be independently=N-or=CR
10-;
R
3And R
10Be independently selected from hydrogen, halogen, cyano group, formamyl, C
1-6Alkyl and C
1-6Alkoxy carbonyl; R wherein
3And R
10Can choose wantonly independently of one another on carbon by one or more R
13Replace;
R
4Hydrogen;
R
5And R
6Be independently selected from hydrogen or C
1-6Alkyl; R wherein
5And R
6Can choose wantonly independently of one another on carbon by one or more R
16Replace;
A is direct key or C
1-2Alkylidene group; Wherein said C
1-2Alkylidene group can be chosen wantonly by one or more R
18Replace;
Ring C is carbocylic radical or heterocyclic radical;
R
7Be selected from halogen and C
1-6Alkyl; R wherein
7Can choose wantonly on carbon by one or more R
20Replace;
N is 0,1 or 2; R wherein
7Value can be identical or different;
R
13Be selected from hydroxyl, amino and C
1-6Alkanoylamino;
R
16It is hydroxyl;
R
18It is hydroxyl;
R
20It is halogen;
Or its pharmacologically acceptable salt.
Therefore, in another aspect of this invention, provide formula (I) compound (describing as mentioned), wherein:
R
1And R
2Be independently selected from hydrogen, C
1-6Alkyl, C
1-6Alkoxyl group and carbocylic radical;
X
1, X
2And X
3Be independently=N-or=CR
10-;
R
3And R
10Be independently selected from hydrogen, halogen, cyano group, formamyl, C
1-6Alkyl and C
1-6Alkoxy carbonyl; R wherein
3And R
10Can choose wantonly independently of one another on carbon by one or more R
13Replace;
R
4Hydrogen;
R
5And R
6Be independently selected from hydrogen or C
1-6Alkyl; R wherein
5And R
6Can choose wantonly independently of one another on carbon by one or more R
16Replace;
A is direct key;
Ring C is carbocylic radical;
R
7It is halogen;
N is 1;
R
13It is hydroxyl; And
R
16It is hydroxyl;
Or its pharmacologically acceptable salt.
Therefore, in another aspect of this invention, provide formula (I) compound (describing as mentioned), wherein:
R
1Be selected from methyl, isopropoxy and cyclopropyl;
R
2Hydrogen;
X
1, X
2And X
3Be independently=N-or=CR
10-;
R
3Be selected from hydrogen, cyano group, formamyl, methyl, hydroxymethyl and methoxycarbonyl;
R
10Be selected from hydrogen, fluorine, chlorine, cyano group, formamyl, methyl, amino methyl and acetylamino methyl;
R
4Hydrogen;
R
5Be selected from hydrogen, methyl, ethyl or hydroxymethyl;
R
6Be selected from hydrogen or hydroxymethyl;
A is direct key, methylene radical or hydroxy methylene;
Ring C is phenyl, pyridine-2-base, 1,3-benzodioxole-5-base or 1H-indol-3-yl;
R
7Trifluoromethyl and fluorine;
N is 0,1 or 2; R wherein
7Value can be identical or different;
Or its pharmacologically acceptable salt.
Therefore, in another aspect of this invention, provide formula (I) compound (describing as mentioned), wherein:
R
1Be selected from methyl, isopropoxy and cyclopropyl;
R
2Hydrogen;
X
1, X
2And X
3Be independently=N-or=CR
10-;
R
3Be selected from hydrogen, methyl and hydroxymethyl;
R
4Hydrogen;
R
5Be selected from hydrogen, methyl or hydroxymethyl;
R
6Be selected from hydrogen or hydroxymethyl;
A is direct key;
Ring C is phenyl;
R
7It is fluorine;
N is 1; And
R
10Be selected from hydrogen, fluorine, chlorine, cyano group, formamyl and ethoxy carbonyl;
Or its pharmacologically acceptable salt.
In another aspect of this invention, the preferred compound of the present invention is any one embodiment or its pharmacologically acceptable salt.
In another aspect of this invention, provide embodiment 1,3,8,13,21,22,23,24,27 or 43 or its pharmacologically acceptable salt.
In other embodiments of the present invention, provide the compound or pharmaceutically acceptable salt thereof of the formula (I) as medicine.
In other embodiments of the present invention, be provided for formula (I) compound or pharmaceutically acceptable salt thereof for the preparation of the medicine that suppresses the Trk activity.
In other embodiments of the present invention, be provided for formula (I) compound or pharmaceutically acceptable salt thereof for the preparation of the medicine for the treatment of or preventing cancer.
In other embodiments of the present invention, be provided for for the preparation of at warm-blooded animal formula (I) compound or pharmaceutically acceptable salt thereof of the medicine for the treatment of cancer among the mankind for example.
In other embodiments of the present invention, be provided for for the preparation of in for example treatment or prevent formula (I) compound or pharmaceutically acceptable salt thereof of following disease among the mankind of warm-blooded animal: cancer (noumenal tumour and leukemia), fibroplasia and differentiation illness, psoriasis, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, congee sample spot, atherosclerosis, arterial restenosis, autoimmune disorders, acute and chronic inflammation, osteopathy and have the illness in eye of retinal vessel hyperplasia.
In other embodiments of the present invention, be provided for formula (I) compound or pharmaceutically acceptable salt thereof for the preparation of the medicine that produces anti-proliferative effect.
In other embodiments of the present invention, the method that suppresses the Trk activity is provided, described method comprises to formula (I) compound or pharmaceutically acceptable salt thereof of host's drug treatment significant quantity of the such treatment of needs.
In other embodiments of the present invention, the method for the treatment of cancer is provided, described method comprises to formula (I) compound or pharmaceutically acceptable salt thereof of host's drug treatment significant quantity of the such treatment of needs.
In other embodiments of the present invention, the method for the treatment of or preventing cancer is provided, described method comprises formula (I) compound or pharmaceutically acceptable salt thereof of drug treatment significant quantity.
In other embodiments of the present invention, be provided at the method that warm-blooded animal comprises among the mankind treatment or following disease: cancer (noumenal tumour and leukemia), fibroplasia and differentiation illness, psoriasis, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, congee sample spot, atherosclerosis, arterial restenosis, autoimmune disorders, acute and chronic inflammation, osteopathy and have the illness in eye of retinal vessel hyperplasia, described method comprises formula (I) compound or pharmaceutically acceptable salt thereof of drug treatment significant quantity.
In other embodiments of the present invention, be provided at the method that the warm-blooded animal that needs like this treatment for example produces anti-proliferative effect among the mankind, the method comprises to the formula of described animals administer significant quantity (I) compound or pharmaceutically acceptable salt thereof.
In other embodiments of the present invention, provide the pharmaceutical composition that comprises formula (I) compound or pharmaceutically acceptable salt thereof and at least a pharmaceutically acceptable carrier, thinner or vehicle.
In other embodiments of the present invention, be provided for suppressing the pharmaceutical composition of Trk activity, described pharmaceutical composition comprises formula (I) compound or pharmaceutically acceptable salt thereof and at least a pharmaceutically acceptable carrier, thinner or vehicle.
In other embodiments of the present invention, be provided for treating the pharmaceutical composition of cancer, described pharmaceutical composition comprises formula (I) compound or pharmaceutically acceptable salt thereof and at least a pharmaceutically acceptable carrier, thinner or vehicle.
In other embodiments of the present invention, be provided for treating or the pharmaceutical composition of preventing cancer, described pharmaceutical composition comprises formula (I) compound or pharmaceutically acceptable salt thereof and at least a pharmaceutically acceptable carrier, thinner or vehicle.
In other embodiments of the present invention, the pharmaceutical composition that is provided for treatment or preventing cancer (noumenal tumour and leukemia), fibroplasia and differentiation illness, psoriasis, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, congee sample spot, atherosclerosis, arterial restenosis, autoimmune disorders, acute and chronic inflammation, osteopathy and has the illness in eye of retinal vessel hyperplasia, described pharmaceutical composition comprises formula (I) compound or pharmaceutically acceptable salt thereof and at least a pharmaceutically acceptable carrier, thinner or vehicle.
In other embodiments of the present invention, be provided for for example producing among the mankind warm-blooded animal the pharmaceutical composition of anti-proliferative effect, described pharmaceutical composition comprises formula (I) compound or pharmaceutically acceptable salt thereof and at least a pharmaceutically acceptable carrier, thinner or vehicle.
In other embodiments of the present invention, be provided for suppressing formula (I) compound or pharmaceutically acceptable salt thereof of Trk activity.
In other embodiments of the present invention, be provided for treating or formula (I) compound or pharmaceutically acceptable salt thereof of preventing cancer.
In other embodiments of the present invention, be provided at warm-blooded animal formula (I) compound or pharmaceutically acceptable salt thereof for the treatment of cancer among the people for example.
In other embodiments of the present invention, formula (I) compound or pharmaceutically acceptable salt thereof that is provided for treatment or preventing cancer (noumenal tumour and leukemia), fibroplasia and differentiation illness, psoriasis, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, congee sample spot, atherosclerosis, arterial restenosis, autoimmune disorders, acute and chronic inflammation, osteopathy and has the illness in eye of retinal vessel hyperplasia.
In other embodiments of the present invention, be provided for producing formula (I) compound or pharmaceutically acceptable salt thereof of anti-proliferative effect.
In relating to an embodiment that suppresses the Trk activity, specifically refer to suppress Trk A active.
In relating to another active embodiment of Trk inhibition, specifically refer to suppress Trk B active.
In the situation that relate to treatment (or prevention) cancer, specifically refer to treatment (or prevention) congenital fibrosarcoma, mesoblastic nephroma, mesothelioma, acute myelocytic leukemia, acute lymphoblastic leukemia, multiple myeloma, melanoma, esophagus cancer, myelomatosis, hepatocellular carcinoma, carcinoma of the pancreas, cervical cancer, Ewing sarcoma, neuroblastoma, Kaposi sarcoma, ovarian cancer, the mammary cancer that comprises secretion property mammary cancer, colorectal carcinoma, the prostate cancer that comprises hormone-refractory prostate cancer, bladder cancer, melanoma, nonsmall-cell lung cancer (NSCLC) and small cell lung cancer (SCLC), cancer of the stomach, head and neck cancer, kidney, lymphoma, the thyroid carcinoma that comprises papillary thyroid carcinoma, mesothelioma, leukemia, the tumour of maincenter and peripheral nervous system, melanoma, the fibrosarcoma and the osteosarcoma that comprise congenital fibrosarcoma.More specifically refer to prostate cancer.In addition, more specifically refer to SCLC, NSCLC, colorectal carcinoma, ovarian cancer and/or mammary cancer.On the other hand, refer to hormone-refractory prostate cancer.
In another aspect of this invention, provide the method for preparation formula (I) compound or pharmaceutically acceptable salt thereof, described method (wherein variable group is, unless stipulate in addition, suc as formula defined in (I)) comprising:
Method a) makes (II) compound:
Wherein Pg is nitrogen-protecting group; With formula (III) compound:
Wherein L is displaceable group, reacts;
Method b) for R wherein
5Hydroxymethyl and R
6It is formula (I) compound of hydrogen; Make the epoxide reaction of formula (II) compound and formula (IV):
Method c) for X wherein
1Be=CR
10-formula (I) compound; Make formula (V) compound:
React with formula (VI) compound:
Method d) for X wherein
1Be=formula (I) compound of N-; Make formula (V) compound and NaNO
2The aqueous solution reacts;
Method e) make formula (VII) compound:
Wherein L is that displaceable group and Pg are nitrogen-protecting groups; React with formula (VIII) amine:
And thereafter if necessary:
I) a kind of formula (I) compound is converted into another kind of formula (I) compound;
Ii) remove any protecting group;
Iii) form pharmacologically acceptable salt.
L is displaceable group, and the suitable value of L is for example halogen or sulfonyloxy, for example chlorine, bromine, mesyloxy or toluene-4-sulfonyloxy.
Pg is nitrogen-protecting group.The suitable value of Pg is described in down.
The concrete reaction conditions of above-mentioned reaction is as follows:
Method is formula (II) and (III) compound can be under standard nucleophilic addition condition a), and for example for example salt of wormwood and suitable solvent under temperature range 25-100 ℃, react for example in the presence of the DMF together at suitable alkali.
Formula (II) compound can prepare according to reaction scheme 1:
Reaction scheme 1
Formula (III), (IIa), (IIb) and (IId) compound be the compound that can buy from the market, perhaps it is known in the literature, perhaps it can prepare by standard method known in the art.
Method b) formula (II) and (IV) compound can be under epoxide ring-opening reaction condition is for example at suitable catalyzer LiClO for example
4, NaClO
4, Mg (ClO
4)
2With at suitable solvent CH for example
3CN exists lower, and under temperature range 25-80 ℃, reacts together.
Formula (IV) compound is the compound that can buy from the market, and perhaps it is known in the literature, and perhaps it can prepare by standard method known in the art.
Method c) formula (V) and formula (VI) compound can at suitable solvent ethanol for example, under reflux temperature, react together.
Compound (V) can prepare according to reaction scheme 2:
Reaction scheme 2
Formula (Va), (Vb) and (VI) compound be the compound that can buy from the market, perhaps it is known in the literature, perhaps it can prepare by standard method known in the art.
Method d) formula (V) compound and NaNO
2The aqueous solution can be in acetic acid aqueous solution one reacts.
Method e) formula (VII) and (VIII) compound can method in a) listed condition next react.
Formula (VII) compound can prepare according to reaction scheme 3:
Reaction scheme 3
Formula (VIII) compound is the compound that can buy from the market, and perhaps it is known in the literature, and perhaps it can prepare by standard method known in the art.
Some intermediate disclosed herein is new, and therefore described intermediate consists of another feature of the present invention.
Should be appreciated that some ring substituents in the compounds of this invention, can or be right after before aforesaid method thereafter, the aromatics substitution reaction by standard is introduced or the modified with functional group by routine produces, and therefore is included within the method for the present invention aspect.Such reaction and modification comprise, for example, introduce substituting group by aromatics substitution reaction, substituent reduction, substituent alkylation and substituent oxidation.The reagent and the reaction conditions that are used for described method are well-known at chemical field.The specific examples of aromatics substitution reaction comprises: introduce nitro with concentrated nitric acid, come under Ford (Friedel Crafts) condition at Fu Ruide-Ke, example such as carboxylic acid halides and Lewis acid (for example aluminum chloride) are introduced acyl group; Come under the Ford condition at Fu Ruide-Ke, use alkylogen and Lewis acid (for example aluminum chloride) to introduce alkyl; And introducing halogen radical.The specific examples of modifying comprises, by for example using the catalytic hydrogenation of nickel catalyzator, perhaps processing with iron in the presence of the hydrochloric acid and under the heating, and be amino with nitroreduction; Alkylthio is oxidized to alkyl sulphinyl or alkyl sulphonyl.
It is also understood that in some reaction as herein described, be necessary/wish any sensitive group in the compound is protected.The example of the situation of necessity or hope protection and suitable guard method is known to those skilled in the art.Can use conventional protecting group (in order to illustrate, referring to T.W.Green, the protecting group in the organic synthesis, John Wiley and Sons, 1999) according to standard practices.Therefore, if reactant comprises group for example amino, carboxyl or hydroxyl, in reaction as herein described, may need these radical protections.
The suitable protecting group of amino or alkylamino is, for example, and acyl group; alkyloyl ethanoyl for example for example; alkoxy carbonyl is methoxycarbonyl, ethoxy carbonyl or tert-butoxycarbonyl for example, and the aryl methoxy carbonyl is benzyloxycarbonyl for example, or aroyl benzoyl for example.The deprotection condition of above-mentioned protecting group must change with the selection of protecting group.Therefore, for example, acyl group for example alkyloyl or alkoxy carbonyl or aroyl can be for example by removing with suitable basic hydrolysis, described alkali is for example lithium hydroxide or sodium hydroxide of alkali metal hydroxide for example.Perhaps; acyl group for example tert-butoxycarbonyl can be for example by removing with suitable acid treatment; described acid is for example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid; and the aryl methoxy carbonyl for example benzyloxycarbonyl can be for example by for example carrying out hydrogenation under the catalysis of palladium on carbon at catalyzer, perhaps by with Lewis acid for example three (trifluoroacetic acid) boron process to remove.For primary amino, suitable protecting group is phthaloyl for example in addition, and it can be by with alkylamine dimethylamino propylamine or process to remove with hydrazine for example.
The suitable blocking group of hydroxyl is, for example, acyl group, alkyloyl ethanoyl for example for example, aroyl is benzoyl for example, or arylmethyl benzyl for example.The deprotection condition of above-mentioned blocking group must change with the selection of blocking group.Therefore, for example, acyl group for example alkyloyl or aroyl can be for example by removing with suitable basic hydrolysis, described alkali is for example alkali metal hydroxide such as lithium hydroxide or sodium hydroxide.Perhaps, arylmethyl for example benzyl can be for example remove by for example carrying out hydrogenation under the catalysis of palladium on carbon at catalyzer.
The suitable protecting group of carboxyl is; for example; esterified group; for example methyl or ethyl; its can be for example by with alkali for example sodium hydroxide hydrolysis remove, the perhaps tertiary butyl, its can be for example by for example organic acid such as trifluoroacetic acid are processed to remove with acid; perhaps benzyl for example, it can be for example removed by for example carrying out hydrogenation under the catalysis of palladium on carbon at catalyzer.
In any suitable stage that can be in synthetic, remove protecting group with the well-known routine techniques of chemical field.
Definition
In this manual, term " alkyl " comprises straight chain and branched-chain alkyl, but for example only refers in particular to linear form when " propyl group " mentioning concrete indivedual alkyl.For example, " C
1-6Alkyl " and " C
1-4Alkyl " comprise methyl, ethyl, propyl group, sec.-propyl and the tertiary butyl.Yet, mentioning concrete indivedual alkyl for example when " propyl group ", only refer in particular to linear form, and mentioning concrete indivedual branched-chain alkyls for example when " sec.-propyl ", only refer in particular to the side chain form.Similar convention also is applicable to other group.Term " halogen " refers to fluorine, chlorine, bromine and iodine.
The substituting group that selects in office is to be selected from the situation of " one or more " group, should be appreciated that this definition comprises that all substituting groups are selected from a group of specifying in the group, and perhaps substituting group is selected from two or more groups of specifying in the group.
" heterocyclic radical " is saturated, fractional saturation or unsaturated list or the dicyclo that contains 4-12 atom, and wherein at least one atom is selected from nitrogen, sulphur or oxygen, and except as otherwise noted, described monocycle or dicyclo are that carbon or nitrogen connect, wherein-and CH
2-group can be chosen wantonly by-C (O)-substitute, and the epithio atom can be chosen oxidized formation S-oxide compound wantonly.Example and the suitable value of term " heterocyclic radical " are morpholinoes, piperidyl, pyridyl, pyranyl, pyrryl, isothiazolyl, indyl, quinolyl, thienyl, 1,3-benzodioxole base, thiadiazolyl group, piperazinyl, thiazolidyl, pyrrolidyl, thiomorpholine generation, pyrrolinyl, the homopiperazine base, 3,5-dioxa piperidyl, THP trtrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl isoxazolyl, N-methylpyrrole base, the 4-pyriconyl, the 1-isoquinolone, 2-Pyrrolidone, the 4-thiazolidone, pyridine-N-oxide and Quinoline-N-oxide.The further example of term " heterocyclic radical " and suitable value are morpholino, piperazinyl and pyrrolidyl.In one aspect of the invention, " heterocyclic radical " is saturated, fractional saturation or unsaturated list or the dicyclo that contains 5 or 6 atoms, and wherein at least one atom is selected from nitrogen, sulphur or oxygen, and unless otherwise indicated, described monocycle or dicyclo are that carbon or nitrogen connect-CH
2-group can be chosen wantonly by-C (O)-substitute, and the epithio atom can be chosen oxidized formation S-oxide compound wantonly.
" carbocylic radical " is saturated, fractional saturation or undersaturated list or the bicyclic carbocyclic that contains 3-12 atom; Wherein-CH
2-group can be chosen wantonly by-C (O)-substitute.Particularly, " carbocylic radical " is the monocycle that contains 5 or 6 atoms, or contains the dicyclo of 9 or 10 atoms.The suitable value of " carbocylic radical " comprises cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, 1,2,3,4-tetralin base, indanyl or 1-oxo indanyl.
Separately or the term " C that uses as prefix
M-n" or " C
M-nBase " refer to have any group of m-n carbon atom.
Term " optional replacement " refers to substituted and unsubstituted group, structure or molecule.
" C
1-6Alkanoyloxy " example be acetoxyl." C
1-6Alkoxy carbonyl " example comprise C
1-4Alkoxy carbonyl, methoxycarbonyl, ethoxy carbonyl, just and tert-butoxycarbonyl." C
1-6Alkoxyl group " example comprise C
1-4Alkoxyl group, C
1-3Alkoxyl group, methoxyl group, oxyethyl group and propoxy-." C
1-6The alkoxyl group imido grpup " example comprise C
1-4Alkoxyl group imido grpup, C
1-3Alkoxyl group imido grpup, methoxyl group imido grpup, oxyethyl group imido grpup and propoxy-imido grpup." 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 C
1-4Alkyl sulphonyl, methylthio group, ethylmercapto group, methylsulfinyl, ethyl sulfinyl, methylsulfonyl and ethylsulfonyl." C
1-6The alkyl sulfenyl " example comprise methylthio group and ethylmercapto group." C
1-6Alkyl sulfonyl-amino " example comprise the amino and ethylsulfonyl amino of methyl sulphonyl." C
1-6Alkyloyl " example comprise C
1-4Alkyloyl, 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.
" RT " or " rt " refers to room temperature.
The suitable pharmacologically acceptable salt of the compounds of this invention is, for example, enough acid salt of the compounds of this invention of alkalescence, for example, with the acid salt that forms of hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid or toxilic acid for example of inorganic or organic acid for example.In addition, enough the pharmacologically acceptable salt of acid the compounds of this invention is an alkali metal salt, for example sodium or sylvite, alkaline earth salt, for example calcium or magnesium salts, ammonium salt or can accept the salt that cationic organic bases forms with physiology is provided, the salt that for example forms with methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three-(2-hydroxyethyl) amine.
Should be understood that, the present invention requires Patent right compound to exist with different resonance structures, therefore this paper requires Patent right compound to comprise all possible resonance structure of formula (I) compound, for example optically active isomer, diastereomer and geometrical isomer and all tautomers.
Should be appreciated that some formula (I) compound can solvation or the form of non-solvent have hydrated form for example.Should be appreciated that all such solvation forms that the present invention includes.
Preparation
The compounds of this invention can be oral, parenteral, oral cavity, vagina, rectum, suck, be blown into, in hypogloeeis, intramuscular, subcutaneous, local, the nose, in the intraperitoneal, intrathoracic, intravenously, epidural, sheath, Intraventricular and by being injected into the joint administration.
When determining for concrete patient's optimum individual program and dosage level, dosage depends on age of seriousness, patient of route of administration, disease and body weight and by the normal other factors of considering of doctor in charge.
The compounds of this invention is used for the treatment of the significant quantity of cancer, is warm-blooded animal particularly among the mankind, be enough to alleviate cancer symptom, slow down the development of cancer or in suffering from the patient of cancer, reduce the amount of progression risk.
For prepared pharmaceutically acceptable composition by the compounds of this invention, inertia pharmaceutically acceptable carrier can be solid or liquid.The formulation of solid form comprises pulvis, tablet, dispersible granule, capsule, cachet and suppository.
Solid carrier can be one or more materials, and it can be used as thinner, seasonings, solubilizing agent, slipping agent, suspension agent, tackiness agent or tablet disintegrant; It can also be the material that forms capsule.
In pulvis, carrier is the solid in small, broken bits that mixes with active ingredient in small, broken bits.In tablet, active ingredient is mixed with suitable ratio with the carrier with necessary binding characteristic, and be pressed into the shape and size that need.
For the preparation suppository composition, at first with the low melt wax mixture melt of glycerin fatty acid ester and Oleum Cocois for example, and by for example stirring active ingredient is interspersed among wherein.Then the uniform mixture of fusing is poured in the mould of suitable size into cooling and solidify.
Suitable carrier comprises magnesiumcarbonate, Magnesium Stearate, talcum powder, lactose, sucrose, pectin, dextrin, starch, tragacanth, methylcellulose gum, Xylo-Mucine, low melt wax, coconut wet goods.
Some compound of the present invention can form salt with various inorganic and organic bronsted lowry acids and bases bronsted lowries, and such salt also belongs within the scope of the present invention.The example of such acid salt comprises acetate, adipate, ascorbate salt, benzoate, benzene sulfonate, two carbonate, hydrosulfate, butyrates, camphorate, camsilate, salt with choline formation, Citrate trianion, cyclohexyl-n-sulfonate, salt with diethylenediamine formation, esilate, fumarate, glutaminate, glycolate, Hemisulphate, 2-hydroxyethyl sulfonate, enanthate, hexanoate, hydrochloride, hydrobromate, hydriodate, hydroxymaleic acid salt, lactic acid salt, malate, maleate, mesylate, salt with meglumine formation, the 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulphate, phenylacetate, phosphoric acid salt, hydrophosphate, picrate, pivalate, propionic salt, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, vitriol, tartrate, tosylate (tosilate), trifluoroacetate and undecylate.Subsalt comprises ammonium salt, an alkali metal salt is sodium salt, lithium salts and sylvite for example, alkaline earth salt is aluminium salt, calcium salt and magnesium salts for example, and the salt that forms with organic bases is dicyclohexyl amine salt, N-methyl-D-glucamine salt for example, and the salt that forms with amino acid such as arginine, Methionin, ornithine etc.And, can be with such quaternizing agent that alkaline nitrogen-containing group is quaternized: low alkyl group halogen, for example methyl halide, ethyl halide, propyl halide and butyl halide; Dialkylsulfates is dimethyl sulphide acid esters, diethyl sulfide acid esters, dibutyl sulfide acid esters, diamyl sulfuric ester for example; Long-chain halogenide is decyl halogen, lauryl halogen, myristyl halogen and stearyl halogen for example; Aralkyl halogen such as bromotoluene etc.The acceptable salt of nontoxic physiology is preferred, but other salt also is useful, for example is used in the separation and purifying of product.
Salt can form by ordinary method, for example by with the free alkali form of product and one or the suitable acid of many equivalents salt be insoluble to wherein solvent or medium in react, perhaps for example react in the water at solvent, vacuum is removed described solvent, perhaps remove described solvent by lyophilize, or negatively charged ion and another kind of anionresin by on suitable ion exchange resin, having salt.
For formula (I) compound or pharmaceutically acceptable salt thereof is used for the treatment (comprising prophylactic treatment) that Mammals comprises the people, usually according to the standard pharmaceutical practice it is formulated as pharmaceutical composition.
Except the compounds of this invention, pharmaceutical composition of the present invention can also be included in valuable one or more medicines in one or more illnesss mentioned in this article for the treatment of, perhaps with described medicine co-administered (simultaneously or in succession).
The term composition means to comprise the preparation of active ingredient or pharmacologically acceptable salt and pharmaceutically acceptable carrier.For example can use methods known in the art, the present invention is made for example following form: aerosol or propellant that tablet, capsule, water or oil solution, suspension, emulsion, emulsifiable paste, ointment, gel, nasal spray, suppository, powder in small, broken bits or be used for sucks, and parenteral uses the sterilized water of (comprising intravenously, intramuscular or infusion) or solution or suspension or the aseptic milk sap of oil.
Liquid composition comprises solution, suspension and emulsion.The sterilized water of active compound or water-propylene glycol solution can be lifted the example of doing the liquid preparation that is applicable to administered parenterally.Liquid composition also can be prepared in the aqueous solution of polyoxyethylene glycol.Can by with solubilization of active ingredient in water, and add on demand suitable tinting material, seasonings, stablizer and thickening material, come the aqueous solution for the preparation of oral administration.By active ingredient in small, broken bits is interspersed among in the water with cohesive material, prepare the aqeous suspension that orally uses, described cohesive material is natural and synthetic other known suspension agent of natural gum, resin, methylcellulose gum, Xylo-Mucine and field of pharmaceutical preparations for example.
Pharmaceutical composition can be the form with unit dosage.In such form, composition is distributed in the unitary dose of the active ingredient that contains sufficient quantity.Unit dosage can be the formulation of packing, and described packing contains the preparation of discrete magnitude, for example tablet, capsule and the bottle of packing or the pulvis in the ampoule.Unit dosage also can be capsule, cachet or tablet itself, and perhaps unit dosage can be any these packaged forms of suitable number.
Associating
Anticancer therapy described herein perhaps, except the compounds of this invention, can comprise conventional surgical operation or radiotherapy or chemotherapy applicable to independent treatment.Such chemotherapy can comprise the anti-tumor agents of one or more following kinds:
(i) the anti-hyperplasia/antitumor drug that uses in the medical oncology and their associating, for example alkylating agent (for example cis-platinum, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan and and nitrosourea); Metabolic antagonist (for example antifol for example for example 5 FU 5 fluorouracil and Tegafur, Raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea of 5-FU class); Antitumor antibiotics (for example anthracycline antibiotics for example Dx, bleomycin, Dx, daunomycin, epirubicin, darubicin, ametycin, actinomycin and Plicamycin); Anti-mitosis medicine (for example vinca alkaloids for example for example PTX class and taxotere of vincristine(VCR), vinealeucoblastine(VLB), vindesine and vinorelbine and taxoids); And topoisomerase enzyme inhibitor (for example epipodophyllotoxin for example Etoposide and teniposide, amsacrine, Hycamtin and camptothecine);
(ii) medicine that suppresses cell for example the estrogen antagonist material (for example tamoxifen divides, toremifene, raloxifene, droloxifene and iodoxyfene), adjust under the estrogen receptor (for example fulvestrant), antiandrogen (bicalutamide for example, flutamide, Nilutamide and cyproterone acetate), lhrh antagonist or LHRH agonist (goserelin for example, Leuprolide and buserelin), progestogen (for example Magace), aromatase inhibitor (Anastrozole for example, letrozole, vorazole and Exemestane) and 5 alpha reductase inhibitors finasteride for example;
(iii) medicine of anticancer invasion and attack (for example inhibitors of metalloproteinase for example Marimastat and urokinase proplasmin activator function of receptors inhibitor);
(iv) somatomedin depressant of functions, for example such inhibitor comprises that growth factor antibodies, growth factor receptor antibody (for example resist-erbb2 antibody trastuzumab[Herceptin
TM] and anti--erbbl antibody Cetuximab [C225]), farnesyl transferase inhibitor, tyrosine kinase inhibitor and serine/threonine kinase inhibitor, the inhibitor of Urogastron family (EGFR family tyrosine kinase inhibitor N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (gefitinib for example for example for example, AZD1839), N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy) quinazoline-4-amine (erlotinib, OSI-774) and 6-acrylamide-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033)), for example by the inhibitor of platelet-derived growth factor family and for example inhibitor of pHGF family;
(v) anti-angiogenic medicaments for example suppresses the medicine of the effect of vascular endothelial growth factor, (anti-angiogenic epithelical cell growth factor antibody rhuMAb-VEGF [Avastin for example
TM], for example be disclosed in those compounds among International Patent Application WO 97/22596, WO97/30035, WO97/32856 and the WO98/13354) and the compound that works by other mechanism (for example Li Nuoan, integrin alpha v beta 3 depressant of functions and angiogenesis inhibitor element);
(vi) angiolysis medicine combretastatin A4 and be disclosed in compound among International Patent Application WO 99/02166, WO00/40529, WO00/41669, WO01/92224, WO02/04434 and the WO02/08213 for example;
(vii) antisense therapy, for example for the antisense therapy of target listed above, ISIS2503 for example, a kind of anti--agent of ras antisense therapy;
(viii) gene therapy method, comprise and for example replace for example method of unusual p53 or unusual BRCA1 or BRCA2 of aberrant gene, GDEPT (gene mediated enzyme prodrug therapy) method, for example use the method for Isocytosine deaminase, thymidine kinase or bacterium nitroreductase, with the method for increase patient to chemotherapy and radiocurable tolerance, for example multiple medicines tolerance gene therapeutics;
(ix) immunotherapy method, comprise and for example increase the interior method of the immunogenic indirectly external and body of patient tumors cell, for example with for example interleukin II, interleukin-4 or rHuGM-CSF transfection of cytokine, reduce the method for T cell anergy, the immunocyte of use transfection is the method for the dendritic cell of cytokine transfection for example, uses the method and the method for using antiidiotypic antibody of the tumor cell line of cytokine transfection.
(x) other treatment plan comprises: use after dexamethasone, proteasome inhibitor (comprising bortezomib), isotretinoin (Accutane), Thalidomide, revemid, Rituxamab, ALIMTA, Cephalon ' s kinase inhibitor CEP-701 and CEP-2563, anti--Trk or anti--NGF monoclonal antibody, the target radiotherapy of using 131I-polyphenyl iodine guanidine (131I-MIBG), the chemotherapy or resisting-G (D2) mab treatment without granulocyte-macrophage collection Lip river stimulating factor (GM-CSF).
Such combination therapy can be by simultaneously, mutually continuous or respectively the independent component of drug treatment realize.Such combination product is used the compounds of this invention or its pharmacologically acceptable salt in the described dosage range of preamble, and the other medicines promoting agent in the permissible dose scope.
Synthetic
The compounds of this invention or its pharmacologically acceptable salt can use that well-known some methods prepare for the technician in organic synthesis field.The compounds of this invention or its pharmacologically acceptable salt can be with the methods that the following describes, and the known method in synthetic organic chemistry field, perhaps it changed to prepare according to understanding by those skilled in the art.Such method includes, but not limited to following described method.The reference that this paper quotes is quoted as a reference on the whole at it accordingly.
New compound of the present invention or its pharmacologically acceptable salt can prepare with reaction described herein and technology.Reaction can be to carry out in the suitable solvent for agents useful for same and material, and reaction is suitable for the realization that transforms.And, in the description of synthetic method below, should be appreciated that reaction conditions to all suggestions comprises that the time length of solvent, reaction atmosphere, temperature of reaction, test and post-processing operation select, and is the easily standard conditions of the described reaction of understanding of those skilled in the art.The technician in organic synthesis field should be appreciated that the functional group of the different piece that is present in molecule must be compatible with the reaction of reagent and suggestion.To the substituent such restriction compatible with reaction conditions, be apparent for a person skilled in the art, and must use alternative method.
Embodiment
The present invention is described further referring now to following illustrative embodiment, wherein, and unless otherwise indicated:
(i) temperature with degree centigrade (℃) expression; Operation is to carry out between 18-25 ℃ in room temperature or envrionment temperature;
(ii) organic solution anhydrous magnesium sulfate drying; Organic solvent is up at decompression (4.5-30mmHg), bath temperature under 60 ℃ the condition, evaporates with rotatory evaporator;
(iii) chromatography means the flash chromatography that carries out at silica gel; Tlc (TLC) is carried out at silica-gel plate;
(iv) generally speaking, reaction process is followed the tracks of by TLC or liquid chromatography/mass spectrometry method (LC/MS), only is for explanation and provide the reaction times;
(v) final product has satisfactory proton magnetic resonance (PMR) (NMR) spectrum and/or mass-spectrometric data;
(vi) only be used for illustration purpose for the rate of output, and nonessential be the productive rate of improving one's methods and can obtain by making great efforts; If need more material, can repeatedly prepare;
(vii) except as otherwise noted, the NMR data that provide are the forms with the δ value of principal character proton, with respect to what provide as 1,000,000/(ppm) of interior target tetramethylsilane (TMS), are in DMSO-d at 300MHz
6Middle mensuration;
(viii) chemical symbol has its ordinary meaning;
(ix) solvent ratio volume: volume (v/v) expression.
(x) use following abbreviation:
The EtOAc acetoacetic ester;
EtOH ethanol;
The THF tetrahydrofuran (THF);
The DIEA diisopropylethylamine
MeOH methyl alcohol; With
The DCM methylene dichloride.
Embodiment 1
(2R)-2-[9-(5-cyclopropyl-1H-pyrazole-3-yl)-6-methyl-9H-purine-2-base is amino]-2-(4-fluorophenyl) ethanol
(R)-2-[5-amino-4-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-6-methylpyrimidine-2-base is amino]-2-(4-fluorophenyl) ethanol (method 40; 0.3g, 0.8mmol) and the mixture heating up of acetic acid carbonamidine (0.2g, 1.6mmol) in EtOH (8ml) to refluxing 12 hours.Then will react concentrated, and be dissolved among the DCM (50ml), and use saturated NaHCO
3Solution (50ml) washing.Organic layer is dry, filtration and concentrated.The gained solid has obtained this title compound (0.11g, 35%) by column chromatography purifying (DCM:MeOH=20:1).NMR (400MHz, CD
3OD) 8.32 (s, 1H), 7.46-7.43 (m, 2H), (7.06-7.02 m, 2H), 6.24 (s, 1H), (5.10-5.02 m, 1H), 3.87-3.75 (m, 2H), 2.61 (s, 3H), (1.99-1.96 m, 1H), 1.10-1.08 (m, 2H), 0.80-0.75 (m, 2H) .MS: calculated value: 393; Measured value: [M+H]
+394.
Embodiment 2-8
According to method similar to Example 1, by suitable amino-pyrimidine, by processing with acetic acid carbonamidine (or use acetamidine hydrochloride for embodiment 6), synthesize following compounds.
[0314]
Embodiment 9
(2R)-and 2-[3-(5-cyclopropyl-1H-pyrazole-3-yl)-7-methyl-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-base amino]-2-(4-fluorophenyl) ethanol
In 25 ℃, amino to (R)-2-[5-amino-4-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-6-methylpyrimidine-2-base]-2-(4-fluorophenyl) ethanol (method 40; 0.18g, 0.47mmol) acetic acid aqueous solution (5%, in the solution in 3ml), drip NaNO
2(0.032g, 0.47mmol, 1ml H
2O).To react restir 5 minutes, water (10ml) is processed, with DCM (3x25ml) extraction.With the saturated NaHCO of organic layer
3Solution (50ml) washing, drying is filtered and is concentrated.The gained solid has obtained this title compound (0.15g, 81%) by column chromatography purifying (DCM:MeOH=30:1).NMR (400MHz, CD
3OD) 7.46-7.42 (m, 2H), 7.06-7.01 (m, 2H), 6.21 (s, 1H), (5.14-5.06 m, 1H), 3.86-3.79 (m, 2H), 2.74 (s, 3H), (2.03-2.01 m, 1H), 1.11-1.08 (m, 2H), 0.83-0.79 (m, 2H) .MS: calculated value: 394; Measured value: [M+H]
+395.
Embodiment 10
3-(5-cyclopropyl-1H-pyrazole-3-yl)-N-[(S)-1-(4-fluorophenyl) ethyl]-3H-[1,2,3] triazolo [4,5-d] pyrimidine-5-amine
To (S)-N
4-(5-cyclopropyl-1H-pyrazole-3-yl)-N
2-[1-(4-fluorophenyl) ethyl] pyrimidine-2,4,5-triamine (method 8; 0.04g, 0.1mmol) acetic acid aqueous solution (5%, in the solution in 3ml), slowly add NaNO
2The aqueous solution (0.008g, 0.1mmol, 1ml H
2O).To react restir 5 minutes, water (10ml) is processed, and extracts with DCM (3x25ml).With the saturated NaHCO of organic layer that merges
3Solution (50ml) washing, drying is filtered, and concentrated.The gained solid has obtained this title compound (0.015g, 40%) by column chromatography purifying (DCM:MeOH=15:1).NMR (400MHz, CD
3OD) 9.05 (s, 1H), 7.44-7.41 (m, 2H), (7.03-6.99 m, 2H), 6.23 (s, 1H), 5.16-5.07 (m, 1H), (2.03-2.00 m, 1H), 1.55 (d, J=6.8Hz, 3H), 1.11-1.09 (m, 2H), 0.85-0.80 (m, 2H) .MS: calculated value: 364; Measured value: [M+H]
+365.
Embodiment 11
9-(5-cyclopropyl-1H-pyrazole-3-yl)-2-[(S)-1-(4-fluorophenyl) ethylamino]-9H-purine-6-ethyl formate
With (S)-ethyl 5-amino-6-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-2-[1-(4-fluorophenyl) ethylamino] pyrimidine-4-manthanoate (method 47; 0.6g, 1.4mmol) and the mixture heating up of acetic acid carbonamidine (0.32g, 3.1mmol) in EtOH (20ml) to refluxing 12 hours.Concentrated reaction, the gained resistates is dissolved among the EtOAc (50ml) and uses saturated NaHCO
3Solution (50ml) washing.Organic layer is dry, filter and concentrate.The gained solid has obtained this title compound (0.058g, 8%) by column chromatography purifying (DCM:MeOH=20:1).NMR (400MHz, CD
3OD) 8.48 (s, 1H), 7.45-7.41 (m, 2H), 7.03-6.99 (m, 2H), 6.25 (s, 1H), 5.12-5.03 (m, 1H), 4.50 (q, J=7.2Hz, 2H), (2.00-1.96 m, 1H), 1.54 (d, J=7.0Hz, 3H), 1.44 (t, J=7.2Hz, 3H), (1.10-1.08 m, 2H), 0.81-0.74 (m, 2H) .MS: calculated value: 435; Measured value: [M+H]
+436.
Embodiment 12
[9-(5-cyclopropyl-1H-pyrazole-3-yl)-2-[(S)-1-(4-fluorophenyl) the ethylamino]-fast cry of certain animals of 9H--6-yl] methyl alcohol
9-(5-cyclopropyl-1H-pyrazole-3-yl)-2-[(S)-1-(4-fluorophenyl) ethylamino]-(embodiment 11 for 9H-purine-6-ethyl formate; 0.03g 0.069mmol) solution in THF (3ml) is cooled to 0 ℃.In this solution, slowly add lithium aluminum hydride (solution of 1.0M in THF, 0.076ml, 1.1eq.).Reaction mixture was in 0 ℃ of stirring 30 minutes, and add the sodium sulfate decahydrate until stop the bubble of overflowing this moment.Then will react by plug of celite and filter, with THF (3x30ml) washing, and concentrated.The gained resistates has obtained this title compound (0.09g, 33%) by column chromatography purifying (DC M:MeOH=15:1).NMR (400MHz, CDCl
3) 8.27 (s, 1H), 7.39-7.36 (m, 2H), 7.03-6.98 (m, 2H), 6.32 (s, 1H), 5.65-5.64 (m, 1H), 5.10-5.07 (m, 1H), 5.03 (s, 2H), 3.87-3.85 (m, 1H), 1.93-1.88 (m, 1H), 1.57 (d, J=6.8Hz, 3H), (1.08-1.06 m, 2H), 0.81-0.77 (m, 2H) .MS: calculated value: 393; Measured value: [M+H]
+394.
Embodiment 13
3-(5-cyclopropyl-1H-pyrazole-3-yl)-N-[(S)-1-(4-fluorophenyl) ethyl]-3H-imidazo [4,5-b] pyridin-5-amine
With (S)-N
2-(5-cyclopropyl-1H-pyrazole-3-yl)-N
6-[1-(4-fluorophenyl) ethyl] pyridine-2,3,6-triamine (method 48; 0.240g, 0.68mmol) heated 2 hours under refluxing with the mixture of acetic acid carbonamidine (0.113g, 1.09mmol) in EtOH (5ml).After being cooled to 25 ℃, the saturated NaHCO of reaction mixture
3Solution (10ml) and EtOAc (30ml) process.Organic layer is separated, with salt solution (10ml) washing, and use Na
2SO
4Dry.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane: EtOAc=1:3), obtained this title compound, be pale solid (0.144g, 58%).NMR (400MHz) 12.57 (s, 1H), 8.25 (s, 1H), 7.72 (d, J=8.4Hz, 1H), 7.41 (m, 2H), 7.32 (d, J=6.4Hz, 1H), 7.10 (m2H), 6.56 (d, J=8.8Hz, 1H), 6.26 (s, 1H), 4.99 (m, 1H), (1.97 m, 1H), 1.45 (d, J=6.8Hz, 3H), (1.04 m, 2H), 0.78-0.69 (m, 2H) .MS: calculated value: 362; Measured value: [M+H]
+363.
Embodiment 14-26
According to method similar to Example 13, by suitable amino-pyridine, by process synthetic following compounds with the acetic acid carbonamidine.
[0333]
[0334]
[0335]
Embodiment 27
3-(5-cyclopropyl-1H-pyrazole-3-yl)-N-[(S)-1-(4-fluorophenyl) ethyl]-3H-benzo [d] imidazoles-5-amine
With (S)-N
3-(5-cyclopropyl-1H-pyrazole-3-yl)-N
1-[1-(4-fluorophenyl) ethyl] benzene-1,3,4-triamine (method 62; 0.395g, 1.12mmol) heated 2 hours under refluxing with the mixture of acetic acid carbonamidine (0.234g, 2.25mmol) in EtOH (5ml).After being cooled to 25 ℃, reaction mixture is processed with saturated sodium bicarbonate aqueous solution (10ml) and EtOAc (30ml).Organic layer is separated, with salt solution (10ml) washing, and use Na
2SO
4Dry.Removal of solvent under reduced pressure, and the gained resistates obtained this title compound by column chromatography purifying (EtOAc), is pale solid (0.205g, 50%).NMR (400MHz) 12.65 (s, 1H), 8.17 (s, 1H), 7.43 (m, 2H), (7.33 d, J=8.8Hz, 1H), 7.10 (m, 2H), 6.90 (s, 1H), 6.62 (d, J=8.8Hz, 1H), 6.25 (d, J=6.4Hz, 1H), 6.08 (s, 1H), 4.51 (m, 1H), 1.96 (m, 1H), 1.43 (d, J=6.8Hz, 3H), 1.02 (m, 2H), 0.76 (m, 2H) .MS: calculated value: 361; Measured value: [M+H]
+362.
Embodiment 28-32
According to embodiment 27 similar methods, by suitable amino-benzene, by process synthetic following compounds with the acetic acid carbonamidine.
[0342]
Embodiment 33
1-(5-cyclopropyl-1H-pyrazole-3-yl)-6-[(S)-1-(4-fluorophenyl) ethylamino]-1H-benzo [d] imidazoles-5-formonitrile HCN
With (S)-5-amino-4-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-2-[1-(4-fluorophenyl) ethylamino] benzonitrile (method 69; 3.85g, 10.2mmol) heated 2 hours under refluxing with the mixture of acetic acid carbonamidine (2.13g, 20.5mmol) in EtOH (50ml).After the cooling, reaction mixture is processed with saturated sodium bicarbonate solution (10ml) and EtOAc (30ml).Organic layer is separated, with salt solution (10ml) washing, and use Na
2SO
4Dry.Removal of solvent under reduced pressure, and the gained resistates obtained this title compound by column chromatography purifying (EtOAc:MeOH=30:1), is pale solid (3.23g, 82%).NMR (400MHz) .12.79 (s, 1H), 8.44 (s, 1H), 7.95 (s, 1H), 7.53 (m, 2H), 7.14 (m, 2H), (7.01 s, 1H), 6.10 (s, 1H), 6.09 (d, J=7.6Hz, 1H), 4.63 (m, 1H), 1.97 (m, 1H), 1.55 (d, J=6.8Hz, 3H), (1.03 m, 2H), 0.76 (m, 2H) .MS: calculated value: 386; Measured value: [M+H]
+387.
Embodiment 34
1-(5-cyclopropyl-1H-pyrazole-3-yl)-6-[(S)-1-(4-fluorophenyl) ethylamino]-1H-benzo [d] imidazoles-5-methane amide
1-(5-cyclopropyl-1H-pyrazole-3-yl)-6-[(S)-1-(4-fluorophenyl) ethylamino]-1H-benzo [d] imidazoles-(embodiment 33 for the 5-formonitrile HCN; 0.30g, 0.77mmol) be dissolved among the MeOH (10ml), then add the 25%KOH aqueous solution (0.87ml, 3.88mol) and 15 30%H
2O
2Solution.To react 75 ℃ of heating 48 hours.After the cooling, reaction H
2O (5ml) dilution.Collect the gained solid via filtering, and dry under vacuum, obtained this title compound (0.137g, 44%), be white solid.NMR (400MHz) 12.70 (s, 1H), 8.66 (d, J=4.8Hz, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 8.03 (br, 1H), 7.42 (m, 2H), 7.24 (br, 1H), 7.13 (m, 1H), (6.80 s, 1H), 6.00 (s, 1H), 4.57 (m, 1H), 1.95 (m, 1H), 1.47 (d, J=6.0Hz, 3H), 1.02 (m, 2H), 0.74 (m, 2H) .MS: calculated value: 404; Measured value: [M+H]
+405.
Embodiment 35
According to embodiment 33 similar methods, by suitable amino-benzene, by process synthetic following compound with the acetic acid carbonamidine.
Embodiment 36
3-(5-cyclopropyl-1H-pyrazole-3-yl)-4-fluoro-N-[(S)-1-(4-fluorophenyl) ethyl]-3H-benzo [d] imidazoles-5-amine
With (S)-N
3-(5-cyclopropyl-1H-pyrazole-3-yl)-2-fluoro-N
1-[1-(4-fluorophenyl) ethyl] benzene-1,3,4-triamine (method 71; 0.370g, 1.00mmol) heated 1 hour under refluxing with the mixture of acetic acid carbonamidine (0.209g, 2.00mmol) in EtOH (10ml).After the cooling, reaction mixture is processed with saturated sodium bicarbonate solution (5ml) and EtOAc (15ml).Organic layer is separated, with salt solution (3ml) washing, and use Na
2SO
4Dry.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane: EtOAc=1:1), obtained this title compound, be pale solid (0.125g, 33%).NMR (400MHz) 12.79 (s, 1H), 8.08 (s, 1H), 7.45 (m, 2H), (7.20 d, J=8.4Hz, 1H), 7.09 (t, J=8.8Hz, 2H), 6.60 (t, J=8.2Hz, 1H), 6.19 (s, 1H), 5.68 (d, J=7.2Hz, 1H), 4.65 (m, 1H), 1.98 (m, 1H), 1.47 (d, J=6.8Hz, 3H), 1.01 (m, 2H), 0.77 (m, 2H) .MS: calculated value: 379; Measured value: [M+H]
+380.
Embodiment 37
According to embodiment 36 similar methods, by suitable amino-benzene, by process synthetic following compound with the acetic acid carbonamidine.
Embodiment 38
3-(5-cyclopropyl-1H-pyrazole-3-yl)-6-fluoro-N-[(S)-1-(4-fluorophenyl) ethyl]-3H-benzo [d] imidazoles-5-amine
With (S)-N
3-(5-cyclopropyl-1H-pyrazole-3-yl)-6-fluoro-N
1-[1-(4-fluorophenyl) ethyl] benzene-1,3,4-triamine (method 73; 0.302g, 0.816mmol) heated 1 hour under refluxing with the mixture of acetic acid carbonamidine (0.170g, 1.63mmol) in EtOH (10ml).. after the cooling, reaction mixture is processed with saturated sodium bicarbonate solution (5ml) and EtOAc (15ml).Organic layer is separated, with salt solution (3ml) washing, and use Na
2SO
4Dry.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane: EtOAc=1:1), obtained this title compound, be pale solid (0.170g, 55%).NMR (400MHz) 12.69 (s, 1H), 8.27 (s, 1H), 7.47 (m, 2H), (7.39 d, J=12.0Hz, 1H), 7.12 (t, J=9.0Hz, 2H), 6.96 (d, J=8.0Hz, 1H), 6.07 (s, 1H), 5.90 (d, J=4.8Hz, 1H), 4.56 (m, 1H), 1.96 (m, 1H), 1.51 (d, J=6.8Hz, 3H), 1.02 (m, 2H), 0.76 (m, 2H) .MS: calculated value: 379; Measured value: [M+H]
+380.
Embodiment 39
According to embodiment 38 similar methods, by suitable amino-benzene, by process synthetic following compound with the acetic acid carbonamidine.
Embodiment 40
1-(5-cyclopropyl-1H-pyrazole-3-yl)-N-((S)-1-(4-fluorophenyl) ethyl)-1H-imidazo [4,5-c] pyridine-6-amine
With (S)-N
4-(5-cyclopropyl-1H-pyrazole-3-yl)-N
2-(1-(4-fluorophenyl) ethyl) pyridine-2,4,5-triamine (method 88,0.15g, 0.43mmol) and the mixture of acetic acid carbonamidine (0.089g, 0.85mmol) in EtOH (5ml) heated 2 hours under refluxing.After being cooled to 25 ℃, the saturated NaHCO of reaction mixture
3Solution (10ml) and EtOAc (30ml) process.Organic layer is separated, with salt solution (10ml) washing, and use dried over sodium sulfate.Removal of solvent under reduced pressure, and the gained resistates obtained this title compound by column chromatography purifying (EtOAc-MeOH=40:1), is pale solid (0.092g, 60%).
1H NMR (400MHz) 12.75 (s, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 7.42 (m.., 2H), 7.08 (m, 2H), (6.90 s, 1H), 6.89 (d, J=2.8Hz, 1H), (6.26 d, J=1.6Hz, 1H), 5.00 (m, 1H), (1.96 m, 1H), 1.42 (d, J=6.8Hz, 3H), (1.02 m, 2H), 0.76 (m, 2H) .MS: calculated value: 362; Measured value: [M+H]
+363.
Embodiment 41
(2R)-2-(1-(5-cyclopropyl-1H-pyrazole-3-yl)-1H-imidazo [4,5-c] pyridine-6-base is amino)-2-(4-fluorophenyl) ethanol
With (R)-2-(5-amino-4-(5-cyclopropyl-1H-pyrazole-3-yl is amino) pyridine-the 2-base is amino)-2-(4-fluorophenyl) ethanol (method 93,0.14g, 0.38mmol) and the heating 2 hours under refluxing of the mixture of acetic acid carbonamidine (0.079g, 0.76mmol) in EtOH (5ml).After being cooled to 25 ℃, the saturated NaHCO of reaction mixture
3Solution (10ml) and EtOAc (30ml) process.Organic layer is separated, with salt solution (10ml) washing, and use dried over sodium sulfate.Removal of solvent under reduced pressure, and the gained resistates obtained this title compound by column chromatography purifying (EtOAc-MeOH=20:1), is pale solid (0.22g, 32%).
1H NMR (400MHz) 12.76 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 7.43 (m, 2H), 7.10 (m, 2H), (6.92 s, 1H), 6.72 (d, J=7.2Hz, 1H), (6.25 s, 1H), 4.92 (m, 2H), (3.62 m, 2H), 1.97 (m, 1H), (1.02 m, 2H), 0.77 (m, 2H) .MS: calculated value: 378; Measured value: [M+H]
+379.
Embodiment 42
6-(amino methyl)-3-(5-cyclopropyl-1H-pyrazole-3-yl)-N-((S)-1-(4-fluorophenyl) ethyl)-3H-benzo [d] imidazoles-5-amine
((S)-1-(4-fluorophenyl) ethylamino)-1H-benzo [d] imidazoles-(embodiment 33 for the 5-formonitrile HCN to 1-(5-cyclopropyl-1H-pyrazole-3-yl)-6-, 1.25g, 3.2mmol) and the mixture of 10% palladium on carbon (0.69g, 0.65mmol) in MeOH (40ml) in add 15 dense HCl.Reaction is applied 45psi hydrogen and shook 30 hours.Desolventizing.Resistates is dissolved among the EtOAc (200ml), with saturated sodium bicarbonate (50ml) washing, and uses dried over sodium sulfate.After the desolventizing, resistates is by reversed-phase column chromatography method purifying (5-50%CH
3CN is at H
2Mixture among the O), obtained this title compound, be pale solid (0.81g, 61%).
1H NMR (400MHz) 12.65 (s, 1H), 8.15 (s, 1H), 7.46 (m, 2H), 7.36 (s, 1H), 7.11 (m, 2H), (6.91 d, J=5.6Hz, 1H), 6.74 (s, 1H), (5.94 s, 1H), 4.54 (m, 1H), 3.92 (s, 2H), 2.07-1.91 (m, 3H), 1.48 (d, J=6.4Hz, 3H), 1.01 (m, 2H), 0.72 (m, 2H) .MS: calculated value: 390; Measured value: [M+H]
+391.
Embodiment 43
N-((1-(5-cyclopropyl-1H-pyrazole-3-yl)-6-((S)-1-(4-fluorophenyl) ethylamino)-1H-benzo [d] imidazoles-5-yl) methyl) ethanamide
((S)-1-(4-fluorophenyl) ethyl)-3H-benzo [d] imidazoles-(embodiment 42 for 5-amine with 6-(amino methyl)-3-(5-cyclopropyl-1H-pyrazole-3-yl)-N-with the round-bottomed flask loading in 0 ℃; 0.10g, 0.256mmol) and load the mixture of TFP resin (1.0mmol/g charge capacity, 0.256g, 0.256mmol) in THF-DCM (1:1,3ml) of acetic acid arranged.Gained solution is in 0 ℃ of vigorous stirring 1 hour, and filters by the Jones pipe.The gained resin washs with THF-DCM solution (1:1,3x5ml).After the desolventizing, the gained resistates has obtained this title compound by column chromatography purifying (EtOAc-MeOH=20:1), is pale solid (0.083g, 75%).
1H NMR (400MHz) 12.67 (s, 1H), 8.50 (m, 1H), (8.18 s, 1H), 7.39 (m, 3H), (7.11 m, 2H), 6.73 (s, 1H), (6.09 d, J=6.0Hz, 1H), 5.96 (s, 1H), 4.53 (m, 1H), (4.42 m, 1H), 4.31 (m, 1H), 1.93 (m, 1H), (1.93 s, 3h), 1.47 (d, J=6.4Hz, 3H), 1.02 (m, 2H), 0.76 (m, 2H) .MS: calculated value: 432; Measured value: [M+H]
+433.
Embodiment 44
1-(5-cyclopropyl-1H-pyrazole-3-yl)-6-((S)-1-(4-fluorophenyl) ethylamino)-1H-benzo [d] imidazoles-4-formonitrile HCN
With (S)-2-amino-3-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-5-(1-(4-fluorophenyl) ethylamino) benzonitrile (method 96,3.95g, 10mmol) heated 36 hours under refluxing with the mixture of acetic acid carbonamidine (2.2g, 21mmol) in EtOH (50ml).After the cooling, reaction mixture is processed with saturated sodium bicarbonate solution (30ml) and EtOAc (80ml).Organic layer is separated, with salt solution (30ml) washing, and use dried over sodium sulfate.Removal of solvent under reduced pressure, and the gained resistates obtained this title compound by column chromatography purifying (EtOAc), is pale solid (1.05g, 26%).
1HNMR (400MHz) 12.80 (s, 1H), 8.45 (s, 1H), 7.43 (m, 2H), (7.31 d, J=2.0Hz, 1H), 7.12 (m, 2H), (7.00 d, J=2.0Hz, 1H), 6.75 (d, J=6.8Hz, 1H), 6.22 (d, J=2.0Hz, 1H), 4.58 (m, 1H), 1.97 (m, 1H), 1.44 (d, J=6.4Hz, 3H), 1.03 (m, 2H), 0.75 (m, 2H) .MS: calculated value: 386; Measured value: [M+H]
+387.
Embodiment 45
1-(5-cyclopropyl-1H-pyrazole-3-yl)-6-((S)-1-(4-fluorophenyl) ethylamino)-1H-benzo [d] imidazoles-4-methane amide
With (S)-2-amino-3-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-5-(1-(4-fluorophenyl) ethylamino) benzamide (method 100,3.95g, 10mmol) heated 36 hours under refluxing with the mixture of acetic acid carbonamidine (2.2g, 21mmol) in EtOH (50ml).After the cooling, reaction mixture is processed with saturated sodium bicarbonate solution (30ml) and EtOAc (80ml).Organic layer is separated, with salt solution (30ml) washing, and use dried over sodium sulfate.Removal of solvent under reduced pressure, and the gained resistates obtained this title compound by column chromatography purifying (EtOAc-MeOH=30:1), is pale solid (0.45g, 11%).
1H NMR (400MHz) 12.79 (s, 1H), 9.00 (d, J=2.8Hz, 1H), 8.42 (s, 1H), 7.67 (d, J=2.8Hz, 1H), 7.43 (m, 2H), (7.38 d, J=2.0 Hz, 1H), 7.09 (m, 3H), 6.59 (d, J=6.4Hz, 1H), 6.16 (d, J=1.6Hz, 1H), 4.54 (m, 1H), (1.97 m, 1H), 1.43 (d, J=6.4Hz, 3H), 1.02 (m, 2H), 0.76 (m, 2H) .MS: calculated value: 404; Measured value: [M+H]
+405.
Embodiment 46
3-(5-cyclopropyl-1H-pyrazole-3-yl)-4,6-two fluoro-N-((S)-1-(4-fluorophenyl) ethyl)-3H-benzo [d] imidazoles-5-amine
With (S)-N
3-(5-cyclopropyl-1H-pyrazole-3-yl)-2,6-two fluoro-N
1-(1-(4-fluorophenyl) ethyl) benzene-1,3,4-triamine (method 101,0.278g, 0.718mmol) and the mixture of acetic acid carbonamidine (0.149g, 1.44mmol) in EtOH (10ml) heated 1 hour under refluxing.Add saturated sodium bicarbonate solution (5ml) and EtOAc (15ml).Organic layer is separated, with salt solution (3ml) washing, and use dried over sodium sulfate.Removal of solvent under reduced pressure, and resistates passes through chromatography purification, and (Hex (hexane)-EtOAc=1:1) has obtained this title compound, is white solid (0.120g, 42%).
1HNMR (400MHz) 12.83 (s, 1H), 8.20 (s, 1H), 7.36 (m, 2H), 7.31 (d, J=11.2Hz, 1H), 7.06 (t, J=8.8Hz, 2H), 6.15 (s, 1H), 5.15 (d, J=10.4Hz, 1H), 4.67 (m, 1H), 1.98 (m, 1H), 1.46 (d, J=6.8Hz, 3H), (1.00 m, 2H), 0.76 (m, 2H) .MS: calculated value: 397; Measured value: [M+H]
+398.
Embodiment 47
(2R)-2-(3-(5-cyclopropyl-1H-pyrazole-3-yl)-4,6-two fluoro-3H-benzo [d] imidazoles-5-base is amino)-2-(4-fluorophenyl) ethanol
With (R)-2-(4-amino-3-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-2, the 6-difluorophenyl is amino)-2-(4-fluorophenyl) ethanol (method 104,0.230g, 0.57mmol) and the heating 1 hour under refluxing of the mixture of acetic acid carbonamidine (0.119g, 1.14mmol) in EtOH (10ml).Add saturated sodium bicarbonate solution (5ml) and EtOAc (15ml).Organic layer is separated, and (3ml) washs and uses dried over sodium sulfate with salt solution.Removal of solvent under reduced pressure, resistates has obtained this title compound by chromatography purification (Hex-EtOAc=1:1), is pale solid (0.070g, 30%).
1HNMR (400MHz) 12.83 (s, 1H), 8.20 (s, 1H), 7.34 (m, 3H), 7.07 (t, J=8.8Hz, 2H), 6.14 (s, 1H), 5.14 (d, J=9.6Hz, 1H), 4.97 (t, J=5.6Hz, 1H), 4.62 (m, 1H), (3.64-3.74 m, 2H), 1.97 (m, 1H), (1.00 m, 2H), 0.76 (m, 2H) .MS: calculated value: 413; Measured value: [M+H]
+414.
Embodiment 48
N-(1,3-benzodioxole-5-ylmethyl)-3-(5-cyclopropyl-1H-pyrazole-3-yl)-3H-imidazo [4,5-b] pyridin-5-amine
With 6-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-3-nitropyridine-2-amine (method 77,70mg, 0.25mmol), piperonyl amine (54mg, 0.36mmol), saturated NaHCO
3(0.5ml) mixture with anhydrous Isosorbide-5-Nitrae-dioxs (0.5ml) heated 3 hours in 100 ℃.Make reaction be cooled to room temperature, and solvent is evaporated in Genevac.The gained resistates is processed with zinc powder (195mg, 2.98mmol), formic acid (140 μ L, 3.71mmol) and Isosorbide-5-Nitrae-dioxs (0.5ml), and the gained mixture is reheated to 100 ℃.Heat after 4 hours, reaction is cooled off, and go volatile constituent with the Genevac evaporation.Concentrated reaction mixture MeOH (1ml), DCM (1ml) and Na
2CO
3(125mg) process.This mixture loads on entire mixture the top (the long x1.5cm diameter of～3cm) of short silica gel in stirring at room 45 minutes this moment.With post with MeOH (～15ml) washing, and elutriant is concentrated in Genevac.By from CHCl
3Crystallization among the/MeOH obtains this title compound (7.2mg) by resistates.
1H NMR (400MHz) 0.65-0.76 (m, 2H), 0.99 (m, 2H), 1.96 (m, 1H), 4.41 (m, 2H), 5.94 (s, 2H), (6.45 s, 1H), 6.52 (m, 1H), 6.75 (m, 1H), 6.83 (m, 1H), 6.92 (m, 1H), (7.35 m, 1H), 7.71 (m, 2H), (8.27 s, 1H), 12.60 (s, 1H) .MS: calculated value: 374; Measured value: [M+H]
+375.
Embodiment 49-54
According to embodiment 48 similar methods, by the synthetic following compound of suitable pyridine.
[0394]
[0395]
The preparation parent material:
Method 1
(R)-2-[4-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-6-methyl-5-nitro pyrimidine-2--amino]-2-(4-fluorophenyl) ethanol
With 2-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-6-methyl-5-nitro pyrimidine-4-amine (method 75; 1.0g, 3.4mmol), DIEA (0.57g, 4.4mmol) and (the R)-solution of 2-amino-2-(4-fluorophenyl) ethanol (0.58g, 3.7mmol) in n-BuOH (15ml) be heated to 60 ℃ 2 hours.Then reaction is cooled to 25 ℃, concentrates, and process with hexane.Collect the gained solid via filtering, obtained this title compound (1.3g, 93%).MS: calculated value: 413; Measured value: [M+H]
+414.
Method 2-7
According to method 1 similar method, by 2-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-5-nitro-pyrimidine-4-amine (method 76) or 2-chloro-N-(5-isopropoxy-1H-pyrazole-3-yl)-5-nitro-pyrimidine-4-amine (method 87) and the suitable synthetic following compound of amine.
[0403]
Method 8
(S)-N
4
-(5-cyclopropyl-1H-pyrazole-3-yl)-N
2
-[1-(4-fluorophenyl) ethyl] pyrimidine-2,4, the 5-triamine
In 25 ℃, to (S)-N
4-(5-cyclopropyl-1H-pyrazole-3-yl)-N
2-[1-(4-fluorophenyl) ethyl]-5-nitro-pyrimidine-2,4-diamines (method 9; 0.8g, 2.0mmol) and in the suspension of zinc powder (0.7g, 10.0mmol) in MeOH:THF (1:1,50ml), slowly add saturated NH
4Cl solution (10ml).After 3 hours, the saturated NH of reaction mixture
4The OAc aqueous solution (40ml) is processed, and stirs 30 minutes.Then will react by plug of celite and filter, with EtOAc (100ml) wash-out, and with EtOAc (2x100ml) extraction of gained water layer, drying is filtered, and concentrated, has obtained this title compound (0.04g, 5%).MS: calculated value: 353; Measured value: [M+H]
+354.
Method 9
(S)-N
4
-(5-cyclopropyl-1H-pyrazole-3-yl)-N
2
-[1-(4-fluorophenyl) ethyl]-5-nitro-pyrimidine-2, the 4-diamines
With 2-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-5-nitro-pyrimidine-4-amine (method 76; 1.0g, 3.6mmol), (S)-1-(4-fluorophenyl) ethamine (0.5g, 3.6mmol) and the mixture of DIEA (0.6g, 4.6mmol) in n-BuOH (15ml) stirred 1 hour at 25 ℃, and be then concentrated.Gained oily matter has obtained this title compound (0.8g, 60%) by column chromatography (DCM:MeOH=50:1) purifying.MS: calculated value: 383; Measured value: [M+H]
+384.
Method 10
(S)-ethyl 6-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-2-[1-(4-fluorophenyl) ethylamino]-5-nitro-pyrimidine-4-manthanoate
With 2-chloro-6-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-5-nitro-pyrimidine-4-ethyl formate (method 11; 1.0g, 2.8mmol) and (S)-solution of 1-(4-fluorophenyl) ethamine (0.43g, 3.1mmol) in EtOH (20ml) stirred 1 hour at 25 ℃.To react concentrated, water (50ml) is processed, and with DCM (3x50ml) extraction, drying is filtered, and concentrated.Then resistates has obtained this title compound (0.7g, 53%) by column chromatography purifying (DCM:MeOH=50:1).MS: calculated value: 455; Measured value: [M+H]
+456.
Method 11
2-chloro-6-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-5-nitro-pyrimidine-4-ethyl formate
In THF (20ml) solution of 2,6-, two chloro-5-nitro-pyrimidine-4-ethyl formates (1.0g, 3.80mmol), slowly add the 5-cyclopropyl-mixture of 1H-pyrazoles-3-amine (0.48g, 3.85mmol) in THF (5ml) in 0 ℃.To react on 0 ℃ and stir 10 minutes, water (50ml) is processed, and then uses DCM (3x50ml) extraction, and drying is filtered, and concentrated, has obtained this title compound (1.2g).MS: calculated value: 352; Measured value: [M+H]
+353.
Method 12
(S)-N
2
-(5-cyclopropyl-1H-pyrazole-3-yl)-N
6
-[1-(4-fluorophenyl) ethyl]-3-nitropyridine-2, the 6-diamines
With 6-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-3-nitropyridine-2-amine (method 77; 0.30g, 1.07mmol), (S)-1-(4-fluoro-phenyl) ethylamine (0.23g, 1.61mmol) and the mixture of DIEA (0.23ml, 1.34mmol) in n-BuOH (5ml) the sealing pipe in 165 ℃ the heating 18 hours.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane: EtOAc=1:1), obtained this title compound, be yellow solid (0.41g, 99%).NMR (400MHz) 12.22 (s, 1H), 10.98 (s, 1H), 8.70 (d, J=7.2Hz, 1H), 8.10 (d, J=9.2Hz, 1H), (7.39 m, 2H), 7.18 (m, 2H), 6.22 (d, J=9.2Hz, 1H), 6.17 (s, 1H), 5.27 (m, 1H), 1.89 (m, 1H), 1.52 (d, J=6.4Hz, 3H), 0.95 (m, 2H), 0.64 (m2H) .MS: calculated value: 382; Measured value: [M+H]
+383.
Method 13-15
According to method 12 similar methods, by 6-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-3-nitropyridine-2-amine (method 77) and suitable amine, synthetic following compound.
Method 16
(S)-3-chloro-N
6
-(5-cyclopropyl-1H-pyrazole-3-yl)-N
2
-[1-(4-fluorophenyl) ethyl]-5-nitropyridine-2, the 6-diamines
With 5,6-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-3-nitropyridine-2-amine (method 79; 0.26g, 0.83mmol), (S)-1-(4-fluoro-phenyl) ethylamine (0.17g, 1.25mmol) and the mixture of DIEA (0.22ml, 1.25mmol) in n-BuOH (5ml) the sealing pipe in 165 ℃ the heating 3 hours.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane: EtOAc=1:1), obtained (S)-3-chloro-N
6-(5-cyclopropyl-1H-pyrazole-3-yl)-N
2-(1-(4-fluorophenyl) ethyl)-5-nitropyridine-2, the 6-diamines is yellow solid (0.34g, 99%).NMR (400MHz) .12.29 (s, 1H), 10.68 (s, 1H), 8.27 (s, 1H), 8.24 (d, J=8.0Hz, 1H), 7.39 (m, 2H), 7.16 (m, 2H), 6.11 (s, 1H), 5.42 (m, 1H), 1.89 (m, 1H), 1.60 (d, J=7.2Hz, 3H), (0.95 m, 2H), 0.61 (m, 2H) .MS: calculated value: 416; Measured value: [M+H]
+417.
Method 17-25
According to method 16 similar methods, by suitable parent material and the synthetic following compound of amine.
[0428]
[0429]
[0430]
Method 26
(S)-N
3
-(5-cyclopropyl-1H-pyrazole-3-yl)-N
1
-[1-(4-fluorophenyl) ethyl]-4-oil of mirbane-1, the 3-diamines
With 5-cyclopropyl-N-(5-fluoro-2-nitrophenyl)-1H-pyrazoles-3-amine (method 82; 0.27g, 1.03mmol), (S)-1-(4-fluoro-phenyl)-ethylamine (0.72g, 5.15mmol) and the mixture of DIEA (0.27ml, 1.54mmol) in n-BuOH (5ml) the sealing pipe in 230 ℃ the heating 23 hours.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane: EtOAc=1:2), obtained this title compound, be yellow solid (0.38g, 97%).NMR (400MHz) 12.25 (s, 1H), 10.14 (s, 1H), 7.87 (d, J=9.6Hz, 1H), 7.76 (d, J=6.4Hz, 1H), 7.36 (m, 2H), 7.15 (m, 2H), 6.68 (s, 1H), (6.22 d, J=8.4Hz, 1H), 5.60 (br, 1H), (4.57 m, 1H), 1.87 (m, 1H), 1.44 (d, J=6.8Hz, 3H), 0.98 (m, 2H), 0.70 (m2H) .MS: calculated value: 381; Measured value: [M+H]
+382.
Method 27-31
According to method 26 similar methods, by the synthetic following compound of suitable parent material.
[0437]
Method 32
(S)-4-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-2-[1-(4-fluorophenyl) ethylamino]-the 5-nitrobenzonitrile
With 4-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-2-fluoro-5-nitrobenzonitrile (method 33; 3.0g, 10.4mmol), (S)-1-(4-fluoro-phenyl) ethylamine (1.60g, 11.5mmol) and the mixture of DIEA (2.3ml, 13.1mmol) in n-BuOH (20ml) in sealed tube in 230 ℃ of heating 2 hours.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane: EtOAc=1:2), obtained this title compound, be yellow solid (4.1g, 97%).NMR (400MHz) 12.41 (s, 1H), 9.95 (s, 1H), 8.39 (s, 1H), 7.44 (m, 2H), 7.38 (d, J=6.4Hz, 1H), 7.13 (m, 2H), 6.95 (s, 1H), (5.68 s, 1H), 4.56 (m, 1H), (1.91 m, 1H), 1.55 (d, J=6.8Hz, 3H), 0.96 (m, 2H), 0.72 (m2H) .MS: calculated value: 406; Measured value: [M+H]
+407.
Method 33
4-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-2-fluoro-5-nitrobenzonitrile
In 0 ℃ to 2,4-two fluoro-5-nitrobenzonitrile (method 34,5.0g, 27mmol) and DIEA (5.4ml, 31mmol) drip the 5-cyclopropyl-mixture of 1H-pyrazoles-3-amine (3.2g, 26mmol) in THF (5ml) in the solution in THF (20ml).After the adding, reaction mixture stirred 1 hour in 25 ℃.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane: EtOAc=3:1), obtained this title compound, be yellow solid (5.5g, 74%).NMR (400MHz) 12.54 (s, 1H), 10.13 (s, 1H), 8.78 (d, J=7.2Hz, 1H), 8.10 (d, J=13.6Hz, 1H), 6.02 (s, 1H), (1.91 m, 1H), 0.97 (m, 2H), 0.72 (m, 2H) .MS: calculated value: 287; Measured value: [M+H]
+288.
Method 34
2,4-, two fluoro-5-nitrobenzonitriles
In 0 ℃ saltpetre (16.4g, 147.4mmol) is added to concentrated H
2SO
4In (85ml, 1582mmol), slowly adding 2, the 4-difluoro benzonitrile (11.0g, 79.1mmol) that continues.With suspension this temperature restir 4 hours, then with ice/water (800ml) termination.Filter and collect gained solid and dry, obtained this title compound (13.8g, 95%), be white solid.NMR(400MHz，CDCl
3)8.48(m，1H)，7.24(m，1H).
Method 35
According to method 32 similar methods, by 4-(5-cyclopropyl-1H-pyrazole-3-yl amino)-2-fluoro-5-nitrobenzonitrile (method 33) and suitable amine, synthesize following compound.
[0450]
Method 36
(S)-N
3
-(5-cyclopropyl-1H-pyrazole-3-yl)-2-fluoro-N
1
-[1-(4-fluorophenyl) ethyl]-4-oil of mirbane-1, the 3-diamines
With 5-cyclopropyl-N-(2,3-, two fluoro-6-nitrophenyls)-1H-pyrazoles-3-amine (method 85; 0.400g, 1.43mmol), (S)-1-(4-fluoro-phenyl) ethylamine (0.209g, 1.50mmol) and the mixture of DIEA (0.373ml, 2.14mmol) in n-BuOH (3ml) the sealing pipe in 160 ℃ the heating 8 hours.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane: EtOAc=4:1), obtained this title compound, be orange solids (0.40g, 70%).NMR (400MHz) .11.95 (s, 1H), 8.74 (s, 1H), 7.72 (d, J=9.2Hz, 1H), 7.43 (t, J=7.0Hz, 2H), 7.25 (d, J=6.4Hz, 1H), 7.15 (t, J=8.8Hz, 2H), 6.26 (t, J=8.6Hz, 1H), 5.63 (s, 1H), 4.78 (m, 1H), 1.84 (m, 1H), 1.48 (d, J=6.8Hz, 3H), 0.91 (m, 2H), 0.66 (m, 2H) .MS: calculated value: 399; Measured value: [M+H]
+400.
Method 37
According to method 36 similar methods, by 5-cyclopropyl-N-(2,3-, two fluoro-6-nitrophenyls)-1H-pyrazoles-3-amine (method 85) and suitable amine, synthetic following compound.
Method 38
(S)-N
1
-(5-cyclopropyl-1H-pyrazole-3-yl)-4-fluoro-N
3
-[1-(4-fluorophenyl) ethyl]-6-oil of mirbane-1, the 3-diamines
With 5-cyclopropyl-N-(4,5-, two fluoro-2-nitrophenyls)-1H-pyrazoles-3-amine (method 86; 0.3001.07mmol), (S)-1-(4-fluoro-phenyl) ethylamine (0.164g, 1.18mmol) and the mixture of DIEA (0.280ml, 1.61mmol) in n-BuOH (2ml) the sealing pipe in 160 ℃ the heating 16 hours.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane: EtOAc=3:1), obtained this title compound, be orange solids (0.360g, 84%).NMR (400MHz) 12.29 (s, 1H), 10.14 (s, 1H), 7.75 (d, J=12.8Hz, 1H), 7.63 (d, J=6.4Hz, 1H), 7.41 (m, 2H), 7.14 (t, J=8.8Hz, 2H), 7.00 (d, J=8.0Hz, 1H), 5.63 (s, 1H), 4.55 (m, 1H), 1.90 (m, 1H), 1.52 (d, J=6.8Hz, 3H), 0.98 (m, 2H), 0.71 (m, 2H) .MS: calculated value: 399; Measured value: [M+H]
+400
Method 39
According to method 38 similar methods, by 5-cyclopropyl-N-(4,5-, two fluoro-2-nitrophenyls)-1H-pyrazoles-3-amine (method 86) and suitable amine, synthetic following compound.
Method 40
(R)-2-[5-amino-4-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-6-methylpyrimidine-2-base is amino]-2-(4-fluorophenyl) ethanol
To (R)-2-[4-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-6-methyl-5-nitro pyrimidine-2--amino]-2-(4-fluorophenyl) ethanol (method 1,1.0g, 2.4mmol) and zinc powder (0.79g, 12.0mmol) at MeOH:THF (1:1, in the suspension in mixture 70ml), slowly add saturated NH
4Cl solution (10ml).After 3 hours, will react and use saturated NH
4The OAc aqueous solution (40ml) is processed, and the gained mixture was stirred 30 minutes.Then react by plug of celite and filter, with EtOAc (100ml) wash-out.The gained water layer is extracted with EtOAc (2x100ml), and drying is filtered, and concentrated, obtains (0.8g, 90%) product.MS: calculated value: 383; Measured value: [M+H]
+384.
Method 41-46
According to method 40 similar methods, by the synthetic following compound of suitable nitro-pyrimidine.
[0468]
Method 47
(S)-and ethyl 5-amino-6-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-2-[1-(4-fluorophenyl) ethylamino] pyrimidine-4-manthanoate
To (S)-ethyl 6-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-2-[1-(4-fluorophenyl) ethylamino]-5-nitro-pyrimidine-4-manthanoate (method 10; 0.7g, slowly add saturated NH 1.5mmol) and in the suspension of zinc powder (0.5g, 7.7mmol) in EtOH:THF (1:1,20ml)
4The Cl aqueous solution (3ml).After 1 hour, reaction mixture is cooled to 0 ℃, to wherein adding saturated NH
4OAc solution (10ml).Then the gained mixture filters by plug of celite in 0 ℃ of stirring 10 minutes, with EtOAc (100ml) wash-out.The gained water layer extracts with EtOAc (2x100ml), and drying is filtered, and concentrated, has obtained this title compound (0.60g, 92%), and it uses without being further purified.
Method 48
(S)-N
2
-(5-cyclopropyl-1H-pyrazole-3-yl)-N
6
-[1-(4-fluorophenyl) ethyl] pyridine-2,3, the 6-triamine
To (S)-N
2-(5-cyclopropyl-1H-pyrazole-3-yl)-N
6-[1-(4-fluorophenyl) ethyl]-3-nitropyridine-2,6-diamines (method 12; 0.26g, slowly add saturated ammonium chloride solution (1.5ml) 0.68mmol) and in the suspension of zinc powder (0.223g, 3.41mmol) in MeOH:THF (1:1,12ml).Reaction mixture stirred 1 hour at 25 ℃, then to wherein adding saturated ammonium acetate solution (5ml).Gained mixture restir 30 minutes.Remove by filter zinc powder, and wash with EtOAc (20ml).Organic layer is separated, with salt solution (10ml) washing, use Na
2SO
4Drying, and concentrated.This title compound is not further purified and is directly used in next step.
Method 49-61
According to method 48 similar methods, by the synthetic following compound of suitable nitro-pyridine.
[0477]
[0478]
Method 62
(S)-N
3
-(5-cyclopropyl-1H-pyrazole-3-yl)-N
1
-[1-(4-fluorophenyl) ethyl] benzene-1,3, the 4-triamine
To (S)-N
3-(5-cyclopropyl-1H-pyrazole-3-yl)-N
1-[1-(4-fluorophenyl) ethyl]-4-oil of mirbane-1,3-diamines (method 26; 0.37g, slowly add saturated ammonium chloride (3.0ml) 0.97mmol) and in the suspension of zinc powder (0.317g, 4.85mmol) in MeOH:THF (1:1,24ml).Reaction mixture is in 25 ℃ of stirrings 1 hour, then to wherein adding saturated ammonium acetate solution (5ml).Gained mixture restir 30 minutes.Remove by filter zinc powder, and wash with EtOAc (20ml).Organic layer is separated, with salt solution (10ml) washing, use Na
2SO
4Drying, and concentrated.This crude product is not further purified and is directly used in next step.MS: calculated value: 351; Measured value: [M+H]
+352.
Method 63-68
According to method 62 similar methods, by suitable oil of mirbane, by reduction reaction, synthetic following compound.
Method 69
(S)-and 5-amino-4-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-2-[1-(4-fluorophenyl) ethylamino] benzonitrile
To (S)-4-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-2-[1-(4-fluorophenyl) ethylamino]-5-nitrobenzonitrile (method 32; 4.10g, slowly add saturated ammonium chloride (40ml) 10.1mmol) and in the suspension of zinc powder (3.30g, 50.4mmol) in MeOH:THF (1:1,100ml).Reaction mixture is in 25 ℃ of stirrings 1 hour, to wherein adding saturated ammonium acetate solution (50ml).Gained mixture restir 30 minutes.Remove by filter zinc powder, and wash with EtOAc (200ml).Organic layer is separated, with salt solution (100ml) washing, use Na
2SO
4Drying, and concentrated.This title compound is directly used in next step without being further purified.MS: calculated value: 376; Measured value: [M+H]
+377.
Method 70
According to method 69 similar methods, by the synthetic following compound of suitable oil of mirbane.
Method 71
(S)-N
3
-(5-cyclopropyl-1H-pyrazole-3-yl)-2-fluoro-N
1
-[1-(4-fluorophenyl) ethyl] benzene-1,3, the 4-triamine
To (S)-N
3-(5-cyclopropyl-1H-pyrazole-3-yl)-2-fluoro-N
1-[1-(4-fluorophenyl) ethyl]-4-oil of mirbane-1,3-diamines (method 36; 0.40g, slowly add saturated ammonium chloride (4ml) 1.00mmol) and in the suspension of zinc powder (0.327g, 5.00mmol) in MeOH:THF (1:1,10ml).Mixture was stirred 2 hours in 25 ℃, then to wherein adding saturated ammonium acetate solution (5ml).Gained mixture restir 30 minutes.Remove by filter zinc powder, and wash with EtOAc (15ml).Organic layer is separated, use the salt water washing, use Na
2SO
4Drying, and concentrated.This title compound is directly used in next step without being further purified.
Method 72
With the method that is similar to method 71, by the synthetic following compound of suitable oil of mirbane.This title compound need not be further purified and be directly used in next step.
Method 73
(S)-N
3
-(5-cyclopropyl-1H-pyrazole-3-yl)-6-fluoro-N
1
-[1-(4-fluorophenyl) ethyl] benzene-1,3, the 4-triamine
To (S)-N
1-(5-cyclopropyl-1H-pyrazole-3-yl)-4-fluoro-N
3-[1-(4-fluorophenyl) ethyl]-6-oil of mirbane-1,3-diamines (method 38; 0.33g, slowly add saturated ammonium chloride (4ml) 0.826mmol) and in the suspension of zinc powder (0.270g, 4.13mmol) in MeOH:THF (1:1,10ml).Mixture was stirred 2 hours in 25 ℃, to wherein adding saturated ammonium acetate solution (5ml).Gained mixture restir 30 minutes.Remove by filter zinc powder, and wash with EtOAc (15ml).Organic layer separated and use Na
2SO
4Dry.After the desolventizing, this title compound is directly used in next step without being further purified.
Method 74
According to method 73 similar methods, by the synthetic following compound of suitable oil of mirbane.This compound is directly used in next step without being further purified.
Method 75
2-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-6-methyl-5-nitro pyrimidine-4-amine
5-cyclopropyl-1H-pyrazoles-3-amine (1.8g, 14.0mmol) solution in n-BuOH (25ml) is added to 2, in n-BuOH (60ml) solution of 4-two chloro-6-methyl-5-nitro pyrimidines (3.0g, 14.0mmol) and DIEA (2.4g, 19.0mmol).After 5 minutes, reaction is diluted with hexane (100ml).Filter and collect the gained throw out, obtain title compound (4.1g, 96%).MS: calculated value: 294; Measured value: [M+H]
+295.
Method 76
2-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-5-nitro-pyrimidine-4-amine
In 25 ℃, in the solution in n-BuOH (30ml), slowly add 5-cyclopropyl-1H-pyrazoles-3-amine (2.0g, 16.2mmol) to 2,4-, two chloro-5-nitro-pyrimidines (3.0g, 15mmol) and DIEA (2.4g, 18.5mmol).Gained solution stirred 5 minutes in 25 ℃, and was concentrated into driedly, had obtained this title compound (3.1g).NMR(CDCl
3)0.80(m，2H)，1.05(m，2H)， 6.60(s，1H)，9.20(s，1H)，9.70(br s，1H)，10.40(br s，1H).
Method 77
6-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-3-nitropyridine-2-amine
In 0 ℃, to 2,6-dichloro-3-nitropyridine (0.67g, 3.2mmol) and DIEA (0.46ml, 2.65mmol) in the solution in EtOH (20ml), drip the 5-cyclopropyl-solution of 1H-pyrazoles-3-amine (0.26g, 2.12mmol) in EtOH (5ml).After the adding, reaction mixture stirred 24 hours in 25 ℃.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane: EtOAc=5:1), obtained this title compound, be yellow solid (0.58g, 98%).NMR (400MHz) 12.36 (s, 1H), 10.20 (s, 1H), (8.54 d, J=8.4Hz, 1H), (7.01 d, J=8.4Hz, 1H), (6.39 d, J=1.6Hz, 1H), (1.94 m, 1H), 0.96 (m, 2H), 0.71 (m, 2H) .MS: calculated value: 279; Measured value: [M+H]
+280.
Method 78
According to method 77 similar methods, by nitropyridine, by making itself and suitable amine reaction, synthesized following compound.
Method 79
5,6-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-3-nitropyridine-2-amine
In 0 ℃, to 2,3, in 6-three chloro-5-nitropyridines (1.62g, 7.10mmol) and the solution of DIEA (1.24ml, 7.1mmol) in THF (25ml), drip the 5-cyclopropyl-solution of 1H-pyrazoles-3-amine (0.70g, 5.68mmol) in THF (5ml).After the adding, reaction mixture stirred 24 hours in 25 ℃.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane: EtOAc=1.5:1), obtained this title compound, be yellow solid (0.83g, 47%).NMR (400MHz) 12.39 (s, 1H), 10.12 (s, 1H), 8.77 (d, J=1.2Hz, 1H), 6.35 (s, 1H), 1.95 (m, 1H), 0.96 (m, 2H), 0.71 (m, 2H) .MS: calculated value: 313; Measured value: [M+H]
+314.
Method 80-81
According to method 79 similar methods, by 2,3,6-, three chloro-5-nitropyridines, by making itself and suitable amine reaction, synthesized following compound.
Method 82
5-cyclopropyl-N-(5-fluoro-2-nitrophenyl)-1H-pyrazoles-3-amine
In 25 ℃, to 2,4-, two fluoro-1-oil of mirbane (1.76g, 11.1mmol) and DIEA (1.93ml, 11.1mmol) in the solution in THF (20ml), drip the 5-cyclopropyl-solution of 1H-pyrazoles-3-amine (0.91g, 7.39mmol) in THF (5ml).After the adding, reaction mixture stirred 48 hours in 80 ℃.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane: DCM:EtOAc=2:1:1), obtained this title compound, be yellow solid (0.62g, 32%).NMR(400MHz)12.37(s，1H)，9.83(s，1H)，8.25(m，1H)，7.98(d，J＝11.2Hz，1H)，6.75(m，1H)，5.95(s，1H)，1.90(m，1H)，0.96(m，2H)，0.72(m，2H).
Method 83-84
According to method 82 similar methods, synthesized following compound by 2,4-, two fluoro-1-oil of mirbane and suitable amine.
Method 85
5-cyclopropyl-N-(2,3-, two fluoro-6-nitrophenyls)-1H-pyrazoles-3-amine
In 0 ℃, to 1,2, in 3-three fluoro-4-oil of mirbane (3.2g, 18mmol) and the solution of DIEA (4.2ml, 24mmol) in dry THF (20ml), drip the 5-cyclopropyl-solution of 1H-pyrazoles-3-amine (2.0g, 16mmol) in THF (5ml).After the adding, reaction mixture stirred 21 hours in 25 ℃.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane: EtOAc=5:2).From EtOAc (10ml) and hexane (～100ml) recrystallize, obtained this title compound, be red crystals (1.5g, 33%).NMR (400MHz) 11.90 (s, 1H), 8.78 (s, 1H), 7.86 (t, J=7.6Hz, 1H), 7.08 (q, J=8.7Hz, 1H), 5.60 (s, 1H), (1.83 m, 1H), 0.89 (m, 2H), 0.65 (m, 2H) .MS: calculated value: 280; Measured value: [M+H]
+281.
Method 86
5-cyclopropyl-N-(4,5-, two fluoro-2-nitrophenyls)-1H-pyrazoles-3-amine
In 0 ℃, to 1,2, in 4-three fluoro-5-oil of mirbane (3.0g, 18mmol) and the solution of DIEA (4.2ml, 24mmol) in dry THF (20ml), drip the 5-cyclopropyl-solution of 1H-pyrazoles-3-amine (2.0g, 16mmol) in THF (5ml).After the adding, reaction mixture stirred 20 hours in 25 ℃.Then be heated to 40 ℃ 40 hours.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane: EtOAc=5:2).From EtOAc (10ml) and hexane (～100ml) recrystallize, obtained this title compound, be red crystals (0.8g, 18%).NMR (400MHz) 12.36 (s, 1H), 9.79 (s, 1H), 8.27 (m, 2H), 5.93 (s, 1H), 1.90 (m, 1H), 0.93 (m, 2H), 0.72 (m, 2H) .MS: calculated value: 280; Measured value: [M+H]
+281.
Method 87
2-chloro-N-(5-isopropoxy-1H-pyrazole-3-yl)-5-nitro-pyrimidine-4-amine
In 0 ℃, in 2,4-, two chloro-5-nitro-pyrimidines (0.41g, 2.1mmol) and the solution of DIEA (0.31ml, 1.8mmol) in THF (10ml), add 5-isopropoxy-1H-pyrazoles-3-amine (0.20g, 1.4mmol).Reaction mixture stirred 1 hour in 0 ℃.Removal of solvent under reduced pressure, and the gained resistates obtained this title compound by column chromatography purifying (DCM:EtOAc=2.5:1), is yellow solid (0.19g, 45%).MS: calculated value: 298; Measured value: [M+H]
+299.
Method 88
(S)-N
4
-(5-cyclopropyl-1H-pyrazole-3-yl)-N
2
-(1-(4-fluorophenyl) ethyl) pyridine-2,4, the 5-triamine
To (S)-N
4-(5-cyclopropyl-1H-pyrazole-3-yl)-N
2-(1-(4-fluorophenyl) ethyl)-5-nitropyridine-2,4-diamines (method 89,0.15g, 0.40mmol) and zinc powder (0.13g, 2.0mmol) in the suspension in MeOH-THF (1:1,16ml), slowly add saturated ammonium chloride solution (2ml).Reaction mixture is in 25 ℃ of stirrings 1 hour, to wherein adding saturated ammonium acetate solution (5ml).Gained mixture restir 30 minutes.Remove by filter zinc powder, and wash with EtOAc (20ml).Organic layer is separated, with salt solution (10ml) washing, use Na
2SO
4Drying, and concentrated.This crude product is directly used in next step without being further purified.MS: calculated value: 352; Measured value: [M+H]
+353.
Method 89
(S)-N
4
-(5-cyclopropyl-1H-pyrazole-3-yl)-N
2
-(1-(4-fluorophenyl) ethyl)-5-nitropyridine-2, the 4-diamines
With 2-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-5-nitropyridine-4-amine (method 90,0.15g, 0.54mmol), (S)-1-(4-fluoro-phenyl)-ethylamine (0.093g, 0.67mmol) and the mixture of DIEA (0.12ml, 0.67mmol) in n-BuOH (5ml) the sealing pipe in 180 ℃ the heating 32 hours.Removal of solvent under reduced pressure, and the gained resistates passes through the column chromatography purifying, and (hexane-EtOAc=1:1), obtained this title compound is yellow solid (0.168g, 82%).
1HNMR (400MHz) 12.37 (s, 1H), 9.59 (b, 1H), 8.83 (s, 1H), 8.20 (b, 1H), 7.37 (m, 2H), (7.13 m, 2H), 6.69 (b, 1H), (5.88 b, 1H), 5.29 (m, 1H), (1.91 m, 1H), 1.43 (d, J=6.4Hz, 3H), 0.97 (m, 2H), 0.71 (m2H) .MS: calculated value: 382; Measured value: [M+H]
+383.
Method 90
2-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-5-nitropyridine-4-amine
In 0 ℃, to 2,4-two chloro-5-nitropyridines (method 91,0.42g, 2.18mmol) and DIEA (0.46ml, 2.61mmol) in the solution in THF (10ml), drip the 5-cyclopropyl-solution of 1H-pyrazoles-3-amine (0.31g, 2.50mmol) in THF (5ml).After the adding, reaction mixture stirred 17 hours in 25 ℃.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane: EtOAc=3:1), obtained this title compound, be yellow solid (0.54g, 89%).
1H NMR (400MHz) 12.55 (s, 1H), 9.95 (s, 1H), 8.97 (s, 1H), (8.09 s, 1H), 6.02 (d, J=2.0Hz, 1H), 1.93 (m, 1H), 0.97 (m, 2H), 0.71 (m, 2H) .MS: calculated value: 279; Measured value: [M+H]
+280.
Method 91
2,4-, two chloro-5-nitropyridines
In 0-5 ℃, in the mixture of 4-chloro-5-nitropyridine-2-amine (method 92,4.40g, 21.0mmol) in dense HCl (70ml), add Sodium Nitrite (4.36g, 63.1mmol) in batches., reaction is warmed to room temperature, and stirred 50 hours after 1 hour in 0-5 ℃ of placement.Add ice (100g), and mixture is extracted with ether (2x50ml), and use dried over sodium sulfate.Removal of solvent under reduced pressure, and the gained resistates passes through the column chromatography purifying, and (hexane-DCM=1:5), obtained this title compound is white solid (1.47g, 33%).
1H NMR(400MHz)9.18(s，1H)，8.22(s，1H).
Method 92
4-chloro-5-nitropyridine-2-amine
In the mixture of 4-chloro-3-nitropyridine (10.0g, 63.1mmol) in 500ml liquefied ammonia, add potassium permanganate (19.9g, 126.1mmol).Reaction was stirred 5 hours in this temperature (33 ℃), then slowly was warmed to room temperature.After the ammonia evaporation, add entry (1L).Filter and collect the solid that forms, and water (2L) washing.This solid is extracted with 1:1=DCM:EtOAc (5x500ml).Desolventizing, and with gained solid recrystallize from EtOAc (400ml), obtained this title compound, be yellow solid (4.4g, 33%).
1H NMR(400MHz)8.88(s，1H)，7.65(b，2H)，6.62(s，1H).
Method 93
(R)-2-(5-amino-4-(5-cyclopropyl-1H-pyrazole-3-yl is amino) pyridine-the 2-base is amino)-2-(4-fluorophenyl) ethanol
To (R)-2-(4-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-5-nitropyridine-2-base is amino)-2-(4-fluorophenyl) ethanol (method 94,0.14g, 0.36mmol) and zinc powder (0.12g, 1.78mmol) slowly add saturated ammonium chloride (2.0ml) in the suspension in MeOH-THF (1:1,16ml).Reaction mixture is in 25 ℃ of stirrings 1 hour, then to wherein adding saturated ammonium acetate solution (5ml).Gained mixture restir 30 minutes.Remove by filter zinc powder, and wash with EtOAc (20ml).Organic layer is separated, with salt solution (10ml) washing, use dried over sodium sulfate, and concentrated.This crude product is directly used in next step without being further purified.MS: calculated value: 368; Measured value: [M+H]
+369.
Method 94
(R)-2-(4-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-5-nitropyridine-2-base is amino)-2-(4-fluorophenyl) ethanol
With 2-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-5-nitropyridine-4-amine (method 90,0.15g, 0.54mmol), (R)-2-amino-2-(4-fluorophenyl) ethanol (0.10g, 0.67mmol) and the mixture of DIEA (0.12ml, 0.67mmol) in n-BuOH (5ml) the sealing pipe in 195 ℃ the heating 52 hours.Removal of solvent under reduced pressure, and the gained resistates obtained this title compound by column chromatography purifying (EtOAc), is yellow solid (0.15g, 72%).
1H NMR (400MHz) 12.38 (s, 1H), 9.59 (b, 1H), 8.83 (s, 1H), 8.16 (b, 1H), 7.37 (m, 2H), (7.13 m, 2H), 6.75 (b, 1H), 5.92 (b, 1H), 5.25 (b, 1H), 4.98 (m, 1H), (3.61 t, J=6.4Hz, 2H), 1.92 (m, 1H), (0.97 m, 2H), 0.72 (m, 2H) .MS: calculated value: 398; Measured value: [M+H]
+399.
Method 95
6-chloro-N-(5-isopropoxy-1H-pyrazole-3-yl)-3-nitropyridine-2-amine
In the solution in THF (20ml), add 5-isopropoxy-1H-pyrazoles-3-amine (0.50g, 3.5mmol) to 2,6-dichloro-3-nitropyridine (1.0g, 5.3mmol) and DIEA (0.77ml, 4.4mmol).Reaction mixture stirred 3 days in 25 ℃, and stirred 1 hour in 60 ℃.Removal of solvent under reduced pressure, and the gained resistates passes through the column chromatography purifying, and (hexane-EtOAc=3:1), obtained this title compound is yellow solid (0.62g, 59%).
1H NMR (400MHz) 12.25 and 11.66 (s, 1H), 10.46 and 10.13 (s, 1H), 8.56 (m, 1H), 7.11 and 7.02 (d, J=8.4Hz, 1H), 6.08 with 5.97 (s, 1H), 4.70 and 4.48 (m, 1H), 1.32 and 1.27 (d, J=6.0Hz, 6H) .MS: calculated value: 297; Measured value: [M+H]
+298.
Method 96
(S)-2-amino-3-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-5-(1-(4-fluorophenyl) ethylamino) benzonitrile
To (S)-3-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-5-(1-(4-fluorophenyl) ethylamino)-2-nitrobenzonitrile (method 97,4.20g, 10.0mmol) and zinc powder (3.40g, 52mmol) at MeOH-THF (1:1, in the suspension 100ml), slowly add saturated ammonium chloride (40ml).Reaction mixture is in 25 ℃ of stirrings 1 hour, then to wherein adding saturated ammonium acetate solution (50ml).Gained mixture restir 30 minutes.Remove by filter zinc powder, and wash with EtOAc (200ml).Organic layer is separated, with salt solution (100ml) washing, use dried over sodium sulfate, and concentrated.This crude product is directly used in next step without being further purified.MS: calculated value: 376; Measured value: [M+H]
+377.
Method 97
(S)-3-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-5-(1-(4-fluorophenyl) ethylamino)-2-nitrobenzonitrile
With 3-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-5-fluoro-2-nitrobenzonitrile (method 98,3.50g, 12.2mmol), (S)-1-(4-fluoro-phenyl) ethylamine (1.87g, 13.4mmol) and the mixture of DIEA (2.6ml, 14.6mmol) in n-BuOH (20ml) the sealing pipe in 230 ℃ the heating 2 hours.Removal of solvent under reduced pressure, and the gained resistates passes through the column chromatography purifying, and (hexane-EtOAc=1:2), obtained this title compound is yellow solid (4.4g, 89%).
1H NMR (400MHz) 12.38 (s, 1H), 10.12 (b, 1H), 8.07 (d, J=6.4Hz, 1H), 7.34 (m, 2H), 7.16 (m, 2H), 6.89 (b, 1H), 6.77 (s, 1H), (5.63 m, 1H), 4.55 (m, 1H), (1.90 m, 1H), 1.45 (d, J=6.8Hz, 3H), 0.97 (m, 2H), 0.70 (m2H) .MS: calculated value: 406; Measured value: [M+H]
+407.
Method 98
3-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-5-fluoro-2-nitrobenzonitrile
In 0 ℃, to 3,5-, two fluoro-2-nitrobenzonitrile (methods 99,5.8g, 31.5mmol) and in the solution of DIEA (5.5ml, 31.5mmol) in THF (50ml), drip the 5-cyclopropyl-solution of 1H-pyrazoles-3-amine (4.66g, 37.8mmol) in THF (5ml).After the adding, reaction mixture stirred 20 hours in 25 ℃.Removal of solvent under reduced pressure, and the gained resistates obtained this title compound by column chromatography purifying (DCM-EtOAc=10:1), is yellow solid (5.5g, 61%).
1H NMR (400MHz) 12.43 (s, 1H), 9.70 (s, 1H), 8.22 (dd, J=11.2 and 2.0Hz, 1H), 7.51 (d, J=5.2Hz, 1H), 5.92 (s, 1H), (1.90 m, 1H), 0.95 (m, 2H), 0.71 (m, 2H) .MS: calculated value: 287; Measured value: [M+H]
+288.
Method 99
3,5-, two fluoro-2-nitrobenzonitriles
In 0 ℃ saltpetre 6.56g, 64.8mmol) be added to dense H
2SO
4In (33.7ml, 633mmol), slowly adding 3, the 5-difluoro benzonitrile (4.4g, 31.6mmol) that continues.Then gained suspension use frozen water (500ml) to end in this temperature restir 3 hours.Filter and collect gained solid and dry, obtained this title compound (5.55g, 95%), be white solid.
1H NMR(400MHz，CDCl
3)7.43(m，1H)，7.35(m，1H).
Method 100
(S)-2-amino-3-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-5-(1-(4-fluorophenyl) ethylamino) benzamide
To (S)-3-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-5-(1-(4-fluorophenyl) ethylamino)-2-nitrobenzonitrile (method 97; 4.20g, 10.0mmol) and in the suspension of zinc powder (3.40g, 52mmol) in MeOH-THF (1:1,100ml), slowly add saturated ammonium chloride (40ml).Reaction mixture is in 25 ℃ of stirrings 1 hour, then to wherein adding saturated ammonium acetate solution (50ml).Gained mixture restir 30 minutes.Remove by filter zinc powder, and wash with EtOAc (200ml).Organic layer is separated, with salt solution (100ml) washing, use dried over sodium sulfate, and concentrated.This crude product is directly used in next step without being further purified.MS: calculated value: 394; Measured value: [M+H]
+395.
Method 101
(S)-N
3
-(5-cyclopropyl-1H-pyrazole-3-yl)-2,6-two fluoro-N
1
-(1-(4-fluorophenyl) ethyl) benzene-1,3, the 4-triamine
Saturated ammonium chloride (4ml) solution slowly is added to (S)-N
1-(5-cyclopropyl-1H-pyrazole-3-yl)-2,4-two fluoro-N
3-(1-(4-fluorophenyl) ethyl)-6-oil of mirbane-1 is in 3-diamines (method 102,0.30g, 0.719mmol) and the suspension of zinc powder (0.235g, 3.59mmol) in MeOH/THF (10ml, 1:1).This mixture stirred 2 hours in 25 ℃.Add saturated ammonium acetate solution (5ml), and with mixture restir 30 minutes.Remove by filter zinc powder, and filter cake is washed with EtOAc (15ml).Organic layer is separated, and use dried over sodium sulfate.After the desolventizing, this product is directly used in next step without being further purified.
Method 102
(S)-N
1
-(5-cyclopropyl-1H-pyrazole-3-yl)-2,4-two fluoro-N
3
-(1-(4-fluorophenyl) ethyl)-6-oil of mirbane-1, the 3-diamines
With 5-cyclopropyl-N-(2,3,4-three fluoro-6-nitrophenyls)-1H-pyrazoles-3-amine (method 103,0.300g, 1.01mmol), (S)-1-(4-fluorophenyl) ethylamine (0.154g, 1.11mmol) and the heating 8 hours in setting 135 ℃ oil bath in the pipe of sealing of the mixture of DIEA (0.263ml, 1.51mmol) in n-BuOH (2ml).Removal of solvent under reduced pressure, and resistates passes through chromatography purification, and (hexane-EtOAc=3:1), obtained this title compound is orange solids (0.30g, 71%).
1H NMR (400MHz) 11.89 (s, 1H), 8.57 (s, 1H), 7.69 (d, 1H, J=13.6Hz), 7.35 (m, 2H), 7.14 (t, J=8.8Hz, 2H), 6.81 (d, 1H, 7.6Hz), (5.39 s, 1H), 5.00 (m, 1H), 1.80 (m, 1H), 1.49 (d, J=6.8Hz, 3H), (0.90 m, 2H), 0.62 (m, 2H) .MS: calculated value: 417; Measured value: [M+H]
+418.
Method 103
5-cyclopropyl-N-(2,3,4-, three fluoro-6-nitrophenyls)-1H-pyrazoles-3-amine
In 0 ℃, to 1,2,3, in 4-tetrafluoro-5-oil of mirbane (3.0g, 15.4mmol) and DIEA (3.7ml, the 21.0mmol) mixture in dry THF (20ml), drip the 5-cyclopropyl-mixture of 1H-pyrazoles-3-amine (1.7g, 14.0mmol) in THF (5ml).After the adding, reaction mixture stirred 16 hours in 25 ℃.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane-EtOAc=4:1).With it from Et
2O (20ml) and hexane (～150ml) in recrystallize, obtained this title compound, be red crystals (0.650g, 16%).
1H NMR (400MHz) 11.84 (s, 1H), 8.67 (s, 1H), 8.06 (m, 1H), 5.57 (s, 1H), 1.82 (m, 1H), 0.89 (m, 2H), 0.65 (m, 2H) .MS: calculated value: 298; Measured value: [M+H]
+299.
Method 104
(R)-2-(4-amino-3-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-2, the 6-difluorophenyl is amino)-2-(4-fluorophenyl) ethanol
Saturated ammonium chloride (4ml) solution slowly is added to (R)-2-(3-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-2,6-two fluoro-4-nitrophenyls are amino)-2-(4-fluorophenyl) ethanol (method 105,0.250g, 0.577mmol) and zinc powder (0.189g, 2.88mmol) in the suspension in MeOH/THF (10ml, 1:1).This mixture stirred 5 minutes in 25 ℃.Add saturated ammonium acetate solution (5ml), and with mixture restir 30 minutes.Remove by filter zinc powder, and filter cake is washed with EtOAc (15ml).Organic layer is separated, and use dried over sodium sulfate.After the desolventizing, this product is directly used in next step without being further purified.
Method 105
(R)-2-(3-(5-cyclopropyl-1H-pyrazole-3-yl is amino)-2,6-two fluoro-4-nitrophenyls are amino)-2-(4-fluorophenyl) ethanol
With 5-cyclopropyl-N-(2,3,4-three fluoro-6-nitrophenyls)-1H-pyrazoles-3-amine (method 103,0.300g, 1.01mmol), (R)-2-amino-2-(4-fluorophenyl) ethanol (0.172g, 1.11mmol) and the mixture of DIEA (0.263ml, 1.51mmol) in n-BuOH (2ml) in the pipe of sealing, be set in 135 ℃ the oil bath heating 8 hours.Removal of solvent under reduced pressure, and resistates passes through chromatography purification, and (hexane-EtOAc=1:1), obtained this title compound is orange solids (0.25g, 57%).
1H NMR (400MHz) 11.88 (s, 1H), 8.57 (s, 1H), 7.70 (d, J=13.2Hz, 1H), 7.34 (m, 2H), 7.15 (t, J=8.8Hz, 2H), 6.61 (b, 1H), 5.38 (s, 1H), 5.07 (t, J=5.6Hz, 1H), 4.88 (m, 1H), 3.62-3.71 (m, 2H), 1.80 (m, 1H), (0.90 m, 2H), 0.61 (m, 2H) .MS: calculated value: 433; Measured value: [M+H]
+434.
Purposes
The compounds of this invention is by suppressing Tyrosylprotein kinase, particularly Trk, more especially Trk A and B, and has effectiveness for the treatment cancer.Active and the method for Trk A and B activity more especially for the treatment of target tyrosine kinase activity, particularly Trk, described activity relate to various and process related to cancer.Therefore, Tyrosylprotein kinase, Trk particularly, and the inhibitor of Trk A and B more especially, expectation has activity for ND, and described ND is the cancer of mammary cancer, ovarian cancer, lung cancer, colorectal carcinoma, prostate cancer or other tissue for example, and leukemia and lymphoma, maincenter and peripheral nervous system tumour, and other tumor type for example melanoma, fibrosarcoma and osteosarcoma.Tyrosine kinase inhibitor, particularly Trk inhibitor, and more especially Trk A and B inhibitor are also estimated to can be used for treating other proliferative disease, include but not limited to autoimmune disorder, inflammatory diseases, sacred disease and cardiovascular disorder.
In addition, the compounds of this invention estimates to can be used for to treat or prevent to be selected from the cancer that the Trk kinases of constitutive activation raises, and includes but not limited to, causes ETV6-TrkC fusion, TRP-TrkA fusion rotein, AML-ETO (t8; 21) tumorigenesis is reset, and causes autocrine or the transmission of paracrine signal of the high serum level of NGF, BDNF, neurenergen-III, or the tumour with constitutive activity Trk relevant with affect, tumor growth and hyperplasia or survival signaling transmission.
As described hereinly measure by Trk A test, the compounds of this invention has been proved to be able to suppress Tyrosylprotein kinase, Trk particularly, and more especially Trk A and B.
Compound provided by the invention can also be as measure suppressing Tyrosylprotein kinase, particularly Trk, and more especially standard substance and the reagent of the ability of the potential drug of Trk A and B.Described standard substance and reagent provide with the form of the test kit that comprises the compounds of this invention.
Trk A test frame
Use Amplified Luminescent Proximity Assay (Alphascreen) technology (PerkinElmer, 549 Albany Street, Boston, MA), measure the TrkA kinase activity, to obtain the ability of its phosphorylation synthetic hydroxyphenylaminopropionic acid residue in general peptide substrate.
In order to measure Trk A kinase activity, at the people Trk A of SF9 cells HIS-mark kinases (the amino acid 442-796 of Trk A, Swiss-Prot Primary Accession Number P04629) cell intracellular domain, and Application standard nickel column chromatography is carried out purifying.Kinases and biotinylated substrate and Triphosaden (ATP) after 20 minutes, are ended kinase reaction by adding 30mM ethylenediamine tetraacetic acid (EDTA) (EDTA) in incubated at room temperature.This reaction is to carry out in 384 hole microtiter plates, and after incubated at room temperature is spent the night, use EnVision Multilabel Plate Reader, Acceptor Beads with the Donor Beads that covers streptoavidin and covering Tyrosine O-phosphate specific antibody comes the detection reaction product.
Although the pharmacological characteristic of formula (I) compound changes along with the change of structure, the general activity that formula (I) compound has can be passed through IC
50Concentration (reaching 50% concentration that suppresses) or the dosage range of (0.01 μ M-10 μ M) show.
When in above-mentioned in vitro tests, measuring, recorded with following IC
50It is active that the Trk of the following example compound of expression suppresses.
Claims (7)
1. formula (I) compound:
Wherein:
R
1Methyl, isopropoxy or cyclopropyl;
R
2Hydrogen;
X
1And X
2Be independently selected from=CR
10-and X
3Be-N=;
R
3Hydrogen;
R
4Hydrogen;
R
5And R
6Be independently selected from hydrogen and C
1-6Alkyl;
A is direct key;
Ring C is pyrimidine-2-base;
R
7It is halogen;
R
10Hydrogen; With
N is 1;
Or its pharmacologically acceptable salt.
2. the formula of claim 1 (I) compound or pharmaceutically acceptable salt thereof, wherein R
1It is isopropoxy; R
2Hydrogen; X
1And X
2Be independently selected from=CR
10-, and X
3Be-N=; R
3Hydrogen; R
4Hydrogen; R
5It is methyl; R
6Hydrogen; A is direct key; Ring C is pyrimidine-2-base; R
7It is fluorine; R
10Hydrogen, and n=1.
3. the method for preparation formula (I) compound or pharmaceutically acceptable salt thereof, variable group wherein, unless other regulation, as defined in claim 1, described method comprises:
Method a) makes (II) compound:
Wherein Pg is nitrogen-protecting group; With formula (III) compound:
Wherein L is displaceable group, reacts;
Method c) for X wherein
1Be=CR
10-formula (I) compound; Make formula (V) compound:
React with formula (VI) compound:
And then if necessary:
I) remove any protecting group;
Ii) form pharmacologically acceptable salt.
4. formula (I) compound or pharmaceutically acceptable salt thereof of any one claim in the claim 1 or 2 is in the application aspect the medicine that suppresses the Trk activity.
5. formula (I) compound or pharmaceutically acceptable salt thereof of any one claim in the claim 1 or 2 is in the application aspect the medicine for the treatment of or preventing cancer.
6. formula (I) compound or pharmaceutically acceptable salt thereof of any one claim in the claim 1 or 2 is in the application aspect the medicine that produces anti-proliferative effect.
7. comprise formula (I) compound or pharmaceutically acceptable salt thereof of any one claim in claim 1 or 2 and the pharmaceutical composition of at least a pharmaceutically acceptable carrier, thinner or vehicle.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US65357505P | 2005-02-16 | 2005-02-16 | |
| US60/653,575 | 2005-02-16 | ||
| US74213805P | 2005-12-01 | 2005-12-01 | |
| US60/742,138 | 2005-12-01 | ||
| PCT/GB2006/000513 WO2006087530A1 (en) | 2005-02-16 | 2006-02-15 | Chemical compounds |
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| Publication Number | Publication Date |
|---|---|
| CN101119988A CN101119988A (en) | 2008-02-06 |
| CN101119988B true CN101119988B (en) | 2013-03-06 |
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ID=39055584
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|---|---|---|---|
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|---|---|
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| EP2964649B1 (en) * | 2013-03-05 | 2017-05-10 | Merck Patent GmbH | Triazolo[4,5-d]pyrimidine derivatives for the treatment of diseases such as cancer |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6455525B1 (en) * | 1999-11-04 | 2002-09-24 | Cephalon, Inc. | Heterocyclic substituted pyrazolones |
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- 2006-02-15 CN CN200680005004.2A patent/CN101119988B/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6455525B1 (en) * | 1999-11-04 | 2002-09-24 | Cephalon, Inc. | Heterocyclic substituted pyrazolones |
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|---|---|
| CN101119988A (en) | 2008-02-06 |
| UA93198C2 (en) | 2011-01-25 |
| ZA200706493B (en) | 2008-08-27 |
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