CN101119988A - Chemical compouns - Google Patents
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- CN101119988A CN101119988A CN200680005004.2A CN200680005004A CN101119988A CN 101119988 A CN101119988 A CN 101119988A CN 200680005004 A CN200680005004 A CN 200680005004A CN 101119988 A CN101119988 A CN 101119988A
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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 of treatment with preventing cancer, and relate to these pyrazole derivatives and be used for the treatment of application in the medicine with preventing cancer in preparation.
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 solvable somatomedin activated high affinity acceptor that is known as 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 (part combination), strides film district and born of the same parents' intracellular domain (comprising kinase domain).When combining with part, kinase catalytic automatic phosphorylation 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 back 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, people such as A., Current Opinion inNeurobiology, 2001,11,272-280).
In in the past 10 years, delivered a large amount of documents that 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 is expressed in the advanced prostate cancer to be increased.The tumor of prostate that normal prostate tissue and male sex hormone rely on 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 that 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, people such as A.T., TheProstate, 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), 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, people such as D., Cancer Research, 1999,59,2395-2341) and other indolocarbazole analogue (WO0114380).Evidence suggests, compare that when eliminating when linked together with the male sex hormone of operation or chemical induction, CEP-701 and/or CEP751 provide better effectiveness with single therapy.GlaxoSmithKline discloses some the oxindole compound as the TrkA inhibitor in WO0220479 and WO0220513.Recently, Japan Tobacco has reported the pyrazolyl fused ring compound (JP2003231687A) as the Trk inhibitor.
Except that 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 preparation be used for warm-blooded animal for example the mankind produce application in the medicine of anti-hyperplasia and/or apoptosis-promoting effect.
According to the present invention, the applicant also provides described pyrazole compound or its pharmacologically acceptable salt is used for the treatment of method for cancer.
The character of claimed compounds of the present invention is estimated valuable in the treatment of conditions 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 outgrowth illness in eye of retinal vessel.
In addition, The compounds of this invention or its pharmacologically acceptable salt are estimated in being selected from following treatment for 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 the intractable prostate cancer of hormone, 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 the intractable prostate cancer of hormone 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
4Be hydrogen 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
2Be hydrogen.
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
4Be hydrogen.
R
4Be 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 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
6Be hydrogen.
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 hydroxyl methylene radical.
Ring C is a heterocyclic radical; If wherein described heterocyclic radical contains-the NH-part, nitrogen can be chosen wantonly and is selected from R so
19Group replace;
Ring C is a 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 a phenyl.
Ring C is a pyridyl.
Ring C is pyridine-2-base.
Ring C is a pyrimidyl.
Ring C is a 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
7Be trifluoromethyl 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 4-fluorophenyl together, 5-fluorine pyridine-2-base or 5-fluorine pyrimidine-2-base.
Ring C, R
7Form the 4-fluorophenyl together with n.
Ring C, R
7Form 5-fluorine pyridine-2-base together with n.
Ring C, R
7Form 5-fluorine pyrimidine-2-base together 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
4Be hydrogen;
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
4Be hydrogen;
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 a 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
2Be hydrogen;
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
4Be hydrogen;
R
5Be selected from hydrogen, methyl, ethyl or hydroxymethyl;
R
6Be selected from hydrogen or hydroxymethyl;
A is direct key, methylene radical or hydroxyl methylene radical;
Ring C is phenyl, pyridine-2-base, 1,3-benzodioxole-5-base or 1H-indol-3-yl;
R
7Be trifluoromethyl 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
2Be hydrogen;
X
1, X
2And X
3Be independently=N-or=CR
10-;
R
3Be selected from hydrogen, methyl and hydroxymethyl;
R
4Be hydrogen;
R
5Be selected from hydrogen, methyl or hydroxymethyl;
R
6Be selected from hydrogen or hydroxymethyl;
A is direct key;
Ring C is a 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 preparing formula (I) compound or pharmaceutically acceptable salt thereof that is used to suppress the active medicine of Trk.
In other embodiments of the present invention, be provided for preparing and be used for the treatment of or formula (I) compound or pharmaceutically acceptable salt thereof of the medicine of preventing cancer.
In other embodiments of the present invention, be provided for preparing and be used at warm-blooded animal formula (I) compound or pharmaceutically acceptable salt thereof of the medicine of mankind treatment cancer for example.
In other embodiments of the present invention, be provided for preparing and be used for: 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 outgrowth illness in eye of retinal vessel in for example mankind treatment or prevent formula (I) compound or pharmaceutically acceptable salt thereof of following disease of warm-blooded animal.
In other embodiments of the present invention, be provided for preparing formula (I) compound or pharmaceutically acceptable salt thereof of the medicine that is used to produce anti-proliferative effect.
In other embodiments of the present invention, provide and suppress the active method of Trk, described method comprises formula (I) compound or pharmaceutically acceptable salt thereof of host's drug treatment significant quantity for the treatment of like this to needs.
In other embodiments of the present invention, the treatment method for cancer is provided, described method comprises formula (I) compound or pharmaceutically acceptable salt thereof of host's drug treatment significant quantity for the treatment of like this to needs.
In other embodiments of the present invention, the method for treatment 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 outgrowth illness in eye of retinal vessel, 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 treatment so for example produces anti-proliferative effect among the mankind, this 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 active pharmaceutical composition of Trk, 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 outgrowth illness in eye of retinal vessel, 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 the active formula of Trk (I) compound or pharmaceutically acceptable salt thereof.
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 of treatment 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 outgrowth illness in eye of retinal vessel.
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 the active embodiment of inhibition Trk, specifically be meant and suppress the TrkA activity.
In relating to active another embodiment of Trk inhibition, specifically be meant and suppress the TrkB activity.
Under the situation that relates to treatment (or prevention) cancer, specifically be meant 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 the intractable prostate cancer of hormone, 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 be meant prostate cancer.In addition, more specifically be meant SCLC, NSCLC, colorectal carcinoma, ovarian cancer and/or mammary cancer.On the other hand, be meant the intractable prostate cancer of hormone.
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 other regulation, suc as formula defined in (I)) comprising:
Method a) makes (II) compound:
Wherein Pg is a nitrogen-protecting group; With formula (III) compound:
Wherein L is a displaceable group, reacts;
Method b) for R wherein
5Be hydroxymethyl 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 the 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 a 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 a 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 The suitable solvent under temperature range 25-100 ℃, are reacted 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 document, 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 The suitable solvent CH for example
3CN exists down, 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 document, and perhaps it can prepare by standard method known in the art.
Method c) formula V and formula (VI) compound can under reflux temperature, react together at The suitable solvent ethanol for example.
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 document, 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 document, and perhaps it can prepare by standard method known in the art.
Some intermediate disclosed herein is new, and therefore described intermediate constitutes another feature of the present invention.
Should be appreciated that some ring substituents in the The compounds of this invention, can or be right after before aforesaid method thereafter that 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, use for example carboxylic acid halides and Lewis acid (for example aluminum chloride) introducing 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 handling 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 handle and remove.For primary amino, suitable in addition protecting group is a phthaloyl for example, and it can be by with alkylamine dimethylamino propylamine or handle with hydrazine and to remove 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 handled and removed 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.
Can remove protecting group with the well-known routine techniques of chemical field in any suitable stage in synthetic.
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, only refer in particular to the side chain form mentioning concrete indivedual branched-chain alkyls for example when " sec.-propyl ".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 under 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.The 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, high piperazinyl, 3,5-two oxa-piperidyls, THP trtrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, different azoles base, N-methylpyrrole base, the 4-pyriconyl, the 1-isoquinolone, 2-Pyrrolidone, the 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide compound.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 " be meant any group with m-n carbon atom.
Term " optional replacement " is meant 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 " is meant room temperature.
The suitable pharmacologically acceptable salt of The compounds of this invention is, for example, enough acid salt of Jian Xing The compounds of this invention, 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, the pharmacologically acceptable salt of enough tart The compounds of this invention is an 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, for example salt that forms with methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three-(2-hydroxyethyl) amine with physiology is provided.
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-solventization 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 route of administration, severity of disease, patient's age 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 granules agent, 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 to form capsular material.
In pulvis, carrier is the solid in small, broken bits with active ingredient blended in small, broken bits.In tablet, active ingredient and the carrier with necessary binding characteristic with suitable mixed, and are pressed into the shape and size that need.
For the preparation suppository composition, active ingredient is interspersed among wherein at first with the low melt wax mixture melt of glycerin fatty acid ester and Oleum Cocois for example, and by for example stirring.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, the salt that forms with organic bases for example dicyclohexyl amine salt, N-methyl-D-glucamine salt and with the amino acid salt that forms such as arginine, Methionin, ornithine for example.And, can be alkaline nitrogen-containing group is quaternized: low alkyl group halogen, for example methyl halide, ethyl halide, propyl halide and butyl halide with such quaternizing agent; 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 is bromotoluene etc. for example.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 how normal suitable acid 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, according to the standard pharmaceutical practice it is formulated as pharmaceutical composition usually.
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 of treatment, perhaps with described medicine co-administered (simultaneously or in succession).
The term composition means the preparation that comprises 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: tablet, capsule, water or oil solution, suspension, emulsion, emulsifiable paste, ointment, gel, nasal spray, suppository, powder or aerosol that is used to suck or propellant in small, broken bits, and parenteral uses the sterilized water of (comprising intravenously, intramuscular or infusion) or solution or the 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 suitable tinting material, seasonings, stablizer and thickening material on demand, prepare the aqueous solution that is used for 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 for example natural and synthetic natural gum, resin, methylcellulose gum, Xylo-Mucine and known other suspension agent of field of pharmaceutical preparations.
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 the pulvis in Bao Zhuan tablet, capsule and bottle or the ampoule.Unit dosage also can be capsule, cachet or a tablet itself, and perhaps unit dosage can be any of these packaged form 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 fluorine miazines); 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 vincristine(VCR), vinealeucoblastine(VLB), vindesine and vinorelbine and for example safe plain class of taxoids and taxotere); And topoisomerase enzyme inhibitor (for example epipodophyllotoxin for example Etoposide and teniposide, amsacrine, Hycamtin and camptothecine);
The medicine that (ii) suppresses cell is estrogen antagonist material (tamoxifen branch for example for example, 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;
The (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 comprise growth factor antibodies, growth factor receptor antibody (anti--erbb2 antibody trastuzumab[Herceptin for example
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 somatomedin 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, (for example anti-angiogenic epithelical cell growth factor antibody rhuMAb-VEGF [Avastin
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 angiogenic growth statin);
(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 at the antisense therapy of the target of listing above, ISIS2503 for example, a kind of anti--agent of ras antisense therapy;
(viii) gene therapy method, comprise the method for for example replacing for example unusual p53 of aberrant gene or unusual BRCA1 or BRCA2, 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 method in the immunogenic external indirectly and body that for example increases the 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 (13-cis-retinoic acid), 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 Several Methods prepares for the technician in organic synthesis field.The compounds of this invention or its pharmacologically acceptable salt can be with the methods that describes below, and the known method in synthetic organic chemistry field, perhaps prepared according to understanding it is changed 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 in view of the above.
New compound of the present invention or its pharmacologically acceptable salt can use reaction described herein and technology to prepare.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 those skilled in the art's standard conditions of the described reaction of understanding easily.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, be conspicuous for a person skilled in the art, and must use alternative method with reaction conditions.
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 on silica gel; Tlc (TLC) is carried out on 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 to be used for explanation and provide the reaction times;
(v) final product has satisfactory proton magnetic resonance (PMR) (NMR) spectrum and/or mass-spectrometric data;
(only be used for illustration purpose vi) for the rate of output, and nonessential be the productive rate of improving one's methods and can obtain by making great efforts; More if desired material can prepare repeatedly;
(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 ethyl acetate;
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 amino)-6-methylpyrimidine-2-base is amino]-2-(4-fluorophenyl) ethanol (method 40; 0.3g 0.8mmol) (0.2g, 1.6mmol) mixture heating up in EtOH (8ml) is to refluxing 12 hours with the acetate carbonamidine.To react concentrated then, and be dissolved among the DCM (50ml), and use saturated NaHCO
3Solution (50ml) washing.With organic layer drying, filtration and concentrated.The gained solid is by column chromatography purifying (DCM: MeOH=20: 1), obtained this title compound (0.11g, 35%).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,,, synthesize following compounds by handling with acetate carbonamidine (or use acetamidine hydrochloride for embodiment 6) by suitable amino-pyrimidine.
| Embodiment | Compound | NMR | Synthetic method |
| 2 | 9-(5-cyclopropyl-1H-pyrazoles-3-yl)-N-[(1S)-1-(4-fluorophenyl) ethyl]-9H-purine-2-amine | 0.77(m，2H)，1.02(m，2H)，1.42(m， 3H)，1.98(m，1H)，5.04(brs，1H)， 6.30(m，1H)，7.09(m，2H)，7.43(m， 2H)，7.85(brs，1H)，8.38(s，1H)， 8.68(s，1H)，12.73(s，1H) | Method 41 |
| 3 | (2R)-and 2-{[9-(5-cyclopropyl-1H-pyrazole-3-yl)-9H-purine-2-yl] amino }-2-(4-fluorophenyl) ethanol | 0.77(m，2H)，1.04(m，2H)，1.99(m， 1H)，3.63(m，2H)，4.91(m，1H)， 6.20(m，1H)，7.09(m，2H)，7.43(m， 2H)，7.60(brs，1H)，8.38(s，1H)， 8.68(s，1H)，12.73(s，1H) | Method 42 |
| 4 | 9-(5-cyclopropyl-1H-pyrazoles-3-yl)-N-(4-luorobenzyl)-9H-purine-2-amine | 0.71(m，2H)，0.99(m，2H)，1.96(m， 1H)，4.50(m，2H)，6.34(m，1H)， 7.09(m，2H)，7.39(m，2H)，7.88(brs， 1H)，8.39(s，1H)，8.70(s，1H)， 12.74(s，1H) | Method 43 |
| Embodiment | Compound | NMR | Synthetic method |
| 5 | 9-(5-cyclopropyl-1H-pyrazoles-3-yl)-N-[(1R)-1-(4-fluorophenyl) ethyl]-9H-purine-2-amine | 0.75(m，2H)，1.02(m，2H)，1.42(m， 3H)，1.98(m，1H)，5.04(brs，1H)， 6.28(m，1H)，7.09(m，2H)，7.44(m， 2H)，7.85(brs，1H)，8.37(s，1H)， 8.67(s，1H)，12.73(s，1H) | Method 44 |
| 6 | 9-(5-cyclopropyl-1H-pyrazoles-3-yl)-N-[(1S)-1-(4-fluorophenyl) ethyl]-8-methyl-9H-purine-2-amine | (CDCl 3)：0.71(m，2H)，0.95(m，2H)， 1.45(m，3H)，1.86(m，1H)，2.60(s， 3H)，5.07(m，1H)，5.80(brs，1H)， 6.05(s，1H)，6.90(m，2H)，7.30(m， 2H)，8.59(s，1H)，11.74(brs，1H) | Method 41 |
| 7 | (2R)-2-(4-fluorophenyl)-2-(9-(5-methyl isophthalic acid H-pyrazoles-3-yl)-9H-purine-2-base is amino) ethanol | (400MHz) 12.68 (s, 1H), 8.70 (s, 1H), 8.40 (s, 1H), 7.61 (b, 1H), 7.46 (m, 2H), 7.12 (m, 2H), 6.38 (b, 1H), 4.93 (m, 2H), 3.65 (m, 2H), 2.34 (s, 3H) .MS: calculated value: 353; Measured value: [M+H] +354. | Method 45 |
| 8 | N-((S)-1-(4-fluorophenyl) ethyl)-9-(5-isopropoxy-1H-pyrazole-3-yl)-9H-purine-2-amine | (400MHz) 12.57 (s, 1H), 8.70 (s, 1H), 8.39 (s, 1H), 7.92 (b, 1H), 7.44 (m, 2H), 7.09 (m, 2H), 6.05 (b, 1H), 5.10 (b, 1H), 4.53 (m, 1H), 1.46 (d, J=6.8Hz, 3H), 1.40 and 1.35 (d, J=6.0 Hz, 6H) .MS: calculated value: 381; Measured value: [M+H] +382. | Method 46 |
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 is amino]-2-(4-fluorophenyl) ethanol
In 25 ℃, amino to (R)-2-[5-amino-4-(5-cyclopropyl-1H-pyrazole-3-yl amino)-6-methylpyrimidine-2-base]-2-(4-fluorophenyl) ethanol (method 40; 0.18g, 0.47mmol) acetic acid aqueous solution (5%, 3ml) in the solution in, drip NaNO
2(0.032g, 0.47mmol, 1ml H
2O).To react restir 5 minutes, water (10ml) is handled, with DCM (3 * 25ml) extractions.With the saturated NaHCO of organic layer
3Solution (50ml) washing, drying is filtered and is concentrated.The gained solid is by column chromatography purifying (DCM: MeOH=30: 1), obtained this title compound (0.15g, 81%).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] triazole
And [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%, 3ml) in the solution in, slowly add NaNO
2The aqueous solution (0.008g, 0.1mmol, 1ml H
2O).To react restir 5 minutes, water (10ml) is handled, and (3 * 25ml) extract with DCM.With the saturated NaHCO of organic layer that merges
3Solution (50ml) washing, drying is filtered, and concentrates.The gained solid is by column chromatography purifying (DCM: MeOH=15: 1), obtained this title compound (0.015g, 40%).NMR (400MHz, CD
3OD) 9.05 (s, 1H), 7.44-7.41 (m, 2H), 7.03-6.99 (m, 2H), 6.23 (s, 1H), and 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]-the 9H-purine-
The 6-ethyl formate
With (S)-ethyl 5-amino-6-(5-cyclopropyl-1H-pyrazole-3-yl amino)-2-[1-(4-fluorophenyl) ethylamino] pyrimidine-4-manthanoate (method 47; 0.6g 1.4mmol) (0.32g, 3.1mmol) mixture heating up in EtOH (20ml) is to refluxing 12 hours with the acetate carbonamidine.Reaction is concentrated, and the gained resistates is dissolved among the EtOAc (50ml) and uses saturated NaHCO
3Solution (50ml) washing.With the organic layer drying, filter and concentrate.The gained solid is by column chromatography purifying (DCM: MeOH=20: 1), obtained this title compound (0.058g, 8%).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) ethylamino]-9H-purine-
The 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 ℃.Slow adding lithium aluminum hydride in this solution (solution of 1.0M in THF, 0.076ml, 1.1eq.).Reaction mixture stirred 30 minutes in 0 ℃, added the sodium sulfate decahydrate this moment till the bubble that stops to overflow.To react then by plug of celite and filter, (3 * 30ml) wash, and concentrate with THF.The gained resistates is by column chromatography purifying (DCM: MeOH=15: 1), obtained this title compound (0.09g, 33%).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), and 5.10-5.07 (m, 1H), 5.03 (s, 2H), and 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]-the 3H-imidazo
[4,5-b] pyridine-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) (0.113g, 1.09mmol) mixture in EtOH (5ml) heated 2 hours under refluxing with the acetate carbonamidine.After being cooled to 25 ℃, the saturated NaHCO of reaction mixture
3Solution (10ml) and EtOAc (30ml) handle.Organic layer is separated,, and use Na with salt solution (10ml) washing
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 (m 2H), 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 handle synthetic following compounds with the acetate carbonamidine.
| Embodiment | Compound | NMR/MS | Synthetic method |
| 14 | N-(4-luorobenzyl)-3-(5-cyclopropyl-1H-pyrazole-3-yl)-3H-imidazo [4,5-b] pyridine-5-amine | NMR (400MHz) .12.59 (s, 1H), 8.27 (s, 1H), 7.74 (d, J=8.4Hz, 1 H), 7.40 (m, 2H), 7.13 (m, 2H), 6.54 (d, J=8.8Hz, 1H), 6.36 (s, 1H), 4.50 (d, J=5.6Hz, 2H), 1.95 (m, 1H), 1.00 (m, 2H), 0.68 (m, 2H) .MS: calculated value: 348; Measured value: [M+H] +349. | Method 49 |
| 15 | (2R)-2-[3-(5-cyclopropyl-1H-pyrazole-3-yl)-3H-imidazo [4,5-b] pyridine-5-base is amino]-2-(4-fluorophenyl) ethanol | (400MHz) .12.58 (s, 1H), 8.26 (s, 1H), 7.72 (d, J=8.8Hz, 1H), 7.43 (m, 2H), 7.24 (d, J=6.4Hz, 1H), 7.09 (m, 2H), 6.62 (d, J=8.8Hz, 1H), 6.28 (s, 1H), 4.91 (m, 1H), 3.64 (t, J=6.0Hz, 1H), 3.30 (m, 2H), 2.00 (m, 1H), 1.06 (m, 2H), 0.70-0.80 (m, 2H) .MS: calculated value: 378; Measured value: [M+H] +379 | Method 50 |
| 16 | 2-[3-(5-cyclopropyl-1H-pyrazole-3-yl)-3H-imidazo [4,5-b] pyridine-5-base is amino]-2-(4-fluorophenyl) the third-1, the 3-glycol | (400MHz) .12.49 (s, 1H), 8.20 (s, 1H), 7.71 (d, J=8.8Hz, 1H), 7.45 (m, 2H), 7.07 (m, 2H), 6.75 (s, 1H), 6.71 (d, J=8.8Hz, 1H), 5.55 (s, 1H), 4.86 (t, J=5.2Hz, 2H), 3.96 (m, 4H), 1.86 (m, 1H), 1.00 (m, 2H), 0.60 (m, 2H) .MS: calculated value: 408; Measured value: [M+H] +409 | Method 51 |
| Embodiment | Compound | NMR/MS | Synthetic method |
| 17 | 6-chloro-3-(5-cyclopropyl-1H-pyrazole-3-yl)-N-[(S)-1-(4-fluorophenyl) ethyl]-3H-imidazo [4,5-b] pyridine-5-amine | (400MHz). 12.65 (s, 1H), 8.36 (s, 1H), 8.05 (s, 1H), 7.46 (m, 2H), 7.10 (m, 2H), 5.80 (d, J=6.8Hz, 1H), 6.21 (s, 1H), 5.17 (m, 1H), 1.99 (m, 1H), 1.56 (d, J=7.20Hz, 3H), 1.06 (m, 2H), 0.70-0.80 (m, 2H) .MS: calculated value: 396; Measured value: [M+H] +397. | Method 52 |
| 18 | N-(4-luorobenzyl)-6-chloro-3-(5-cyclopropyl-1H-pyrazoles-3-yl)-3H-imidazo [4,5-b] pyridine-5-amine | (400MHz). 12.66 (s, 1H), 8.37 (s, 1H), 8.06 (s, 1H), 7.40 (m, 3H), 7.11 (m, 2H), 6.20 (s, 1H), 4.60 (d, J=6.0Hz, 1H), 1.94 (m, 1H), 1.01 (m, 2H), 0.65 (m, 2H) .MS: calculated value: 382; Measured value: [M+H] +383. | Method 53 |
| 19 | (2R)-2-[6-chloro-3-(5-cyclopropyl-1H-pyrazole-3-yl)-3H-imidazo [4,5-b] pyridine-5-base is amino]-2-(4-fluorophenyl) ethanol | (400MHz) 12.64 (s, 1H), 8.38 (s, 1H), 8.09 (s, 1H), 7.44 (m, 2H), 7.12 (m, 2H), 6.65 (d, J=6.0Hz, 1H), 6.13 (s, 1H), 5.14 (t, J=5.6Hz, 1H), 5.04 (m, 1H), 3.69-3.80 (m, 2H), 1.98 (m, 1H), 1.06 (m, 2H), 0.70-0.80 (m, 2H) .MS: calculated value: 412; Measured value: [M+H] +413. | Method 54 |
| 20 | (2R)-2-[6-chloro-3-(5-methyl isophthalic acid H-pyrazole-3-yl)-3H-imidazo [4,5-b] pyridine-5-base is amino]-2-(4-fluorophenyl) ethanol | (400MHz) 12.57 (s, 1H), 8.39 (s, 1H), 8.10 (s, 1H), 7.46 (m, 2H), 7.13 (m, 2H), 6.63 (d, J=5.2Hz, 1H), 6.15 (s, 1H), 5.16 (t, J=5.6Hz, 1H), 4.99 (m, 1H), 3.67-3.79 (m, 2H), 2.31 (s, 3H). MS: calculated value: 386; Measured value: [M+H] +387. | Method 55 |
| Embodiment | Compound | NMR/MS | Synthetic method |
| 21 | 3-(5-isopropoxy-1H-pyrazole-3-yl)-N-((S)-1-(pyridine-2-yl) ethyl)-3H-imidazo [4,5-b] pyridine-5-amine | (400MHz) 12.38 (s, 1H), 8.49 (d, J=4.0 Hz, 1H), 8.27 (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.67 (m.., 1H), 7.44 (d, J=6.4Hz, 1H), 7.36 (d, J=7.6Hz, 1H), 7.20 (m, 1H), 6.63 (d, J=8.8Hz, 1H), 6.02 (s, 1H), 5.06 (m, 1H), 4.49 (m, 1H), 1.49 (d, J=6.8Hz, 3H), 1.40 (d, J=6.0Hz, 3H), 1.35 (d, J=5.6Hz, 3H). MS: calculated value: 363; Measured value: [M+H] +364. | Method 56 |
| 22 | N-((S)-1-(4-fluorophenyl) ethyl)-3-(5-isopropoxy-1H-pyrazole-3-yl)-3H-imidazo [4,5-b] pyridine-5-amine | (400MHz) 12.42 (s, 1H), 8.26 (s, 1H), 7.73 (d, J=8.8Hz, 1H), 7.42 (m.., 2H), 7.36 (d, J=6.8Hz, 1H), 7.09 (m 2H), 6.58 (d, J=8.8Hz, 1H), 5.99 (s, 1H), 5.04 (m, 1H), 4.46 (m, 1H), 1.46 (d, J=6.8Hz, 3H), 1.40 (d, J=6.0 Hz, 3H), 1.33 (d, J=6.0Hz, 3H) .MS: calculated value: 380; Measured value: [M+H] +381. | Method 57 |
| 23 | (2R)-2-(4-fluorophenyl)-2-(3-(5-isopropoxy-1H-pyrazole-3-yl)-3H-imidazo [4,5-b] pyridine-5-base is amino) ethanol | (400MHz) 12.43 (b, 1H), 8.26 (s, 1H), 7.74 (d, J=8.8Hz, 1H), 7.42 (m, 2H), 7.30 (d, J=6.8Hz, 1H), 7.10 (m, 2H), 6.64 (d, J=8.8Hz, 1H), 6.01 (s, 1H), 5.00 (t, J=6.4Hz, 1H), 4.95 (m, 1H), 3.67 (m, 2H), 1.41 (d, J=6.0Hz, 3H), 1.35 (d, J=60Hz, 3H) .MS: calculated value: 396; Measured value: [M+H] +397. | Method 58 |
| Embodiment | Compound | NMR/MS | Synthetic method |
| 24 | 6-chloro-N-((S)-1-(4-fluorophenyl) ethyl)-3-(5-isopropoxy-1H-pyrazole-3-yl)-3H-imidazo [4,5-b] pyridine-5-amine | (400MHz) 12.52 (s, 1H), 8.39 (s, 1H), 8.08 (s, 1H), 7.46 (m, 2H), 7.09 (m, 2H), 6.83 (d, J=7.2Hz, 1H), 5.95 (s, 1H), 5.23 (m, 1H), 4.49 (m, 1H), 1.57 (d, J=6.8Hz, 3H), 1.41 and 1.34 (d, J=6.0Hz, 6H) .MS: calculated value: 414; Measured value: [M+H] +415. | Method 59 |
| 25 | 3-(5-cyclopropyl-1H-pyrazoles-3-yl)-N-((S)-1-(pyridine-2-yl) ethyl)-3H-imidazo [4,5-b] pyridine-5-amine | (400MHz) 12.56 (s, 1H), 8.54 (d, J=4.8 Hz, 1H), 8.26 (s, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.67 (m.., 1H), 7.43 (d, J=6.0Hz, 1H), 7.36 (d, J=8.0Hz, 1H), 7.20 (m, 1H), 6.62 (d, J=8.8Hz, 1H), 6.22 (s, 1H), 5.01 (m, 1H), 1.97 (m, 1H), 1.49 (d, J=6.8Hz, 3H), 1.03 (m, 2H), 0.81-0.70 (m, 2H) .MS: calculated value: 345; Measured value: [M+H] +346. | Method 60 |
| 26 | (2R)-2-(4-fluorophenyl)-2-(3-(5-methyl isophthalic acid H-pyrazoles-3-yl)-3H-imidazo [4,5-b] pyridine-5-base is amino) ethanol | (400MHz) 12.53 (b, 1H), 8.27 (s, 1H), 7.73 (d, J=8.8Hz, 1H), 7.44 (m, 2H), 7.24 (d, J=6.8Hz, 1H), 7.13 (m, 2H), 6.62 (d, J=8.8Hz, 1H), 6.34 (s, 1H), 4.96 (t, J=5.6Hz, 1H), 4.91 (m, 1H), 3.65 (m, 2H), 2.32 (s, 3H) .MS: calculated value: 352; Measured value: [M+H] +353. | Method 61 |
Embodiment 27
3-(5-cyclopropyl-1H-pyrazole-3-yl)-N-[(S)-1-(4-fluorophenyl) ethyl]-3H-benzo [d] miaow
Azoles-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) (0.234g, 2.25mmol) mixture in EtOH (5ml) heated 2 hours under refluxing with the acetate carbonamidine.After being cooled to 25 ℃, reaction mixture is handled with saturated sodium bicarbonate aqueous solution (10ml) and EtOAc (30ml).Organic layer is separated,, and use Na with salt solution (10ml) washing
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 handle synthetic following compounds with the acetate carbonamidine.
| Embodiment | Compound | NMR/MS | Synthetic method |
| 28 | (2R)-2-[3-(5-cyclopropyl-1H-pyrazole-3-yl)-3H-benzo [d] imidazoles-5-base is amino]-2-(4-fluorophenyl) ethanol | (400MHz) .12.65 (s, 1H), 8.18 (s, 1H), 7.44 (m, 2H), 7.34 (d, J=8.8Hz, 1H), 7.11 (m, 2H), 6.92 (s, 1H), 6.65 (d, J=8.8Hz, 1H), 6.08 (s, 1H), 6.07 (d, J=5.6Hz, 1H), 4.95 (t, J=5.6 Hz, 1H), 4.40 (m, 1H), 3.61 (t, J=5.6 Hz, 2H), 1.95 (m, 1H), 1.01 (m, 2H), 0.76 (m, 2H) .MS: calculated value: 377; Measured value: [M+H] +378. | Method 63 |
| 29 | N-(4-luorobenzyl)-3-(5-cyclopropyl-1H-pyrazole-3-yl)-3H-benzo [d] imidazoles-5-amine | (400MHz) .12.66 (s, 1H), 8.21 (s, 1H), 7.42 (m, 2H), 7.38 (d, J=8.8Hz, 1H), 7.12 (m, 2H), 7.04 (s, 1H), 6.66 (d, J=8.8Hz, 1H), 6.32 (t, J=6.0 Hz, 1H), 6.20 (s, 1H), 4.28 (d, J=4.8 Hz, 2H), 1.96 (m, 1H), 0.99 (m, 2H), 0.75 (m, 2H) .MS: calculated value: 347; Measured value: [M+H] +348. | Method 64 |
| Embodiment | Compound | NMR/MS | Synthetic method |
| 30 | N-[(S)-1-(4-fluorophenyl) ethyl]-3-(5-isopropoxy-1H-pyrazole-3-yl)-3H-benzo [d] imidazoles-5-amine | (400MHz) .12.45 (s, 1H), 8.18 (s, 1H), 7.42 (m, 2H), 7.34 (d, J=8.4Hz, 1H), 7.09 (m, 2H), 6.93 (s, 1H), 6.63 (d, J=8.4Hz, 1H), 6.27 (d, J=6.4 Hz, 1H), 5.88 (s, 1H), 4.50 (m, 2H), 1.43 (d, J=6.8Hz, 3H), 1.36 (m, 6H). MS: calculated value: 379; Measured value: [M+H] +380. | Method 65 |
| 31 | 3-(5-cyclopropyl-1H-pyrazoles-3-yl)-N-((S)-1-(pyridine-2-yl) ethyl)-3H-benzo [d] imidazoles-5-amine | (400MHz) 12.68 (s, 1H), 8.52 (d, J=4.4 Hz, 1H), 8.18 (s, 1H), 7.69 (m, 1H), 7.40 (d, J=7.6Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.21 (m, 1H), 6.91 (s, 1H), 6.64 (d, J=7.6Hz, 1H), 6.34 (d, J=6.8 Hz, 1H), 6.10 (d, J=1.6Hz, 1H), 4.53 (m, 1H), 1.96 (m, 1H), 1.47 (d, J=6.8Hz, 3H), 1.03 (m, 2H), 0.76 (m, 2H) .MS: calculated value: 344; Measured value: [M+H] +345. | Method 67 |
| 32 | (2R)-2-(4-fluorophenyl)-2-(3-(5-methyl isophthalic acid H-pyrazoles-3-yl)-3H-benzo [d] imidazoles-5-base is amino) ethanol | (400MHz) 12.61 (s, 1H), 8.22 (s, 1H), 7.44 (m, 2H), 7.35 (d, J=8.8Hz, 1H), 7.12 (m, 2H), 6.98 (s, 1H), 6.64 (d, J=8.4Hz, 1H), 6.19 (s, 1H), 6.11 (d, J=6.0Hz, 1H), 4.96 (t, J=5.6Hz, 1H), 4.40 (m, 1H), 3.61 (t, J=5.6Hz, 2H), 2.30 (s, 3H) .MS: calculated value: 351; Measured value: [M+H] +352. | Method 68 |
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 amino)-2-[1-(4-fluorophenyl) ethylamino] benzonitrile (method 69; 3.85g 10.2mmol) (2.13g, 20.5mmol) mixture in EtOH (50ml) heated 2 hours under refluxing with the acetate carbonamidine.After the cooling, reaction mixture is handled with saturated sodium bicarbonate solution (10ml) and EtOAc (30ml).Organic layer is separated,, and use Na with salt solution (10ml) washing
2SO
4Dry.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (EtOAc: MeOH=30: 1), obtained this title compound, be 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), (0.87ml is 3.88mol) with 15 30%H to add the 25%KOH aqueous solution then
2O
2Solution.To be reflected at 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 handle synthetic following compound with the acetate carbonamidine.
| Embodiment | Compound | NMR/MS | Synthetic method |
| 35 | 1-(5-cyclopropyl-1H-pyrazoles-3-yl)-6-[(R)-1-(4-fluorophenyl)-2-hydroxyethyl amino]-1H-benzo [d] imidazoles-5-formonitrile HCN | (400MHz) .12.77 (s, 1H), 8.45 (s, 1H), 7.99 (s, 1H), 7.49 (m, 2H), 7.15 (m, 2H), 6.95 (s, 1H), 6.06 (s, 1H), 5.95 (d, J=4.8Hz, 1H), 5.32 (t, J=4.8Hz, 1H), 3.79 (m, 1H), 3.76 (m, 1H), 3.65 (m, 1H), 1.97 (m, 1H), 1.03 (m, 2H), 0.74 (m, 2H) .MS: calculated value: 402; Measured value: [M+H] +403. | Method 70 |
Embodiment 36
3-(5-cyclopropyl-1H-pyrazole-3-yl)-4-fluoro-N-[(S)-1-(4-fluorophenyl) ethyl]-the 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) (0.209g, 2.00mmol) mixture in EtOH (10ml) heated 1 hour under refluxing with the acetate carbonamidine.After the cooling, reaction mixture is handled with saturated sodium bicarbonate solution (5ml) and EtOAc (15ml).Organic layer is separated,, and use Na with salt solution (3ml) washing
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 handle synthetic following compound with the acetate carbonamidine.
| Embodiment | Compound | NMR/MS | Synthetic method |
| 37 | (2R)-2-[3-(5-cyclopropyl-1H-pyrazole-3-yl)-4-fluoro-3H-benzo [d] imidazoles-5-base is amino]-2-(4-fluorophenyl) ethanol | (400MHz) .12.78 (s, 1H), 8.09 (s, 1H), 7.44 (m, 2H), 7.20 (d, J=8.8Hz, 1H), 7.12 (t, J=9.0Hz, 2H), 6.51 (t, J=8.2Hz, 1H), 6.21 (s, 1H), 5.50 (d, J=4.4Hz, 1H), 5.07 (t, J=5.8Hz, 1H), 4.51 (q, J=6.0Hz, 1H), 3.58-3.70 (m, 2H), 1.98 (m, 1H), 1.00 (m, 2H), 0.77 (m, 2H) .MS: calculated value: 395; Measured value: [M+H] +396. | Method 72 |
Embodiment 38
3-(5-cyclopropyl-1H-pyrazole-3-yl)-6-fluoro-N-[(S)-1-(4-fluorophenyl) ethyl]-the 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) (0.170g, 1.63mmol) mixture in EtOH (10ml) heated 1 hour under refluxing with the acetate carbonamidine.After the cooling, reaction mixture is handled with saturated sodium bicarbonate solution (5ml) and EtOAc (15ml).Organic layer is separated,, and use Na with salt solution (3ml) washing
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 handle synthetic following compound with the acetate carbonamidine.
| Embodiment | Compound | NMR/MS | Synthetic method |
| 39 | (2R)-2-[3-(5-cyclopropyl-1H-pyrazole-3-yl)-6-fluoro-3H-benzo [d] imidazoles-5-base is amino]-2-(4-fluorophenyl) ethanol | (400MHz) .12.69 (s, 1H), 8.29 (s, 1H), 7.47 (m, 3H), 7.14 (t, J=8.8Hz, 2H), 6.93 (d, J=8.0Hz, 1H), 6.03 (s, 1H), 5.70 (br, 1H), 5.18 (t, J=5.8Hz, 1H), 4.45 (m, 1H), 3.62-3.73 (m, 2H), 1.95 (m, 1H), 1.02 (m, 2H), 0.74 (m, 2H) .MS: calculated value: 395; Measured value: [M+H] +396. | Method 74 |
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, (0.43mmol) (0.089g, 0.85mmol) mixture in EtOH (5ml) heated 2 hours under refluxing the 5-triamine with the acetate carbonamidine for method 88,0.15g.After being cooled to 25 ℃, the saturated NaHCO of reaction mixture
3Solution (10ml) and EtOAc (30ml) handle.Organic layer is separated,, and use dried over sodium sulfate with salt solution (10ml) washing.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (EtOAc-MeOH=40: 1), obtained this title compound, be 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 ammonia
Base)-2-(4-fluorophenyl) ethanol
With (R)-2-(5-amino-4-(5-cyclopropyl-1H-pyrazole-3-yl amino) pyridine-2-base is amino)-2-(4-fluorophenyl) ethanol (method 93,0.14g, 0.38mmol) and acetate carbonamidine (0.079g, the 0.76mmol) heating 2 hours under refluxing of the mixture in EtOH (5ml).After being cooled to 25 ℃, the saturated NaHCO of reaction mixture
3Solution (10ml) and EtOAc (30ml) handle.Organic layer is separated,, and use dried over sodium sulfate with salt solution (10ml) washing.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (EtOAc-MeOH=20: 1), obtained this title compound, be 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 10% palladium on carbon (0.69g, 0.65mmol) 15 dense HCl of adding in the mixture in MeOH (40ml).Reaction is applied 45psi hydrogen and shook 30 hours.Remove and desolvate.Resistates is dissolved among the EtOAc (200ml), with saturated sodium bicarbonate (50ml) washing, and uses dried over sodium sulfate.Except that after desolvating, 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), and 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-benzene
And [d] imidazoles-5-yl) ethanamide methyl)
((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 have acetate the TFP resin (the 1.0mmol/g charge capacity, 0.256g, 0.256mmol) THF-DCM (1: 1, the 3ml) mixture in.Gained solution is in 0 ℃ of vigorous stirring 1 hour, and filters by the Jones pipe.(1: 1,3 * 5ml) washed the gained resin with THF-DCM solution.Except that after desolvating, the gained resistates is by column chromatography purifying (EtOAc-MeOH=20: 1), obtained this title compound, be 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 amino)-5-(1-(4-fluorophenyl) ethylamino) benzonitrile (method 96,3.95g, 10mmol) (2.2g, 21mmol) mixture in EtOH (50ml) heated 36 hours under refluxing with the acetate carbonamidine.After the cooling, reaction mixture is handled with saturated sodium bicarbonate solution (30ml) and EtOAc (80ml).Organic layer is separated,, and use dried over sodium sulfate with salt solution (30ml) washing.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 amino)-5-(1-(4-fluorophenyl) ethylamino) benzamide (method 100,3.95g, 10mmol) (2.2g, 21mmol) mixture in EtOH (50ml) heated 36 hours under refluxing with the acetate carbonamidine.After the cooling, reaction mixture is handled with saturated sodium bicarbonate solution (30ml) and EtOAc (80ml).Organic layer is separated,, and use dried over sodium sulfate with salt solution (30ml) washing.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (EtOAc-MeOH=30: 1), obtained this title compound, be 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=2.0Hz, 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, (0.718mmol) (0.149g, 1.44mmol) mixture in EtOH (10ml) heated 1 hour under refluxing the 4-triamine with the acetate carbonamidine for method 101,0.278g.Add saturated sodium bicarbonate solution (5ml) and EtOAc (15ml).Organic layer is separated,, and use dried over sodium sulfate with salt solution (3ml) washing.Removal of solvent under reduced pressure, and resistates is by chromatography purification (Hex (hexane)-EtOAc=1: 1), obtained this title compound, be 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 ammonia
Base)-2-(4-fluorophenyl) ethanol
With (R)-2-(4-amino-3-(5-cyclopropyl-1H-pyrazole-3-yl amino)-2,6-difluorophenyl amino)-2-(4-fluorophenyl) ethanol (method 104,0.230g, 0.57mmol) and acetate carbonamidine (0.119g, the 1.14mmol) heating 1 hour under refluxing of the mixture 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 is by chromatography purification (Hex-EtOAc=1: 1), obtained this title compound, be 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)-
The 3H-imidazole is [4,5-b] pyridine-5-amine also
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) and anhydrous 1, the mixture of 4-two alkane (0.5ml) was in 100 ℃ of heating 3 hours.Make reaction be cooled to room temperature, and solvent is evaporated in Genevac.The gained resistates with zinc powder (195mg, 2.98mmol), formic acid (140 μ L, 3.71mmol) and 1, handle, and with gained mixture reheat to 100 ℃ by 4-two alkane (0.5ml).Heat after 4 hours, reaction is cooled off, and go volatile constituent with the Genevac evaporation.Spissated reaction mixture MeOH (1ml), DCM (1ml) and Na
2CO
3(125mg) handle.This mixture is in stirring at room 45 minutes, this moment whole mixtures loaded on the top (～3cm length * 1.5cm diameter) of short silica gel.With post with MeOH (～15ml) washing, and elutriant 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.
| Embodiment | Compound | NMR/MS | Synthetic method |
| 49 | 3-(5-cyclopropyl-1H-pyrazoles-3-yl)-N-[3-(trifluoromethyl) benzyl]-3H-imidazo [4,5-b] pyridine-5-amine | 1H NMR (400MHz) 0.61-0.71 (m, 2H) 0.96 (m, 2H) 1.91 (m, 1H) 4.61 (m, 2 H) 6.32 (s, 1H) 6.57 (m, 1H) 7.49-7.60 (m, 2H) 7.67 (m, 1H) 7.71 (m, 1 H), 7.76 (m, 1H) 8.28 (s, 1H) 12.59 (s, 1H) .MS: calculated value: 398; Measured value: [M+H] +399. | Method 77 |
| Embodiment | Compound | NMR/MS | Synthetic method |
| 50 | 3-(5-cyclopropyl-1H-pyrazoles-3-yl)-N-(3, the 4-difluorobenzyl)-3H-imidazo [4,5-b] pyridine-5-amine | 1H NMR (400MHz) 0.65 (m, 2H) 0.94-1.04 (m, 2H) 1.92 (m, 1H) 4.48 (m, 2H) 6.29 (s, 1H) 6.55 (m, 1H) 7.19 (m, 1H) 7.33-7.40 (m, 1H) 7.46 (m, 1H) 7.75 (m, 1H) 8.27 (s, 1H) 12.60 (s, 1H) .MS: calculated value: 366; Measured value: [M+H] +367. | Method 77 |
| 51 | 3-(5-cyclopropyl-1H-pyrazoles-3-yl)-N-((1S)-1-phenyl propyl)-3H-imidazo [4,5-b] pyridine-5-amine | 1H NMR (400MHz) 0.75 (m, 2H) 0.92 (m, 3H) 1.06 (m, 2H) 1.72 (m, 1 H), 1.84 (m, 1H) 1.92-2.03 (m, 1H) 4.74 (m, 1H) 6.34 (s, 1H) 6.58 (m, 1H) 7.18 (m, 2H) 7.24-7.33 (m, 3H) 7.34-7.41 (m, 12H) 7.69 (m, and 1H) 8.24 (s, 1H), 12.60 (s, 1H) .MS: calculated value: 358; Measured value: [M+H] +359. | Method 77 |
| 52 | 3-(5-cyclopropyl-1H-pyrazoles-3-yl)-N-[2-(1H-indoles-3-yl) ethyl]-3H-imidazo [4,5-b] pyridine-5-amine | 1H NMR (400MHz) 0.61-0.69 (m, 2H) 0.84-0.94 (m, 2H) 1.90 (m, 1H) 3.00 (m, 2H) 3.60 (s, 2H) 6.48 (m, 1H) 6.64 (s, 1H) 6.94 (m, 1H) 7.05 (m, 1H) 7.18 (s, 1H) 7.33 (m, 1H) 7.53 (m, 1H) 7.71 (m, 1H) 8.22s, 1H) 10.82 (s, 1H) 12.60 (s, 1H) .MS: calculated value: 383; Measured value: [M+H] +384. | Method 77 |
| 53 | 3-(5-cyclopropyl-1H-pyrazoles-3-yl)-N-(2-pyridine-2-base ethyl)-3H-imidazo [4,5-b] pyridine-5-amine | 1H NMR (400MHz) 0.73 (m, 2H) 0.92-1.02 (m, 2H) 1.97 (m, 1H) 3.02-3.11 (m, 2H) 3.62-3.72 (m, 2H) 6.47 (m, 1H) 6.70 (s, 1H) 6.94-7.03 (m, 1H) 7.22 (m, 1H) 7.29 (m, 1 H) 7.67-7.77 (m, 2H) 8.31 (s, 1H) 8.53 (m, 1H) 12.64 (s, 1H) .MS: calculated value: 345; Measured value: [M+H] +346. | Method 77 |
| Embodiment | Compound | NMR/MS | Synthetic method |
| 54 | 2-{[3-(5-cyclopropyl-1H-pyrazole-3-yl)-3H-imidazo [4,5-b] pyridine-5-yl] amino }-1-phenyl third-1-alcohol | 1H NMR (400MHz) 0.77 (m, 2H) 0.94 (d, J=6.8Hz, 34 H) 1.03 (m, 2H) 1.98-2.09 (m, 1H) 4.20 (m, 1H) 4.89-4.99 (m, 1H) 5.30 (m, 1H) 6.57 (m, 1H) 6.62 (s, 1H) 6.77 (m, 1H) 7.21 (m, 2H) 7.33 (m, 2H) 7.38-7.47 (m, 1H) 7.72 (m, 1H) 8.25 (s, 1H) 12.69 (s, 1H) .MS: calculated value: 374; Measured value: [M+H] +375. | Method 77 |
The preparation parent material:
Method 1
(R)-2-[4-(5-cyclopropyl-1H-pyrazole-3-yl amino)-6-methyl-5-nitro pyrimidine-2-base ammonia
Base]-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 (R)-2-amino-2-(4-fluorophenyl) ethanol (0.58g, 3.7mmol) solution in n-BuOH (15ml) be heated to 60 ℃ 2 hours.Reaction is cooled to 25 ℃ then, concentrates, and handle 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.
| Method | Product | NMR/MS | Amine |
| 2 | N 4-(5-cyclopropyl-1H-pyrazole-3-yl)-N 2-[(1S)-1-(4-fluorophenyl) ethyl]-5-nitro-pyrimidine-2, the 4-diamines | 0.62 (m, 2H), 0.95 (m, 2H), 1.49 (m, 3H), 1.90 (m, 1H), 5.12 (m, 1H), 6.13 (s, 1H), 7.15 (m, 2H), 7.37 (m, 2H), 8.97 (s, 1H), 10.40 (s, 1H) .MS: calculated value: 383; Measured value: [M+H] +384.17 | [(1S)-and 1-(4-fluorophenyl) ethyl] amine |
| 3 | (2R)-2-(4-[(5-cyclopropyl-1H-pyrazoles-3-yl) amino]-5-nitro-pyrimidine-2-yl } amino)-2-(4-fluorophenyl) ethanol | 0.68 (m, 2H), 0.98 (m, 2H), 1.93 (m, 3H), 3.67 (m, 2H), 5.02 (m, 1H), 6.20 (s, 1H), 7.19 (m, 2H), 7.37 (m, 2H), 8.97 (s, 1H), 10.40 (s, 1H), 12.36 (brs, 1H) .MS: calculated value: 399; Measured value: [M+H] +400.20 | (2R)-2-amino-2-(4-fluorophenyl) ethanol |
| 4 | N 4-(5-cyclopropyl-1H-pyrazole-3-yl)-N 2-(4-luorobenzyl)-5-nitro-pyrimidine-2, the 4-diamines | 0.68 (m, 2H), 0.80 (m, 2H), 1.75 (m, 3H), 4.51 (m, 2H), 6.05 (s, 1H), 7.09 (m, 2H), 7.30 (m, 2H), 8.97 (s, 1H), 10.40 (s, 1H), MS: calculated value: 369; Measured value: [M+H] +370.16 | (4-luorobenzyl) amine |
| 5 | N 4-(5-cyclopropyl-1H-pyrazole-3-yl)-N 2-[(1R)-1-(4-fluorophenyl) ethyl]-5-nitro-pyrimidine-2, the 4-diamines | 0.63 (m, 2H), 0.95 (m, 2H), 1.49 (m, 3H), 1.90 (m, 1H), 5.11 (m, 1H), 6.14 (s, 1H), 7.15 (m, 2H), 7.37 (m, 2H), 8.97 (s, 1H), 10.40 (s, 1H) .MS: calculated value: 383; Measured value: [M+H] +384.23 | [(1R)-and 1-(4-fluorophenyl) ethyl] amine |
| 6 | (R)-2-(4-fluorophenyl)-2-(4-(5-methyl isophthalic acid H-pyrazole-3-yl amino)-5-nitro-pyrimidine-2-base is amino) ethanol | MS: calculated value: 373; Measured value: [M+H] +374 | (R)-2-amino-2-(4-fluorophenyl) ethanol |
| Method | Product | NMR/MS | Amine |
| 7 | (S)-N 2-(1-(4-fluorophenyl) ethyl)-N 4-(5-isopropoxy-1H-pyrazoles-3-yl)-5-nitro-pyrimidine-2, the 4-diamines | (400MHz) 12.23,11.99 and 11.69 (s, 1H), 10.52,10.48 and 10.37 (s, 1H), 9.15 and 9.97 (d, J=7.2Hz, 1H), 8.99 (s, 1H), and 7.45-7.31 (m, 2H), 7.20-7.08 (m, 2H), 5.99,5.85 and 5.77 (s, 1H), 5.28,5.18 and 5.08 (m, 1H), 4.70,4.63 and 4.32 (m, 1H), 1.50 (d, J=6.8Hz, 3H), 1.34-1.23 (m, 6H) .MS: calculated value: 401; Measured value: [M+H] +402. | (S)-1-(4-fluoro-phenyl)-ethylamine |
Method 8
(S)-N
4
-(5-cyclopropyl-1H-pyrazole-3-yl)-N
2
-[1-(4-fluorophenyl) ethyl] pyrimidine-2,4,5-three
Amine
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 zinc powder (0.7g, 10.0mmol) at MeOH: THF (1: 1,50ml) in the suspension in, slowly add saturated NH
4Cl solution (10ml).After 3 hours, the saturated NH of reaction mixture
4The OAc aqueous solution (40ml) is handled, and stirs 30 minutes.To react then by plug of celite and filter, and use EtOAc (100ml) wash-out, and (2 * 100ml) extractions, drying is filtered, and concentrates, and has obtained this title compound (0.04g, 5%) with EtOAc with the gained water layer.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 DIEA (0.6g, 4.6mmol) mixture in n-BuOH (15ml) stirred 1 hour at 25 ℃, concentrated then.(DCM: MeOH=50: 1) purifying has obtained this title compound (0.8g, 60%) to gained oily matter by column chromatography.MS: calculated value: 383; Measured value: [M+H]
+384.
Method 10
(S)-ethyl 6-(5-cyclopropyl-1H-pyrazole-3-yl amino)-2-[1-(4-fluorophenyl) ethylamino]-
5-nitro-pyrimidine-4-manthanoate
With 2-chloro-6-(5-cyclopropyl-1H-pyrazole-3-yl amino)-5-nitro-pyrimidine-4-ethyl formate (method 11; 1.0g, 2.8mmol) and (S)-(0.43g, 3.1mmol) solution in EtOH (20ml) stirred 1 hour at 25 ℃ 1-(4-fluorophenyl) ethamine.To react concentrated, water (50ml) is handled, and (3 * 50ml) extractions, drying is filtered, and concentrated with DCM.Resistates is by column chromatography purifying (DCM: MeOH=50: 1), obtained this title compound (0.7g, 53%) then.MS: calculated value: 455; Measured value: [M+H]
+456.
Method 11
2-chloro-6-(5-cyclopropyl-1H-pyrazole-3-yl amino)-5-nitro-pyrimidine-4-ethyl formate
In 0 ℃ to 2, (1.0g slowly adds 5-cyclopropyl-1H-pyrazoles-3-amine (0.48g, 3.85mmol) mixture in THF (5ml) to 6-two chloro-5-nitro-pyrimidine-4-ethyl formates in THF 3.80mmol) (20ml) solution.To react on 0 ℃ and stir 10 minutes, water (50ml) is handled, and (3 * 50ml) extractions, drying is filtered, and concentrates, and has obtained this title compound (1.2g) to use DCM then.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 DIEA (0.23ml, 1.34mmol) mixture 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 (m 2H) .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 | Product | NMR/MS | Amine |
| 13 | N 6-(4-luorobenzyl)-N 2-(5-cyclopropyl-1H-pyrazole-3-yl)-3-nitropyridine-2, the 6-diamines | (400MHz) 12.24 (s, 1H), 10.98 (s, 1H), 8.29 (br, 1H), 8.11 (d, J=9.2Hz, 1H), 7.36 (m, 2H), 7.18 (m, 2H), 6.20 (d, J=9.6 Hz, 1H), 6.19 (s, 1H), 4.66 (d, J=5.2Hz, 2H), 1.79 (m, 1H), 0.86 (m, 2H), 0.45 (m, 2H) .MS: calculated value: 368; Measured value: [M+H] +369 | (4-luorobenzyl) amine |
| 14 | (R)-2-[6-(5-cyclopropyl-1H-pyrazole-3-yl amino)-5-nitropyridine-2-base is amino]-2-(4-fluorophenyl) ethanol | (400MHz) 12.21 (s, 1H), 10.97 (s, 1H), 8.74 (d, J=7.6Hz, 1H), 8.09 (d, J=9.6Hz, 1H), 7.38 (m, 2H), 7.18 (m, 2H), 6.31 (d, J=9.2Hz, 1H), 6.20 (s, 1H), 5.21 (d, J=5.6 Hz, 1H), 5.09 (t, J=5.2Hz, 1H), 3.64-3.75 (m, 2H), 1.91 (m, 1H), 0.98 (m, 2H), 0.66 (m, 2H) .MS: calculated value: 398; Measured value: [M+H] +399. | (R)-2-amino-2-(4-fluorophenyl) ethanol |
| 15 | 2-[6-(5-cyclopropyl-1H-pyrazole-3-yl amino)-5-nitropyridine-2-base is amino]-2-(4-fluorophenyl) the third-1, the 3-glycol | (400MHz) 12.02 (s, 1H), 10.95 (s, 1H), 8.07 (d, J=9.2Hz, 1H), 7.93 (s, 1H), 7.35 (m, 2H), 7.14 (m, 2H), 6.48 (d, J=9.2 Hz, 1H), 5.04 (s, 1H), 4.81 (s, 2H), 4.04 (m, 2H), 3.90 (m, 2H), 1.68 (m, 1H), 0.90 (m, 2H), 0.51 (m, 2H) .MS: calculated value: 428; Measured value: [M+H] +429. | 2-amino-2-(4-fluorophenyl) the third-1, the 3-glycol |
Method 16
(S)-3-chloro-N
6
-(5-cyclopropyl-1H-pyrazole-3-yl)-N
2
-[1-(4-fluorophenyl) ethyl]-5-nitro
Pyridine-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 DIEA (0.22ml, 1.25mmol) mixture 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.
| Method | Product | NMR/MS | Synthetic method | Amine 2 |
| 17 | N 2-(4-luorobenzyl)-3-chloro-N 6-(5-cyclopropyl-1H-pyrazoles-3-yl)-5-nitropyridine-2, the 6-diamines | (400MHz) .12.29 (s, 1H), 10.73 (s, 1H), 8.70 (t, J=6.0Hz, 1H), 8.12 (b, 1H), 7.30 (m, 2H), 7.16 (m, 2H), 6.02 (s, 1H), 4.71 (d, J=6.0Hz, 2H), 1.77 (m, 1H), 0.86 (m, 2H), 0.41 (m, 2H) .MS: calculated value: 402; Measured value: [M+H] +403. | Method 79 | (4-fluoro-phenyl) methylamine |
| 18 | (R)-2-[3-chloro-6-(5-cyclopropyl-1H-pyrazole-3-yl amino)-5-nitropyridine-2-base is amino]-2-(4-fluorophenyl) ethanol | (400MHz) 12.27 (s, 1H), 10.70 (s, 1H), 8.29 (d, J=1.6Hz, 1H), 8.03 (d, J=7.6Hz, 1H), 7.39 (m, 2H), 7.14 (m, 2H), 6.15 (s, 1H), 5.31 (m, 1H), 5.13 (t, J=4.8Hz, 1H), 3.32-3.86 (m, 2H), 1.92 (m, 1H), 0.98 (m, 2H), 0.68 (m, 2H) .MS: calculated value: 432; Measured value: [M+H] +433. | Method 80 | 5-cyclopropyl-1H-pyrazoles-3-amine |
| Method | Product | NMR/MS | Synthetic method | Amine 2 |
| 19 | (2R)-2-(3-chloro-6-[(5-methyl isophthalic acid H-pyrazole-3-yl) amino]-5-nitropyridine-2-yl } amino)-2-(4-fluorophenyl) ethanol | (400MHz) 12.23 (s, 1H), 10.69 (s, 1H), 8.30 (s, 1H), 8.00 (d, J=7.6Hz, 1H), 7.41 (m 2H), 7.17 (m, 2H), 6.12-5.26 (m, 1H), 5.13 (t, J=5.2 Hz, 1H), 3.73-3.86 (m, 2H), 2.25 (s, 3H) .MS: calculated value: 406; Measured value: [M+H] +407 | Method 80 | 5-methyl-1H-pyrazoles-3-amine |
| 20 | (S)-N 2-(5-isopropoxy-1H-pyrazoles-3-yl)-3-nitro-N 6-(1-(pyridine-2-yl) ethyl) pyridine-2, the 6-diamines | (400MHz) 12.10,12.05 and 11.84 (s, 1H), 10.96,10.94 and 10.74 (s, 1H), 9.09,8.88 and 8.83 (d, J=7.6Hz, 1H), 8.56 and 8.53 (m, 1H), 8.15 and 8.11 (d, J=9.6Hz, 1H), 7.77 (m, 1H), 7.33 (m, 1H), 7.28 (m, 1H), 6.28 and 6.07 (d, J=9.6Hz, 1H), 5.99 and 5.83 (s, 1H), 5.78 and 5.77 (s, 1H), 5.35,5.26 and 4.92 (m, 1H), 4.69,4.68 and 4.50 (m, 1H), 1.55 (d, J=6.8Hz, 3H), 1.36 and 1.28 (m, 6H). MS: calculated value: 383; Measured value: [M+H] +384. | Method 95 | (S)-1-(pyridine-2-yl)-ethylamine |
| 21 | (S)-N 6-(1-(4-fluorophenyl) ethyl)-N 2-(5-isopropoxy-1H-pyrazole-3-yl)-3-nitropyridine-2, the 6-diamines | (400MHz) 12.09,12.05 and 11.64 (s, 1H), 10.94,10.87 and 10.72 (s, 1H), 8.98,8.76 and 8.70 (d, J=7.6Hz, 1H), 8.16 and 8.11 (d, J=9.6 Hz, 1H), 7.45,7.39 and 7.34 (m, 2H), 7.15 (m, 2H), 6.24 and 6.04 (d, J=9.6Hz, 1H), 6.03,5.88 and 5.76 (s, 1H), 5.32,5.21 and 4.89 (m, 1H), 4.71,4.59 and 4.27 (m, 1H), 1.52 (m, 3H), 1.26 (m, 6H) .MS: calculated value: 400; Measured value: [M+H] +401. | Method 95 | (S)-1-(4-fluoro-phenyl)-ethylamine |
| Method | Product | NMR/MS | Synthetic method | Amine 2 |
| 22 | (R)-2-(4-fluorophenyl)-2-(6-(5-isopropoxy-1H-pyrazole-3-yl amino)-5-nitropyridine-2-base is amino) ethanol | (400MHz) 12.12,12.10 and 11.61 (s, 1H), 10.94,10.87 and 10.74 (s, 1H), 9.05,8.82 and 8.73 (d, J=7.2Hz, 1H), 8.15 and 8.11 (d, J=9.2 Hz, 1H), 7.45,7.38 and 7.32 (m, 2H), 7.15 (m, 2H), 6.32 and 6.07 (d, J=9.2Hz, 1H), 5.90,5.83 and 5.79 (s, 1H), 5.32,5.21 and 4.89 (m, 1H), 5.23 (m, 1H), 5.12 (m, 1H), 4.78,4.64 and 4.37 (m, 1H), 4.69 (m, 2H), 1.30 (m, 6H) .MS: calculated value: 416; Measured value: [M+H] +417. | Method 95 | (R)-2-amino-2-(4-fluorophenyl) ethanol |
| 23 | (S)-3-chloro-N 2-(1-(4-fluorophenyl) ethyl)-N 6-(5-isopropoxy-1H-pyrazoles-3-yl)-5-nitropyridine-2, the 6-diamines | (400MHz) 12.16 and 11.72 (s, 1H), 10.64 and 10.58 (s, 1H), 8.30 (m, 2H), 7.33 and 7.31 (m, 2H), 7.16 and 7.08 (m, 2H), 5.81 and 5.71 (s, 1H), 5.48 and 5.33 (m, 1H), 4.60 and 4.21 (m, 1H), 1.61 and 1.57 (d, J=6.8 Hz, 3H), 1.26 (m, 6H) .MS: calculated value: 434; Measured value: [M+H] +435. | Method 81 | (S)-1-(4-fluoro-phenyl)-ethylamine |
| 24 | (S)-N 2-(5-cyclopropyl-1H-pyrazoles-3-yl)-3-nitro-N 6-(1-(pyridine-2-yl) ethyl) pyridine-2, the 6-diamines | (400MHz) 12.24 (s, 1H), 11.01 (s, 1H), 8.30 (d, J=7.2Hz, 1H), 8.56 (m, 1H), 8.10 (d, J=9.6Hz, 1H), 7.76 (m, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.28 (m, 1H), 6.28 (d, J=9.2Hz, 1H), 6.15 (s, 1H), 5.28 (m, 1H), 1.85 (m, 1H), 1.54 (d, J=6.8Hz, 3H), 0.97 (m, 2H), 0.84 (m, 2H) .MS: calculated value: 365; Measured value: [M+H] +366. | Method 77 | (S)-1-(pyridine-2-yl)-ethylamine |
| Method | Product | NMR/MS | Synthetic method | Amine 2 |
| 25 | (R)-2-(4-fluorophenyl)-2-(6-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-5-nitropyridine-2-base is amino) ethanol | (400MHz) 12.18 (s, 1H), 10.96 (s, 1H), 9.05,8.79 (d, J=7.2Hz, 1H), 8.09 (d, J=9.2Hz, 1H), 7.39 (m, 2H), 7.18 (m, 2H), 6.33 (d, J=9.6 Hz, 1H), 6.19 (s, 1H), 5.17 (m, 1H), 5.11 (t, J=5.6Hz, 1H), 3.68 (m, 2H), 2.24 (s, 3H) .MS: calculated value: 372; Measured value: [M+H] +373. | Method 78 | (R)-2-amino-2-(4-fluorophenyl) ethanol |
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 DIEA (0.27ml, 1.54mmol) mixture 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 (m 2H) .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.
| Method | Product | NMR/MS | Synthetic method | Amine |
| 27 | (R)-2-[3-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-4-nitrophenyl amino]-2-(4-fluorophenyl) ethanol | (400MHz) .12.25 (s, 1H), 10.14 (s, 1H), 7.87 (d, J=9.6Hz, 1H), 7.72 (d, J=6.8Hz, 1H), 7.35 (m, 2H), 7.15 (m, 2H), 6.74 (br, 1H), 6.27 (br, 1H), 5.62 (br, 1H), 5.03 (t, J=5.6Hz, 1H), 4.46 (m, 1H), 3.62 (t, J=5.6Hz, 2H), 1.89 (m, 1H), 0.97 (m, 2H), 0.71 (m, 2H) .MS: calculated value: 397; Measured value: [M+H] +398. | Method 82 | (R)-2-amino-2-(4-fluorophenyl) ethanol |
| 28 | N 1-(4-luorobenzyl)-N 3-(5-cyclopropyl-1H-pyrazole-3-yl)-4-oil of mirbane-1, the 3-diamines | (400MHz) .12.26 (s, 1H), 10.22 (s, 1H), 7.91 (d, J=9.2Hz, 1H), 7.86 (t, J=5.6Hz, 1H), 7.36 (m, 2H), 7.17 (m, 2H), 6.90 (s, 1H), 6.24 (d, J=9.6Hz, 1H), 5.70 (s, 1H), 4.44 (d, J=5.6Hz, 2H), 1.87 (m, 1H), 0.94 (m, 2H), 0.69 (m 2H). MS: calculated value: 367; Measured value: [M+H] +368. | Method 82 | (4-fluoro-phenyl) methylamine |
| 29 | (S)-N 1-[1-(4-fluorophenyl) ethyl]-N 3-(5-isopropoxy-1H-pyrazole-3-yl)-4-oil of mirbane-1, the 3-diamines | MS: calculated value: 399; Measured value: [M+H] +400. | Method 83 | (S)-1-(4-fluoro-phenyl)-ethylamine |
| Method | Product | NMR/MS | Synthetic method | Amine |
| 30 | (S)-N 3-(5-cyclopropyl-1H-pyrazoles-3-yl)-4-nitro-N 1-(1-(pyridine-2-yl) ethyl) benzene-1, the 3-diamines | (400MHz) 12.28 (s, 1H), 10.18 (b, 1H), 8.54 (s, 1H), 7.89 (d, J=9.2Hz, 1H), 7.84 (d, J=6.0Hz, 1H), 7.77 (m, 2H), 7.34 (d, J=8.0Hz, 1H), 7.28 (m, 1H), 6.65 (m, 1H), 6.24 (m, 1H), 5.60 (m, 1H), 4.60 (m, 1H), 1.89 (m, 1H), 1.49 (d, J=6.4 Hz, 3H), 0.97 (m, 2H), 0.73 (m, 2H). MS: calculated value: 363; Measured value: [M+H] +365. | Method 82 | (S)-1-(pyridine-2-yl)-ethylamine |
| 31 | (R)-2-(4-fluorophenyl)-2-(3-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-4-nitrophenyl amino) ethanol | (400MHz) 12.22 (s, 1H), 10.15 (s, 1H), 7.87 (d, J=9.6Hz, 1H), 7.75 (d, J=6.0Hz, 1H), 7.36 (m, 2H), 7.17 (m, 2H), 6.67 (b, 1H), 6.28 (m, 1H), 5.53 (m, 1H), 5.06 (t, J=5.6Hz, 1H), 4.45 (m, 1H), 3.62 (t, J=5.6Hz, 2H), 2.23 (s, 3H) .MS: calculated value: 371; Measured value: [M+H] +372. | Method 84 | (R)-2-amino-2-(4-fluorophenyl) ethanol |
Method 32
(S)-4-(5-cyclopropyl-1H-pyrazole-3-yl amino)-2-[1-(4-fluorophenyl) ethylamino]-5-nitre
The base benzonitrile
With 4-(5-cyclopropyl-1H-pyrazole-3-yl amino)-2-fluoro-5-nitrobenzonitrile (method 33; 3.0g, 10.4mmol), (S)-1-(4-fluoro-phenyl) ethylamine (1.60g, 11.5mmol) and DIEA (2.3ml, 13.1mmol) mixture in n-BuOH (20ml) in sealed tube in 230 ℃ the 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 (m, 2H) .MS: calculated value: 406; Measured value: [M+H]
+407.
Method 33
4-(5-cyclopropyl-1H-pyrazole-3-yl amino)-2-fluoro-5-nitrobenzonitrile
In O ℃ to 2,4-two fluoro-5-nitrobenzonitriles (method 34,5.0g, 27mmol) and DIEA (5.4ml, 31mmol) Dropwise 5-cyclopropyl in the solution in THF (20ml)-1H-pyrazoles-3-amine (3.2g, 26mmol) mixture in THF (5ml).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
(16.4g 147.4mmol) is added to concentrated H saltpetre in 0 ℃
2SO
4(85ml, 1582mmol) in, that continues slowly adds 2,4-difluoro benzonitrile (11.0g, 79.1mmol).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, synthetic following compound.
| Method | Product | NMR/MS | Amine 2 |
| 35 | (R)-4-(5-cyclopropyl-1H-pyrazole-3-yl amino)-2-[1-(4-fluorophenyl)-2-hydroxyethyl amino]-the 5-nitrobenzonitrile | (400MHz) .12.40 (s, 1H), 9.95 (s, 1H), 8.42 (s, 1H), 7.41 (m, 1H), 7.12 (m, 4H), 6.93 (s, 1H), 5.64 (s, 1H), 5.24 (t, J=5.2Hz, 1H), 4.47 (m, 1H), 3.75 (m, 1H), 3.69 (m, 1H), 1.91 (m, 1H), 0.99 (m, 2H), 0.71 (m, 2H) .MS: calculated value: 422; Measured value: [M+H] +423. | (R)-2-amino-2-(4-fluorophenyl) ethanol |
Method 36
(S)-N
3
-(5-cyclopropyl-1H-pyrazole-3-yl)-2-fluoro-N
1
-[1-(4-fluorophenyl) ethyl]-4-nitro
Benzene-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 DIEA (0.373ml, 2.14mmol) mixture 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 | Product | NMR/MS | Amine 2 |
| 37 | (R)-2-[3-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-2-fluoro-4-nitrophenyl amino]-2-(4-fluorophenyl) ethanol | (400MHz) .11.95 (s, 1H), 8.74 (s, 1H), 7.72 (d, J=9.6Hz, 1H), 7.42 (m, 2H), 7.15 (t, J=8.8Hz, 2H), 7.02 (d, J=4.4Hz, 1H), 6.23 (t, J=8.6Hz, 1H), 5.63 (s, 1H), 5.04 (t, J=5.8Hz, 1H), 4.65 (m, 1H), 3.61-3.74 (m, 2H), 1.84 (m, 1H), 0.91 (m, 2H), 0.66 (m, 2H) .MS: calculated value: 415; Measured value: [M+H] +416. | (R)-2-amino-2-(4-fluorophenyl) ethanol |
Method 38
(S)-N
1
-(5-cyclopropyl-1H-pyrazole-3-yl)-4-fluoro-N
3
-[1-(4-fluorophenyl) ethyl]-6-nitro
Benzene-1, the 3-diamines
With 5-cyclopropyl-N-(4,5-two fluoro-2-nitrophenyls)-1H-pyrazoles-3-amine (method 86; 0.300g, 1.07mmol), (S)-1-(4-fluoro-phenyl) ethylamine (0.164g, 1.18mmol) and DIEA (0.280ml, 1.61mmol) mixture 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 | Product | NMR/MS | Amine |
| 39 | (R)-2-[5-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-2-fluoro-4-nitrophenyl amino]-2-(4-fluorophenyl) ethanol | (400MHz) 12.29 (s, 1H), 10.13 (s, 1H), 7.77 (d, J=12.8Hz, 1H), 7.41 (m, J=6.4Hz, 3H), 7.15 (t, J=8.8Hz, 2H), 7.04 (d, J=8.0 Hz, 1H), 5.60 (s, 1H), 5.08 (t, J=5.8Hz, 1H), 4.45 (m, 1H), 3.62-3.80 (m, 2H), 1.90 (m, 1H), 0.98 (m, 2H), 0.71 (m, 2H) .MS: calculated value: 415; Measured value: [M+H] +416. | (R)-2-amino-2-(4-fluorophenyl) ethanol |
Method 40
(R)-2-[5-amino-4-(5-cyclopropyl-1H-pyrazole-3-yl amino)-6-methylpyrimidine-2-base ammonia
Base]-2-(4-fluorophenyl) ethanol
To (R)-2-[4-(5-cyclopropyl-1H-pyrazole-3-yl 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) 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 handled, and the gained mixture was stirred 30 minutes.React then by plug of celite and filter, with EtOAc (100ml) wash-out.(2 * 100ml) extractions, drying is filtered, and concentrates, and obtains (0.8g, 90%) product with EtOAc with the gained water layer.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.
| Method | Compound | NMR/MS | Synthetic method |
| 41 | N 4-(5-cyclopropyl-1H-pyrazoles-3-yl)-N 2-[(1S)-and 1-(4-fluorophenyl) ethyl] pyrimidine-2,4, the 5-triamine | 0.70 (m, 2H), 0.96 (m, 2H), 1.48 (d, J=6Hz, 3H), (1.90 m 1H), 5.05 (t, J=6Hz, 1H), 6.20 (s, 1H), 7.16 (m, 2H), 7.45 (m, 2H), 8.83 (brs, 1H), 10.35 (brs, 1H) .MS: calculated value: 353; Measured value: [M+H] +354.21 | Method 2 |
| 42 | (2R)-2-(5-amino-4-[(5-cyclopropyl-1H-pyrazole-3-yl) and amino] pyrimidine-2-base } amino)-2-(4-fluorophenyl) ethanol | 0.65 (m, 2H), 0.90 (m, 2H), 1.80 (m, 1H), 3.56 (m, 2H), 4.80 (m, 1H), 6.50 (s, 1H), 7.10 (m, 2H), 7.36 (m, 2H), 8.25 (brs, 1H) .MS: calculated value: 369; Measured value: [M+H] +370.22 | Method 3 |
| 43 | N 4-(5-cyclopropyl-1H-pyrazoles-3-yl)-N 2-(4-luorobenzyl) pyrimidine-2,4, the 5-triamine | MS: calculated value: 339; Measured value: [M+H] +340.19 | Method 4 |
| 44 | N 4-(5-cyclopropyl-1H-pyrazoles-3-yl)-N 2-[(1R)-and 1-(4-fluorophenyl) ethyl] pyrimidine-2,4, the 5-triamine | MS: calculated value: 353; Measured value: [M+H] +354.21 | Method 5 |
| 45 | (R)-2-(5-amino-4-(5-methyl-1H-pyrazole-3-yl amino) pyrimidine-2-base is amino)-2-(4-fluorophenyl) ethanol | MS: calculated value: 343; Measured value: [M+H] +344 | Method 6 |
| 46 | (S)-N 2-(1-(4-fluorophenyl) ethyl)-N 4-(5-isopropoxy-1H-pyrazole-3-yl) pyrimidine-2,4, the 5-triamine | MS: calculated value: 371; Measured value: [M+H] +372 | Method 7 |
Method 47
(S)-ethyl 5-amino-6-(5-cyclopropyl-1H-pyrazole-3-yl amino)-2-[1-(4-fluorophenyl) second
Base is amino] pyrimidine-4-manthanoate
To (S)-ethyl 6-(5-cyclopropyl-1H-pyrazole-3-yl amino)-2-[1-(4-fluorophenyl) ethylamino]-5-nitro-pyrimidine-4-manthanoate (method 10; 0.7g, 1.5mmol) and zinc powder (0.5g, 7.7mmol) at EtOH: THF (1: 1,20ml) slowly add saturated NH in the suspension in
4The Cl aqueous solution (3ml).After 1 hour, reaction mixture is cooled to 0 ℃, to wherein adding saturated NH
4OAc solution (10ml).The gained mixture filters by plug of celite then in 0 ℃ of stirring 10 minutes, with EtOAc (100ml) wash-out.(2 * 100ml) extract the gained water layer, and drying is filtered, and concentrates, and has obtained this title compound (0.60g, 92%), and it uses without being further purified with EtOAc.
Method 48
(S)-N
2
-(5-cyclopropyl-1H-pyrazole-3-yl)-N
6
-[1-(4-fluorophenyl) ethyl] pyridine-2,3,6-three
Amine
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, 0.68mmol) and zinc powder (0.223g, 3.41mmol) at MeOH: THF (1: 1,12ml) slowly add saturated ammonium chloride solution (1.5ml) in the suspension in.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,, use Na with salt solution (10ml) washing
2SO
4Drying, and concentrate.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.
| Method | Compound | NMR/MS | Synthetic method |
| 49 | N 2-(5-cyclopropyl-1H-pyrazoles-3-yl)-N 6-(4-luorobenzyl) pyridine-2,3, the 6-triamine | MS: calculated value: 338; Measured value: [M+H] +339 | Method 13 |
| Method | Compound | NMR/MS | Synthetic method |
| 50 | (2R)-2-(5-amino-6-[(5-cyclopropyl-1H-pyrazole-3-yl) and amino] pyridine-2-yl } amino)-2-(4-fluorophenyl) ethanol | MS: calculated value: 368; Measured value: [M+H] +369 | Method 14 |
| 51 | 2-(5-amino-6-[(5-cyclopropyl-1H-pyrazole-3-yl) and amino] pyridine-2-yl } amino)-2-(4-fluorophenyl) the third-1, the 3-glycol | MS: calculated value: 398; Measured value: [M+H] +399 | Method 15 |
| 52 | 5-chloro-N 2-(5-cyclopropyl-1H-pyrazole-3-yl)-N 6-[(1S)-and 1-(4-fluorophenyl) ethyl] pyridine-2,3, the 6-triamine | MS: calculated value: 386; Measured value: [M+H] +387 | Method 16 |
| 53 | 5-chloro-N 2-(5-cyclopropyl-1H-pyrazole-3-yl)-N 6-(4-luorobenzyl) pyridine-2,3, the 6-triamine | MS: calculated value: 372; Measured value: [M+H] +373 | Method 17 |
| 54 | (2R)-2-({ 5-amino-3-chloro-6-[(5-cyclopropyl-1H-pyrazoles-3-yl) amino] pyridine-2-yl } amino)-2-(4-fluorophenyl) ethanol | MS: calculated value: 402; Measured value: [M+H] +403 | Method 18 |
| 55 | (2R)-2-({ 5-amino-3-chloro-6-[(5-methyl isophthalic acid H-pyrazole-3-yl) amino] pyridine-2-yl } amino)-2-(4-fluorophenyl) ethanol | MS: calculated value: 376; Measured value: [M+H] +377 | Method 19 |
| 56 | (S)-N 2-(5-isopropoxy-1H-pyrazole-3-yl)-N 6-(1-(pyridine-2-yl) ethyl) pyridine-2,3, the 6-triamine | MS: calculated value: 353; Measured value: [M+H] +354 | Method 20 |
| Method | Compound | NMR/MS | Synthetic method |
| 57 | (S)-N 6-(1-(4-fluorophenyl) ethyl)-N 2-(5-isopropoxy-1H-pyrazole-3-yl)-pyridine-2,3, the 6-triamine | MS: calculated value: 370; Measured value: [M+H] +371. | Method 21 |
| 58 | (R)-2-(5-amino-6-(5-isopropoxy-1H-pyrazole-3-yl amino) pyridine-2-base is amino)-2-(4-fluorophenyl) ethanol | MS: calculated value: 386; Measured value: [M+H] +387. | Method 22 |
| 59 | (S)-5-chloro-N 6-(1-(4-fluorophenyl) ethyl)-N 2-(5-isopropoxy-1H-pyrazole-3-yl) pyridine-2, the 3.6-triamine | MS: calculated value: 404; Measured value: [M+H] +405. | Method 23 |
| 60 | (S)-N 2-(5-cyclopropyl-1H-pyrazole-3-yl)-N 6-(1-(pyridine-2-yl) ethyl) pyridine-2,3, the 6-triamine | MS: calculated value: 335; Measured value: [M+H] +336. | Method 24 |
| 61 | (R)-2-(5-amino-6-(5-methyl-1H-pyrazole-3-yl amino) pyridine-2-base is amino)-2-(4-fluorophenyl) ethanol | MS: calculated value: 342; Measured value: [M+H] +343. | Method 25 |
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, 0.97mmol) and zinc powder (0.317g, 4.85mmol) at MeOH: THF (1: 1,24ml) slowly add saturated ammonium chloride (3.0ml) in the suspension in.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,, use Na with salt solution (10ml) washing
2SO
4Drying, and concentrate.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 | Compound | NMR/MS | Synthetic method |
| 63 | (2R)-2-(4-amino-3-[(5-cyclopropyl-1H-pyrazole-3-yl) and amino] phenyl } amino)-2-(4-fluorophenyl) ethanol | MS: calculated value: 367; Measured value: [M+H] +368 | Method 27 |
| 64 | N 2-(5-cyclopropyl-1H-pyrazoles-3-yl)-N 4-(4-luorobenzyl) benzene-1,2, the 4-triamine | MS: calculated value: 337; Measured value: [M+H] +338 | Method 28 |
| 65 | N 4-[(1S)-1-(4-fluorophenyl) ethyl]-N 2-(5-isopropoxy-1H-pyrazole-3-yl) benzene-1,2, the 4-triamine | MS: calculated value: 369; Measured value: [M+H] +370 | Method 29 |
| 67 | (S)-N 3-(5-cyclopropyl-1H-pyrazole-3-yl)-N 1-(1-(pyridine-2-yl) ethyl) benzene-1,3, the 4-triamine | MS: calculated value: 334; Measured value: [M+H] +335. | Method 30 |
| 68 | (R)-2-(4-amino-3-(5-methyl-1H-pyrazole-3-yl amino) phenyl amino)-2-(4-fluorophenyl) ethanol | MS: calculated value: 341; Measured value: [M+H] +342. | Method 31 |
Method 69
(S)-5-amino-4-(5-cyclopropyl-1H-pyrazole-3-yl amino)-2-[1-(4-fluorophenyl) ethylamino]
Benzonitrile
To (S)-4-(5-cyclopropyl-1H-pyrazole-3-yl amino)-2-[1-(4-fluorophenyl) ethylamino]-5-nitrobenzonitrile (method 32; 4.10g, 10.1mmol) and zinc powder (3.30g, 50.4mmol) at MeOH: THF (1: 1,100ml) slowly add saturated ammonium chloride (40ml) in the suspension in.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,, use Na with salt solution (100ml) washing
2SO
4Drying, and concentrate.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 | Compound | NMR/MS | Synthetic method |
| 70 | 5-amino-4-[(5-cyclopropyl-1H-pyrazole-3-yl) amino]-2-[(1R)-and 1-(4-fluorophenyl)-2-hydroxyethyl] amino } benzonitrile | MS: calculated value: 392; Measured value: [M+H] +393 | Method 35 |
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, 1.00mmol) and zinc powder (0.327g, 5.00mmol) at MeOH: THF (1: 1,10ml) slowly add saturated ammonium chloride (4ml) in the suspension in.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 concentrate.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 | Compound | Synthetic method |
| 72 | (2R)-2-(4-amino-3-[(5-cyclopropyl-1H-pyrazole-3-yl) amino]-the 2-fluorophenyl } amino)-2-(4-fluorophenyl) ethanol | Method 37 |
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, 0.826mmol) and zinc powder (0.270g, 4.13mmol) at MeOH: THF (1: 1,10ml) slowly add saturated ammonium chloride (4ml) in the suspension in.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.Except that after desolvating, 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 | Compound | Synthetic method |
| 74 | (2R)-2-(4-amino-5-[(5-cyclopropyl-1H-pyrazole-3-yl) amino]-the 2-fluorophenyl } amino)-2-(4-fluorophenyl) ethanol | Method 39 |
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 2,4-two chloro-6-methyl-5-nitro pyrimidines (3.0g, 14.0mmol) and DIEA (2.4g is in n-BuOH 19.0mmol) (60ml) solution.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 ℃, to 2,4-two chloro-5-nitro-pyrimidines (3.0g, 15mmol) and DIEA (2.4g, 18.5mmol) in the solution in n-BuOH (30ml), slowly add 5-cyclopropyl-1H-pyrazoles-3-amine (2.0g, 16.2mmol).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(brs，1H)，10.40(brs，1H).
Method 77
6-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-3-nitropyridine-2-amine
In 0 ℃, to 2,6-two chloro-3-nitropyridines (0.67g, 3.2mmol) and DIEA (0.46ml, 2.65mmol) in the solution in EtOH (20ml), Dropwise 5-cyclopropyl-1H-pyrazoles-3-amine (0.26g, 2.12mmol) solution 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,, synthesized following compound by making itself and suitable amine reaction.
| Method | Product | NMR/MS | Amine |
| 78 | 6-chloro-N-(5-methyl isophthalic acid H-pyrazole-3-yl)-3-nitropyridine-2-amine | (400MHz) 12.36 (s, 1H), 10.24 (s, 1H), 8.55 (d, J=8.8Hz, 1H), 7.02 (d, J=8.8Hz, 1H), 6.48 (s, 1H), 2.27 (s, 3H) .MS: calculated value: 253; Measured value: [M+H] +254. | 5-methyl isophthalic acid H-pyrazoles-3-amine |
Method 79
5,6-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl)-3-nitropyridine-2-amine
In 0 ℃, to 2,3,6-three chloro-5-nitropyridines (1.62g, 7.10mmol) and DIEA (1.24ml, 7.1mmol) in the solution in THF (25ml), Dropwise 5-cyclopropyl-1H-pyrazoles-3-amine (0.70g, 5.68mmol) solution 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, have synthesized following compound.
| Method | Product | NMR/MS | Amine |
| 80 | (R)-2-(3,6-two chloro-5-nitropyridines-2-base is amino)-2-(4-fluorophenyl) ethanol | (400MHz)8.46(s，1H)，8.22(d， J＝8.0Hz，1H)，7.45(m，2H)， 7.16(m，2H)，5.22(m，1H)，5.05(t， J＝6.0Hz，1H)，3.87(m，1H)， 3.72(m，1H) | (R)-2-amino-2-(4-fluorophenyl) ethanol |
| 81 | 5,6-chloro-N-(5-isopropoxy-1H-pyrazole-3-yl)-3-nitropyridine-2-amine | (400MHz) 12.26 and 11.64 (s, 1H), 10.42 and 10.04 (s, 1H), 8.81 and 8.77 (s, 1H), 6.02 and 5.94 (s, 1H), 4.70 and 4.48 (m, 1H), 1.32 and 1.27 (d, J=6.0Hz, 6H) .MS: calculated value: 331; Measured value: [M+H] +332. | 5-isopropoxy-1H-pyrazoles-3-amine |
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), Dropwise 5-cyclopropyl-1H-pyrazoles-3-amine (0.91g, 7.39mmol) solution in THF (5ml).After the adding, reaction mixture stirred 48 hours in 80 ℃.Removal of solvent under reduced pressure, and the gained resistates obtained this title compound by column chromatography purifying (hexane: DCM: EtOAc=2: 1: 1), is 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, by 2,4-two fluoro-1-oil of mirbane and suitable amine have synthesized following compound.
| Method | Product | NMR/MS | Amine |
| 83 | N-(5-fluoro-2-nitrophenyl)-5-isopropoxy-1H-pyrazoles-3-amine | MS: calculated value: 280; Measured value: [M+H] +281 | 5-isopropoxy 1-1H-pyrazoles-3-amine |
| 84 | 5-methyl-N-(5-fluoro-2-nitrophenyl)-1H-pyrazoles-3-amine | (400MHz) 12.34 (s, 1H), 9.85 (s, 1H), 8.25 (m, 1H), 7.99 (dd, J=12.8 and 2.8Hz, 1H), 6.75 (m, 1H), 6.03 (d, J=2.0Hz, 1H), 2.24 (s, 3H). MS: calculated value: 236; Measured value: [M+H] +237. | 5-methyl isophthalic acid H-pyrazoles-3-amine |
Method 85
5-cyclopropyl-N-(2,3-two fluoro-6-nitrophenyls)-1H-pyrazoles-3-amine
In 0 ℃, to 1,2,3-three fluoro-4-oil of mirbane (3.2g, 18mmol) and DIEA (4.2ml, 24mmol) in the solution in dry THF (20ml), Dropwise 5-cyclopropyl-1H-pyrazoles-3-amine (2.0g, 16mmol) solution 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 1,2,4-three fluoro-5-oil of mirbane (3.0g, 18mmol) and DIEA (4.2ml, 24mmol) in the solution in dry THF (20ml), Dropwise 5-cyclopropyl-1H-pyrazoles-3-amine (2.0g, 16mmol) solution in THF (5ml).After the adding, reaction mixture stirred 20 hours in 25 ℃.Be heated to then 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-(different third hydrogen base of 5--1H-pyrazole-3-yl)-5-nitro-pyrimidine-4-amine
In 0 ℃, 2,4-two chloro-5-nitro-pyrimidines (0.41g, 2.1mmol) and DIEA (0.31ml, 1.8mmol) in the solution 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 is by column chromatography purifying (DCM: EtOAc=2.5: 1), obtained this title compound, be 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-2,4,5-three
Amine
To (S)-N
4-(5-cyclopropyl-1H-pyrazole-3-yl)-N
2-(1-(4-fluorophenyl) ethyl)-5-nitropyridine-2, the 4-diamines (method 89,0.15g, 0.40mmol) and zinc powder (0.13g, 2.0mmol) MeOH-THF (1: 1,16ml) in the suspension in, 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,, use Na with salt solution (10ml) washing
2SO
4Drying, and concentrate.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 DIEA (0.12ml, 0.67mmol) mixture in n-BuOH (5ml) the sealing pipe in 180 ℃ the heating 32 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 (0.168g, 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 (m 2H) .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-nitropyridine (methods 91,0.42g, 2.18mmol) and DIEA (0.46ml is 2.61mmol) in the solution in THF (10ml), Dropwise 5-cyclopropyl-1H-pyrazoles-3-amine (0.31g, 2.50mmol) solution 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, 2 H), 0.71 (m, 2H) .MS: calculated value: 279; Measured value: [M+H]
+280.
Method 91
2,4-two chloro-5-nitropyridines
In 0-5 ℃, to 4-chloro-5-nitropyridine-2-amine (method 92,4.40g, 21.0mmol) in the mixture in dense HCl (70ml), add in batches Sodium Nitrite (4.36g, 63.1mmol)., reaction is warmed to room temperature, and stirred 50 hours after 1 hour in 0-5 ℃ of placement.Add ice (100g), and (2 * 50ml) extract, and use dried over sodium sulfate with ether with mixture.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (hexane-DCM=1: 5), obtained this title compound, be white solid (1.47g, 33%).
1H NMR(400MHz)9.18(s，1H)，8.22(s，1H).
Method 92
4-chloro-5-nitropyridine-2-amine
To 4-chloro-3-nitropyridine (10.0g, 63.1mmol) in the mixture in 500ml liquefied ammonia, add potassium permanganate (19.9g, 126.1mmol).Be reflected at this temperature (33 ℃) and stirred 5 hours, slowly be warmed to room temperature then.After the ammonia evaporation, add entry (1L).Filter and collect the solid that forms, and water (2L) washing.With this solid with 1: 1=DCM: EtOAc (5 * 500ml) extraction.Remove and desolvate, and, obtained this title compound, be yellow solid (4.4g, 33%) gained solid recrystallize from EtOAc (400ml).
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 amino) pyridine-2-base is amino)-2-(4-
Fluorophenyl) ethanol
To (R)-2-(4-(5-cyclopropyl-1H-pyrazole-3-yl amino)-5-nitropyridine-2-base is amino)-2-(4-fluorophenyl) ethanol (method 94,0.14g, 0.36mmol) and zinc powder (0.12g, 1.78mmol) MeOH-THF (1: 1,16ml) slowly add saturated ammonium chloride (2.0ml) in the suspension in.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 concentrate.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 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 DIEA (0.12ml, 0.67mmol) mixture 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-(different third hydrogen base of 5--1H-pyrazole-3-yl)-3-nitropyridine-2-amine
To 2,6-two chloro-3-nitropyridines (1.0g, 5.3mmol) and DIEA (0.77ml, 4.4mmol) in the solution in THF (20ml), add 5-isopropoxy-1H-pyrazoles-3-amine (0.50g, 3.5mmol).Reaction mixture stirred 3 days in 25 ℃, and stirred 1 hour in 60 ℃.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 (0.62g, 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 and 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 amino)-5-(1-(4-fluorophenyl) ethylamino)
Benzonitrile
To (S)-3-(5-cyclopropyl-1H-pyrazole-3-yl amino)-5-(1-(4-fluorophenyl) ethylamino)-2-nitrobenzonitrile (method 97,4.20g, 10.0mmol) and zinc powder (3.40g, 52mmol) 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 concentrate.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 amino)-5-(1-(4-fluorophenyl) ethylamino)-2-nitre
The base benzonitrile
With 3-(5-cyclopropyl-1H-pyrazole-3-yl amino)-5-fluoro-2-nitrobenzonitrile (method 98,3.50g, 12.2mmol), (S)-1-(4-fluoro-phenyl) ethylamine (1.87g, 13.4mmol) and DIEA (2.6ml, 14.6mmol) mixture in n-BuOH (20ml) the sealing pipe in 230 ℃ the 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 (4.4g, 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 (m 2H) .MS: calculated value: 406; Measured value: [M+H]
+407.
Method 98
3-(5-cyclopropyl-1H-pyrazole-3-yl amino)-5-fluoro-2-nitrobenzonitrile
In 0 ℃, to 3,5-two fluoro-2-nitrobenzonitriles (method 99,5.8g, 31.5mmol) and DIEA (5.5ml, 31.5mmol) in the solution in THF (50ml), Dropwise 5-cyclopropyl-1H-pyrazoles-3-amine (4.66g, 37.8mmol) solution in THF (5ml).After the adding, reaction mixture stirred 20 hours in 25 ℃.Removal of solvent under reduced pressure, and the gained resistates is by column chromatography purifying (DCM-EtOAc=10: 1), obtained this title compound, be 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
4(33.7ml, 633mmol) in, that continues slowly adds 3,5-difluoro benzonitrile (4.4g, 31.6mmol).Gained suspension uses frozen water (500ml) to end in this temperature restir 3 hours then.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 amino)-5-(1-(4-fluorophenyl) ethylamino)
Benzamide
To (S)-3-(5-cyclopropyl-1H-pyrazole-3-yl amino)-5-(1-(4-fluorophenyl) ethylamino)-2-nitrobenzonitrile (method 97; 4.20g, 10.0mmol) and zinc powder (3.40g, 52mmol) MeOH-THF (1: 1,100ml) in the suspension in, 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 concentrate.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, the 3-diamines (method 102,0.30g, 0.719mmol) and zinc powder (0.235g is 3.59mmol) in the suspension among the 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.Except that after desolvating, 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 DIEA (0.263ml, the 1.51mmol) heating 8 hours in setting 135 ℃ oil bath in the pipe of sealing of the mixture in n-BuOH (2ml).Removal of solvent under reduced pressure, and resistates is by chromatography purification (hexane-EtOAc=3: 1), obtained this title compound, be 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, and 4-tetrafluoro-5-oil of mirbane (3.0g, 15.4mmol) and DIEA (3.7ml, 21.0mmol) in the mixture in dry THF (20ml), Dropwise 5-cyclopropyl-1H-pyrazoles-3-amine (1.7g, 14.0mmol) mixture 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 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 amino)-2,6-difluorophenyl amino)-2-
(4-fluorophenyl) ethanol
Saturated ammonium chloride (4ml) solution slowly is added to (R)-2-(3-(5-cyclopropyl-1H-pyrazole-3-yl amino)-2,6-two fluoro-4-nitrophenyl amino)-2-(4-fluorophenyl) ethanol (method 105,0.250g, 0.577mmol) and zinc powder (0.189g, 2.88mmol) in the suspension among the 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.Except that after desolvating, this product is directly used in next step without being further purified.
Method 105
(R)-2-(3-(5-cyclopropyl-1H-pyrazole-3-yl amino)-2,6-two fluoro-4-nitrophenyl 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 DIEA (0.263ml, 1.51mmol) mixture in n-BuOH (2ml) had been set in 135 ℃ the oil bath heating 8 hours in the pipe of sealing.Removal of solvent under reduced pressure, and resistates is by chromatography purification (hexane-EtOAc=1: 1), obtained this title compound, be 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 TrkA and B, and has effectiveness for the treatment cancer.Treatment target tyrosine kinase activity, particularly Trk activity and more especially TrkA and the active method of B, described activity relate to various and process related to cancer.Therefore, Tyrosylprotein kinase, Trk particularly, and the inhibitor of TrkA 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 TrkA 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 the 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 the transmission of existence signal.
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 TrkA and B.
Compound provided by the invention can also be as measure suppressing Tyrosylprotein kinase, particularly Trk, and the more especially standard substance and the reagent of the ability of the potential drug of TrkA and B.Described standard substance and reagent provide with the form of the test kit that comprises The compounds of this invention.
The TrkA 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 the TrkA kinase activity, in the SF9 cell, express people TrkA kinases (the amino acid 442-796 of TrkA of HIS-mark, Swiss-Prot Primary Accession Number P04629) cell intracellular domain, and use the standard nickel column chromatography to carry 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 Donor Beads that covers streptoavidin and covering Tyrosine O-phosphate specific antibody comes the detection reaction product.
| Peptide substrates | PolyEY-vitamin H (PGT-bio.) |
| ATP Km | 70μM |
| Analysis condition | 0.838ng/ml TrkA，9mM HEPES，45μg/ml BSA，10mM MnCl 2，5nM PGT-bio，0.01％TritonX-100，70μM ATP |
| Cultivate | 20 minutes, room temperature |
| Termination/testing conditions | 6.3mM HEPES，30mM EDTA，525μg/ml BSA，40mM NaCl，0.007％TritonX-100，12ng/ml Donor Beads， 12ng/ml Acceptor Beads |
| Detect and cultivate | Spend the night room temperature |
| Fluometer sets | Excite=the total minute=550ms of 680nM radiation=570nM firing time=180ms |
Though the pharmacological characteristic of formula (I) compound changes along with the change of structure, formula (I) the general activity that compound had can be passed through IC
50The concentration (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.
| Embodiment | IC 50(μM) |
| Embodiment 4 | 0.020 |
| Embodiment 14 | 0.022 |
| Embodiment 29 | 0.015 |
Claims (28)
1. formula (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 0-2
1-6Alkyl S (O)
a, C
1-6Alkoxy carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical or heterocyclic radical; R wherein
1And R
2Can choose wantonly independently of one another on carbon by one or more R
8Replace; And if wherein described heterocyclic radical contains-the NH-part, nitrogen can be chosen wantonly and is selected from R so
9Group replace;
X
1, X
2And X
3Be independently=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
4Be hydrogen or the optional C that replaces
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; 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.
2. the formula of claim 1 (I) compound or pharmaceutically acceptable salt thereof, wherein R
1Be selected from C
1-6Alkyl, C
1-6Alkoxyl group and carbocylic radical.
3. the formula of claim 1 or claim 2 (I) compound or pharmaceutically acceptable salt thereof, wherein R
2Be hydrogen.
4. formula (I) compound or pharmaceutically acceptable salt thereof of any one claim among the claim 1-3, wherein 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; And R
13It is hydroxyl.
5. formula (I) compound or pharmaceutically acceptable salt thereof of any one claim among the claim 1-4, wherein R
4Be hydrogen.
6. formula (I) compound or pharmaceutically acceptable salt thereof of any one claim among the claim 1-5, wherein 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; R wherein
16It is hydroxyl.
7. formula (I) compound or pharmaceutically acceptable salt thereof of any one claim among the claim 1-6, wherein 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; R wherein
18It is hydroxyl.
8. formula (I) compound or pharmaceutically acceptable salt thereof of any one claim among the claim 1-7, wherein encircling C is phenyl, pyridyl, 1,3-benzodioxole base or 1H-indyl.
9. formula (I) compound or pharmaceutically acceptable salt thereof of any one claim among the claim 1-8, wherein R
7Be selected from halogen and C
1-6Alkyl; R wherein
7Can choose wantonly on carbon by one or more R
20Replace; R wherein
20Be halogen.
10. formula (I) compound or pharmaceutically acceptable salt thereof of any one claim among the claim 1-3, wherein n is 0,1 or 2; R wherein
7Value can be identical or different.
11. formula (I) compound:
Wherein:
R
1Be selected from methyl, isopropoxy and cyclopropyl;
R
2Be hydrogen;
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
4Be hydrogen;
R
5Be selected from hydrogen, methyl, ethyl or hydroxymethyl;
R
6Be selected from hydrogen or hydroxymethyl;
A is direct key, methylene radical or hydroxyl methylene radical;
Ring C is phenyl, pyridine-2-base, 1,3-benzodioxole-5-base or 1H-indol-3-yl;
R
7Be trifluoromethyl and fluorine; And
N is 0,1 or 2; R wherein
7Value can be identical or different;
Or its pharmacologically acceptable salt.
12. be selected from formula (I) compound of following compounds:
(2R)-2-[9-(5-cyclopropyl-1H-pyrazole-3-yl)-6-methyl-9H-purine-2-base is amino]-2-(4-fluorophenyl) ethanol;
(2R)-and 2-{[9-(5-cyclopropyl-1H-pyrazole-3-yl)-9H-purine-2-yl] amino }-2-(4-fluorophenyl) ethanol;
N-((S)-1-(4-fluorophenyl) ethyl)-9-(5-isopropoxy-1H-pyrazole-3-yl)-9H-purine-2-amine;
3-(5-cyclopropyl-1H-pyrazole-3-yl)-N-[(S)-1-(4-fluorophenyl) ethyl]-3H-imidazo [4,5-b] pyridine-5-amine;
3-(5-isopropoxy-1H-pyrazole-3-yl)-N-((S)-1-(pyridine-2-yl) ethyl)-3H-imidazo [4,5-b] pyridine-5-amine;
N-((S)-1-(4-fluorophenyl) ethyl)-3-(5-isopropoxy-1H-pyrazole-3-yl)-3H-imidazo [4,5-b] pyridine-5-amine;
(2R)-2-(4-fluorophenyl)-2-(3-(5-isopropoxy-1H-pyrazole-3-yl)-3H-imidazo [4,5-b] pyridine-5-base is amino) ethanol;
6-chloro-N-((S)-1-(4-fluorophenyl) ethyl)-3-(5-isopropoxy-1H-pyrazole-3-yl)-3H-imidazo [4,5-b] pyridine-5-amine;
3-(5-cyclopropyl-1H-pyrazole-3-yl)-N-[(S)-1-(4-fluorophenyl) ethyl]-3H-benzo [d] imidazoles-5-amine; With
N-((1-(5-cyclopropyl-1H-pyrazole-3-yl)-6-((S)-1-(4-fluorophenyl) ethylamino)-1H-benzo [d] imidazoles-5-yl) methyl) ethanamide;
Or its pharmacologically acceptable salt.
13. the method for preparation formula (I) compound or pharmaceutically acceptable salt thereof, wherein variable group, unless stipulate that in addition as defined in claim 1, described method comprises:
Method a) makes (II) compound:
Pg nitrogen-protecting group wherein; With formula (III) compound:
Wherein L is a displaceable group, reacts;
Method b) for R wherein
5Be hydroxymethyl and R
6It is formula (I) compound of hydrogen; Make formula (II) compound and the epoxide reaction that makes (IV):
Method c) for X wherein
1Be=CR
10-formula (I) compound; Make the 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
2Reactant aqueous solution;
Method e) make formula (VII) compound:
Wherein L is that displaceable group and Pg are nitrogen-protecting groups; React with formula (VIII) amine:
And then 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.
14. formula (I) compound or pharmaceutically acceptable salt thereof as any one claim among the claim 1-12 of medicine.
15. the formula of any one claim among the claim 1-12 (I) compound or pharmaceutically acceptable salt thereof is used to suppress application aspect the active medicine of Trk in preparation.
16. the formula of any one claim among the claim 1-12 (I) compound or pharmaceutically acceptable salt thereof preparation be used for the treatment of or the medicine of preventing cancer aspect application.
17. the formula of any one claim among the claim 1-12 (I) compound or pharmaceutically acceptable salt thereof is used to produce the application aspect the medicine of anti-proliferative effect in preparation.
18. suppress the active method of Trk, described method comprises formula (I) compound or pharmaceutically acceptable salt thereof of any one claim in the claim 1-12 of host's drug treatment significant quantity that needs are treated like this.
19. the method for treatment or preventing cancer, described method comprises formula (I) compound or pharmaceutically acceptable salt thereof of any one claim among the administration claim 1-12.
20. needs like this warm-blooded animal of treatment for example produce the method for anti-proliferative effect among the people, described method comprises formula (I) compound or pharmaceutically acceptable salt thereof of any one claim in the claim 1-12 of described animals administer significant quantity.
21. comprise formula (I) compound or pharmaceutically acceptable salt thereof of any one claim among the claim 1-12 and the pharmaceutical composition of at least a pharmaceutically acceptable carrier, thinner or vehicle.
22. be used for suppressing active formula (I) compound or pharmaceutically acceptable salt thereof of any one claim of claim 1-12 and the pharmaceutical composition of at least a pharmaceutically acceptable carrier, thinner or vehicle of comprising of Trk.
23. be used for the treatment of or the formula that comprises any one claim among the claim 1-12 (I) compound or pharmaceutically acceptable salt thereof of preventing cancer and the pharmaceutical composition of at least a pharmaceutically acceptable carrier, thinner or vehicle.
24. be used for warm-blooded animal for example the people produce the formula that comprises any one claim among the claim 1-12 (I) compound or pharmaceutically acceptable salt thereof of anti-proliferative effect and the pharmaceutical composition of at least a pharmaceutically acceptable carrier, thinner or vehicle.
25. be used for suppressing formula (I) compound or pharmaceutically acceptable salt thereof of any one claim of the active claim 1-12 of Trk.
26. be used for the treatment of or the claim 1-12 of preventing cancer in formula (I) compound or pharmaceutically acceptable salt thereof of any one claim.
27. be used for producing formula (I) compound or pharmaceutically acceptable salt thereof of any one claim of the claim 1-12 of anti-proliferative effect.
28. claim 16,19,23 or 26 method or application, wherein said cancer is selected from 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 the intractable prostate cancer of hormone, bladder cancer, melanoma, nonsmall-cell lung cancer (NSCLC) and small cell lung cancer (SCLC), cancer of the stomach, head and neck cancer, kidney, lymphoma, papillary thyroid carcinoma is in interior thyroid carcinoma, mesothelioma and leukemia.
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 |
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| CN101119988A true CN101119988A (en) | 2008-02-06 |
| CN101119988B CN101119988B (en) | 2013-03-06 |
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| CN200680005004.2A Expired - Fee Related CN101119988B (en) | 2005-02-16 | 2006-02-15 | Chemical compouns |
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|---|---|
| CN (1) | CN101119988B (en) |
| UA (1) | UA93198C2 (en) |
| ZA (1) | ZA200706493B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105026398A (en) * | 2013-03-05 | 2015-11-04 | 默克专利股份公司 | Triazolo[4,5-d]pyrimidine derivatives for the treatment of diseases such as cancer |
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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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- 2006-02-15 CN CN200680005004.2A patent/CN101119988B/en not_active Expired - Fee Related
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105026398A (en) * | 2013-03-05 | 2015-11-04 | 默克专利股份公司 | Triazolo[4,5-d]pyrimidine derivatives for the treatment of diseases such as cancer |
| CN105026398B (en) * | 2013-03-05 | 2018-05-18 | 默克专利股份公司 | For treating the triazol of diseases such as cancer [4,5-d] pyrimidine derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101119988B (en) | 2013-03-06 |
| UA93198C2 (en) | 2011-01-25 |
| ZA200706493B (en) | 2008-08-27 |
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