CN100528865C - Imidazolo-5-yl-anilinopyrimidines as agents for the inhibition of cell proliferation - Google Patents
Imidazolo-5-yl-anilinopyrimidines as agents for the inhibition of cell proliferation Download PDFInfo
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- CN100528865C CN100528865C CNB2005800100579A CN200580010057A CN100528865C CN 100528865 C CN100528865 C CN 100528865C CN B2005800100579 A CNB2005800100579 A CN B2005800100579A CN 200580010057 A CN200580010057 A CN 200580010057A CN 100528865 C CN100528865 C CN 100528865C
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Abstract
Compounds of the formula (I), wherein variable groups are as defined within and a pharmaceutically acceptable salts and in vivo hydrolysable esters are described. Also described are processes for their preparation and their use as medicaments, particularly medicaments for producing a cell cycle inhibitory (anti cell proliferation) effect in a warm blooded animal, such as man.
Description
The present invention relates to hydrolyzable ester in pyrimidine derivatives or its pharmacy acceptable salt or the body, they have a cell cycle and suppress active, so their inhibition of cell proliferation (for example anticancer) activity is useful, and therefore are used for the treatment of the method for human or animal body.The invention still further relates to the method for the described pyrimidine derivatives of preparation, the medicinal compositions that contains them and their purposes in the preparation medicine, these medicines are used in for example people's generation inhibition of cell proliferation effect of warm-blooded animal.
Cell cycle is the basis of cell survival, adjusting and propagation, is subjected to highly regulation and control and is undertaken by timely orderly mode to guarantee each step.Several members' the order that cell development by the cell cycle comes from kinases (CDK) family of cyclin dependent activates and inactivation.CDKs activates and depends on they and the interaction that is called the intracellular protein family of cyclin.Cyclin combines with CDKs, and this combination is active most important for intracellular CDK (for example CDK1, CDK2, CDK4 and/or CDK6).Different cyclins is expressed and degraded at the difference of cell cycle, to guarantee that CDKs activation and inactivation are by correctly occurring in sequence by the cell cycle development.
In addition, the downstream of the seemingly multiple oncogene signal pathway of CDKs.By the active imbalance of the CDK that cyclin raises and/or the endogenous inhibitor disappearance causes, obviously be the important axis between mitogenesis signal pathway and the tumor cell proliferation.
Therefore, people recognize cell cycle kinase inhibitors, and especially CDK1, CDK2 and/or CDK4 inhibitor (they act on G2/M, G1/S-S-G2/M and G1-S phase respectively) should have for example value of the activity inhibitor of mammalian cancer cells growth of cell proliferation.
Estimate to suppress the value that cell-cycle kinases has treatment and abnormal cells cycle and cell proliferation diseases associated, for example cancer (solid tumor and leukemia), fiber proliferative and branchs voltinism disease, psoriatic, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, sebaceous cyst, atherosclerosis, arterial restenosis, autoimmune disorder, acute and chronic inflammation, osteopathy and the illness in eye of following retinal vessel to breed.
WO 02/20512, WO 03/076435, WO 03/076436, WO 03/076434 and WO 03/076433 describe some the 2-anilino-4-imidazolyl pyrimidines derivative that suppresses the cell-cycle kinases effect.The present invention is based on discovery: new 2-(4-heterocyclic radical anilino)-4-imidazolyl pyrimidines compounds suppresses the effect of cell-cycle kinases unexpectedly, shows the especially activity of CDK2 of anti-CDK1 and CDK2, thereby has the character of inhibition of cell proliferation.More than the equal concrete The compounds of this invention openly of any application, according to they one or more pharmacologically actives (compound that especially suppresses CDK2) and/or make their especially suitable warm-blooded animals for example pharmacokinetics, validity, metabolism and toxicological characteristics after the administration in the human body, we find that unexpectedly these compounds have beneficial property.Especially with previous those disclosed compound contrast, the health and the metabolic characteristic of these compounds improve.
Therefore, the invention provides hydrolyzable ester in formula (I) compound or its pharmacy acceptable salt or the body:
Wherein:
The optional 4-7 unit saturated rings that contains other nitrogen, oxygen or sulphur atom that the A ring connects for nitrogen;
If wherein the A ring contains other nitrogen-atoms, then this nitrogen can be chosen wantonly by R
7Replace;
R
1Be halogen, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, C
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl or C
2-6Alkynyl;
P is 0-4; R wherein
1Value can be identical or different;
R
2Be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, azido-, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkyloyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, carbocylic radical-R
34-, heterocyclic radical-R
35-, wherein a is the C of 0-2
1-6Alkyl S (O)
a, C
1-6Alkoxy carbonyl, N-(C
1-6Alkyl) sulfamyl or N, N-(C
1-6Alkyl)
2Sulfamyl; R wherein
2Can independently choose wantonly on carbon by one or more R
8Replace; Or R
2For-NHR
9,-NR
10R
11Or-O-R
12
Q is 0-2; R wherein
2Value can be identical or different;
R
3Be halogen, nitro, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-3Alkyl, C
2-3Thiazolinyl, C
2-3Alkynyl, C
1-3Alkoxyl group, C
1-3Alkyloyl, N-(C
1-3Alkyl) amino, N, N-(C
1-3Alkyl)
2Amino, C
1-3Alkanoylamino, N-(C
1-3Alkyl) formamyl, N, N-(C
1-3Alkyl)
2Formamyl, wherein a is the C of 0-2
1-3Alkyl S (O)
a, N-(C
1-3Alkyl) sulfamyl or N, N-(C
1-3Alkyl)
2Sulfamyl; R wherein
3Can independently choose wantonly on carbon by one or more R
13Replace;
N is 0-2, wherein R
3Value can be identical or different;
R
4Be hydrogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6The heterocyclic radical that alkynyl, carbocylic radical or carbon connect; R wherein
4Can choose wantonly on carbon by one or more R
14Replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly and is selected from R
15Group replace;
R
5And R
6Independently be 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
1-6Alkyloyl oxygen base, 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, C
3-8Cycloalkyl or 4-7 unit saturated heterocyclic group; R wherein
5And R
6Independently of one another, can choose wantonly on carbon by one or more R
16If replace and wherein 4-7 unit saturated heterocyclic group contain-the NH-part, then this nitrogen can be chosen wantonly and is selected from R
17Group replace;
R
7, R
9, R
10, R
11And R
12Independently be selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
2-6Thiazolinyl alkylsulfonyl, C
2-6Alkynyl alkylsulfonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, carbocylic radical, heterocyclic radical, carbocylic radical-R
18-or heterocyclic radical-R
19-; R wherein
7, R
9, R
10, R
11And R
12Can be independently optional selected on carbon from R
20Group replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly by R
21Replace;
R
14And R
20Independently be selected from halogen, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
2-6Alkene oxygen base, C
2-6Alkynyloxy group, C
1-6Alkoxy C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkoxy C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkyloyl oxygen base, 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, heterocyclic radical, carbocylic radical C
1-6Alkyl-R
22-, heterocyclic radical C
1-6Alkyl-R
23-, carbocylic radical-R
24-or heterocyclic radical-R
25-; R wherein
14And R
20Can be independently optional by one or more R on carbon
26Replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly and is selected from R
27Group replace;
R
18, R
19, R
22, R
23, R
24, R
25, R
34Or R
35Independently be selected from-O-,-N (R
28)-,-C (O)-,-N (R
29) C (O)-,-C (O) N (R
30)-,-S (O)
s-,-SO
2N (R
31)-or-N (R
32) SO
2-; R wherein
28, R
29, R
30, R
31And R
32Independently be selected from hydrogen or C
1-6Alkyl, s are 0-2;
R
15, R
17, R
21And R
27Independently be selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and benzenesulfonyl; R wherein
15, R
17, R
21And R
27Independently of one another, can choose wantonly on carbon by one or more R
33Replace; With
R
8, R
13, R
16, R
26And R
33Independently be selected from halogen; nitro; cyano group; hydroxyl; trifluoromethoxy; trifluoromethyl; amino; carboxyl; formamyl; sulfydryl; sulfamyl; methyl; ethyl; methoxyl group; oxyethyl group; ethanoyl; acetoxyl group; methylamino-; ethylamino; dimethylamino; diethylin; 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.
In accordance with a further aspect of the present invention, provide hydrolyzable ester in formula (I) compound (as above-mentioned) or its pharmacy acceptable salt or the body, wherein:
The optional 4-7 unit saturated rings that contains other nitrogen, oxygen or sulphur atom that the A ring connects for nitrogen;
If wherein the A ring contains other nitrogen-atoms, then this nitrogen can be chosen wantonly by R
7Replace;
R
1Be halogen, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, C
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl or C
2-6Alkynyl;
P is 0-4; R wherein
1Value can be identical or different;
R
2Be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkyloyl, 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 or N, N-(C
1-6Alkyl)
2Sulfamyl; R wherein
2Can independently choose wantonly on carbon by one or more R
8Replace; Or R
2For-NHR
9,-NR
10R
11Or-O-R
12
Q is 0-2; R wherein
2Value can be identical or different;
R
3Be halogen, nitro, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-3Alkyl, C
2-3Thiazolinyl, C
2-3Alkynyl, C
1-3Alkoxyl group, C
1-3Alkyloyl, N-(C
1-3Alkyl) amino, N, N-(C
1-3Alkyl)
2Amino, C
1-3Alkanoylamino, N-(C
1-3Alkyl) formamyl, N, N-(C
1-3Alkyl)
2Formamyl, wherein a is the C of 0-2
1-3Alkyl S (O)
a, N-(C
1-3Alkyl) sulfamyl or N, N-(C
1-3Alkyl)
2Sulfamyl; R wherein
3Can independently choose wantonly on carbon by one or more R
13Replace;
N is 0-2, wherein R
3Value can be identical or different;
R
4Be hydrogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6The heterocyclic radical that alkynyl, carbocylic radical or carbon connect; R wherein
4Can choose wantonly on carbon by one or more R
14Replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly and is selected from R
15Group replace;
R
5And R
6Independently be 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
1-6Alkyloyl oxygen base, 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, C
3-8Cycloalkyl or 4-7 unit saturated heterocyclic group; R wherein
5And R
6Independently of one another, can choose wantonly on carbon by one or more R
16Replace; If wherein 4-7 unit saturated heterocyclic group contains-the NH-part, then this nitrogen can be chosen wantonly and is selected from R
17Group replace;
R
7, R
9, R
10, R
11And R
12Independently be selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
2-6Thiazolinyl alkylsulfonyl, C
2-6Alkynyl alkylsulfonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, carbocylic radical, heterocyclic radical, carbocylic radical-R
18-or heterocyclic radical-R
19-; R wherein
7, R
9, R
10, R
11And R
12Can be independently optional selected on carbon from R
20Group replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly by R
21Replace;
R
14And R
20Independently be selected from halogen, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkoxy C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkyloyl oxygen base, 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, heterocyclic radical, carbocylic radical C
1-6Alkyl-R
22-, heterocyclic radical C
1-6Alkyl-R
23-, carbocylic radical-R
24-or heterocyclic radical-R
25-; R wherein
14And R
20Can choose wantonly on carbon by one or more R
26Replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly and is selected from R
27Group replace;
R
18, R
19, R
22, R
23, R
24, R
25Independently be selected from-O-,-N (R
28)-,-C (O)-,-N (R
29) C (O)-,-C (O) N (R
30)-,-S (O)
s-,-SO
2N (R
31)-or-N (R
32) SO
2-; R wherein
28, R
29, R
30, R
31And R
32Independently be selected from hydrogen or C
1-6Alkyl, s are 0-2;
R
15, R
17, R
21And R
27Independently be selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and benzenesulfonyl; R wherein
15, R
17, R
21And R
27Independently of one another, can choose wantonly on carbon by one or more R
33Replace; With
R
8, R
13, R
16, R
26And R
33Independently be selected from halogen; nitro; cyano group; hydroxyl; trifluoromethoxy; trifluoromethyl; amino; carboxyl; formamyl; sulfydryl; sulfamyl; methyl; ethyl; methoxyl group; oxyethyl group; ethanoyl; acetoxyl group; methylamino-; ethylamino; dimethylamino; diethylin; 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.
In accordance with a further aspect of the present invention, provide hydrolyzable ester in formula (I) compound (as above-mentioned) or its pharmacy acceptable salt or the body, wherein:
The optional 4-7 unit saturated rings that contains other nitrogen, oxygen or sulphur atom that the A ring connects for nitrogen; If wherein the A ring contains other nitrogen-atoms, then this nitrogen can be chosen wantonly by R
7Replace;
R
1Be halogen, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, C
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Thiazolinyl or C
2-6Alkynyl;
P is 0-4; R wherein
1Value can be identical or different;
R
2Be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkyloyl, 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 or N, N-(C
1-6Alkyl)
2Sulfamyl; R wherein
2Can be independently optional by one or more R on carbon
8Replace; Or R
2For-NHR
9,-NR
10R
11Or-O-R
12
Q is 0-2; R wherein
2Value can be identical or different;
R
3Be halogen, nitro, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-3Alkyl, C
2-3Thiazolinyl, C
2-3Alkynyl, C
1-3Alkoxyl group, C
1-3Alkyloyl, N-(C
1-3Alkyl) amino, N, N-(C
1-3Alkyl)
2Amino, C
1-3Alkanoylamino, N-(C
1-3Alkyl) formamyl, N, N-(C
1-3Alkyl)
2Formamyl, wherein a is the C of 0-2
1-3Alkyl S (O)
a, N-(C
1-3Alkyl) sulfamyl or N, N-(C
1-3Alkyl)
2Sulfamyl; R wherein
3Can be independently optional by one or more R on carbon
13Replace;
N is 0-2, wherein R
3Value can be identical or different;
R
4Be hydrogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6The heterocyclic radical that alkynyl, carbocylic radical or carbon connect; R wherein
4Can on carbon, choose wantonly by one or more R
14Replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly and is selected from R
15Group replace;
R
5And R
6Independently be 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
1-6Alkyloyl oxygen base, 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, C
3-8Cycloalkyl or 4-7 unit saturated heterocyclic group; R wherein
5And R
6Independently of one another, can choose wantonly on carbon by one or more R
16Replace; If wherein 4-7 unit saturated heterocyclic group contains-the NH-part, then this nitrogen can be chosen wantonly and is selected from R
17Group replace;
R
7, R
9, R
10, R
11And R
12Independently be selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
2-6Thiazolinyl alkylsulfonyl, C
2-6Alkynyl alkylsulfonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, carbocylic radical, heterocyclic radical, carbocylic radical-R
18-or heterocyclic radical-R
19-; R wherein
7, R
9, R
10, R
11And R
12Can be independently optional selected on carbon from R
20Group replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly by R
21Replace;
R
14And R
20Independently be selected from halogen, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
2-6Alkene oxygen base, C
2-6Alkynyloxy group, C
1-6Alkoxy C
1-6Alkoxyl group, C
1-6Alkoxy C
1-6Alkoxy C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkyloyl oxygen base, 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)
8, C
1- 6Alkoxy carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical, heterocyclic radical, carbocylic radical C
1-6Alkyl-R
22-, heterocyclic radical C
1-6Alkyl-R
23-, carbocylic radical-R
24-or heterocyclic radical-R
25-; R wherein
14And R
20Can on carbon, choose wantonly by one or more R
26Replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly and is selected from R
27Group replace;
R
18, R
19, R
22, R
23, R
24, R
25Independently be selected from-O-,-N (R
28)-,-C (O)-,-N (R
29) C (O)-,-C (O) N (R
30)-,-S (O)
s-,-SO
2N (R
31)-or-N (R
32) SO
2-; R wherein
28, R
29, R
30, R
31And R
32Independently be selected from hydrogen or C
1-6Alkyl, s are 0-2;
R
15, R
17, R
21And R
27Independently be selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and benzenesulfonyl; R wherein
15, R
17, R
21And R
27Independently of one another, can choose wantonly on carbon by one or more R
33Replace; With
R
8, R
13, R
16, R
26And R
33Independently be selected from halogen; nitro; cyano group; hydroxyl; trifluoromethoxy; trifluoromethyl; amino; carboxyl; formamyl; sulfydryl; sulfamyl; methyl; ethyl; methoxyl group; oxyethyl group; ethanoyl; acetoxyl group; methylamino-; ethylamino; dimethylamino; diethylin; N-methyl-N-ethylamino; kharophen; N-methylamino formyl radical; N-base formamyl; 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.
In this manual, term " alkyl " comprises straight chain and branched-chain alkyl, but relates to single alkyl, and for example " propyl group " then only refers in particular to linear form." C for example
1-6Alkyl " and " C
1-4Alkyl " comprise methyl, ethyl, propyl group, sec.-propyl and the tertiary butyl.But, relate to single alkyl for example " propyl group " then only refer in particular to linear form, and relate to single branched-chain alkyl for example ' sec.-propyl ' only refer in particular to side chain form.Similarly convention is applicable to other group, for example " carbocylic radical C
1-6Alkyl-R
20" comprise carbocylic radical methyl-R
20, 1-carbocylic radical ethyl-R
20With 2-carbocylic radical ethyl-R
20Term " halogen " refers to fluorine, chlorine, bromine and iodine.
When optional substituting group is selected from " one or more " group, is interpreted as this definition and comprises all substituting groups that are selected from one of appointment group, or be selected from two or more substituting group in the appointment group.
" heterocyclic radical " saturated, fractional saturation or unsaturated monocycle or dicyclo for containing 4-12 atom, wherein at least one atom is selected from nitrogen, sulphur or oxygen, and except that referring else, it can be connected with carbon or nitrogen, wherein-CH
2-group can be chosen wantonly by-C (O)-displacement, and theheterocyclic nitrogen atom can be chosen wantonly and have C
1-6Alkyl, and form the tetravalence compound, maybe can choose oxidation ring nitrogen and/or sulphur atom wantonly, form N-oxide compound and or S-oxide compound.The example of term " heterocyclic radical " and suitable value are morpholino, piperidyl, pyridyl, pyranyl, pyrryl, isothiazolyl, indyl, quinolyl, thienyl, 1,3-benzo dioxolyl, thiadiazolyl group, piperazinyl, thiazolidyl, pyrrolidyl, thiomorpholine generation, pyrrolinyl, high piperazinyl, 3,5-two oxa-piperidyls, THP trtrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl isoxazolyl, N-methylpyrrole base, the 4-pyridone, the 1-isoquinolone, 2-Pyrrolidone, the 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide compound.In one aspect of the invention, " heterocyclic radical " saturated, fractional saturation or undersaturated monocycle or dicyclo for containing 5 or 6 atoms, wherein at least one atom is selected from nitrogen, sulphur or oxygen, and except that referring else, it can be connected with carbon or nitrogen ,-CH
2-group can be chosen wantonly by-C (O)-displacement, can choose oxidation epithio atom wantonly, forms the S-oxide compound.
" carbocylic radical " saturated, fractional saturation or unsaturated monocycle or bicyclic carbocyclic for containing 3-12 atom; Wherein-CH
2-group can be chosen wantonly by-C (O)-displacement." carbocylic radical " especially is the dicyclo that contains the monocycle of 5 or 6 atoms or contain 9 or 10 atoms.The desired value of " carbocylic radical " comprises cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, 1,2,3,4-tetralin base, 2,3-indanyl or 1-oxo-2,3-indanyl.
" 4-7 unit saturated heterocyclic group " for containing the saturated monocycle of 4-7 atom, wherein at least one atom is selected from nitrogen, sulphur or oxygen, and except that referring else, it can be connected with carbon or nitrogen, wherein-and CH
2-group can be chosen wantonly by-C (O)-displacement, can choose the sulfur oxide atom wantonly and form the S-oxide compound.The example and the suitable value of term " 4-7 unit saturated heterocyclic group " are morpholino, piperidyl, 1,4-alkyl dioxin, 1,3-dioxolanyl, 1,2-oxa-thia cyclopentyl, imidazolidyl, pyrazolidyl, piperazinyl, thiazolidyl, pyrrolidyl, thiomorpholine generation, high piperazinyl and THP trtrahydropyranyl.
The A ring is " the optional 4-7 unit saturated rings that contains other nitrogen, oxygen or sulphur atom that nitrogen connects "." the 4-7 unit saturated rings that the optional nitrogen that contains other nitrogen, oxygen or sulphur atom connects " is for containing the saturated monocycle of 4-7 atom, this ring is connected with the phenyl moiety of formula (I) by contained nitrogen-atoms in the ring, the optional other heteroatoms that is selected from nitrogen, sulphur or oxygen that contains of this ring, wherein-CH
2-group can be chosen wantonly by-C (O)-displacement, can choose the optional sulphur atom of oxidation wantonly and form the S-oxide compound.
" C
1-3Alkyl " example comprise methyl, ethyl, propyl group and sec.-propyl." C
1-6Alkyloyl oxygen base " example be acetoxyl group." C
1-6Alkoxy carbonyl " example comprise methoxycarbonyl, ethoxy carbonyl, just and tert-butoxycarbonyl." C
1-6Alkoxyl group " and " C
1-3Alkoxyl group " example comprise methoxyl group, oxyethyl group and propoxy-." C
1-6Alkanoylamino " and " C
1-3Alkanoylamino " example comprise formamido group, kharophen and propionamido." wherein a is the C of 0-2
1-6Alkyl S (O)
a" and " wherein a is the C of 0-2
1-3Alkyl S (O)
a" example comprise methylthio group, ethylmercapto group, methylsulfinyl, ethyl sulfinyl, methylsulfonyl and ethylsulfonyl." wherein r is the C of 1-2
1-6Alkyl S (O)
r" example comprise methylsulfinyl, ethyl sulfinyl, methylsulfonyl and ethylsulfonyl." C
1-6Alkyloyl " and " C
1-3Alkyloyl " example comprise propionyl and ethanoyl." N-C
1-6Alkylamino " and " N-C
1-3Alkylamino " example comprise methylamino-and ethylamino." N, N-(C
1-6Alkyl)
2Amino " and " N, N-(C
1-3Alkyl)
2Amino " example comprise the amino and N-ethyl-N-methylamino of two-N-methylamino, two-(N-ethyl)." C
2-6Thiazolinyl " and " C
2-3Thiazolinyl " example be vinyl, allyl group and 1-propenyl." C
2-6Alkynyl " and " C
2-3Alkynyl " example be ethynyl, 1-proyl and 2-propynyl." N-(C
1-6Alkyl) sulfamyl " and " N-(C
1-3Alkyl) sulfamyl " example be N-(methyl) sulfamyl and N-(ethyl) sulfamyl." N, N-(C
1-6Alkyl)
2Sulfamyl " and " N, N-(C
1-3Alkyl)
2Sulfamyl " example be N, N-(dimethyl) sulfamyl and N-(methyl)-N-(ethyl) sulfamyl." N-(C
1-6Alkyl) formamyl " and " N-(C
1-3Alkyl) formamyl " example be amino-carbonyl and B aminocarbonyl." N, N-(C
1-6Alkyl)
2Formamyl " and " N, N-(C
1-3Alkyl)
2Formamyl " example be dimethylamino carbonyl and methylethyl aminocarboxyl." C
3-8Cycloalkyl " example be cyclopropyl, cyclobutyl, cyclopropyl and cyclohexyl." C
1-6Alkyl sulfonyl-amino " example comprise methyl sulphonyl amino, sec.-propyl sulfuryl amino and tert-butyl sulfuryl amino." C
1-6Alkyl sulphonyl " example comprise methylsulfonyl, sec.-propyl alkylsulfonyl and tert-butyl alkylsulfonyl." C
2-6The thiazolinyl alkylsulfonyl " example comprise vinylsulfonyl, allyl group alkylsulfonyl and 1-propenyl alkylsulfonyl." C
2-6The alkynyl alkylsulfonyl " example comprise ethynyl alkylsulfonyl, 1-proyl alkylsulfonyl and 2-propynyl alkylsulfonyl." C
1-6Alkoxy C
1-6Alkoxyl group " example comprise methoxy ethoxy, 2-oxyethyl group propoxy-and 2-isopropoxy butoxy." C
1-6Alkoxy C
1-6Alkoxy C
1-6Alkoxyl group " example comprise methoxy ethoxy methoxyl group, 2-ethoxy-c Oxymethoxy and 3-(2-isopropoxy butoxy) oxyethyl group.
" C
2-6Alkene oxygen base " example comprise vinyloxy group and allyloxy." C
2-6Alkynyloxy group " example comprise second alkynyloxy group and 2-third alkynyloxy group.
The suitable pharmacy acceptable salt of The compounds of this invention is, the acid salt that the The compounds of this invention of enough alkalescence is for example arranged, the acid salt of for example following acid: for example mineral acid or organic acid, for example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid or toxilic acid.In addition, the suitable pharmacy acceptable salt that enough tart The compounds of this invention are arranged is an an alkali metal salt, for example sodium or sylvite; Alkaline earth salt, for example calcium or magnesium salts; Ammonium salt or provide and to accept cationic organic alkali salt on the physiology, for example salt of methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three-(2-hydroxyethyl) amine.
The interior hydrolyzable ester of body that contains formula (I) compound of carboxyl or hydroxyl is for example hydrolysis in human or animal body, produces the pharmaceutically acceptable ester of parent acid or alcohol.The suitable pharmaceutically acceptable ester of carboxyl comprises C
1-6Alkoxy methyl ester, for example methoxymethyl ester; C
1-6Alkyloyl oxygen ylmethyl ester, for example oxy acid methyl neopentyl ester, phthalidyl ester; C
3-8Cyclo alkoxy carbonyl oxygen base C
1-6Alkyl ester, for example 1-cyclohexyl-carbonyl oxygen base ethyl ester; 1,3-dioxole-2-ketone group methyl ester, 5-methyl isophthalic acid for example, 3-dioxole-2-ketone group methyl ester; And C
1-6Alkoxy-carbonyl oxy ethyl ester, for example 1-methoxycarbonyl oxygen base ethyl ester and can on any carboxyl of The compounds of this invention, forming.
Hydrolyzable ester comprises inorganic ester in the body of the formula of hydroxyl (I) compound, for example phosphoric acid ester, α-acyloxy alkyl oxide and because the ester hydrolysis allied compound that the generation parent hydroxy obtains that dissociates in vivo.The example of α-acyloxy alkyl oxide comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy-methoxyl group.Can make the group of hydrolyzable ester in the hydroxyl organizer select to comprise benzoyl and phenyl acetyl, alkoxy carbonyl (obtaining alkyl carbonate), dialkyl amido formyl radical and N-(dialkyl amido ethyl)-N-alkyl-carbamoyl (generation carbamate), dialkyl amido ethanoyl and the carboxyl ethanoyl of alkyloyl, benzoyl, phenyl acetyl and replacement.Substituting group example on the benzoyl comprises morpholino and piperazine-1-base, and the theheterocyclic nitrogen atom of morpholino and piperazine-1-base is connected by methylene radical 3 or 4 with the benzoyl basic ring.
Some formula (I) compound can have chiral centre and/or rotamerism center (E-and Z-isomer), should understand the present invention includes to have CDK inhibition active all these type of optically-active diastereomer and geometrical isomers.
The present invention relates to have any and all tautomers that CDK suppresses active formula (I) compound.Especially in the industry the reader will appreciate that, works as R
4During for hydrogen, the imidazole ring of describing in the formula (I) is interconvertible.
Should also be understood that some formula (I) compound can exist solvation and not solvation form, for example hydrate forms.Should understand the present invention includes and have active all these type of solvation forms of CDK inhibition.
Not isoplastic occurrence is as follows.When any definition that limits in the suitable upper and lower literary composition, claim or embodiment, can use this type of value.
The optional 4-7 unit saturated rings that contains other nitrogen or Sauerstoffatom that the A ring connects for nitrogen; If wherein the A ring contains other nitrogen-atoms, then this nitrogen can be chosen wantonly by R
7Replace; Wherein
R
7Be selected from C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
2-6Thiazolinyl alkylsulfonyl, carbocylic radical-R
18-or heterocyclic radical-R
19-; R wherein
7Can be independently optional selected on carbon from R
20Group replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly by R
21Replace;
R
18And R
19For-C (O)-;
R
20Be selected from halogen, cyano group, hydroxyl, C
1-6Alkoxyl group, C
2-6Alkynyloxy group, C
1-6Alkyloyl oxygen base, N, N-(C
1-6Alkyl)
2Amino, wherein a is 2 C
1-6Alkyl S (O)
aOr heterocyclic radical; R wherein
20Can on carbon, choose wantonly by one or more R
26Replace;
R
21Be C
1-6Alkyl; With
R
26Be hydroxyl.
Ring A is the optional 4-6 unit saturated rings that contains other nitrogen or Sauerstoffatom that nitrogen connects; If wherein the A ring contains other nitrogen-atoms, then this nitrogen can be chosen wantonly by R
7Replace; Wherein
R
7Be selected from C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
2-6Thiazolinyl alkylsulfonyl, carbocylic radical-R
18-or heterocyclic radical-R
19-; R wherein
7Can be independently optional selected on carbon from R
20Group replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly by R
21Replace;
R
18And R
19For-C (O)-;
R
20Be selected from halogen, cyano group, hydroxyl, C
1-6Alkoxyl group, C
2-6Alkynyloxy group, C
1-6Alkyloyl oxygen base, N, N-(C
1-6Alkyl)
2Amino, wherein a is 2 C
1-6Alkyl S (O)
aOr heterocyclic radical; R wherein
20Can on carbon, choose wantonly by one or more R
26Replace;
R
21Be C
1-6Alkyl; With
R
26Be hydroxyl.
The optional 4-7 unit saturated rings that contains other nitrogen, oxygen or sulphur atom that the A ring connects for nitrogen; If wherein the A ring contains other nitrogen-atoms, then this nitrogen can be chosen wantonly by R
7Replace; Wherein
R
7Be selected from C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
2-6Thiazolinyl alkylsulfonyl, carbocylic radical-R
18-or heterocyclic radical-R
19-; R wherein
7Can be independently optional selected on carbon from R
20Group replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly by R
21Replace;
R
20Be selected from halogen, cyano group, hydroxyl, C
1-6Alkoxyl group, C
2-6Alkynyloxy group, C
1-6Alkyloyl oxygen base, N, N-(C
1-6Alkyl)
2Amino, wherein a is 2 C
1-6Alkyl S (O)
aOr heterocyclic radical; R wherein
20Can on carbon, choose wantonly by one or more R
26Replace;
R
18And R
19For-C (O)-;
R
21Be C
1-6Alkyl; With
R
26Be hydroxyl.
Optional 6 yuan of saturated rings that contain other nitrogen-atoms that the A ring connects for nitrogen; If wherein the A ring contains other nitrogen-atoms, then this nitrogen can be chosen wantonly by R
7Replace; Wherein
R
7Be selected from C
1-6Alkyloyl, C
1-6Alkyl sulphonyl and C
2-6The thiazolinyl alkylsulfonyl; R wherein
7Can on carbon, choose wantonly selected from R
20Group replace; Wherein
R
20Be selected from hydroxyl, C
1-6Alkoxyl group, C
1-6Alkyloyl oxygen base and N, N-(C
1-6Alkyl)
2Amino.
The A ring is piperazine-1-base, morpholino, pyrrolidyl or azetidinyl; Wherein said piperazine-1-base can be chosen wantonly by R on nitrogen
7Replace; Wherein
R
7Be selected from ethanoyl, propionyl, 2,2-dimethyl propylene acyl group, 3-methylbutyryl base, butyryl radicals, isobutyryl, methylsulfonyl, ethylsulfonyl, vinylsulfonyl, cyclopropyl-R
18-, tetrahydrofuran base-R
19-or pyrrolidyl-R
19-; R wherein
7Can be independently optional selected on carbon from R
20Group replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly by R
21Replace;
R
18And R
19For-C (O)-;
R
20Be selected from fluorine, chlorine, cyano group, hydroxyl, methoxyl group, third-2-alkynes-1-base oxygen base, acetoxyl group, dimethylamino, diethylin, methylsulfonyl, tetrazyl, pyrrolidyl, morpholino, azetidinyl; R wherein
20Can on carbon, choose wantonly by one or more R
26Replace;
R
21Be methyl; With
R
26Be hydroxyl.
The A ring is piperazine-1-base or morpholino; Wherein said piperazinyl can be chosen wantonly by R on nitrogen
7Replace; Wherein
R
7Be selected from ethanoyl, propionyl, 2-methylpropionyl, 2,2-dimethyl propylene acyl group, butyryl radicals, 3-methylbutyryl base, methylsulfonyl, vinylsulfonyl, cyclopropyl-R
18-, tetramethyleneimine-2-base-R
19-, tetrahydrofuran (THF)-2-base-R
19-or tetrahydrofuran (THF)-3-base-R
19-; R wherein
7Can be independently optional selected on carbon from R
20Group replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly by R
21Replace;
R
20Be selected from fluorine, chlorine, cyano group, hydroxyl, methoxyl group, 2-third alkynyloxy group, acetoxyl group, dimethylamino, diethylin, methylsulfonyl, azetidine-1-base, tetramethyleneimine-1-base, morpholino, tetrazolium-1-base or tetrazolium-5-base; R wherein
20Can on carbon, choose wantonly by one or more R
26Replace;
R
18And R
19For-C (O)-;
R
21Be methyl; With
R
26Be hydroxyl.
The A ring is morpholino or piperazine-1-base; If wherein A ring is piperazine-1-base, then-the NH-part can choose wantonly by R
7Replace; Wherein
R
7Be selected from ethanoyl, methyl sulphonyl, ethylsulfonyl and vinylsulfonyl; R wherein
7Can on carbon, choose wantonly selected from R
20Group replace; Wherein
R
20Be selected from hydroxyl, methoxyl group, acetoxyl group and dimethylamino.
A ring, R
2Form together with q:
1) piperazine-1-base,
2) morpholino,
3) 4-methylsulfonyl piperazine-1-base,
4) 4-ethanoyl piperazine-1-base,
5) 4-(2-acetoxyl group ethanoyl) piperazine-1-base,
6) 4-(2-hydroxyacetyl) piperazine-1-base,
7) 4-(2-chloracetyl) piperazine-1-base,
8) 4-(2-methoxyl group ethanoyl) piperazine-1-base,
9) (3-methoxy propyl acyl group) piperazine-1-base,
10) (3-hydroxy-3-methyl butyryl radicals) piperazine-1-base,
11) (3-hydroxyl-2,2-dimethyl propylene acyl group) piperazine-1-base,
12) ((R)-3-methyl-2-maloyl group) piperazine-1-base,
13) ((S)-3-methyl-2-maloyl group) piperazine-1-base,
14) 4-(2-dimethylamino ethanoyl) piperazine-1-base,
15) 4-[2-(dimethylamino) ethylsulfonyl] piperazine-1-base,
16) 4-[2-(methoxyl group) ethylsulfonyl] piperazine-1-base,
17) 4-[2-(hydroxyl) ethylsulfonyl] piperazine-1-base,
18) 4-(cyclopropyl carbonyl) piperazine-1-base,
19) 4-(1-hydroxyl cyclopropyl carbonyl) piperazine-1-base,
20) 4-(1-cyano group cyclopropyl carbonyl) piperazine-1-base,
21) 4-(2-hydroxy-2-methyl propionyl) piperazine-1-base,
22) 4-((R)-2-hydroxyl propionyl) piperazine-1-base,
23) 4-((S)-2-hydroxyl propionyl) piperazine-1-base,
24) 4-((R)-2-methoxy propyl acyl group) piperazine-1-base,
25) 4-((S)-2-methoxy propyl acyl group) piperazine-1-base,
26) 4-((R)-tetrahydrofuran (THF)-2-base carbonyl) piperazine-1-base,
27) 4-((S)-tetrahydrofuran (THF)-2-base carbonyl) piperazine-1-base,
28) 4-(isobutyryl) piperazine-1-base,
29) 4-((R)-2-maloyl group) piperazine-1-base,
30) 4-((S)-2-maloyl group) piperazine-1-base,
31) (R)-3-acetylamino tetramethyleneimine-1-base,
32) (S)-3-acetylamino tetramethyleneimine-1-base,
33) (R)-2-(cyclopropyl aminocarboxyl) tetramethyleneimine-1-base,
34) (R)-2-(N-methylamino formyl radical) tetramethyleneimine-1-base,
35) (S)-2-(N, N-formyl-dimethylamino) tetramethyleneimine-1-base,
36) 4-(vinylsulfonyl) piperazine-1-base,
37) 4-[2-(2-propine-1-base oxygen base) ethanoyl] piperazine-1-base,
38) 4-(tetrahydrofuran (THF)-3-base carbonyl) piperazine-1-base,
39) 4-(3-dimethylamino propionyl) piperazine-1-base,
40) 4-[2-(N-methyl-N-hydroxyl methylamino-) ethanoyl] piperazine-1-base,
41) 4-[3-hydroxyl-2-(methylol) propionyl] piperazine-1-base,
42) 4-[2-(pyrrotriazole-1-yl) ethanoyl] piperazine-1-base,
43) 4-[2-(pyrrotriazole-5-yl) ethanoyl] piperazine-1-base,
44) 4-(1-methyl-L-prolyl) piperazine-1-base,
45) 4-[2-(methylsulfonyl) ethanoyl] piperazine-1-base,
46) 4-(2,2-difluoro ethanoyl) piperazine-1-base,
47) 4-[2-(tetramethyleneimine-1-yl) ethanoyl] piperazine-1-base,
48) 4-[2-(morpholino) ethanoyl] piperazine-1-base,
49) 4-[2-(diethylin) ethanoyl] piperazine-1-base,
50) 4-(propionyl) piperazine-1-base,
51) 4-(3-hydroxyl propionyl) piperazine-1-base,
52) 4-[2-(azetidine-1-yl) ethanoyl] piperazine-1-base,
53) (R)-3-amino-pyrrolidine-1-base,
54) (S)-3-amino-pyrrolidine-1-base,
55) (3R, 5S)-4-ethanoyl-3,5-lupetazin-1-base,
56) (2S, 5R)-4-ethanoyl-2,5-lupetazin-1-base,
57) (2RS, 6SR)-2,6-thebaine-4-yl] phenyl,
58) 3-hydroxy azetidine-1-base,
59) 3-acetylamino azetidine-1-base,
60) 3-(2-glycoloyl amino) azetidine-1-base,
61) the amino azetidine of 3-methylsulfonyl-1-base,
62) 3-methylsulfonyl oxygen base azetidine-1-base,
63) 3-azido-azetidine-1-base,
64) the amino azetidine of 3--1-base,
65) (3R)-3-{[(2S)-and 2-hydroxyl propionyl] amino } tetramethyleneimine-1-base,
66) (3S)-3-{[(2S)-and 2-hydroxyl propionyl] amino } tetramethyleneimine-1-base,
67) (3S)-3-(glycoloyl amino) tetramethyleneimine-1-base and
68) (3R)-3-(glycoloyl amino) tetramethyleneimine-1-base.
The A ring is
1) [4-(2-acetoxyl group ethanoyl) piperazine-1-base;
2) [4-(hydroxyacetyl) piperazine-1-base;
3) 4-((R)-2-maloyl group) piperazine-1-base;
4) 4-((R)-2-hydroxyl propionyl) piperazine-1-base;
5) 4-((R)-2-methoxy propyl acyl group) piperazine-1-base;
6) 4-((R)-3-methyl-2-maloyl group) piperazine-1-base;
7) 4-((R)-tetrahydrofuran (THF)-2-base carbonyl) piperazine-1-base;
8) 4-((S)-2-maloyl group) piperazine-1-base;
9) 4-((S)-2-methoxy propyl acyl group) piperazine-1-base;
10) 4-((S)-3-methyl-2-maloyl group) piperazine-1-base;
11) 4-((S)-tetrahydrofuran (THF)-2-base carbonyl) piperazine-1-base;
12) 4-(1-cyano group ring third-1-base carbonyl) piperazine-1-base;
13) 4-(1-hydroxyl ring third-1-base carbonyl) piperazine-1-base;
14) 4-(1-methyl-L-prolyl carbonyl) piperazine-1-base;
15) 4-(2-(R)-tetrahydrofuran (THF)-2-base carbonyl) piperazine-1-base;
16) piperazine-1-base 4-(2-(S)-2-hydroxyl propionyl) piperazine-1-yl);
17) 4-(2-(S)-tetrahydrofuran (THF)-2-yl) piperazine-1-base;
18) 4-(2,2-difluoro ethanoyl) piperazine-1-base;
19) 4-(2-acetoxyl group ethanoyl) piperazine-1-base;
20) 4-(2-dimethylamino ethanoyl) piperazine-1-base;
21) 4-(2-dimethylaminoethyl alkylsulfonyl) piperazine-1-base;
22) 4-(2-hydroxy-2-methyl propionyl) piperazine-1-base;
23) 4-(2-hydroxyacetyl) piperazine-1-base;
24) 4-(2-hydroxyethyl alkylsulfonyl) piperazine-1-base;
25) 4-(2-hydroxyl propionyl) piperazine-1-base;
26) 4-(2-methylsulfonyl ethanoyl) piperazine-1-base;
27) 4-(2-methoxyl group ethanoyl) piperazine-1-base;
28) 4-(2-methoxy ethyl alkylsulfonyl) piperazine-1-base;
29) 4-(2-methyl-2-hydroxyl propionyl) piperazine-1-base;
30) 4-(2-methylpropionyl) piperazine-1-base;
31) 4-(2-morpholino ethanoyl) piperazine-1-base;
32) 4-(2-tetramethyleneimine-1-base ethanoyl) piperazine-1-base;
33) 4-(3-dimethylamino propionyl) piperazine-1-base;
34) 4-(3-hydroxyl-2,2-dimethyl propylene acyl group) piperazine-1-base;
35) 4-(3-hydroxyl propionyl) piperazine-1-base;
36) 4-(3-methoxy propyl acyl group) piperazine-1-base;
37) 4-(3-methyl-3-maloyl group) piperazine-1-base;
38) 4-(4-maloyl group) piperazine-1-base;
39) 4-(acetoxyl group ethanoyl) piperazine-1-base;
40) 4-(ethanoyl) piperazine-1-base;
41) 4-(azetidine-1-base ethanoyl) piperazine-1-base;
42) 4-(chloracetyl) piperazine-1-base;
43) 4-(cyclopropyl) piperazine-1-base;
44) 4-(propionyl) piperazine-1-base;
45) 4-(tetrahydrofuran (THF)-3-base carbonyl) piperazine-1-base;
46) 4-(vinylsulfonyl) piperazine-1-base;
47) piperazine-1-base 4-[2-(1H-tetrazolium-5-yl) ethanoyl);
48) 4-[2-(2-third alkynyloxy group) ethanoyl] piperazine-1-base;
49) 4-[2-(N-methylol-N-methylamino) ethanoyl] piperazine-1-base;
50) 4-[2-(tetrazolium-1-yl) ethanoyl] piperazine-1-base;
51) 4-ethanoyl piperazine-1-base;
52) 4-methylsulfonyl piperazine-1-base;
53) morpholino; With
54) piperazine-1-base.
The A ring is 4-methylsulfonyl piperazine-1-base, 4-vinylsulfonyl piperazine-1-base, 4-ethanoyl piperazine-1-base, 4-(acetoxyl group ethanoyl) piperazine-1-base, 4-(hydroxyacetyl) piperazine-1-base, 4-(dimethylamino ethanoyl) piperazine-1-base, 4-(2-dimethylamino ethylsulfonyl) piperazine-1-base, 4-(2-methoxyl group ethylsulfonyl) piperazine-1-base, 4-(2-hydroxyl ethylsulfonyl) piperazine-1-base, piperazine-1-base or morpholino.
R
1Be halogen or C
1-6Alkyl.
R
1Be fluorine, chlorine or methyl.
P is 0-2; R wherein
1Value can be identical or different.
P is 0 or 1.
P is 1.
P is 0.
R
2Be selected from hydroxyl, amino, azido-, C
1-6Alkyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, carbocylic radical-R
34,-NHR
9Or-O-R
12
R
9And R
12Independently be selected from C
1-6Alkyloyl or C
1-6Alkyl sulphonyl; R wherein
9And R
12Can be independently optional selected on carbon from R
20Group replace;
R
20Be hydroxyl; With
R
34For-N (R
29) C (O)-; R wherein
29Be hydrogen.
R
2Be selected from hydroxyl, amino, azido-, methyl, N-methylamino formyl radical, N, N-formyl-dimethylamino, cyclopropyl-R
34-,-NHR
9Or-O-R
12
R
9And R
12Independently be selected from ethanoyl, propionyl or methylsulfonyl; R wherein
9And R
12Can be independently optional selected on carbon from R
20Group replace;
R
20Be hydroxyl; With
R
34For-N (R
29) C (O)-; R wherein
29Be hydrogen.
R
2Be selected from hydroxyl, amino, azido-, methyl, N-methylamino formyl radical, N, N-formyl-dimethylamino, kharophen, { [(2S)-2-hydroxyl propionyl] amino }, glycoloyl amino, methylsulfonyl amino, 2-glycoloyl amino, mesyloxy or N-cyclopropyl formamyl.
Q is 0 or 1.
Q is 2.
Q is 1.
Q is 0.
R
3Be halogen.
R
3Be fluorine or chlorine.
R
3Be 5-fluorine or 5-chlorine.
R
3Be the 5-fluorine.
R
3Be 5-chlorine.
N is 0 or 1.
N is 1.
N is 0.
R
4Be C
1-6Alkyl or carbocylic radical; R wherein
4Can on carbon, choose wantonly by one or more R
14Replace; Wherein
R
14Be carbocylic radical.
R
4Be C
1-4Alkyl or cyclobutyl; R wherein
4Can on carbon, choose wantonly by one or more R
14Replace; Wherein
R
14Be cyclopropyl.
R
4Be ethyl, sec.-propyl, isobutyl-, cyclobutyl or cyclopropyl methyl.
R
4Be sec.-propyl.
R
5And R
6Independently be selected from hydrogen or C
1-6Alkyl; R wherein
5And R
6Independently of one another, can choose wantonly on carbon by one or more R
16Replace; Wherein
R
16Be selected from methoxyl group.
R
5And R
6Independently be selected from hydrogen, methyl, ethyl or propyl group; R wherein
5And R
6Independently of one another, can choose wantonly on carbon by one or more R
16Replace; Wherein
R
16Be selected from methoxyl group.
R
5And R
6Independently be selected from hydrogen, methyl, ethyl, methoxymethyl, propyl group.
R
5Be C
1-6Alkyl; R wherein
5Can on carbon, choose wantonly by one or more R
16Replace;
Wherein
R
16Be methoxyl group.
R
5Be C
1-4Alkyl; R wherein
5Can on carbon, choose wantonly by one or more R
16Replace;
Wherein
R
16Be methoxyl group.
R
5Be methyl, ethyl, propyl group or methoxymethyl.
R
5Be methyl.
R
6Be hydrogen.
R
4Be sec.-propyl,
R
5Be methyl, and
R
6Be hydrogen.
Therefore, provide hydrolyzable ester in formula (I) compound (with above-mentioned) or its pharmacy acceptable salt or the body more on the one hand of the present invention, wherein:
The optional 4-7 unit saturated rings that contains other nitrogen or Sauerstoffatom that the A ring connects for nitrogen; If wherein the A ring contains other nitrogen-atoms, then this nitrogen can be chosen wantonly by R
7Replace;
R
1Be halogen or C
1-6Alkyl;
P is 0 or 1;
R
2Be selected from hydroxyl, amino, azido-, C
1-6Alkyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, carbocylic radical-R
34-,-NHR
9Or-O-R
12
Q is 0-2; R wherein
2Value can be identical or different;
R
3Be halogen;
N is 0 or 1;
R
4Be C
1-6Alkyl or carbocylic radical; R wherein
4Can on carbon, choose wantonly by one or more R
14Replace;
R
5And R
6Independently be selected from hydrogen or C
1-6Alkyl; R wherein
5And R
6Independently of one another, can choose wantonly on carbon by one or more R
16Replace;
R
7Be selected from C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
2-6Thiazolinyl alkylsulfonyl, carbocylic radical-R
18-or heterocyclic radical-R
19-; R wherein
7Can be independently optional selected on carbon from R
20Group replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly by R
21Replace;
R
9And R
12Independently be selected from C
1-6Alkyloyl or C
1-6Alkyl sulphonyl; R wherein
9And R
12Can be independently optional selected on carbon from R
20Group replace;
R
14Be carbocylic radical;
R
16Be selected from methoxyl group;
R
18And R
19For-C (O)-;
R
20Be selected from halogen, cyano group, hydroxyl, C
1-6Alkoxyl group, C
2-6Alkynyloxy group, C
1-6Alkyloyl oxygen base, N, N-(C
1-6Alkyl)
2Amino, wherein a is 2 C
1-6Alkyl S (O)
aOr heterocyclic radical; R wherein
20Can on carbon, choose wantonly by one or more R
26Replace;
R
21Be C
1-6Alkyl;
R
26Be hydroxyl; Or
R
34For-N (R
29) C (O)-, R wherein
29Be hydrogen.
Therefore, provide hydrolyzable ester in formula (I) compound (with above-mentioned) or its pharmacy acceptable salt or the body more on the one hand of the present invention, wherein:
A ring, R
2Form together with q:
1) piperazine-1-base,
2) morpholino,
3) 4-methylsulfonyl piperazine-1-base,
4) 4-ethanoyl piperazine-1-base,
5) 4-(2-acetoxyl group ethanoyl) piperazine-1-base,
6) 4-(2-hydroxyacetyl) piperazine-1-base,
7) 4-(2-chloracetyl) piperazine-1-base,
8) 4-(2-methoxyl group ethanoyl) piperazine-1-base,
9) (3-methoxy propyl acyl group) piperazine-1-base,
10) (3-hydroxy-3-methyl butyryl radicals) piperazine-1-base,
11) (3-hydroxyl-2,2-dimethyl propylene acyl group) piperazine-1-base,
12) ((R)-3-methyl-2-maloyl group) piperazine-1-base,
13) ((S)-3-methyl-2-maloyl group) piperazine-1-base,
14) 4-(2-dimethylamino ethanoyl) piperazine-1-base,
15) 4-[2-(dimethylamino) ethylsulfonyl] piperazine-1-base,
16) 4-[2-(methoxyl group) ethylsulfonyl] piperazine-1-base,
17) 4-[2-(hydroxyl) ethylsulfonyl] piperazine-1-base,
18) 4-(cyclopropyl carbonyl) piperazine-1-base,
19) 4-(1-hydroxyl cyclopropyl carbonyl) piperazine-1-base,
20) 4-(1-cyano group cyclopropyl carbonyl) piperazine-1-base,
21) 4-(2-hydroxy-2-methyl propionyl) piperazine-1-base,
22) 4-((R)-2-hydroxyl propionyl) piperazine-1-base,
23) 4-((S)-2-hydroxyl propionyl) piperazine-1-base,
24) 4-((R)-2-methoxy propyl acyl group) piperazine-1-base,
25) 4-((S)-2-methoxy propyl acyl group) piperazine-1-base,
26) 4-((R)-tetrahydrofuran (THF)-2-base carbonyl) piperazine-1-base,
27) 4-((S)-tetrahydrofuran (THF)-2-base carbonyl) piperazine-1-base,
28) 4-(isobutyryl) piperazine-1-base,
29) 4-((R)-2-maloyl group) piperazine-1-base,
30) 4-((S)-2-maloyl group) piperazine-1-base,
31) (R)-3-kharophen tetramethyleneimine-1-base,
32) (S)-3-kharophen tetramethyleneimine-1-base,
33) (R)-2-(cyclopropyl aminocarboxyl) tetramethyleneimine-1-base,
34) (R)-2-(N-methylamino formyl radical) tetramethyleneimine-1-base,
35) (S)-2-(N, N-formyl-dimethylamino) tetramethyleneimine-1-base,
36) 4-(vinylsulfonyl) piperazine-1-base,
37) 4-[2-(2-propine-1-base oxygen base) ethanoyl] piperazine-1-base,
38) 4-(tetrahydrofuran (THF)-3-base carbonyl) piperazine-1-base,
39) 4-(3-dimethylamino propionyl) piperazine-1-base,
40) 4-[2-(N-methyl-N-hydroxyl methylamino-) ethanoyl] piperazine-1-base,
41) 4-[3-hydroxyl-2-(methylol) propionyl] piperazine-1-base,
42) 4-[2-(pyrrotriazole-1-yl) ethanoyl] piperazine-1-base,
43) 4-[2-(pyrrotriazole-5-yl) ethanoyl] piperazine-1-base,
44) 4-(1-methyl-L-prolyl) piperazine-1-base,
45) 4-[2-(methylsulfonyl) ethanoyl] piperazine-1-base,
46) 4-(2,2-difluoro ethanoyl) piperazine-1-base,
47) 4-[2-(tetramethyleneimine-1-yl) ethanoyl] piperazine-1-base,
48) 4-[2-(morpholino) ethanoyl] piperazine-1-base,
49) 4-[2-(diethylin) ethanoyl] piperazine-1-base,
50) 4-(propionyl) piperazine-1-base,
51) 4-(3-hydroxyl propionyl) piperazine-1-base,
52) 4-[2-(azetidine-1-yl) ethanoyl] piperazine-1-base,
53) (R)-3-amino-pyrrolidine-1-base,
54) (S)-3-amino-pyrrolidine-1-base,
55) (3R, 5S)-4-ethanoyl-3,5-lupetazin-1-base,
56) (2S, 5R)-4-ethanoyl-2,5-lupetazin-1-base,
57) (2RS, 6SR)-2,6-thebaine-4-yl] phenyl,
58) 3-hydroxy azetidine-1-base,
59) 3-kharophen azetidine-1-base,
60) 3-(2-glycoloyl amino) azetidine-1-base,
61) the amino azetidine of 3-methylsulfonyl-1-base,
62) 3-mesyloxy azetidine-1-base,
63) 3-azido-azetidine-1-base,
64) the amino azetidine of 3--1-base,
65) (3R)-3-{[(2S)-and 2-hydroxyl propionyl] amino } tetramethyleneimine-1-base,
66) (3S)-3-{[(2S)-and 2-hydroxyl propionyl] amino } tetramethyleneimine-1-base,
67) (3S)-3-(glycoloyl amino) tetramethyleneimine-1-base and
68) (3R)-3-(glycoloyl amino) tetramethyleneimine-1-base;
R
1Be fluorine, chlorine or methyl;
P is 0 or 1;
R
2Be selected from hydroxyl, amino, azido-, methyl, N-methylamino formyl radical, N, N-formyl-dimethylamino, kharophen, { [(2S)-2-hydroxyl propionyl] amino }, glycoloyl amino, methylsulfonyl amino, 2-glycoloyl amino, mesyloxy or N-cyclopropyl formamyl.
Q is 0-2; R wherein
2Value can be identical or different;
R
3Be 5-fluorine or 5-chlorine;
N is 0 or 1;
R
4Be ethyl, sec.-propyl, isobutyl-, cyclobutyl or cyclopropyl methyl;
R
5And R
6Independently be selected from hydrogen, methyl, ethyl, methoxymethyl, propyl group.
Therefore, provide hydrolyzable ester in formula (I) compound (with above-mentioned) or its pharmacy acceptable salt or the body more on the one hand of the present invention, wherein:
The optional 4-7 unit saturated rings that contains other nitrogen, oxygen or sulphur atom that the A ring connects for nitrogen; If wherein the A ring contains other nitrogen-atoms, then this nitrogen can be chosen wantonly by R
7Replace; Wherein
R
3Be halogen;
R
4Be C
1-6Alkyl or carbocylic radical; R wherein
4Can on carbon, choose wantonly by one or more R
14Replace; Wherein
R
5And R
6Independently be selected from hydrogen or C
1-6Alkyl; R wherein
5And R
6Independently of one another, can choose wantonly on carbon by one or more R
16Replace;
R
7Be selected from C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
2-6Thiazolinyl alkylsulfonyl, carbocylic radical-R
18-or heterocyclic radical-R
19-; R wherein
7Can be independently optional selected on carbon from R
20Group replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly by R
21Replace;
R
14Be carbocylic radical;
R
16Be selected from methoxyl group;
R
18And R
19For-C (O)-;
R
20Be selected from halogen, cyano group, hydroxyl, C
1-6Alkoxyl group, C
2-6Alkynyloxy group, C
1-6Alkyloyl oxygen base, N, N-(C
1-6Alkyl)
2Amino, wherein a is 2 C
1-6Alkyl S (O)
aOr heterocyclic radical; R wherein
20Can on carbon, choose wantonly by one or more R
26Replace;
R
21Be C
1-6Alkyl;
R
26Be hydroxyl;
P is 0;
Q is 0;
N is 0 or 1.
Therefore, provide hydrolyzable ester in formula (I) compound (with above-mentioned) or its pharmacy acceptable salt or the body more on the one hand of the present invention, wherein:
Optional 6 yuan of saturated rings that contain other nitrogen-atoms that the A ring connects for nitrogen; If wherein the A ring contains other nitrogen-atoms, then this nitrogen can be chosen wantonly by R
7Replace; Wherein
R
7Be selected from C
1-6Alkyloyl, C
1-6Alkyl sulphonyl and C
2-6The thiazolinyl alkylsulfonyl; R wherein
7Can on carbon, choose wantonly selected from R
20Group replace; Wherein
R
20Be selected from hydroxyl, C
1-6Alkoxyl group, C
1-6Alkyloyl oxygen base and N, N-(C
1-6Alkyl)
2Amino;
P is 0;
Q is 0;
R
3Be halogen;
N is 0 or 1;
R
4Be C
1-6Alkyl or carbocylic radical; R wherein
4Can on carbon, choose wantonly by one or more R
14Replace; Wherein
R
14Be carbocylic radical;
R
5Be C
1-6Alkyl; R wherein
5Can on carbon, choose wantonly by one or more R
16Replace;
Wherein
R
16Be methoxyl group; With
R
6Be hydrogen.
Therefore, in one side more of the present invention, provide hydrolyzable ester in formula (I) compound (with above-mentioned) or its pharmacy acceptable salt or the body, wherein
The A ring is
1) 4-methyl sulphonyl piperazine-1-base,
2) 4-vinylsulfonyl piperazine-1-base,
3) 4-ethanoyl piperazine-1-base,
4) 4-(acetoxyl group ethanoyl) piperazine-1-base,
5) 4-(hydroxyacetyl) piperazine-1-base,
6) 4-(dimethylamino ethanoyl) piperazine-1-base,
7) 4-(2-dimethylaminoethyl alkylsulfonyl) piperazine-1-base,
8) 4-(2-methoxy ethyl alkylsulfonyl) piperazine-1-base,
9) 4-(2-hydroxyethyl alkylsulfonyl) piperazine-1-base,
10) piperazine-1-base or morpholino;
P is 0;
Q is 0;
R
3Be halogen;
N is 0 or 1;
R
4Be ethyl, sec.-propyl, isobutyl-, cyclobutyl or cyclopropyl methyl;
R
5Be methyl, ethyl, propyl group or methoxymethyl; With
R
6Be hydrogen.
In another aspect of this invention, preferred The compounds of this invention is a hydrolyzable ester in arbitrary embodiment compound or its pharmacy acceptable salt or the body.
In another aspect of this invention, preferred The compounds of this invention is arbitrary compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body in embodiment 18,22,87,92,94,96,104,113,118 or 121.
Preferred aspect of the present invention is for relating to those aspects of formula (I) compound or its pharmacy acceptable salt.
Another aspect of the present invention provides the method (wherein unless otherwise indicated, the definition cotype (I) of variable groups) of hydrolyzable ester in preparation formula (I) compound or its pharmacy acceptable salt or the body, and this method comprises:
Method a) makes formula (II) pyrimidine:
Wherein L is a displaceable group; With formula (III) aniline reaction:
Or method b) make formula (IV) compound:
React with the formula V compound:
Wherein T is O or S; R
xCan be identical or different, and be selected from C
1-6Alkyl; Or
Method c) make formula (VI) pyrimidine:
Wherein X is a displaceable group; React with formula (VII) heterocyclic radical:
Or method d) for obtaining formula (I) compound; Make formula (VIII) pyrimidine
React with formula (IX) compound:
Wherein Y is a displaceable group; Thereafter as needing:
I) formula (I) compound is converted into another kind of formula (I) compound;
Ii) remove any blocking group;
Iii) form hydrolyzable ester in pharmacy acceptable salt or the body.
L is a displaceable group, and the desired value of L is for example halogen or sulfonyloxy, for example chlorine, bromine, mesyloxy or toluene-4-sulfonyloxy.
X is a displaceable group, and the desired value of X is for example bromine or iodine.Preferred X is a bromine.
Y is a displaceable group, and the desired value of Y is for example halogen or sulfonyloxy, for example bromine, iodine or trifluoro-methanesulfonyl oxy.Preferred Y is an iodine.
More than Fan Ying concrete reaction conditions is as follows.
Method a) formula (II) pyrimidine and formula (HI) aniline can one react under the following conditions:
I) at suitable solvent ketone acetone for example for example; Or alcohol for example ethanol or butanols; Or aromatic hydrocarbons is chosen wantonly in suitable acid, for example mineral acid, for example hydrochloric acid or sulfuric acid for example under the existence of toluene or N-crassitude; Or organic acid, for example under the existence of acetate or formic acid (or suitable Lewis acid) with at 0 ℃ to reflow temperature range, preferably under reflux temperature; Or
Ii) under standard Buchwald condition (for example referring to J.Am.Chem.Soc., 118,7215; J.Am.Chem.Soc, 119,8451; J.Org.Chem., 62,1568 and 6066), for example in the presence of acid chloride, at suitable solvent, aromatic solvent for example is for example in toluene, benzene or the dimethylbenzene, with suitable alkali for example mineral alkali, for example cesium carbonate; Or organic bases, potassium tert.-butoxide for example, at suitable part, for example 2,2 '-two (diphenyl phosphine)-1,1 '-dinaphthalene exists down, in 25-80 ℃ of scope.
Can preparing wherein by flow process 1, L be formula (II) pyrimidine of chlorine:
Flow process 1
Formula (III) aniline is the commercial compound, or they are known in the literature, or prepares them by standard method as known in the art.
Method b) makes the reaction under the following conditions together of formula (IV) compound and formula V compound: at suitable solvent, for example in N-Methyl pyrrolidone or the butanols, in 100-200 ℃ of temperature range, preferably 150-170 ℃ of scope.Preferred this is reflected at suitable alkali for example to carry out under the existence of sodium hydride, sodium methylate or salt of wormwood.
Can prepare the formula V compounds by flow process 2:
Flow process 2
Formula (IV) and (Va) compound be the commercial compound, or they are known in the literature, or by standard method preparation as known in the art they.
Method c) can make formula (VI) compound and formula (VII) amine together under standard Buchwald condition the reaction (for example referring to J.Am.Chem.Soc., 118,7215; J.Am.Chem.Soc., 119,8451; J.Org.Chem., 62,1568 and 6066), for example in the presence of acid chloride, at suitable solvent aromatic solvent for example, for example in toluene, benzene or the dimethylbenzene, with suitable alkali for example mineral alkali, for example cesium carbonate; Or organic bases, potassium tert.-butoxide for example, suitable part for example 2,2 '-two (diphenyl phosphine)-1,1 '-existence of dinaphthalene under and in 25-80 ℃ of temperature range.
Can be by method preparation formula described in the WO 02/20512 (VI) compound.
Formula (VII) heterocyclyl compounds is the commercial compound, or they are known in the literature, or prepares them by standard method known in the art.
Method d) can be described by method a, formula (VIII) compound and formula (IX) amine are reacted under standard Buchwald condition together.
The synthetic of formula (VIII) compound described in flow process 1.
Formula (IX) compound is the commercial compound, or they are known in the literature, or prepares them by standard method known in the art.
Formula (VI) amine is the commercial compound, or they are known in the literature, or prepares them by standard method known in the art.
It should be understood that in the The compounds of this invention that some Tong Guo the standard aromatics substitution reaction in the various ring substituents introduces, or by before aforesaid method or the modification of carrying out conventional functional group thereafter immediately generate, and therefore be included in the inventive method aspect.This type of reaction and modification for example comprise introduces substituting group by the aromatics substitution reaction, and the reduction substituting group is with substituting group alkylation and oxidation substituting group.In chemical field, know the reagent and the reaction conditions that are used for these class methods.The specific examples of aromatics substitution reaction comprises with concentrated nitric acid introduces nitro; Under the FriedelCrafts condition, introduce acyl group with for example carboxylic acid halides and Lewis acid (for example aluminum chloride); Under Friedel Crafts condition, introduce alkyl with alkylogen and Lewis acid (for example aluminum chloride); With introducing halo group.The specific examples of modifying comprises: by for example using the nickel catalyzator catalytic hydrogenation, or in the presence of hydrochloric acid, use the iron heat treated, is amino with nitroreduction; Alkylthio is oxidized to alkyl sulphinyl or alkyl sulphonyl.
It will also be appreciated that in described in this article some reaction any sensitive group in the possible essential/compound that needs protection.Known situation about wherein must or need protection of those skilled in the art and suitable guard method.Can use GPF (General Protection False group (seeing T.W.Green for details, Protective Groups in Organic Synthesis, John Wiley andSons, 1991) according to standard practices.Therefore, if reactant comprises group for example amino, carboxyl or hydroxyl, in described in this article some reaction, this group may need protection.
The appropriate protection group of amino or alkylamino is for example acyl group, for example alkyloyl, for example ethanoyl; Alkoxy carbonyl, for example methoxycarbonyl, ethoxy carbonyl or uncle-butoxy carbonyl; Aryl methoxy carbonyl, for example benzyloxycarbonyl; Or aroyl, for example benzoyl.The deprotection condition of above blocking group need change according to the blocking group of selecting.Therefore, for example can be by with suitable alkali, alkali metal hydroxide for example, for example lithium hydroxide or sodium hydroxide hydrolysis are for example removed acyl group for example alkyloyl or alkoxy carbonyl or aroyl.Perhaps, can be by for example using suitable acid, for example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid are handled and are removed acyl group, for example uncle-butoxy carbonyl; Can pass through catalyzer, for example palladium on carbon hydrogenation, or use Lewis acid, for example three (trifluoroacetic acids) are changed the boron processing, remove the aryl methoxy carbonyl, for example benzyloxycarbonyl.The suitable alternative blocking group of primary amino is for example phthaloyl, and it can be by use alkylamine, for example dimethylaminopropylamine or remove with the hydrazine processing.
The appropriate protection group of hydroxyl is for example acyl group, for example alkyloyl, for example ethanoyl; Aroyl, for example benzoyl; Or arylmethyl, for example benzyl.The deprotection condition of above blocking group must change according to the blocking group of selecting.Therefore, for example can pass through, for example use suitable alkali, alkali metal hydroxide for example, for example lithium hydroxide or sodium hydroxide hydrolysis are removed acyl group, for example alkyloyl or aroyl.Perhaps, can be by for example catalyzer, for example arylmethyl is removed in palladium on carbon hydrogenation, for example benzyl.
The appropriate protection group of carboxyl is for example esterified group; available bases methyl or the ethyl removed of sodium hydroxide hydrolysis for example for example; or usable acid organic acid for example for example, for example trifluoroacetic acid is handled the tert-butyl of removing, or for example can be by the benzyl removed of palladium on carbon hydrogenation for example of catalyzer for example.
The routine techniques of knowing in the available chemical field, any suitable stage in synthetic is removed blocking group.
As mentioned before, Ding Yi compound has the inhibition of cell proliferation activity in the present invention, and for example antitumour activity it is believed that this activity comes from the CDK inhibition activity of compound.Available for example following method is estimated these character :-
Measure
Use following abbreviation :-
HEPES is the N-[2-hydroxyethyl] piperazine-N '-[2-ethanesulfonic acid]
DTT is a dithiothreitol (DTT)
PMSF is a phenylmethylsulfonyl fluoride
By 96 hole patterns, test these compounds with the vitro kinase assay method, measure test substrate (GST-retinoblastoma protein with scintillation proximity assay (SPA-derives from Amersham); The combination of [γ-33-P]-Triphosaden GST-Rb).In each hole, put into testing compound (being diluted to correct concentration) with DMSO and water, in control wells, do the inhibitor contrast or make positive control with DMSO with roscovitine.
To add each hole with about 0.2 μ l CDK2/ cyclin E partially purified enzyme (consumption depends on enzymic activity) of 25 μ l incubation buffering liquids dilution, add 20 μ l GST-Rb/ATP/ATP33 mixtures (contain 0.5 μ g GST-Rb and 0.2 μ M ATP and 0.14 μ Ci[γ-33-P]-the incubation buffering liquid solution of Triphosaden) then, the mixture that obtains of vibration gently, incubation 60 minutes at room temperature then.
In each hole, add then and contain (0.8mg/ porin A-PVT
SPAPearl (Amersham)) 150 μ l stop buffers, 20pM/ hole are anti--Thiadiazolidine isomerase, rabbit igg (deriving from MolecularProbes), 61mM EDTA and contain the 50mM HEPES pH 7.5 of 0.05% sodiumazide.
With Topseal-S plate sealer closure plate, placed 2 hours, then with 2500rpm, 1124xg rotation 5 minutes.On Topcount, read plate, every hole 30 seconds.
Contain 50mM HEPES pH 7.5,10mM MnCl with the incubation buffering liquid dilution
2, 1mMDTT, 100 μ M vanadic acid sodiums, 100 μ M NaF, 10mM Sodium Glycerophosphate, the enzyme of BSA (1mg/ml final concentration) and the mixture of substrate.
The test substrate
In this is measured, only use part retinoblastoma protein (Science on March 13rd, 1987; 235 (4794): 1394-1399; Lee W.H., Bookstein R., Hong F., Young L.J., Shew J.Y., Lee E.Y.) merge with the GST mark.Make the retinoblastoma gene (taking from retinoblastoma plasmid ATCCpLRbRNL) of coded amino acid 379-928 carry out PCR, and with this sequence clone (SmithD.B. and Johnson in the pGEx 2T fusion vector, K.S.Gene 67,31 (1988); The interior lac I that it contains the tac promotor that is used for inducible expression, uses any intestinal bacteria (E.Coli) host
qThe dissociated coding region of gene and zymoplasm-derive from Pharmacia Biotech), its amino acid 792-928 that is used to increase.This sequence is cloned into pGEx 2T once more.
Express in intestinal bacteria (E.Coli) (BL21 (DE3) pLysS cell) with the retinoblastoma 792-928 sequence that standard inducible expression technology will so obtain, and purifying as follows.
Intestinal bacteria (E.coli) are starched resuspending in 10ml/g NETN damping fluid (50mM TrispH 7.5,120mM NaCl, 1mM EDTA, 0.5% v/v NP-40,1mM PMSF, 1 μ g/ml leupeptin, 1 μ g/ml presses down enzyme peptide and 1 μ g/ml pepstatin), ultrasonic 2 * 45 seconds/100ml homogenate.After centrifugal, supernatant liquor is loaded into 10ml glutathione agarose post, and (Pharmacia Biotech, Herts UK), wash with the NETN damping fluid.With kinase buffer liquid (50mM HEPES pH 7.5,10mM MgCl
2, 1mM DTT, 1mM PMSF, 1 μ g/ml leupeptin, 1 μ g/ml press down enzyme peptide and 1 μ g/ml pepstatin) and after the washing, with the kinase buffer liquor eluted protein of 50mM reductive gsh.Merge the component that contains GST-Rb (792-927), with kinase buffer liquid dialysed overnight.By sodium lauryl sulphate (SDS) PAGE (polyacrylamide gel), (Novex, San Diego USA) analyze end product with 8-16% Tris-glycine gels.
CDK2 and cyclin E
Make template with HeLa cell and activating T cell mRNA,, be cloned into insect expression vector pVL1393 and (derive from Invitrogen 1995 catalog numbers: V1392-20) by the open reading-frame (ORF) of reversed transcriptive enzyme-PCR separation of C DK2 and cyclin E.Then in insect SF21 cell system (being derived from greedy noctuid (Spodoptera Frugiperda) cell-commercially available in meadow of armyworm in autumn (Fall Army Worm) ovary tissue) dual expression CDK2 and cyclin E[with standard virus Baculogold coinfection technology].
The example of preparation cyclin E/CDK2
Following examples are provided at cyclin E﹠amp; Each virus of CDK2 has in the SF21 cell of double infection MOI 3 (in TC100+10%FBS (TCS)+0.2% poloxamer), the details of preparation cyclin E/CDK2.
Roll 2.33 * 10 in the flask culture base with being grown in
6The SF21 cell of cell/ml is seeded to 10 * 500ml with 0.2 * 10E6 cell/ml and rolls in the bottle.Under 28 ℃, will roll bottle and go up incubation at shaking table (roller rig).
After 3 days (72 hours), with cell counting, the mean number of finding 2 bottles is 1.86 * 10E6 cell/ml (99% survival).Use the dual virus infection culture at MOI 3 of each virus then.
Virus is mixed, add substratum then, send substratum back under 28 ℃ shaking table.
After infecting 2 days (48 hours), gather in the crops 5 liters of cultures.Total cell count in the cutting is 1.58 * 10E6 cell/ml (99% survival).Under 4 ℃, criticize among HeraeusOmnifuge 2.0 RS cell centrifugal 30 minutes with 2500rpm at 250 ml.Abandoning supernatant.
With Cdk2 and cyclin E part copurification
With Sf21 cell resuspending in molten born of the same parents' damping fluid (50mM Tris pH 8.2,10mMMgCl
2, 1mM DTT, 10 mM phospho-glycerols, the 0.1mM sodium orthovanadate, 0.1mM NaF, 1mM PMSF, 1 μ g/ml leupeptin and 1 μ g/ml press down the enzyme peptide), homogenate is 2 minutes in 10ml Dounce homogenizer.After centrifugal, with supernatant liquor be loaded into Poros HQ/M 1.4/100 anion-exchange column (PE Biosystems, Hertford, UK) on.When 0-1M NaCl gradient (moving in the molten born of the same parents' damping fluid at no proteinase inhibitor) begins, with CdK2 and cyclin E co-elute 20 column volumes.By western blotting, with antibody (Santa Cruz Biotechnology, California, US) the inspection co-elute of anti-CdK2 and anti-cell cyclin E.
Use analogy procedure, can set up the assay method that design evaluation is suppressed CDK1 and CDK4.CDK2 (EMBL accession number X62071) can use (referring to EMBL accession number M73812) with cyclin A or cyclin E, the more details of this type of assay method are included among the PCT international publication number WO 99/21845, the Sheng Wuhuaxue ﹠amp that it is relevant; The biological assessment chapters and sections are attached to herein by reference.
Although the pharmacological properties of formula (I) compound is different with structural modification, generally speaking, can by IC
50Dosage in concentration or the 250 μ M-1nM scopes confirms the activity that formula (I) compound has.
When testing in order to last external assay method, through measuring, it is IC that the CDK2 of embodiment 8 compounds suppresses activity
50=0.181 μ M.
Can pass through standard technique, for example, estimate the activity in vivo of The compounds of this invention by measuring the cell growth-inhibiting and estimating cytotoxicity.
Can measure the cell growth-inhibiting by make cell dyeing with sulphonyl rhodamine (Sulforhodamine) B (SRB), SRB is the fluorescence dye that makes protein staining, thereby the albumen that obtains estimating in the hole (being cell) amount (referring to Boyd, M.R. (1989) Status of the NCIpreclinical antitumour drug discovery screen (NCI antitumor drug before clinical is found the situation of screening) .Prin.Prac Oncol 10:1-12).Therefore, provide measurement cytostatic following details :-
Seed cells into the suitable culture medium of 100ml volume in 96 orifice plates; Substratum is that the DulbeccoShi that is used for MCF-7, SK-UT-1B and SK-UT-1 improves the Eagle substratum.Allow cell attachment spend the night, add the inhibitor compound of various concentration then, peak concentration wherein is 1% DMSO (v/v).Measure control board, to obtain the precellular value of administration.With cell under 37 ℃, (5% CO
2) in incubation 3 days.
When finishing in 3 days, TCA is added in the entering plate to final concentration 16% (v/v).Then under 4 ℃, with plate incubation 1 hour, remove supernatant liquor, use the tap water wash plate.After the drying, under 37 ℃, in 30 minutes, add 100ml SRB dyestuff (1% acetic acid solution of 0.4% SRB).Remove excessive SRB, with 1% acetate wash plate.With 10mM Tris pH 7.5 dissolvings and protein bound SRB, at room temperature vibrate 30 minutes.Read ODs at the 540nm place, the semilog plot of optical density is determined to cause 50% growth inhibiting inhibitor concentration by inhibitor concentration.The following compound concentration of optical density(OD) that inoculating cell obtains when making optical density(OD) be reduced to the experiment beginning provides the toxicity value.
When with the test of SRB assay method, the typical IC of The compounds of this invention
50The value scope is 1mM-1nM.
Provide medicinal compositions more on the one hand according to of the present invention, this medicinal compositions comprises formula (I) pyrimidine derivatives or its pharmacy acceptable salt or the interior hydrolyzable ester of body that defines in the preamble, and the pharmaceutically acceptable diluent or carrier of applied in any combination.
Composition can be the form of suitable oral administration, for example tablet or capsule; Sterile solution, suspension or the emulsion of suitable parenteral injection (comprising in intravenously, subcutaneous, intramuscular, the blood vessel or infusion); The suppository of the ointment of suitable topical or creme or suitable rectal administration.
Generally speaking, can prepare above composition with conventional excipients according to a conventional method.
Usually, press at 5-5000mg/m
2Unitary dose in the animal body area, promptly about 0.1-100mg/kg scope gives warm-blooded animal formula (I) compound, and this provides the treatment effective dose usually.Unit dosage, for example tablet or capsule contain for example 1-250mg activeconstituents usually.The preferred per daily dose that uses in the 1-50mg/kg scope.But per daily dose must change according to the host who is treated, concrete route of administration and the severity of disease for the treatment of.Therefore, can determine optimal dose by the practitioner who treats any concrete patient.
According to of the present invention more on the one hand, be provided for formula (I) compound that defines in the preamble of the method by the therapy for treating human or animal body or hydrolyzable ester in its pharmacy acceptable salt or the body.
We find that hydrolyzable ester is effective cell cycle inhibitor (an inhibition of cell proliferation medicine) in the compound that defines among the present invention or its pharmacy acceptable salt or the body, it is believed that its character comes from their CDK inhibition activity.Therefore, estimate The compounds of this invention can be used for treating separately or part is mediated by the CDK enzyme disease or medical conditions, promptly available these compounds produce the CDK restraining effect in the warm-blooded animal of this treatment of needs.Therefore, The compounds of this invention provides the method that is characterised in that the malignant cell propagation that suppresses the CDK enzyme for the treatment of, and promptly available these compounds produce by suppressing the antiproliferative effect that CDKs mediates separately or partly.Estimate that such The compounds of this invention has anticancer widely character, because CDKs relates to many common human cancers, for example leukemia and mammary gland, lung, colon, rectum, stomach, prostate gland, bladder, pancreas and ovarian cancer.Therefore, estimate that The compounds of this invention will have the antitumour activity of anti-these cancers.In addition, estimate that also The compounds of this invention will have anti-multiple leukemia, lymphatic cancer and solid tumor, for example organize the cancer in for example liver, kidney prostate gland and the pancreas and the activity of sarcoma.Especially estimate that these The compounds of this invention help delaying for example primary of colon, mammary gland, prostate gland, lung and skin and the growth of recurrent solid tumor.Estimate that more specifically the interior hydrolyzable ester of this type of The compounds of this invention or its pharmacy acceptable salt or body suppresses the growth of those primary relevant with CDKs and recurrent solid tumor, especially suppress those growth of tumor that its growth and diffusion obviously rely on CDKs, comprise for example tumour of some colon, mammary gland, prostate gland, lung, vulva and skin.
In this article, when mentioning cancer, it especially refers to leukemia, mammary cancer, lung cancer, colorectal carcinoma, the rectum cancer, cancer of the stomach, prostate cancer, bladder cancer, carcinoma of the pancreas, ovarian cancer, liver cancer, kidney, skin carcinoma and carcinoma vulvae.
Further estimate, The compounds of this invention will have in other disease of wide region the activity of anti-other cell proliferation disorders, comprise leukemia, fiber proliferative and branchs voltinism disease, psoriatic, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, sebaceous cyst, atherosclerosis, arterial restenosis, autoimmune disorder, acute and chronic inflammation, osteopathy and the illness in eye of following retinal vessel to breed.
Therefore,, provide the formula (I) that defines in the preamble as medicine compound according to this one side of the present invention, or hydrolyzable ester in its pharmacy acceptable salt or the body; With the purposes of hydrolyzable ester in the preparation medicine in the formula that defines in the preamble (I) compound or its pharmacy acceptable salt or the body, this medicine is used in for example people's generation cell cycle inhibition (inhibition of cell proliferation) effect of warm-blooded animal.Especially by suppressing CDK2 and CDK4, especially CDK2 stops and enters or stop and enter or by the M phase, produce restraining effect by the S phase with by suppressing CDK1.
According to a feature more of the present invention, be provided at formula (I) compound that defines in the preamble in the preparation medicine, or hydrolyzable ester in its pharmacy acceptable salt or the body, this medicine is used for the treatment of cancer (solid tumor and leukemia), fiber proliferative and branch voltinism disease, psoriatic, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, sebaceous cyst, atherosclerosis, arterial restenosis, autoimmune disorder, acute and chronic inflammation, osteopathy and follows the illness in eye of retinal vessel propagation, is particularly useful for treating cancer.
According to a feature more of the present invention, provide the formula (I) that defines in preamble compound, or hydrolyzable ester in its pharmacy acceptable salt or the body, be used for the treatment of purposes in the medicine of cancer in preparation.
According to a feature more of the present invention, formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body that define in the preamble are provided, be used for producing the purposes of the inhibiting medicine of CDK in preparation.
According to this feature more on the one hand of the present invention, be provided at the warm-blooded animal that needs this treatment, for example philtrum produces the method for cell cycle inhibition (inhibition of cell proliferation) effect, and this method comprises the compound of the above firm definition that gives described animal effective dose.Especially by suppressing CDK2 and CDK4, especially CDK2 stops and enters or stop and enter or produce restraining effect by the M phase by the S phase with by suppressing CDK1.
According to this feature more on the one hand of the present invention, be provided at the warm-blooded animal that needs this treatment, for example philtrum produces the method for cell cycle inhibition (inhibition of cell proliferation) effect, this method comprises formula (I) compound that defines in the preamble that gives described animal effective dose, or hydrolyzable ester in its pharmacy acceptable salt or the body.Especially by suppressing CDK2 and CDK4, especially CDK2 stops and enters or stop and enter or produce restraining effect by the M phase by the S phase with by suppressing CDK1.
According to this another feature on the one hand of the present invention, provide for example method of people's following disease of warm-blooded animal that treatment needs this treatment: cancer (solid tumor and leukemia), fiber proliferative and branch voltinism disease, psoriatic, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, sebaceous cyst, atherosclerosis, arterial restenosis, autoimmune disorder, acute and chronic inflammation, osteopathy and the illness in eye of following retinal vessel to breed, this method comprises formula (I) compound that defines in the preamble that gives described animal effective dose, or hydrolyzable ester in its pharmacy acceptable salt or the body.
Especially the warm-blooded animal that provides treatment to need this treatment, people's method for cancer for example, this method comprises formula (I) compound that defines in the preamble that gives described animal effective dose, or hydrolyzable ester in its pharmacy acceptable salt or the body.
Especially be provided at the warm-blooded animal that needs this treatment, for example philtrum produces the inhibiting method of CDK, and this method comprises formula (I) compound that defines in the preamble that gives described animal effective dose, or hydrolyzable ester in its pharmacy acceptable salt or the body.
In one side more of the present invention, be provided for for example producing the medicinal compositions that cell cycle inhibition (inhibition of cell proliferation) acts among the people warm-blooded animal, said composition comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body that defines in the preamble, and the pharmaceutically acceptable diluent or carrier of applied in any combination.
In one side more of the present invention, be provided for treating for example medicinal compositions of people's following disease of warm-blooded animal: cancer (solid tumor and leukemia), fiber proliferative and branch voltinism disease, psoriatic, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, sebaceous cyst, atherosclerosis, arterial restenosis, autoimmune disorder, acute and chronic inflammation, osteopathy and the illness in eye of following retinal vessel to breed, said composition comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body that defines in the preamble, and the pharmaceutically acceptable diluent or carrier of applied in any combination.
In one side more of the present invention, be provided for treating for example medicinal compositions of people's cancer of warm-blooded animal, said composition comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body that defines in the preamble, and the pharmaceutically acceptable diluent or carrier of applied in any combination.
In one side more of the present invention, be provided for for example producing the inhibiting medicinal compositions of CDK among the people warm-blooded animal, said composition comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body that defines in the preamble, and the pharmaceutically acceptable diluent or carrier of applied in any combination.
By suppress the main S phase start activity for example CDK2 start to stop cell to enter DNA synthetic, also can be used for protecting the normal cell of health to avoid the toxic infringement of cycle-specific agent.Suppress CDK2 or 4 and will stop normal cell to enter in the cell cycle, but this restriction is in the toxicity of S phase, G2 or mitotic cycle-specific agent.This protection can cause preventing the alopecia relevant with these medicines usually.
Therefore, provide formula (I) compound more on the one hand as the above definition of cell-protecting medicines of the present invention, or hydrolyzable ester in its pharmacy acceptable salt or the body.
Therefore, be provided for preventing formula (I) compound of the above definition of alopecia due to the pharmacological agent malignant disorders more on the one hand of the present invention, or hydrolyzable ester in its pharmacy acceptable salt or the body.
The known example of the malignant disorders medicine of alopecia that causes comprises alkylating agent, for example ifosfamide and endoxan; Antimetabolite, for example methotrexate, 5 FU 5 fluorouracil, gemcitabine and cytosine arabinoside; Vinca alkaloids and analogue, for example vincristine(VCR), vinealeucoblastine(VLB), vindesine, vinorelbine; Taxone, for example taxol and docetaxel; Topoisomerase I inhibitor, for example irinotecan and Hycamtin; Cell toxicant microbiotic, for example Dx, daunorubicin, mitoxantrone, dactinomycin and mitomycin; With other class medicine, for example Etoposide and vitamin A acid.
In another aspect of this invention, in formula (I) compound or its pharmacy acceptable salt or the body hydrolyzable ester can with medication combined giving more than one or more.In this case, can pass through whole body or non-systemic fashion giving construction (I) compound.Especially can be by non-systemic fashion, mode giving construction (I) compound of topical for example.
Therefore, in another feature of the present invention, be provided at warm-blooded animal for example philtrum prophylactic thing treat the method for alopecia during one or more malignant disorders, this method comprises formula (I) compound that gives described animal effective dose, or hydrolyzable ester in its pharmacy acceptable salt or the body.
In another feature of the present invention, be provided at warm-blooded animal for example philtrum prophylactic thing treat the method for alopecia during one or more malignant disorders, this method comprises simultaneously, sequential or give hydrolyzable ester in formula (I) compound of described animal effective dose or its pharmacy acceptable salt or the body respectively, and the described medicine of significant quantity.
According to one side more of the present invention, be provided for the medicinal compositions that prophylactic agent treatment malignant disorders causes alopecia, said composition comprises the pharmaceutically acceptable diluent or carrier of the interior hydrolyzable ester of formula (I) compound or its pharmacy acceptable salt or body and described medicine and applied in any combination.
Provide a kind of medicine box more on the one hand according to of the present invention, this medicine box comprises hydrolyzable ester and the known medicine that causes the treatment malignant disorders of alopecia in formula (I) compound or its pharmacy acceptable salt or the body.
Provide a kind of medicine box more on the one hand according to of the present invention, this medicine box comprises:
A) hydrolyzable ester in the formula of first unit dosage (I) compound or its pharmacy acceptable salt or the body;
B) the known medicine that causes the treatment malignant disorders of alopecia of second unit dosage; With
C) contain the container of described first and second formulations.
According to another feature of the present invention, the purposes of hydrolyzable ester in the preparation medicine in formula (I) compound or its pharmacy acceptable salt or the body is provided, this medicine is used for alopecia during the prophylactic agent treatment malignant disorders.
According to one side more of the present invention, the combination therapy of prevention alopecia is provided, this treatment comprises and gives for example formula of people's significant quantity (I) compound of warm-blooded animal, or hydrolyzable ester and optional pharmaceutically acceptable diluent or carrier in its pharmacy acceptable salt or the body; And simultaneously, sequential or give the medicine of the treatment malignant disorders of significant quantity respectively.
As mentioned above, treatment or the required dosage size of the concrete cell breeding disease of prophylactic treatment must change according to the host who is treated, route of administration and the severity of disease for the treatment of.The unitary dose scope of estimating is 1-100mg/kg for example, preferred 1-50mg/kg.
The CDK that defines in the preamble suppresses activity and can be used as the monotherapy employing, or also comprises one or more other materials and/or treatment employing except that The compounds of this invention.Can realize this combination therapy by while, each component sequential or that treat respectively.In the field of medical science oncology, each patient who adopts the combination therapy of multi-form treatment to suffer from cancer is common practice.In the medical science oncology, except that the cell cycle suppression therapy of preamble definition, other component of this combination therapy can be: operation, radiotherapy or chemotherapy.This chemotherapy can comprise the main medicine of 3 classes:
(i) other identical or different cell cycle of those that define in the mechanism of action and the preamble is suppressed medicine;
(ii) cytostatics, estrogen antagonist (tamoxifen for example for example, toremifene, raloxifene, droloxifene, iodoxyfene), progestogen (for example Magace), aromatase inhibitor (Anastrozole for example, letrozole, vorazole, Exemestane), antiprogestin, androgen antagonist (flutamide for example, Nilutamide, bicalutamide, cyproterone acetate), LHRH agonist and antagonist (goserelin acetate for example, Lu Pulide (luprolide)), testosterone 5 α-dihydro reductase inhibitor (for example finasteride), anti-medicine (for example inhibitors of metalloproteinase such as the Marimastat of invading, with urokinase plasminogen activator function of receptors inhibitor) and the somatomedin depressant of functions (this type of somatomedin comprises for example Thr6 PDGF BB and pHGF, and this type of inhibitor comprises growth factor antibodies, growth factor receptor antibody, tyrosine kinase inhibitor and serine/threonine kinase inhibitor); With
(iii) be used for the antiproliferative/antitumor drug and the combination thereof of medical science oncology, for example antimetabolite (for example antifol, as methotrexate, fluorine pyrimidine such as 5 FU 5 fluorouracil, purine and neplanocin, cytosine arabinoside); Antitumor antibiotics (for example anthracycline, as Dx, daunomycin, epirubicin and idarubicin, Mitomycin-C, dactinomycin, Plicamycin); Platinum derivatives (for example cis-platinum, carboplatin); Alkylating agent (for example mustargen, melphalan, Chlorambucil, busulfan, endoxan, ifosfamide, nitrosourea, plug are for group); Antimitotic drug (for example vinca alkaloids such as vincristine(VCR), and taxanes (taxoids) is as safe plain, taxotere); Isomerase inhibitors (epipodophyllotoxin class for example is as Etoposide and teniposide, amsacrine, Hycamtin) is pounced in holder.According to of the present invention this on the one hand, a kind of medicine that is used for the combination therapy cancer is provided, this medicine comprises other antitumorigenic substance that defines in formula (I) compound that defines in the preamble and the preamble.
Except that their purposes in medicine, formula (I) compound and pharmacy acceptable salt thereof also can be used as a part of seeking new medicine, be used as the pharmacology instrument in the exploitation of test macro and the markization in vitro and in vivo, this system is used for estimating the cell cycle activity inhibitor in for example effect of cat, dog, rabbit, monkey, rat and mouse of laboratory animal.
In above other medicinal compositions, technology, method, purposes and medication preparation feature, also can use substituting and embodiment preferred of the The compounds of this invention described herein.
Embodiment
Now illustrate the present invention by following indefiniteness embodiment, unless otherwise indicated, otherwise wherein:
(i) temperature with degree centigrade (℃) provide; Operate under room temperature or the envrionment temperature, promptly in 18-25 ℃ of temperature range, carry out;
(ii) organic solution is through anhydrous magnesium sulfate drying; The solvent evaporation Rotary Evaporators is being up under 60 ℃ the bath temperature decompression (600-4000 pascal; 4.5-30mmHg) under carry out;
(iii) chromatography refers to that silica gel dodges chromatography; On silica-gel plate, carry out thin-layer chromatography (TLC);
(iv) generally speaking, only be used to illustrate with TLC tracking reaction process and the reaction times that provides;
(v) end product has sufficient proton magnetic resonance (PMR) (NMR) wave spectrum and/or mass-spectrometric data;
(yield that vi) provides only is used to illustrate, and needs not be by making great efforts the yield that development technology obtains; More if desired material can repeat preparation;
(vii) unless otherwise indicated, the MR data are the main δ value form of identifying proton, provide by counting (ppm) very much with respect to the interior target hundred of tetramethylsilane (TMS), with full deuterated dimethyl sulfoxide (DMSO-d
6) make solvent, measure at 300MHz; Unless otherwise indicated,
19F NMR is also at DMSO-d
6Middle record;
(viii) chemical symbol has its common value; Use SI units and symbol;
(ix) the solvent ratio by volume: volume (v/v) term provides; With
(x) under 70 electron-volts electron energy, by using chemi-ionization (CI) the mode operation mass spectrum that directly exposes probe; Wherein the ionization of indication realizes by electron impact (EI), fast atom bombardment(FAB) (FAB) or electron spray(ES) (ESP); Provide the m/z value, usually, only report is represented the ion of parent quality; And the mass ion that unless otherwise indicated, provides is (MH)
+
(xi) unless otherwise indicated, the compound that contains asymmetric replacement carbon and/or sulphur atom is not resolved;
(xii) be described as described syntheticly when similar with previous embodiment when synthetic, the mmole of consumption compares employed identical with previous embodiment;
(xvi) use following abbreviation:
The THF tetrahydrofuran (THF);
DMF N, dinethylformamide;
DMFDMA dimethyl formamide dimethylacetal;
The EtOAc ethyl acetate;
MeOH methyl alcohol;
EtOH ethanol;
DIPEA N, the N-diisopropylethylamine;
HATU phosphofluoric acid O-(7-azepine benzo triazol-1-yl)-1,1,3, the 3-tetramethyl-urea;
The HOBt I-hydroxybenzotriazole;
EDAC 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride
The ether Anaesthetie Ether;
The TFA trifluoroacetic acid;
The DCM methylene dichloride; With
The DMSO methyl-sulphoxide.
Xvii) when mentioning Isolute SCX-2 post, its expression is used to adsorb " ion-exchange " column extractor of basic cpd, promptly contain polypropylene tube based on the strong cation exchange sorbent material of Phenylsulfonic acid, according to deriving from International Sorbent Technologies Limited, DyffrynBusiness Park, Hengeod, Mid Glamorgan, UK, manufacturer's specification sheets of CF82 7RJ uses;
Xviii) when mentioning Isolute amine post, its expression is used to adsorb " ion-exchange " column extractor of acidic cpd, promptly contain polypropylene tube with the covalently bound aminosilane of silica dioxide granule, according to deriving from International Sorbent Technologies Limited, DyffrynBusiness Park, Hengeod, Mid Glamorgan, UK, manufacturer's specification sheets of CF82 7RJ uses;
Xix) when mentioning the Chemelut post, its expression is used for removing the column extractor that anhydrates, and promptly contains diatomaceous polypropylene tube, according to deriving from Varian, Harbor City, California, manufacturer's specification sheets use of USA; With
Xx) when HPLC carries out on the Phenomenex post, it is meant Phenomenex 150 * 21.2mm Luna 10 μ m C18 posts, with the 5-95 gradient of 0.2% TFA water-acetonitrile, with 20ml/ minute flow velocity wash-out 10 minutes;
Xxi) the macroporous polystyrene carbonate resin is meant that every gram resin has the Argonaut Technologies MP carbonate resin of 3.0Mol equivalent ability, available from ArgonautTechnologies, New Road, Hengoed, Mid Glamorgan United Kingdom, CF82 8AU.
In the NMR of following examples data:
The Septuplet=septet
The Sextuplet=sextet
The Quintet=quintet
Under exchangeables=exchange down
+ duetero acetic acid=+ deuterium is for acetate
Alongside exchangeables=exchanges side by side
Under DMSO signal=DMSO signal
Under H
2O signal=H
2The O signal
Exchangeables=is commutative
The peak=peak
Acetic acid=acetate
Water=water
Embodiment 1
2-[4-(4-methylsulfonyl piperazine-1-yl) anilino]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-
The 5-yl) pyrimidine
With 2-amino-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine (method 39 of WO 03/076436; 220mg, 1mmol), 1-bromo-4-(4-methylsulfonyl piperazinyl) benzene (WO2001062742; 319mg, 1mmol), three (dibenzalacetones) close two palladiums (0) (23mg, 2mol%), 2-(two-tertiary butyl phosphino-) biphenyl (6mg, 2mol%) and sodium tert-butoxide (135mg, 1.4mmol) anhydrous 1, the nitrogen emptying of 4-diox (10ml) solution charges into (3 times) again.Under nitrogen, with reactant at 95 ℃ of following heated overnight, reduction vaporizations then.Residue is ground with EtOAc (20ml), filter, revaporization obtains jelly.On silica gel, use MeOH: DCM (2: 98-5: 95) chromatography, obtain title compound, be yellow solid.(70mg 15％)。
NMR：1.39(d，6H)，2.47(s，3H)，2.92(s，3H)，3.17(m，4H)，3.26(m，4H)，5.70(septuplet，1H)，6.92(d，2H)，6.94(d，1H)，7.39(s，1H)，7.48(d，2H)，8.32(d，1H)，9.18(s，1H)；m/z 456.
Embodiment 2
2-[4-(4-methylsulfonyl piperazine-1-yl) anilino]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-
The 5-yl)-the 5-chloropyrimide
Press embodiment 1 method, use 2-amino-5-chloro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine (method 5), heat 30 hours preparation title compounds down at 100 ℃.On silica gel, use MeOH: DCM (2: 98-6: 94) chromatography.
NMR 1.36(d，6H)，2.46(s，3H)，2.80(s，3H)，3.16(m，4H)，3.23(m，4H)，4.79(septuplet，1H)，6.91(d，2H)，7.22(s，1H)，7.49(d，2H)，8.51(d，1H)，9.49(s，1H)；m/z 490.
Embodiment 3
2-[4-(4-methylsulfonyl piperazine-1-yl) anilino]-4-(1-cyclobutyl-2-methyl isophthalic acid H-imidazoles-
The 5-yl) pyrimidine
Under 110 ℃, with 5-(3-dimethylamino third-2-alkene-1-acyl group)-1-cyclobutyl-glyoxal ethyline (method 37 of WO 03/076435; 233mg 1mmol) and N-{4-[4-(methyl sulphonyl) piperazine-1-yl] phenyl guanidine (method 1; The solution stirring of 2-methyl cellosolve 390mg 1.3mmol) (8ml) heated 18 hours.With the reaction mixture reduction vaporization, with residue on silica gel through MeOH: DCM (3: 97-8: 92) chromatography purification.After the evaporation, grind, obtain title compound, be yellow solid with ether.(227mg，48.5％)。
NMR：1.60-1.71(2xm，2H)，2.36(m，4H)，2.49(s，3H)，2.91(s，3H)，3.18(m，4H)，3.25(m，4H)，5.51(quintet，1H)，6.91(d，1H)，6.97(d，2H)，7.30(s，1H)，7.54(d，2H)，8.33(d，1H)，9.23(s，1H)；m/z 468.
Embodiment 4-17
Press embodiment 3 methods, with suitable imidazoles and N-{4-[4-(methylsulfonyl) piperazine-1-yl] phenyl } guanidine (method 1) or N-[4-(4-ethanoyl piperazine-1-yl) phenyl] the following compound of guanidine supercarbonate (method 2) preparation.
| Ex | R 1 | R 2 | R 3 | NMR | m/z | SM |
| 4 1 | Me | The cyclopropyl methyl | MeSO 2- | 0.09(m，2H)，0.28(m，2H)， 1.00(m，1H)，2.39(s，3H)， 2.92(s，3H)，3.18(m，4H)， 3.24(m，4H)，4.49(d，2H)， 6.94(d，2H)，7.02(d，1H)， 7.47(d，2H)，7.58(s，1H)， 8.30(d，1H)，9.15(s，1H) | 468 | Method 41 among the WO 03,/07,643 5 |
| Ex | R 1 | R 2 | R 3 | NMR | m/z | SM |
| 5 2 | Et | Et | MeSO 2- | 1.11(t，3H)，1.24(t，3H)， 2.71(q，2H)，2.91(s，3H)， 3.18(m，4H)，3.23(m，4H)， 4.50(q，2H)，6.95(d，2H)， 7.03(d，1H)，7.47(d，2H)， 7.61(s，1H)，8.28(d，1H)， 9.12(s，1H) | 456 | Method 55 among the WO 03,/07,643 4 |
| 6 3 | Et | i-Pr | MeSO 2- | 1.28(t，3H)，1.40(d，6H)， 2.79(q，2H)，2.91(s，3H)， 3.17(m，4H)，3.24(m，4H)， 5.61(septuplet，1H)，6.93(d， 2H)，6.94(d，1H)，7.40(s， 1H)，7.49(d，2H)，8.32(d， 1H)，9.18(s，1H) | 470 | Method 9 |
| 7 4 | MeOCH 2- | i-Pr | MeSO 2- | 1.42(d，6H)，2.92(s，3H)， 3.17(m，4H)，3.24(m，4H)， 3.27(s，3H)，4.53(s，2H)， 5.52(septuplet，1H)，6.94(d， 2H)，6.99(d，1H)，7.47(s， 1H)，7.49(d，2H)，8.38(d， 1H)，9.21(s，1H) | 486 | Method 50 among the WO 03,/07,643 4 |
| 8 5 | Pr | Et | MeSO 2- | 0.97(t，3H)，1.12(t，3H)， 1.72(sextuplet，2H)，2.68(t， 2H)，2.92(s，3H)，3.16(m， 4H)，3.27(m，4H)，4.51(q， 2H)，6.93(d，2H)，7.02(d， 1H)，7.48(d，2H)，7.62(s， 1H)，8.29(d，1H)，9.12(s， 1H) | 470 | Method 13 |
| Ex | R 1 | R 2 | R 3 | NMR | m/z | SM |
| 9 6 | Me | Et | MeSO 2- | 1.12(t，3H)，2.38(s，3H)， 2.91(s，3H)，3.17(m，4H)， 3.24(m，4H)，4.50(q，2H)， 6.94(d，2H)，7.02(d，1H)， 7.48(d，2H)，7.60(s，1H)， 8.29(d，1H)，9.13(s，1H) | 442 | Method 16 among the WO 02/20512 |
| 10 7 | Me | i-Bu | MeSO 2- | 0.60(d，6H)，1.69(septuplet， 1H)，2.36(s，3H)，2.92(s， 3H)，3.16(m，4H)，3.25(m， 4H)，4.32(d，2H)，6.94(d， 2H)，7.01(d，1H)，7.47(d， 2H)，7.58(s，1H)，8.29(d， 1H)，9.18(s，1H) | 470 | Method 29 among the WO 03,/07,643 6 |
| 11 8 | Et | i-Pr | MeC(O)- | 1.28(t，3H)，1.40(d，6H)， 2.02(s，3H)，2.79(q，2H)， 3.00(t，2H)，3.08(t，2H)， 3.57(m，4H)，5.60 (septuplet，1H)，6.91(d，2H)， 6.94(d，1H)，7.41(s，1H)， 7.48(d，2H)，8.31(d，1H)， 9.18(s，1H) | 434 | Method 9 |
| 12 | Pr | Et | MeC(O)- | 0.95(t，3H)，1.10(t，3H)， 1.70(septuplet，2H)，2.02(s， 3H)，2.68(t，2H)，3.01(t， 2H)，3.08(t，2H)，3.59(q， 4H)，4.51(q，2H)，6.92(d， 2H)，7.02(d，1H)，7.44(d， 2H)，7.62(s，1H)，8.29(d， 1H)，9.11(s，1H) | 434 | Method 13 |
| Ex | R 1 | R 2 | R 3 | NMR | m/z | SM |
| 13 | Me | Cyclobutyl | MeC(O)- | 1.60(sextet，1H)，1.73(q， 1H)，2.05(s，3H)，2.30-2.48 (m，4H)，3.031(t，2H)，3.09 (t，2H)，3.59(q，4H)，5.58 (quintet，1H)，6.93(d，1H)， 6.96(d，2H)，7.32(s，1H)， 7.57(d，2H)，8.34(d，1H)， 9.24(s，1H) | 432 | Method 37 among the WO 03,/07,643 5 |
| 14 | Et | Et | MeC(O)- | 1.12(t，3H)，124(t，3H)， 2.03(s，3H)，2.71(q，2H)， 3.01(t，2H)，3.08(t，2H)， 3.57(q，4H)，4.49(q，2H)， 6.92(d，2H)，7.01(d，1H)， 7.45(d，2H)，7.61(s，1H)， 8.29(d，1H)，9.10(s，1H) | 420 | Method 55 among the WO 03,/07,643 4 |
| 15 | Me | Et | MeC(O)- | 1.11(t，3H)，2.03(s，3H)， 2.38(s，3H)，3.02(t，2H)， 3.08(t，2H)，3.57(q，4H)， 4.50(q，2H)，6.92(d，2H)， 7.01(d，1H)，7.46(d，2H)， 7.59(s，1H)，8.28(d，1H)， 9.09(s，1H) | 406 | Method 16 among the WO 02/20512 |
| 16 9 | MeOCH 2- | i-Pr | MeC(O)- | 1.42(d，6H)，2.03(s，3H)， 3.01(t，2H)，3.08(t，2H)， 3.27(s，3H)，3.57(q，4H)， 4.53(s，2H)，5.52(septuplet， 1H)，6.91(d，2H)，6.99(d， 1H)，7.44(s，1H)，7.47(d， 2H)，8.38(d，1H)，9.20(s， 1H) | 450 | Method 50 among the WO 03,/07,643 4 |
| Ex | R 1 | R 2 | R 3 | NMR | m/z | SM |
| 17 10 | Me | i-Bu | MeC(O)- | 0.60(d，6H)，1.69(septuplet， 1H)，2.02(s，3H)，2.35(s， 3H)，2.99(t，2H)，3.07(t， 2H)，3.58(q，4H)，4.33(d， 2H)，6.93(d，2H)，7.00(d， 1H)，7.45(d，2H)，7.58(s， 1H)，8.28(d，1H)，9.13(s， 1H) | 434 | Method 29 among the WO 03,/07,643 6 |
1This compound need further be used neutral alumina (II level activity) chromatography, uses EtOAc: DCM (1: 1), and then with the EtOAc that contains 5%v/v MeOH: DCM (1: 1) wash-out.Title compound crystallization in MeOH (120mg 25.6%).
2Use MeOH: DCM (2: 98-6: 94) chromatography.Title compound crystallization in acetonitrile (149mg 32.7%).
3Use MeOH: DCM (3: 97-5: 95) chromatography (127mg 27%).
4Use MeOH: DCM (3: 97) chromatography (180mg 37%).
5Use MeOH: DCM (2: 98-6: 94) chromatography (290mg 34.5%).
6Use MeOH: DCM (2: 98-6: 94) chromatography (340mg 38.5%).
7Use MeOH: DCM (2: 98-6: 94) chromatography (350mg 41.7%).
8Under 110 ℃, with 5-(3-dimethylamino third-2-alkene-1-acyl group)-1-sec.-propyl-2-ethyl imidazol(e) (method 9; 470mg, 2mmol) and N-[4-(4-ethanoyl piperazine-1-yl) phenyl] guanidine supercarbonate (method 2; 740mg, 2-methyl cellosolve 2.3mmol) (10ml) solution stirring heated 24 hours.With the reaction mixture reduction vaporization, make residue on silica gel, use MeOH: DCM (2: 98-6: 94) chromatography purification.After the evaporation, grind, obtain title compound, be yellow solid (290mg, 33.4%) with ether.
9Use MeOH: DCM (3: 97-8: 92) chromatography (186mg 20.7%).
10Use MeOH: DCM (2: 98-6: 94) chromatography (372mg 40%).
Embodiment 18
2-[4-(4-ethanoyl piperazine-1-yl) anilino]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-
Base) pyrimidine
Under nitrogen, under 200 ℃, make (2E)-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (WO 03/076436 method 24; 140mg 0.63mmol) and N-[4-(4-ethanoyl piperazine-1-yl) phenyl] guanidine supercarbonate (method 2; 240mg, 2-methyl cellosolve 0.74mmol) (4ml) solution reacted 30 minutes under microwave condition.Behind the reduction vaporization, on silica gel, use MeOH: DCM (2: 98-6: 94) chromatography, obtain title compound, after grinding with ether, be yellow solid (85mg 31.5%).
NMR：1.39(d，6H)，2.02(s，3H)，2.45(s，3H)，3.00(b t，2H)，3.06(b t，2H)，3.56(b q，4H)，5.70(septuplet，1H)，6.91(d，2H)，6.95(d，1H)，7.38(s，1H)，7.46(d，2H)，8.31(d，1H)，9.15(s，1H)；m/z 420.
Embodiment 19
2-[4-(4-ethanoyl piperazine-1-yl) anilino]-4-[1-(cyclopropyl methyl)-2-methyl isophthalic acid H-
Imidazoles-5-yl] pyrimidine
Remove under 200 ℃, in microwave, outside the reacting by heating 40 minutes, press embodiment 18 methods, prepare title compound by 5-(3-dimethylamino third-2-alkene-1-acyl group)-1-cyclopropyl methyl-glyoxal ethyline (WO03/076435 method 41).148mg 53.4％。
NMR：0.10(m，2H)，0.28(m，2H)，1.02(m，1H)，2.03(s，3H)，2.38(s，3H)，3.01(t，2H)，3.08(t，2H)，3.57(q，4H)，4.48(d，2H)，6.92(d，2H)，7.01(d，1H)，7.43(d，2H)，7.57(s，1H)，8.281(d，1H)，9.12(s，1H)；m/z 432.
Embodiment 20
2-[4-(piperazine-1-yl) anilino]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine
Under 90 ℃, with 2-[4-(4-ethanoyl piperazine-1-yl) anilino]-(embodiment 18 for pyrimidine for 4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 1.3g) in Virahol (15ml) and 33% hydrochloric acid (1.5ml), stir, heated 4.5 hours.With the reactant reduction vaporization, the MeOH solution with 7N ammonia alkalizes revaporization then.Add toluene, with mixture revaporization (3 times).Residue is used MeOH: DCM (5: 95) chromatography purification on the active neutral alumina of II level, obtain title compound, be yellow jelly (330mg 28%).
NMR：1.40(d，6H)，2.46(s，3H) 2.82(m，4H)，2.96(m，4H)，5.69(septuplet，1H)，6.85(d，2H)，6.93(d，1H)，7.18(s，1H)，7.42(d，2H)，8.30(d，1H)，9.11(s，1H)；m/z 378.
Embodiment 21
2-{4-[4-(2-acetoxyl group ethanoyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-first
Base-1H-imidazoles-5-yl) pyrimidine
At room temperature, with 2-[4-(piperazine-1-yl) anilino]-(embodiment 20 for pyrimidine for 4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 330mg 0.88mmol) in DCM (6ml), stirs.Add triethylamine (153mg 1.51mmol), be added dropwise to alpha-Acetoxyacetyl chloride (143mg 1.05mmol) subsequently.Stir after 1.25 hours, add DCM (10ml) and salt solution (5ml).With reactant vigorous stirring 10 minutes, then organic layer is separated, drying, reduction vaporization obtains title compound, is yellow foam.Quantitative yield.Solid is ground revaporization with ether.
NMR：1.40(d，6H)，2.08(s，3H)，2.48(s，3H)，3.05(b d，4H)，3.54(b d，4H)，4.81(s，2H)，5.70(septuplet，1H)，6.92(d，2H)，6.95(d，1H)，7.40(s，1H)，7.48(d，2H)，8.31(d，1H)，9.18(s，1H)；m/z 478.
Embodiment 22
2-{4-[4-(2-hydroxyacetyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-methyl-
1H-imidazoles-5-yl) pyrimidine
At room temperature, with 2-{4-[4-(2-acetoxyl group ethanoyl) piperazine-1-yl] anilino }-(embodiment 21 for pyrimidine for 4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 330mg) in MeOH (5ml), stir, add MeOH (1.6ml) solution of 7N ammonia.After 28 hours, with the reactant reduction vaporization.On silica gel, use MeOH: DCM (4: 96-5: 95) chromatography, obtain title compound, be yellow solid (108mg 36%).
NMR：1.39(d，6H)，2.46(s，3H)，3.05(b s，4H)，3.48(b s，2H)，3.61(b s，2H)，4.12(d，2H)，4.57(t，1H)，5.69(septuplet，1H)，6.92(d，2H)，6.95(d，1H)，7.38(s，1H)，7.47(d，2H)，8.31(d，1H)，9.15(s，1H)；m/z 436.
Embodiment 23
2-{4-[4-(2-dimethylamino ethanoyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-first
Base-1H-imidazoles-5-yl) pyrimidine
At room temperature, under agitation, with chloroacetyl chloride (50 μ l 0.65mmol) are added drop-wise to 2-[4-(piperazine-1-yl) anilino]-(embodiment 20 for pyrimidine for 4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 200mg, 0.53mmol) and triethylamine (90 μ l are in DCM 0.65mmol) (5ml) solution.After 50 minutes, (2ml 4mmol), stirs reactant 5 hours, then reduction vaporization the THF solution of adding 2M dimethylamine.Neutral alumina (II level activity) go up use MeOH: DCM (1: 99-3: 97) chromatography, obtain material, need further be used MeOH: DCM on silica gel: 7N NH
3MeOH (3: 97: .0025-10: 90: .0025) purifying, obtain title compound, be yellow foam (150mg 60% yield).
NMR：1.39(d，6H)，2.19(s，6H)，2.46(s，3H)，3.02(b t，2H)，3.06(b t，2H)，3.59(b t，2H)，3.68(b t，2H)，5.69(septuplet，1H)，6.92(d，2H)，6.94(d，1H)，7.39(s，1H)，7.47(d，2H)，8.31(d，1H)，9.17(s，1H)；m/z 463.
Embodiment 24
2-{4-[4-(chloracetyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-methyl isophthalic acid H-miaow
Azoles-5-yl) pyrimidine
Under 0 ℃, with 2-[4-(piperazine-1-yl) anilino]-(embodiment 20 for pyrimidine for 4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 1.89g, 5mmol), (0.956ml, (0.438ml 5.5mmol) handles DCM 5.5mmol) (25ml) solution two-sec.-propyl ethamine with chloroacetyl chloride.Mixture was stirred 2 hours under envrionment conditions, with DCM (25ml) dilution, with saturated sodium bicarbonate aqueous solution (20ml) and saturated sodium-chloride water solution (20ml) washing.With the solution drying, reduction vaporization obtains title compound (1.96g, 87%).
NMR(CDCl
3)8.30(d，1H)，7.44(d，2H)，7.35(s，1H)，6.96(s，1H)，6.92(d，1H)，6.85(d，1H)，5.68-5.56(m，1H)，4.12(s，2H)，3.83-3.76(m，2H)，3.72-3.67(m，2H)，3.22-3.11(m，4H)，2.59(s，3H)，1.48(d，6H)；m/z 454.
Embodiment 25
2-{4-[4-(azetidine-1-base ethanoyl) piperazine-1-yl] anilino }-4-(the 1-sec.-propyl-
2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine hydrochloride
At ambient temperature, with 2-{4-[4-(chloracetyl) piperazine-1-yl] anilino }-(embodiment 24 for pyrimidine for 4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 0.34g, 0.75mmol) and azetidine (2ml) stirred 24 hours.Solution is with EtOAc (20ml) dilution, dry then with saturated sodium bicarbonate aqueous solution (10ml) and saturated sodium-chloride water solution (10ml) washing, reduction vaporization.On the 40g silicagel column, with 3%MeOH-ammoniacal liquor/DCM to 5%MeOH-ammoniacal liquor/DCM gradient elution, chromatography purification obtains amine, by it being dissolved in EtOAc (3ml) and with 1.0mol ether-HCl (0.75ml) solution-treated, making it be converted into hydrochloride with residue.Solid is ground with ether (20ml), filter, obtain title compound (24mg, 7%).
NMR：9.77(s，1H)，8.58(d，1H)，8.20(s，1H)，7.61(d，2H)，7.35-7.24(m，2H)，7.13(d，1H)，5.64-5.55(m，1H)，4.65(brs，1H)，4.44(d，2H)，4.23-4.11(m，2H)，4.09-3.96(m，2H)，3.81-3.71(m，2H)，3.69-3.59(m，2H)，3.42-3.31(m，2H)，3.30-3.17(m，2H)，2.48-2.24(m，2H)，2.81(s，3H)，1.48(d，6H)；m/z 475.
Embodiment 26-28
With embodiment 25 methods, by 2-{4-[4-(chloracetyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine (embodiment 24) and the suitable following salt of amine preparation.
Embodiment 29
2-{4-[4-(vinylsulfonyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-methyl-
1H-imidazoles-5-yl) pyrimidine
At room temperature, with 2-[4-(piperazine-1-yl) anilino]-(embodiment 20 for pyrimidine for 4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 370mg 0.98mmol) in DCM (10ml), stirs.Add triethylamine (150mg 1.49mmol), be added dropwise to DCM (1ml) solution of 2-chloro-1-ethyl sulfonyl chloride (196mg1.2mmol) subsequently.Stir after 1.25 hours,, grind with ether with the reactant reduction vaporization.The solid water (15ml) that obtains is handled, and with the saturated sodium bicarbonate solution alkalization, is extracted into DCM (in 2 * 20ml).Organic liquor is washed with salt solution (10ml), drying, evaporation obtains jelly.Using MeOH: DCM (3: 97-5: 95) behind the chromatography, obtain title compound, be yellow solid (140mg 30.4%) on the silica gel.
NMR1.39(d，6H)，2.46(s，3H)，3.16(s，8H)，5.68(septuplet，1H)，6.20(d，1H)，6.85(dd，1H)，6.91(d，2H)，6.95(d，1H)，7.38(s，1H)，7.47(d，2H)，8.30(d，1H)，9.16(s，1H)；m/z 468.
Embodiment 30
2-{4-[4-(2-dimethylamino ethylsulfonyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-
Methyl isophthalic acid H-imidazoles-5-yl) pyrimidine
At room temperature, under agitation, with THF (1.5ml) solution adding 2-{4-[4-(vinylsulfonyl) piperazine-1-yl of dimethylamine (2.0M)] anilino }-(embodiment 29 for pyrimidine for 4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 140mg 0.3mmol) in THF (3ml) suspension.After 2 hours, add dimethylamine solution (0.5ml) again.Reactant was stirred 1 hour, place then and spend the night.With the reactant reduction vaporization, grind with ether, filter, obtain title compound, be yellow solid (134mg 89%).
NMR:1.40 (d, 6H), 2.46 (s, 3H), 2.62 (t, 2H), 3.13 (t, 4H), 3.20-3.35 (2H and 4H) [under exchangeables], 5.68 (septuplet, 1H), 6.92 (d, 2H), 6.95 (d, 1H), 7.38 (s, 1H), 7.47 (d, 2H), 8.31 (d, 1H), 9.18 (s, and 1H) [+duetero acetic acid:3.01 (b d, 2H), 3.14 (t, 4H), 3.33 (t, 4H), 3.37 (m, 2H)]; M/z478.
Embodiment 31
2-{4-[4-(2-methoxyl group ethylsulfonyl) piperazine-1-yl] phenylamino }-4-(1-sec.-propyl-2-first
Base-1H-imidazoles-5-yl) pyrimidine
Sodium methylate (40mg 0.74mmol) is added 2-{4-[4-(vinylsulfonyl) piperazine-1-yl] anilino }-(embodiment 29 for pyrimidine for 4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 300mg0.64mmol) MeOH (4ml) solution in.After at room temperature stirring 5 hours, reactant is evaporated.After using MeOH: DCM: EtOAc (5: 47.5: 47.5) chromatography on the silica gel, grind with ether, obtain title compound, be yellow solid.
NMR：1.41(d，6H)，2.47(s，3H)，3.13(m，4H)，3.26(4H alongside exchangeables)，3.37(t，2H)，3.67(t，2H)，5.69(septuplet，1H)，6.93(d，2H)，6.96(d，1H)，7.39(s，1H)，7.49(d，2H)，8.32(d，1H)，9.18(s，1H)；m/z 500.
Embodiment 32
2-{4-[4-(2-hydroxyl ethylsulfonyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-methyl-
1H-imidazoles-5-yl) pyrimidine
Under 65 ℃-90 ℃, with 2-{4-[4-(vinylsulfonyl) piperazine-1-yl] anilino }-(embodiment 29 for pyrimidine for 4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 260mg 0.56mmol) and the mixture heating up of hydrated barta (560mg 3.27mmol) in water (10ml) more than 6 hours.After 1,2,3 and 5 hour, add 1,4-diox (1ml).Behind the reduction vaporization, residue water (10ml) and saturated sodium bicarbonate solution (10ml) are handled.With suspension with DCM (30ml and 2 * 20ml) and EtOAc (25ml) extract.Two kinds of extraction liquids are washed (difference) with salt solution (10ml), dry (Na
2SO
4).Extraction liquid is merged evaporation.Using MeOH: DCM (4: 96-8: 92) behind the chromatography, obtain title compound, be yellow solid (108mg40%) on the silica gel.
NMR：1.40(d，6H)，2.49(s，3H)，3.13(m，4H)，3.23(t，2H)，3.30(m，4H)，3.76(q，2H)，5.01(t，1H)，5.69(septuplet，1H)，6.93(d，2H)，6.96(d，1H)，7.39(s，1H)，7.48(d，2H)，8.31(d，1H)，9.18(s，1H)；m/z 486.
Embodiment 33
2-[4-(4-ethanoyl piperazine-1-yl) anilino]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-
Base)-the 5-chloropyrimide
Under nitrogen; under 110 ℃; with (2E)-2-chloro-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (1.68g; from method 3-supposition 5mmol) and N-[4-(4-ethanoyl piperazine-1-yl) phenyl] 2-methyl cellosolve (25ml) solution of guanidine supercarbonate (method 2) (1.94g 6mmol) heated 3.5 hours, reduction vaporization then.Make residue on silica gel, use MeOH: DCM (3: 97-5: 95) chromatography purification, obtain title compound, after grinding with ether, be foam.
NMR：1.36(d，6H)，2.02(s，3H)，2.48(s，3H)，3.00(b t，2H)，3.08(b t，2H)，3.56(b q，4H)，4.80(septuplet，1H)，6.90(d，2H)，7.21(s，1H)，7.47(d，2H)，8.50(s，1H)，9.48(s，1H)；m/z 454.
Embodiment 34
2-[4-(piperazine-1-yl) anilino]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-5-chlorine
Pyrimidine
Press embodiment 20 methods, by 2-[4-(4-ethanoyl piperazine-1-yl) anilino]-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-(embodiment 33 for the 5-chloropyrimide for 4-; 800mg) preparation title compound.Difference is after using MeOH: DCM (3: 97) elution chromatography purifying on the active neutral alumina of II level title compound to be separated, and is yellow jelly.Grind with ether, obtain foam (50mg 7%)
NMR：1.34(d，6H)，2.45(s，3H)，2.82(m，4H)，2.96(m，4H)，4.82(septuplet，1H)，6.85(d，2H)，7.41(s，1H)，7.42(d，2H)，8.49(s，1H)，9.43(s，1H)；m/z 412.
Embodiment 35
2-{4-[4-(acetoxyl group ethanoyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-methyl-
1H-imidazoles-5-yl)-the 5-chloropyrimide
With embodiment 21 methods, with 400mg 0.97mmol 2-[4-(piperazine-1-yl) anilino]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-5-chloropyrimide (embodiment 34) preparation title compound.After the aftertreatment, mixture is used MeOH: DCM on silica gel (3: 97-6: 94) chromatography purification obtains solid (230mg).
NMR：1.35(d，6H)，2.08(s，3H)，2.48(s，3H)，3.04(b d，4H)，3.52(b d，4H)，4.80(septuplet，1H)，4.81(s，2H)，6.92(d，2H)，7.22(s，1H)，7.48(d，2H)，8.51(d，1H)，9.49(s，1H)；m/z 512.
Embodiment 36
2-{4-[4-(hydroxyacetyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-methyl isophthalic acid H-
Imidazoles-5-yl)-the 5-chloropyrimide
Press embodiment 22 methods, make 2-{4-[4-(acetoxyl group ethanoyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-5-chloropyrimide (embodiment 35) deprotection.With the reaction mixture reduction vaporization.Residue is dissolved in DCM (30ml), water (15ml) and salt solution (15ml) washing, drying, evaporation.Residue is ground with ether, and revaporization obtains title compound, is solid (180mg).
NMR：1.34(d，6H)，2.48(s，3H)，3.03(b s，4H)，3.52(b d，4H)，4.11(d，2H)，4.59(t，1H)，4.80(septuplet，1H)，6.91(d，2H)，7.21(s，1H)，7.47(d，2H)，8.51(s，1H)，9.49(s，1H)；m/z 470.
Embodiment 37
2-{4-[4-(2-hydroxy-2-methyl propionyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-
Methyl isophthalic acid H-imidazoles-5-yl)-the 5-chloropyrimide
With the 2-hydroxy-iso-butyric acid (162mg, 1mmol) add 1,1 '-(162mg in DCM 1mmol) (4ml) solution, at room temperature stirred 15 minutes carbonyl dimidazoles.Add 2-[4-(piperazine-1-yl) anilino]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-5-chloropyrimide (embodiment 34,400mg, and DCM 0.97mmol) (8ml) solution continues to stir 19 hours.Add DCM (25ml), organic layer is washed drying, reduction vaporization then with 5% (v/v) acetate (15ml), water (15ml), salt solution (15ml).On silica gel, use MeOH: DCM (4: 96-8: 92) chromatography, obtain title compound, after grinding with ether, be solid (67mg 14%).
NMR：(500MHz)1.30(d，6H)，1.34(d，6H)，2.48(s，3H)，3.04(t，4H)，3.62(b s，4H)，4.00(b s，4H)，4.79(septuplet，1H)，5.41(s，1H)，6.90(d，2H)，7.22(s，1H)，7.48(d，2H)，8.51(s，1H)，9.49(s，1H)；m/z 498.
Embodiment 38
2-{4-[4-(2-(S)-2-hydroxyl propionyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-first
Base-1H-imidazoles-5-yl)-the 5-chloropyrimide
To 2-[4-(piperazine-1-yl) anilino]-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-(embodiment 34 for the 5-chloropyrimide for 4-; 276mg, add in DMF 1.00mmol) (7ml) solution L-lactic acid (90mg, 1.50mmol) and DIPEA (245 μ l, 181mg, 2.1mmol).(330mg, DMF 1.30mmol) (3ml) solution stirred mixture 20 hours then at ambient temperature to be added dropwise to HATU.With solution for vacuum concentration, then residue is dissolved in EtOAc (20ml), use sodium bicarbonate aqueous solution (15ml), salt solution (15ml) washing successively.With the organic extract liquid drying, concentrate.Make residue on silica gel, use 2N NH
3-MeOH: DCM (3: 97-5: 95) chromatography purification, obtain title compound, be white solid (233mg, 72%).
NMR：1.37(d，3H)，1.45(d，6H)，2.58(s，3H)，3.12-3.17(m，4H)，3.56-3.60(m，2H)，3.75-3.92(m，3H)，4.48-4.54(m，1H)，4.96(quintet，1H)，6.91(d，2H)，6.94(s，1H)，7.43(d，2H)，7.50(s，1H)，8.38(s，1H)；m/z 484.
Embodiment 39-47
Press embodiment 38 methods, with suitable acid and 2-[4-(piperazine-1-yl) anilino]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-following compound of 5-chloropyrimide (embodiment 34) preparation.
| Ex | R | NMR(300MHz，CDCl 3) | m/z |
| 39 | (R)-MeCH(OH)- | 1.37(d，3H)，1.45(d，6H)，2.58(s，3H)，3.12-3.17 (m，4H)，3.56-3.60(m，2H)，3.75-3.92(m，3H)， 4.48-4.54(m，1H)，4.96(quintet，1H)，6.91(d，2H)， 6.94(s，1H)，7.43(d，2H)，7.50(s，1H)，8.38(s，1H) | 484 |
| 40 | MeOCH 2- | 1.43(d，6H)，2.57(s，3H)，3.10-3.15(m，4H)，3.44 (s，3H)，3.65-3.69(m，2H)，3.76-3.80(m，2H)4.15 (s，2H)，4.93(quintet，1H)，6.91(d，2H)6.94(s， 1H)，7.41(d，2H)，7.50(s，1H)，8.37(s，1H) | 484 |
| 41 | 1-hydroxyl ring third-1-base | (d6-DMSO)：0.74-0.78(m，2H)，0.90-0.95(m，2H)， 1.34(d，6H)，2.46(s，3H)，3.04-3.08(m，4H)，3.68- 3.80(m，4H)，4.79(quintet，1H)，6.33(s，1H)，6.91 (d，2H)，7.21(s，1H)，7.45，(d，2H)，8.50(s，1H)， 9.48(s，1H) | 496 |
| 42 | (R)-MeCH(OMe)- | 1.42-1.46(m，9H)，2.58(s，3H)，3.11-3.16(m，4H)， 3.37(s，3H)，3.78-3.86(m，4H)，4.20(q，1H)，4.94 (quintet，1H)，6.91(d，2H)，6.93(s，1H)，7.42(d， 2H)，7.51(s，1H)，8.38(s，1H) | 498 |
| Ex | R | NMR(300MHz，CDCl 3) | m/z |
| 43 | (S)-MeCH(OMe)- | 1.42-1.46(m，9H)，2.58(s，3H)，3.11-3.16(m，4H)， 3.37(s，3H)，3.78-3.86(m，4H)，4.20(q，1H)，4.94 (quintet，1H)，6.91(d，2H)，6.93(s，1H)，7.42(d， 2H)，7.51(s，1H)，8.38(s，1H) | 498 |
| 44 | (S)-MeCH 2CH(OH)- | 1.01(t，3H)，1.43(d，6H)，1.49-1.58(m，1H)，1.69- 1.78(m，1H)，2.57(s，3H)，3.11-3.15(m，4H)，3.55- 3.59(m，2H)，3.70-3.90(m，3H)，4.34-4.38(m，1H)， 4.92(quintet，1H)，6.91(d，2H)，6.96(s，1H)，7.42 (d，2H)，7.51(s，1H)，8.37(s，1H) | 498 |
| 45 | MeCH(Me)- | 1.17(d，6H)，1.44(d，6H)，2.58(s，3H)，2.82-2.89 (m，1H)，3.09-3.15(m，4H)，3.66-3.72(m，2H)， 3.76-3.82(m，2H)，4.94(quintet，1H)，6.91(d，2H)， 6.93(s，1H)，7.41(d，2H)，7.51(s，1H)，8.38(s，1H) | 482 |
| 46 | Cyclopropyl- | 0.77-0.83(m，2H)，1.00-1.05(m，2H)，1.44(d，6H)， 1.74-1.81(m，1H)，2.58(s，3H)，3.11-3.19(m，4H)， 3.79-3.87(m，4H)，4.94(quintet，1H)，6.91(d，2H)， 6.94(s，1H)，7.41(d，2H)，7.51(s，1H)，8.37(s，1H) | 480 |
| 47 | (R)-MeCH 2CH(OH)- | 1.01(t，3H)，1.43(d，6H)，1.49-1.58(m，1H)，1.69- 1.78(m，1H)，2.57(s，3H)，3.11-3.15(m，4H)，3.55- 3.59(m，2H)，3.70-3.90(m，3H)，4.34-4.38(m，1H)， 4.92(quintet，1H)，6.91(d，2H)，6.96(s，1H)，7.42 (d，2H)，7.51(s，1H)，8.37(s，1H) | 498 |
Embodiment 48-64
Press embodiment 38 methods, with suitable acid and 2-[4-(piperazine-1-yl) anilino]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-following compound of 5-chloropyrimide (embodiment 34) preparation.Then isolating free alkali is dissolved in EtOAc (3ml), and adds several MeOH hydrotropies.Add the diethyl ether solution (1 equivalent) of 1.0M hydrogenchloride, the hydrochloride that obtains is ground with ether, filter vacuum-drying then.
| Ex | R | NMR | m/z |
| 48 | MeOCH 2CH 2- | 1.42(d，6H)，2.48(s，3H)，2.63(t，2H)，2.79(s， 3H)，3.23-3.30(m，4H)，3.57(t，2H)，3.77-3.82 (m，4H)，4.80(quintet，1H)，7.34-7.38(m，2H)， 7.62(d，2H)，7.99(s，1H)，8.76(s，1H)，10.08 (brs，1H) | 498 |
| 49 | 1-cyano group ring third-1-base- | 1.42(d，6H)，1.52-1.56(m，2H)，1.60-1.64(m， 2H)，2.78(s，3H)，3.27-3.33(m，4H)，3.85-3.91 (m，4H)，4.80(quintet，1H)，7.24(d，2H)，7.59 (d，2H)，7.98(s，1H)，8.74(s，1H)，10.01(brs， 1H) | 505 |
| 50 | (R)-tetrahydrofuran (THF)-2-base- | 1.42(d，6H)，1.79-1.87(m，2H)，1.98-2.11(m， 2H)，2.78(s，3H)，3.19-3.27(m，4H)，3.70-3.83 (m，6H)，4.70(dd，1H)，4.80(quintet，1H)，7.23- 7.30(m，2H)，7.59(d，2H)，7.98(s，1H)，8.74(s， 1H)，10.02(brs，1H) | 510 |
| 51 | (S)-tetrahydrofuran (THF)-2-base- | 1.42(d，6H)，1.79-1.87(m，2H)，1.98-2.11(m， 2H)，2.78(s，3H)，3.19-3.27(m，4H)，3.70-3.83 (m，6H)，4.70(dd，1H)，4.80(quintet，1H)，7.23- 7.30(m，2H)，7.59(d，2H)，7.98(s，1H)，8.74(s， 1H)，10.02(brs，1H) | 510 |
| 52 | MeC(Me)(OH)CH 2- | 1.19(s，6H)，1.42(d，6H)，2.50(s，2H)，2.79(s， 3H)，3.25-3.33(m，4H)，3.81-3.89(m，4H)，4.80 (quintet，1H)，7.34-7.40(m，2H)，7.63(d，2H)， 7.99(s，1H)，8.76(s，1H)，10.08(brs，1H) | 512 |
| Ex | R | NMR | m/z |
| 53 | HOCH 2C(Me) 2- | 1.18(s，6H)，1.42(d，6H)，2.79(s，3H)，3.25- 3.29(m，4H)，3.44(s，2H)，3.84-3.90(m，4H)， 4.80(quintet，1H)，7.32-7.40(m，2H)，7.62(d， 2H)，7.99(s，1H)，8.76(s，1H)，10.07(brs，1H) | 512 |
| 54 | (R)-MeCH(Me)CH(OH)- | 0.84(d，3H)，0.88(d，3H)，1.42(d，6H)，1.82- 1.90(m，1H)，2.79(s，3H)，3.27-3.33(m，4H)， 3.85-3.92(m，4H)，4.06(d，1H)，4.79(quintet， 1H)，7.38-7.42(m，2H)，7.64(d，2H)，7.99(s， 1H)，8.76(s，1H)，10.09(brs，1H) | 512 |
| 55 | (S)-MeCH(Me)CH(OH)- | 0.84(d，3H)，0.88(d，3H)，1.42(d，6H)，1.82- 1.90(m，1H)，2.79(s，3H)，3.27-3.33(m，4H)， 3.85-3.92(m，4H)，4.06(d，1H)，4.79(quintet， 1H)，7.38-7.42(m，2H)，7.64(d，2H)，7.99(s， 1H)，8.76(s，1H)，10.09(brs，1H) | 512 |
| 56 | HC≡CCH 2OCH 2- | 1.42(d，6H)，2.78(s，3H)，3.22-3.30(m，4H)， 3.49(t，1H)，3.67-3.75(m，4H)，4.23(d，2H)， 4.26(s，2H)，4.80(quintet，1H)，7.26-7.33(m， 2H)，7.61(d，2H)，7.99(s，1H)，8.75(s，1H)， 10.04(brs，1H) | 508 |
| 57 | Tetrahydrofuran (THF)-3-base- | 1.42(d，6H)，2.03(q，2H)，2.78(s，3H)，3.22- 3.30(m，4H)，3.36-3.45(m，1H)，3.66-3.76(m， 4H)，3.77-3.84(m，4H)，4.80(quintet，1H)，7.28- 7.36(m，2H)，7.61(d，2H)，7.99(s，1H)，8.75(s， 1H)，10.05(brs，1H) | 510 |
| 58 | (Me) 2NCH 2CH 2- | 1.42(d，6H)，2.74-2.78(m，9H)，2.93(t，2H)， 3.21-3.32(m，6H)，3.72-3.78(m，4H)，4.80 (quintet，1H)，7.22-7.28(m，2H)，7.59(d，2H)， 7.99(s，1H)，8.74(s，1H)，10.01(brs，1H) | 511 |
| Ex | R | NMR | m/z |
| 59 | HOCH 2N(Me)CH 2- | 1.42(d，6H)，2.78(s，3H)，2.88-2.95(7H，m)， 3.20-3.31(m，4H)，3.42-3.51(m，4H)，4.80 (quintet，1H)，7.05(d，2H)，7.52(d，2H)，7.98(s， 1H)，8.71(s，1H)，9.89(brs，1H) | 511 |
| 60 | (HOCH 2) 2C- | 1.42(d，6H)，2.78(s，3H)，3.05-3.11(m，1H)， 3.22-3.30(m，4H)，3.48-3.52(m，4H)，3.78-3.90 (m，4H)，4.80(quintet，1H)，7.29-7.35(m，2H)， 7.61(d，2H)，7.99(s，1H)，8.75(s，1H)，10.04 (brs，1H) | 514 |
| 61 | Tetrazolium-1-base-CH 2- | 1.42(d，6H)，2.78(s，3H)，3.20-3.28(m，2H)， 3.32-3.40(m，2H)，3.70-3.85(m，4H)，4.80 (quintet，1H)，5.72(s，2H)，7.20-7.26(m，2H)， 7.59(d，2H)，7.99(s，1H)，8.74(s，1H)，9.31(s， 1H)，10.04(brs，1H) | 522 |
| 62 | 1H-tetrazolium-5-base-CH 2- | (MeOD)：1.54(d，6H)，2.82(s，3H)，3.57-3.63 (m，2H)，3.75-3.81(m，2H)，4.03-4.12(m，4H)， 4.32(s，2H)，4.92(quintet，1H)，7.55(d，2H)， 7.83(d，2H)，7.86(s，1H)，8.68(s，1H) | 522 |
| 63 | 1-methyl-L-prolyl- | 1.42(d，6H)，1.84-1.92(m，2H)，2.04-2.14(m， 1H)，2.52-2.59(m，1H)，2.79-2.82(m，6H)，3.11- 3.22(m，4H)，3.59-3.85(m，6H)，4.70-4.84(m， 2H)，7.10(d，2H)，7.54(d，2H)，7.97(s，1H)， 8.72(s，1H)，9.66(brs，1H)，9.93(s，1H) | 523 |
| 64 | MeSO 2CH 2- | 1.42(d，6H)，2.79(s，3H)，3.11(s，3H)，3.22- 3.30(m，4H)，3.78-3.88(m，4H)，4.54(s，2H)， 4.80(quintet，1H)，7.23-7.27(m，2H)，7.59(d， 2H)，7.98(s，1H)，8.74(s，1H)，10.02(brs，1H) | 532 |
Embodiment 65-86
Press embodiment 38 methods, with suitable acid and 2-[4-(piperazine-1-yl) anilino]-the following compound of 4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine (embodiment 20) preparation.
| Ex | R | H NMR(300MHz) | m/z |
| 65 | (R)-HOCH(Me) | (CDCl 3)8.31(d，1H)，7.46(d，2H)，7.38(s，1H)， 6.92(d，2H)，6.86(d，2H)，5.66-5.56(m，1H)， 4.51(q，1H)，3.96-3.72(m，2H)，3.64-3.54 (m，2H)，3.21-3.10(m，4H)，2.72(brs，1H)， 2.62(s，3H)，1.48(d，6H)，1.37(d，3H) | 450 |
| 66 | Cyclopropyl | 9.19(s，1H)，8.31(d，1H)，7.47(d，2H)，7.39(s， 1H)，6.97(s，1H)，6.94(d，2H)，5.74-5.65(m， 1H)，3.88-3.71(m，2H)，3.69-3.54(m，2H)， 3.17-2.94(m，4H)，2.42(s，3H)，2.06-1.95(m， 1H)，1.40(d，6H)，0.79-0.67(m，4H) | 447 |
| 67 | MeOCH 2- | 9.18(s，1H)，8.33(d，1H)，7.49(s，1H)，7.47(d， 2H)，6.96(d，1H)，6.92(d，2H)，5.72-5.63(m， 1H)，4.13(s，2H)，3.62-3.49(m，4H)，3.29(s， 3H)，3.11-3.00(m，4H)，2.48(s，3H)，1.40(d， 6H) | 450 |
| 68 | (S)-MeOCH(Me)- | 9.22(s，1H)，8.32(d，1H)，7.47(d，2H)，7.43(s， 1H)，6.93(d，2H)，6.95(s，1H)，5.73-5.64(m， 1H)，4.24(q，1H)，3.65(d，4H)，3.24(s，3H)， 3.10(brs，4H)，2.47(s，3H)，1.40(d，6H)，1.23 (d，3H) | 464 |
| Ex | R | H NMR(300MHz) | m/z |
| 69 | (S)-HOCH(Me)- | 9.18(s，1H)，8.30(s，1H)，7.47(d，2H)，7.40(s， 1H)，6.95(d，2H)，6.92(d，1H)，5.74-5.64(m， 1H)，4.92(d，1H)，4.50-4.41(m，1H)，3.72- 3.50(m，4H)，3.13-2.97(m，4H)，2.47(s，3H)， 1.40(d，6H)，1.20(d，3H) | 450 |
| 70 | (R)-MeOCH(Me)- | 9.20(s，1H)，8.31(d，1H)，7.47(d，2H)，7.41(s， 1H)，6.93(d，2H)，6.95(s，1H)，5.74-5.64(m， 1H)，4.24(q，1H)，3.65(d，4H)，3.23(s，3H)， 2.47(s，3H)，1.40(d，6H)，1.23(d，3H) | 464 |
| 71 | i-Pr- | 9.21(s，1H)，8.31(d，1H)，7.47(d，2H)，7.40(s， 1H)，6.94(d，1H)，6.92(d，2H)，5.74-5.64(m， 1H)，3.67(brs，4H)，3.04(d，4H)，2.94-2.86 (m，1H)，2.47(s，3H)，1.40(d，6H)，1.01(d，6H) | 448 |
| 72 | MeC(Me)(OH)CH 2- | 9.19(s，1H)，8.30(d，1H)，7.47(d，2H)，7.38(d， 1H)，6.94(d，1H)，6.92(d，2H)，5.74-5.64(m， 1H)，4.80(s，2H)，3.68-3.59(m，4H)，3.29(s， 1H)，3.10-2.98(m，4H)，2.47(s，3H)，1.39(d， 6H)，1.20(s，6H) | 478 |
| 73 | 2-(R)-tetrahydrofuran (THF)-2-base- | 9.20(s，1H)，8.31(d，1H)，7.47(d，2H)，7.42(s， 1H)，6.94(d，1H)，6.92(d，2H)，5.73-5.64(m， 1H)，4.69(t，1H)，3.81-3.70(m，2H)，3.69- 3.55(m，4H)，3.10-2.98(m，4H)，2.48(s，3H)， 2.10-1.93(m，2H)，1.90-1.76(m，2H)，1.40 (d，6H) | 476 |
| 74 | 2-(S)-tetrahydrofuran (THF)-2-base- | 9.20(s，1H)，8.32(d，1H)，7.47(d，2H)，7.42(s， 1H)，6.94(d，1H)，6.92(d，2H)，5.73-5.64(m， 1H)，4.69(t，1H)，3.82-3.70(m，2H)，3.69- 3.55(m，4H)，3.10-2.99(m，4H)，2.48(s，3H)， 2.09-1.98(m，2H)，1.90-1.77(m，2H)，1.40 (d，6H) | 476 |
| Ex | R | H NMR(300MHz) | m/z |
| 75 1 | 1-hydroxyl ring third-1-base | 9.95(s，1H)，8.62(d，1H)，8.22(s，1H)，7.76- 7.57(m，4H)，7.18(d，1H)，5.64-5.55(m，1H)， 4.24-3.87(m，4H)，3.51(s，4H)，2.82(s，3H)， 1.50(d，7H)，1.04-0.97(m，2H)，0.83-0.77 (m，2H) | 462 |
| 76 1 | (S)-MeCH 2CH(OH)- | 9.83(s，1H)，8.60(d，1H)，8.20(s，1H)，7.65(d， 2H)，7.50(s，2H)，7.15(d，1H)，5.64-5.54(m， 2H)，4.97(s，1H)，4.25(q，1H)，3.99-3.70(m， 4H)，3.42-3.25(m，4H)，2.81(s，3H)，1.72- 1.58(m，2H)，1.49(d，6H)，0.89(t，3H) | 464 |
| 77 1 | (R)-MeCH 2CH(OH)- | 9.90(s，1H)，8.61(d，1H)，8.21(s，1H)，7.68(d， 2H)，7.50(d，2H)，7.16(d，1H)，5.64-5.55(m， 1H)，4.25(q，1H)，4.02-3.73(m，4H)，3.45- 3.30(m，4H)，2.80(s，3H)，1.72-1.57(m，2H)， 1.49(d，6H)，0.89(t，3H) | 464 |
| 78 1 | 1-cyano group ring third-1-base | 9.74(s，1H)，8.58(d，1H)，8.20(s，1H)，7.58(d， 2H)，7.26(d，2H)，7.12(d，1H)，5.64-5.55(m， 1H)，4.97(brs，1H)，4.00-3.76(m，4H)，3.36- 3.25(m，4H)，2.80(s，3H)，1.65-1.53(m，4H)， 1.48(d，6H) | 471 |
| 79 1 | (R)-MeCH(Me)CH(OH)- | 9.98(s，1H)，8.62(d，1H)，8.23(s，1H)，7.71(d， 2H)，7.58(d，2H)，7.18(d，1H)，5.64-5.55(m， 1H)，5.38(s，2H)，4.07(d，1H)，4.04-3.78(m， 4H)，3.48-3.35(m，4H)，2.82(s，3H)，1.94- 1.82(m，1H)，1.50(d，6H)，0.87(dd，6H) | 478 |
| 80 1 | (S)-MeCH(Me)CH(OH)- | 9.87(s，1H)，8.60(d，1H)，8.21(s，1H)，7.64(d， 2H)，7.47-7.34(m，2H)，7.15(d，1H)，5.64- 5.54(m，1H)，4.20(brs，2H)，4.08(d，1H)，3.98 -3.70(m，4H)，3.38-3.25(m，4H)，2.81(s， 3H)，1.93-1.82(m，1H)，1.49(d，6H)，0.88(d， 3H)，0.85(d，3H) | 478 |
| Ex | R | H NMR(300MHz) | m/z |
| 81 1 | MeOCH 2CH 2- | 10.04(s，1H)，8.62(d，1H)，8.24(s，1H)，7.20 (d，1H)，5.66-5.56(m，1H)，4.80(brs，1H)， 4.02(s，4H)，3.58(t，2H)，3.52(s，4H)，3.26(s， 3H)，2.84(s，3H)，2.65(t，2H)，1.50(d，6H) | 464 |
| 82 1 | HOCH 2C(Me) 2- | 9.98(s，1H)，8.62(d，1H)，8.22(s，1H)，7.79- 7.60(m，4H)，7.19(d，1H)，5.64-5.55(m，2H)， 5.22(s，1H)，4.08-3.90(m，4H)，3.48(s，2H)， 3.46-3.38(m，4H)，2.82(s，3H)，1.50(d，6H)， 1.20(s，6H) | 478 |
| 83 1 | F 2CH- | 9.73(s，1H)，8.57(d，1H)，8.20(s，1H)，7.57(d， 2H)，7.22(d，2H)，7.12(d，1H)，6.79(t，1H)， 5.64-5.55(m，1H)，4.69(s，1H)，3.83-3.71(m， 4H)，3.34-3.21(m，4H)，2.80(s，3H)，1.47(d， 6H) | 456 |
| 84 1 | HC≡CCH 2OCH 2- | 9.89(s，1H)，8.60(d，1H)，8.23(s，1H)，7.67(d， 2H)，7.55-7.41(m，2H)，7.16(d，1H)，5.64- 5.55(m，1H)，4.60(s，1H)，4.29(s，2H)，4.24(d， 2H)，3.49(t，1H)，2.81(s，3H)，1.50(s，6H) | 474 |
| 85 1 | HOC(Me) 2- | 9.24(brs，1H)，8.55(d，1H)，7.54(d，2H)，7.19- 7.13(m，2H)，7.09(d，1H)，5.63-5.54(m，1H)， 4.84(brs，1H)，3.97(s，4H)，3.24(s，4H)，2.81 (s，3H)，1.52(d，6H)，1.41(s，6H) | 464 |
| 86 1 | Et- | 9.89(s，1H)，8.61(d，1H)，8.21(s，1H)，7.68(d， 2H)，7.57(s，2H)，7.16(d，1H)，5.64-5.54(m， 1H)，4.86(s，1H)，3.90(s，4H)，3.44-3.30(m， 4H)，2.81(s，3H)，2.39(q，2H)，1.49(d，6H)， 1.01(t，3H) | 471 |
1Isolating free alkali is dissolved in EtOAc (3ml), adds several MeOH hydrotropies.Add the diethyl ether solution (1 equivalent) of 1.0M hydrogenchloride, the hydrochloride that obtains is ground with ether, filter vacuum-drying then.
Embodiment 87
2-{4-[4-(ethanoyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-
The 5-yl)-5-fluorine pyrimidine
With (2Z)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 14; 6.0g, 25mmol) and N-[4-(4-ethanoyl piperazine-1-yl) phenyl] guanidine supercarbonate (method 2; 12.12g, 2-methyl cellosolve 37.5mmol) (90mol) vlil 18 hours.With the reaction mixture reduction vaporization, on silica gel, separate title compound by MPLC (3%MeOH/DCM).Evaporation obtains crisp foam.Yield=8.9g (81%).
NMR：1.36(d，6H)，2.03(s，3H)，[2.5(s，3H)under DMSO signal]，2.98(m，2H)，3.08(m，2H)，3.57(m，4H)，5.44(septuplet，1H)，6.90(d，2H)，7.34(d，1H)，7.42(d，2H)，8.44(d，1H)，9.24(s，1H)；m/z 438.
Embodiment 88
2-[4-(piperazine-1-yl) anilino]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-5-fluorine
The pyrimidine hydrochloride
Press embodiment 20) method, by 2-{4-[4-(ethanoyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-5-fluorine pyrimidine (embodiment 87) preparation title compound.Title compound is crystallization from reaction mixture, for HCl salt, leaches, with Virahol and ether washing.Yield=8.01g (98%).
NMR：1.46(d，6H)，2.78(s，3H)，3.21(brs，4H)，3.32(m，4H)，5.24(septuplet，1H)，6.96(d，2H)，7.47(d，1H)，8.05(d，2H)，8.70(d，1H)，9.42(brs，1H)，9.65(s，1H)；m/z 396.
Embodiment 89-102
Press embodiment 38 methods, with suitable acid and 2-[4-(piperazine-1-yl) anilino]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-following compound of 5-fluorine pyrimidine hydrochloride (embodiment 88) preparation.
For embodiment 89-96, isolating free alkali is dissolved in EtOAc (3ml), add several MeOH hydrotropies.Add the diethyl ether solution (1 equivalent) of 1.0M hydrogenchloride, the hydrochloride that obtains is ground with ether, filter vacuum-drying then.
| Ex | R | NMR(CDCl 3) | m/z |
| 89 | Et- | 1.01(t，3H)1.46(d，6H)，2.38(q，2H)，2.80(s，3H)， 3.23-3.33(m，4H)，3.73-3.81(m，4H)，5.25(quintet， 1H)，7.32-7.40(m，2H)，7.61(d，2H)，8.07(d，1H)，8.75 (d，1H).9.85(brs，1H). | 452 |
| 90 | HOCH 2CH 2- | 1.46(d，6H)，2.53(t，2H)，2.78(s，3H)，3.10-3.17(m， 4H)，3.62-3.68(m，4H)，3.70(t，2H)，5.28(quintet，1H)， 6.97(d，2H)，7.44(d，2H)，7.90(d，1H)，8.60(d，1H). 9.18(brs，1H). | 468 |
| 91 | MeOCH 2CH 2- | 1.45(d，6H)，2.62(t，2H)，2.79(s，3H)，3.14-3.22(m， 4H)，3.23(s，3H)，3.57(t，2H)，33.69-3.77(m，4H)，5.25 (quintet，1H)，7.18-2.26(m，2H)，7.55(d，2H)，8.06(d， 1H)，8.73(d，1H)，9.76(brs，1H). | 482 |
| 92 | MeOCH 2- | 1.47(d，6H)，2.80(s，3H)，3.30(s，3H)，3.31-3.38(m， 4H)，3.73-3.82(m，4H)，4.15(s，2H)，5.24(quintet，1H)， 7.40-7.47(m，2H)，7.63(d，2H)，8.08(d，1H)，8.76(d， 1H)，9.90(brs，1H). | 468 |
| 93 | i-Pr- | 1.01(d，6H)，1.45(d，6H)，2.75(s，3H)，2.90(quintet， 1H)，3.10-3.18(m，4H)，3.66-3.74(m，4H)，5.25 (quintet，1H)，7.08-7.16(m，2H)，7.51(d，2H)，g.06(d， 1H)，8.72(d，1H)，9.69(brs，1H). | 466 |
| 94 | (R)-MeCH(OH)- | 1.10(d，3H)，1.45(d，6H)，2.79(s，3H)，3.20-3.33(m， 4H)，3.75-3.87(m，4H)，4.47(q，1H)，5.25(quintet，1H)， 7.27-7.33(m，2H)，7.57(d，2H)，8.07(d，1H)，8.73(d， 1H)，9.81(brs，1H). | 468 |
| Ex | R | NMR(CDCl 3) | m/z |
| 95 | MeC(Me)(OH)- | 1.34(s，36H)，1.47(d，6H)，2.80(s，3H)，3.34-3.41(m， 4H)，3.80-4.00(m，4H)，5.24(quintet，1H)，7.47-7.55 (m，2H)，7.65(d，2H)，8.08(d，1H)，8.77(d，1H)，9.92 (brs，1H). | 482 |
| 96 | (S)-MeCH(OH)- | 1.21(d，3H)，1.48(d，6H)，2.78(s，3H)，3.15(b s，4H)， 3.74(b s，4H)，4.46(q，1H)，5.27(septuplet，1H)，7.90 (b s，2H)，7.50(b d，2H)，8.09(d，1H)，8.72(d，1H)，9.57 (b s，1H) | 468 |
| Ex | R 1 | R 2 | Configuration | NMR(CDCl 3) | 19FNMR | m/z |
| 97 | Et | H | R | 1.02(t，3H)，1.47(d，6H)，1.55(m，1H)， 1.75(m，1H)，2.59(s，3H)，3.15(m，4H)， 3.58(brs，2H)，3.69(d，1H)，3.80(m，1H)， 3.88(m，1H)，4.36(m，1H)，5.54(septuplet， 1H)，6.80(s，1H)，6.92(d，2H)，7.40(d， 2H)，7.57(d，1H)，8.23(d，1H) | -147.82 | 482 |
| 98 | Me | Me | R | 1.42(d，3H)，1.47(d，6H)，2.59(s，3H)， 3.15(m，4H)，3.38(s，3H)，3.80(m，4H)， 4.20(q，1H)，5.54(septuplet，1H)，6.80(s， 1H)，6.92(d，2H)，7.40(d，2H)，7.57(d， 1H)，8.23(d，1H) | -147.93 | 482 |
| Ex | R 1 | R 2 | Configuration | NMR(CDCl 3) | 19FNMR | m/z |
| 99 1 | i-Pr | H | R | 0.83(d，3H)，1.10(d，3H)，1.47(d，6H)， 1.55(m，1H)，1.87(septuplet，1H)，2.59(s， 3H)，3.13(m，4H)，3.58(m，3H)，3.69(d， 1H)，3.80(m，1H)，3.88(m，1H)，4.28(dd， 1H)，5.54(septuplet，1H)，6.80(s，1H)，6.91 (d，2H)，7.40(d，2H)，7.57(d，1H)，8.23(d， 1H) | -147.82 | 496 |
| 100 | Et | H | S | 1.02(t，3H)，1.47(d，6H)，1.55(m，1H)， 1.75(m，1H)，2.59(s，3H)，3.15(m，4H)， 3.58(brs，2H)，3.69(d，1H)，3.80(m，1H)， 3.88(m，1H)，4.36(m，1H)，5.54(septuplet， 1H)，6.80(s，1H)，6.92(d，2H)，7.40(d， 2H)，7.57(d，1H)，8.23(d，1H) | -147.82 | 482 |
| 101 | Me | Me | S | 1.42(d，3H)，1.47(d，6H)，2.59(s，3H)， 3.15(m，4H)，3.38(s，3H)，3.80(m，4H)， 4.20(q，1H)，5.54(septuplet，1H)，6.80(s， 1H)，6.92(d，2H)，7.40(d，2H)，7.57(d， 1H)，8.23(d，1H) | -147.93 | 482 |
| 102 2 | i-Pr | H | S | 0.83(d，3H)，1.10(d，3H)，1.47(d，6H)， 1.55(m，1H)，1.87(septuplet，1H)，2.59(s， 3H)，3.13(m，4H)，3.58(m，3H)，3.69(d， 1H)，3.80(m，1H)，3.88(m，1H)，4.28(dd， 1H)，5.54(septuplet，1H)，6.80(s，1H)，6.91 (d，2H)，7.40(d，2H)，7.57(d，1H)，8.23(d， 1H) | -147.82 | 496 |
1Use 5% MeOH.NH
3(7N)/DCM: EtOAc (1: 1) solution chromatography
2Need further use the compound of 5% MeOH/EtOAc elution chromatography
Embodiment 103
2-{4-[4-(2-acetoxyl group ethanoyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-first
Base-1H-imidazoles-5-yl)-5-fluorine pyrimidine
With embodiment 21 methods, with 2-[4-(piperazine-1-yl) anilino]-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-(embodiment 88 for 5-fluorine pyrimidine hydrochloride for 4-; 200mg 0.5mmol) preparation title compound.After the aftertreatment, mixture is used MeOH: DCM on silica gel (3: 97-6: 94) chromatography purification obtains solid 170mg.M/z 496。
Embodiment 104
2-{4-[4-(2-hydroxyacetyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-methyl-
1H-imidazoles-5-yl)-5-fluorine pyrimidine hydrochloride
Press embodiment 22 methods, make 2-{4-[4-(2-acetoxyl group ethanoyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-5-fluorine pyrimidine (embodiment 103) deprotection.With the reaction mixture reduction vaporization.Residue is dissolved in DCM (15ml), water (10ml) and salt solution (10ml) washing, drying, evaporation.Residue is ground with ether, and revaporization obtains title compound, is solid 134mg.This compound is converted into hydrochloride by adding 1M ether/HCl in EtOH.After the evaporation, grind, obtain solid with ether.
NMR：1.46(d，6H)，2.78(s，3H)，3.14(b s，4H)，3.58(b s，2H)，3.68(b s，2H)，4.13(s，2H)，5.26(septuplet，1H)，7.10(b s，2H)，7.50(d，2H)，8.08(d，1H)，8.72(d，1H)，9.68(b s，1H)；m/z 454.
Embodiment 105
2-{4-[4-(ethanoyl) piperazine-1-yl] anilino }-4-(1-cyclobutyl-2-methyl isophthalic acid H-imidazoles-
The 5-yl)-5-fluorine pyrimidine
Press embodiment 18 methods, by (2Z)-1-(1-cyclobutyl-2-methyl isophthalic acid H-imidazoles-5-yl)-3-(dimethylamino)-2-fluorine third-2-alkene-1-ketone (method 16; 1.406g) and N-[4-(4-ethanoyl piperazine-1-yl) phenyl] (method 2,2.71g) the preparation title compound obtains white solid (2.21g, 88%) to the guanidine supercarbonate.
NMR：1.61-1.72(m，2H)，2.06(s，3H)，2.30-2.43(m，4H)，2.75(s，3H)，3.27-3.39(m，4H)，3.77-3.85(m，4H)，5.22(quintet，1H)，7.42-7.48(m，2H)，7.69(d，2H)，8.09(d，1H)，8.74(d，1H)，9.97(brs，1H)；m/z 450.
Embodiment 106
2-[4-(piperazine-1-yl) anilino]-4-(1-cyclobutyl-2-methyl isophthalic acid H-imidazoles-5-yl)-5-fluorine
Pyrimidine
Press embodiment 20 methods, by 2-{4-[4-(ethanoyl) piperazine-1-yl] anilino }-(1-cyclobutyl-2-methyl isophthalic acid H-imidazoles-5-yl)-(embodiment 105 for 5-fluorine pyrimidine for 4-; 1.89g) the preparation title compound, obtain yellow solid (1.538g, 90%).
NMR(CDCl
3)：1.61-1.78(m，2H)，2.35-2.45(m，4H)，2.59(s，3H)，3.03-3.09(m，4H)，3.10-3.15(m，4H)，5.33(quintet，1H)，6.93(s，1H)，6.95(d，2H)，7.42(d，2H)，7.49(d，1H)，8.22(d，1H)；m/z 408.
Embodiment 107-110
Press embodiment 38 methods, with suitable acid and 2-[4-(piperazine-1-yl) anilino]-4-(1-cyclobutyl-2-methyl isophthalic acid H-imidazoles-5-yl)-following compound of 5-fluorine pyrimidine (embodiment 106) preparation.Isolating free alkali is dissolved in EtOAc (3ml), adds several MeOH hydrotropies.Add the diethyl ether solution (1 equivalent) of 1.0M hydrogenchloride, the hydrochloride that obtains is ground with ether, filter vacuum-drying then.
| Ex | R | NMR(300MHz，CDCl 3) | m/z |
| 107 | HOCH 2- | 1.61-1.72(m，2H)，2.31-2.44(m，4H)，2.75(s，3H)，3.28- 3.36(m，4H)，3.70-3.85(m，4H)，4.15(s，2H)，5.22 (quintet，1H)，7.42(m，2H，7.68(d，2H)，8.09(s，1H)， 8.74(1H，s)，9.95(brs，1H). | 466 |
| 108 | (S)-MeCH(OH)- | 1.22(d，3H)，1.63-1.72(m，2H)，2.30-2.43(m，4H)，2.75 (s，3H)，3.30-3.38(m，4H)，3.80-3.96(m，4H)，4.46(q， 1H)，5.22(quintet，1H)，7.39-7.47(m，2H)，7.68(d，2H)， 8.08(d，1H)，8.74(d，1H)，9.95(brs，1H). | 480 |
| 109 | (R)-MeCH(OH)- | 1.22(d，3H)，1.63-1.72(m，2H)，2.30-2.43(m，4H)，2.75 (s，3H)，3.30-3.38(m，4H)，3.80-3.96(m，4H)，4.46(q， 1H)，5.22(quintet，1H)，7.39-7.47(m，2H)，7.68(d，2H)， 8.08(d，1H)，8.74(d，1H)，9.95(brs，1H). | 480 |
| 110 | MeOCH 2- | 1.62-1.72(m，2H)，2.30-2.44(m，4H)，2.75(s，3H)，3.31 (s，3H)，3.32-3.39(m，4H)，3.75-3.85(m，4H)，4.16(s， 2H)，5.22(quintet，1H)，7.43-7.50(m，2H)，7.70(d，2H)， 8.09(d，1H)，8.75(d，1H)，9.99(brs，1H). | 480 |
Embodiment 111
2-[4-(morpholino) anilino]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine
Under 200 ℃, in microwave, with (2E)-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (WO 03/076436 method 24); (110mg0.5mmol) and N-[4-(morpholino) phenyl] guanidine supercarbonate (method 4; 170mg 0.6mmol) N,N-DIMETHYLACETAMIDE (4ml) solution heating 20 minutes.With the reaction mixture reduction vaporization, make residue on silica gel, use MeOH: DCM (4: 96-8: 92) chromatography purification, obtain title compound, after grinding with ether, be solid 90mg 50%.
NMR1.42(d，6H)，2.48(s，3H)，3.06(t，4H)3.75(t，4H)，5.71(septuplet，1H)，6.91(d，2H)，6.97(d，1H)，7.40(s，1H)，7.48(d，2H)，8.32(s，1H)，9.18(s，1H)；m/z 379.
Embodiment 112
2-[4-(morpholino) anilino]-4-(1-ethyl-2-methyl isophthalic acid H-imidazoles-5-yl)-5-fluorine pyrimidine
Hydrochloride
Under 200 ℃, in microwave, with (2E)-3-(dimethylamino)-1-(1-ethyl-2-methyl isophthalic acid H-imidazoles-5-yl)-2-fluoro-third-2-alkene-1-ketone (method 15; 250mg 1.11mmol) and N-[4-(morpholino) phenyl] guanidine supercarbonate (method 4; 405mg 1.44mmol) 2-methyl cellosolve (4.5ml) solution heating 30 minutes.With the reaction mixture reduction vaporization, residue is upward used MeOH: DCM: EtOAc (1: 79.5: 19.5) chromatography purification at neutral alumina (II level activity), obtain title compound, after grinding with ether, be solid 230mg 54%.This compound is converted into hydrochloride with 1M ether/HCl in MeOH.Grind with ether, evaporation obtains title compound, is solid.
NMR 1.19(t，3H)，2.70(s，3H)，3.12(b s，4H)，3.60(b s，exchangeables)，3.79(t，4H)，4.59(q，2H)，7.05(b s，2H)，7.44(d，2H)，8.20(d，1H)，8.68(d，1H)，9.54(s，1H)；m/z 383.
Embodiment 113
2-[4-(morpholino) anilino]-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-the 5-fluorine is phonetic for 4-
Pyridine
In microwave, under 160 ℃, with (2E)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 14; 240mg 1.0mmol) and N-[4-(morpholino) phenyl] guanidine supercarbonate (method 4; 367mg 1.3mmol) 2-methyl cellosolve (4.5ml) solution heating 40 minutes was heated 20 minutes down at 180 ℃ then.With the reaction mixture reduction vaporization, residue is used MeOH: DCM: EtOAc (4: 48: 48-10: 45: 45) chromatography purification on silica gel, obtain title compound, be solid 180mg 45%.With 1M ether/HCl this compound is converted into hydrochloride in MeOH.Grind with ether, evaporation obtains title compound, is solid.
NMR(373K)：1.48(d，6H)，2.77(s，3H)，3.09(t，4H)，3.7g(t，4H)，5.30(septuplet，1H)，6.94(d，2H)，7.43(d，2H)，7.88(d，1H)，8.602(d，1H)；m/z 397.
Embodiment 114
2-[4-(morpholino) anilino]-4-(1-cyclobutyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine
Press embodiment 111 methods, by (2E)-1-(1-cyclobutyl-2-methyl isophthalic acid H-imidazoles-5-yl)-3-(dimethylamino) third-2-alkene-1-ketone (WO 03/076435 method 37; 233mg) and N-(4-morpholine-4-base phenyl) guanidine (method 4,405mg) the preparation title compound obtains white solid (228mg, 61%).
NMR：1.59-1.72(m，2H)，2.32-2.44(m，4H)，2.75(s，3H)，3.21-3.28(m，4H)，3.84-3.92(m，4H)，5.40(quintet，1H)，7.09(d，1H)，7.24-7.32(m，2H)，7.66(d，2H)，8.11(s，1H)，8.57(d，1H)，9.77(brs，1H)；m/z 391.
Embodiment 115
2-[4-(morpholino) anilino]-(1-cyclobutyl-2-methyl isophthalic acid H-imidazoles-5-yl)-the 5-fluorine is phonetic for 4-
Pyridine
Press embodiment 111 methods, by (2Z)-1-(1-cyclobutyl-2-methyl isophthalic acid H-imidazoles-5-yl)-3-(dimethylamino)-2-fluorine third-2-alkene-1-ketone (method 16; 234mg) and N-(4-morpholine-4-base phenyl) guanidine (method 4; 410mg) the preparation title compound obtains white solid (288mg, 76%).
NMR：1.61-1.72(m，2H)，2.29-2.45(m，4H)，2.75(s，3H)，3.26-3.34(m，4H)，3.90-3.97(m，4H)，5.22(quintet，1H)，7.38-7.45(m，2H)，7.68(d，2H)，8.08(d，1H)，8.73(d，1H)，9.95(brs，1H)；m/z 409.
Embodiment 116
2-{4-[4-(ethanoyl) piperazine-1-yl]-the 3-toluidine }-4-(1-sec.-propyl-2-methyl-
1H-imidazoles-5-yl)-5-fluorine pyrimidine
With (2Z)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 14; 1.53g; 6.4mmol) and N-[4-(4-ethanoyl piperazine-1-yl)-3-aminomethyl phenyl] guanidine supercarbonate (method 31; 3.23g, 2-methyl cellosolve 9.60mmol) (10ml) vlil 24 hours.With the reaction mixture reduction vaporization, make residue on silica gel, use MeOH: DCM: EtOAc (1: 49.5: 49.5-10: 45: 45) chromatography purification, obtain solid, this solid need be used MeOH: DCM (1: 99-10: 90) be further purified.After grinding with ether,, obtain title compound, be crisp foam solvent evaporation, with it in vacuum drying oven, at 50 ℃ of following dried overnight (1.91g, 66%).
NMR(400MHz)1.40(d，6H)，2.05(s，3H)，2.26(s，3H)，2.55(s，3H，underDMSO signal)，2.77(dt，4H)，3.58(m，4H)，5.41(septet，1H)，6.98(d，1H)，7.34(d，1H)，7.35(d，1H)，7.42(dd，1H)，8.49(d，1H)，9.28(s，1H)；
19F NMR(400MHz)-149.40(t，1F)；m/z452.
Embodiment 117-118
With embodiment 116 methods, by (2Z)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 14) and the suitable following compound of guanidine preparation.
| Ex 117 1 | R Cl | NMR(400MHz) 1.43(d，6H)，2.05(s，3H)，2.51(s，3H，under DMSO signal)， | m/z 472- | SM method 32 |
| 1 | 2.89(dt，4H)，3.59(m，4H)，5.37(septet，1H)，7.12(d，1H)， 7.36(d，1H)，7.53(dd，1H)，7.77(d，1H)，8.55(d，1H)，9.54 (s，1H)； 19F NMR(400MHz)-148.33(t，1F) | 474 | ||
| 118 2 | F | 1.44(d，6H)，2.04(s，3H)，2.57(s，3H，under DMSO signal)， 2.92(dt，4H)，3.58(m，4H)，5.42(septet，1H)，7.00(t，1H)， 7.30(dd，1H)，7.36(d，1H)，7.58(dd，1H)，8.55(d，1H)，9.55 (s，1H)； 19F NMR(400MHz)-148.47(t，1F) | 456 | Method 33 |
1Use MeOH: DCM: EtOAc (1: 49.5: 49.5-10: 45: 45) chromatography.(469.8mg，69％)。
2Use MeOH: DCM: EtOAc (1: 49.5: 49.5-10: 45: 45) chromatography.(2.72g，72％)。
Embodiment 119
2-{4-[4-(ethanoyl) piperazine-1-yl]-the 3-toluidine }-4-(1-sec.-propyl-2-methyl-
1H-imidazoles-5-yl) pyrimidine
Press embodiment 116 methods, by (2E)-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (WO 03/076436 method 24; 331.8g, 1.5mmol) and N-[4-(4-ethanoyl piperazine-1-yl)-3-aminomethyl phenyl] guanidine supercarbonate (method 31; 758.3mg, 2.25mmol) preparation title compound.With the reaction mixture reduction vaporization, residue is used MeOH: DCM: EtOAc (1: 49.5: 49.5-10: 45: 45) chromatography purification on silica gel, obtain solid (419.4mg, 65%).
NMR：1.41(d，6H)，2.05(s，3H)，2.27(s，3H)，2.48(s，3H)，2.77(dt，4H)，3.58(m，4H)，5.66(septet，1H)，6.97(d，1H)，6.99(d，1H)，7.37(d，1H)，7.41(s，1H)，7.47(dd，1H)，8.35(d，1H)，9.20(s，1H)；m/z434.
Embodiment 120-121
With embodiment 119 methods, by (2E)-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (WO 03/076436 method 24) and the suitable following compound of guanidine preparation.
| Ex | R | NMR(400MHz) | m/z | SM |
| 120 1 | Cl | 1.45(d，6H)，2.05(s，3H)，2.50(s，3H+DMSO)，2.90(dt，4H)， 3.59(m，4H)，5.62(septet，1H)，7.05(d，1H)，7.12(d，1H)，7.43 (s，1H)，7.57(dd，1H)，7.81(d，1H)，8.40(d，1H)，9.45(s，1H) | 454- 456 | Method 32 |
| 121 2 | F | 1.45(d，6H)，2.04(s，3H)，2.57(s，3H+DMSO)，2.93(dt，4H)， 3.59(m，4H)，5.68(septet，1H)，7.00(t，2H)，7.05(d，2H)，7.33 (dd，1H)，7.42(s，1H)，7.64(dd，1H)，8.39(d，1H)，9.46(s，1H) | 438 | Method 33 |
1This compound need prepare in alkalescence uses acetonitrile on the HPLC: 1% NH
3/ H
2O (25: 75-70: 30) further chromatography.(475mg，52％)。
2 (413.5mg，63％)。
Embodiment 122
2-[4-(piperazine-1-yl)-3-toluidine]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-
Base)-5-fluorine pyrimidine
Under 90 ℃, with 2-{4-[4-(ethanoyl) piperazine-1-yl]-the 3-toluidine }-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-(embodiment 116 for 5-fluorine pyrimidine for 4-; 1.89g, 4.19mmol) at Virahol (20ml), H
2The middle stirring of O (5ml) and 33% hydrochloric acid (4ml) was also heated 10 hours.With solvent removed under reduced pressure, obtain residue, it is distributed, with the saturated sodium bicarbonate alkalization, with water layer DCM extracting twice between water and DCM.Organic liquor is merged, use the salt water washing, drying with solvent evaporation, obtains title compound, is crisp foam, with it under 50 ℃, at vacuum drying oven dried overnight (1.53g, 89%).
NMR(400MHz)1.39(d，6H)，2.23(s，3H)，2.51(s，3H，under DMSO signal)，2.72(m，4H)，2.85(m，4H)，3.29(s，1H under H
2O signal)，5.42(septet，1H)，6.95(d，1H)，7.30(d，1H)，7.35(d，1H)，7.40(dd，1H)，8.48(d，1H)，9.24(s，1H)；
19FNMR(400MHz)-149.59(t，1F)；m/z 410.
Embodiment 123
2-[4-(piperazine-1-yl)-3-fluoroanilino]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-
5-fluorine pyrimidine
Press embodiment 122 methods, by 2-{4-[4-(ethanoyl) piperazine-1-yl]-the 3-fluoroanilino }-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-(embodiment 118, and 455mg 1mmol) prepares this compound for 5-fluorine pyrimidine.Obtain title compound, be crisp foam, with it in vacuum drying oven, at 50 ℃ of following dried overnight (337.8mg, 82%).
NMR(400MHz)1.41(d，6H)，2.23(s，3H)，2.50(s，3H，under DMSO signal)，2.90(s，8H)，3.29(s，1H under H
2O signal)，5.43(septet，1H)，6.96(t，1H)，7.29(dd，1H)，7.36(d，1H)，7.53(dd，1H)，8.53(d，1H)，9.50(s，1H)；
19F NMR(400MHz)-148.60(t，1F)；m/z 414.
Embodiment 124
2-{4-[4-((2S)-2-hydroxyl propionyl) piperazine-1-yl]-the 3-toluidine }-(1-different third for 4-
Base-2-methyl isophthalic acid H-imidazoles-5-yl)-5-fluorine pyrimidine
With 2-[4-(piperazine-1-yl)-3-toluidine]-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-(embodiment 122 for 5-fluorine pyrimidine for 4-; 490.8mg, 1.20mmol), L-lactic acid (129.7mg, 1.44mmol), HOBt.H
2O (220.5mg, 1.44mmol) and DIPEA (0.24ml, DMF 1.44mmol) (5ml) solution is cooled to 0 ℃, add then in batches EDAC (230.05mg, 1.44mmol).Then mixture was stirred 3.5 hours at ambient temperature.With solution for vacuum concentration, residue is distributed between DCM and water+saturated sodium bicarbonate.With organic extract liquid water (3 times), salt water washing, drying concentrates.In the MeOH of crude product (5ml) solution, add 1 KOH particle, mixture is stirred 20min at ambient temperature.Obtain after will evaporating residue on silica gel, use MeOH: DCM (1: 99-5: 95) chromatography purification, obtain title compound, after grinding with ether, be solid, with it in vacuum drying oven, at 50 ℃ of following dried overnight (415mg, 72%).
NMR：(500MHz at 373K)1.27(d，3H)，1.40(d，6H)，2.28(s，3H)，2.48(s，3H，under DMSO signal)，2.82(m，4H)，3.65(m，4H)，4.47(m，2H)，5.38(septet，1H)，7.00(d，1H)，7.35(m，2H)，7.40(dd，1H)，8.40(d，1H)，8.80(s，1H)；
19F NMR(400MHz)-149.33(t，1F)；m/z 482.
Embodiment 125-128
Press embodiment 124 methods, with suitable acid and the following compound of pyrimidine preparation.
| Ex | R | R1 | At the NMR of 373K (500MHz) | m/z | SM |
| 125 1 | Me | CH 2OH | 1.40(d，6H)，2.27(s，3H)，2.50(s，3H，under DMSO signal)，2.80(m，4H)，3.57(m，4H)， 4.13(d，2H)，4.20(t，1H)，5.37(septet，1H)， 6.98(d，1H)，7.31(m，2H)，7.38(dd，1H)， 8.40(d，1H)，8.80(s，1H)； 19F NMR (400MHz)-149.31(t，1F) | 468 | Embodiment 122 |
| 126 2 | F | CH 2OH | 1.44(d，6H)，2.59(s，3H under DMSO signal)，2.94(brs，4H)，3.57(brd，4H)，4.13 (brd，2H)，4.59(br t，1H)，5.43(septet，1H)， 7.00(t，1H)，7.30(dd，1H)，7.36(d，1H)，7.58 (dd，1H)，8.55(d，1H)，9.55(s，1H)； 19F NMR -148.46(t，1F) | 472 | Embodiment 123 |
| 127 3 | F | (S)- MeCH(OH)- | 1.25(d，3H)，1.44(d，6H)，2.50(s，3H，under DMSO signal)，3.00(m，4H)，3.66(m，4H)， 4.46(m，2H)，5.38(septet，1H)，6.99(t，1H)， 7.28(dd，1H)，7.33(d，1H)，7.49(dd，1H)， 8.44(d，1H)，9.09(s，1H)； 19F NMR (500MHz)-148.40(t，1F)，-122.6(s，1F) | 486 | Embodiment 123 |
| 128 4 | F | CH 2OMe | 1.43(d，6H)，2.50(s，3H，under DMSO signal)，3.00(m，4H)，3.33(s，3H)，3.60(m， 4H)，4.10(s，2H)，5.40(septet，1H)，7.00(t， 1H)，7.30(dd，1H)，7.33(d，1H)，7.50(dd， 1H)，8.43(d，1H)，9.09(s，1H)； 19F NMR (500MHz)-148.40(t，1F)，-122.7(s，1F) | 486 | Embodiment 123 |
1Add other acid (9mg) and EDAC (23mg), reaction times=4.5h, (365mg, 65%)
2Add other acid (10mg) and EDAC (20mg), reaction times=5.5h, NMR (400MHz, RT).Use MeOH: DCM: (1: 99-6: 94) chromatography, (334.5mg, 71%)
3Add other acid (10mg) and EDAC (19mg), reaction times=6h, (378mg, 78%)
4Need not use the MeOH solution-treated crude product of KOH, (310mg, 64%)
Embodiment 129
2-{4-[(3R, 5S)-4-ethanoyl-3,5-lupetazin-1-yl] anilino }-(1-different third for 4-
Base-2-methyl isophthalic acid H-imidazoles-5-yl)-5-fluorine pyrimidine
Press embodiment 116 methods, by (2Z)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 14,331mg, 1.38mmol) and N-[4-((3R, 5S)-and 4-ethanoyl-3,5-lupetazin-1-yl) phenyl] guanidine (method 34; 737.1mg, 2.10mmol) preparation title compound.With the reaction mixture reduction vaporization, residue is used MeOH: DCM: EtOAc (1: 49.5: 49.5-10: 45: 45) chromatography purification on silica gel, obtain solid, with it in vacuum drying oven, at 50 ℃ of following dried overnight (485mg, 76%)
NMR：(400MHz)1.30(s，6H)，1.41(d，6H)，2.05(s，3H)，2.50(s，3Hunder DMSO signal)，2.73(m，2H)，3.40(d，2H)，4.30(brs，2H)，5.45(septet，1H)，6.95(d，2H)，7.35(d，1H)，7.45(d，2H)，8.49(d，1H)，9.25(s，1H)；
19F NMR(400MHz)-149.80(t，1F)；m/z 466.
Embodiment 130
2-{4-[(2S, 5R)-4-ethanoyl-2,5-lupetazin-1-yl] anilino }-(1-different third for 4-
Base-2-methyl isophthalic acid H-imidazoles-5-yl)-5-fluorine pyrimidine
Press embodiment 116 methods, by (2Z)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 14; 335mg, 1.40mmol) and N-[4-((2S, 5R)-4-ethanoyl-2,5-lupetazin-1-yl) phenyl] guanidine (method 35; 737.1mg, 2.10mmol) preparation title compound.With the reaction mixture reduction vaporization, residue is used MeOH: DCM: EtOAc (1: 49.5: 49.5-6: 47: 47) chromatography purification on silica gel, obtain solid, it need use MeOH: DCM (1: 99-6: 94) be further purified.After grinding with ether,, obtain title compound, be solid solvent evaporation, with it in vacuum drying oven, at 50 ℃ of following dried overnight (330mg, 51%).
NMR：(500MHz)0.95(d，3H)，133(d，3H)，1.40(d，6H)，2.03(s，3H)，2.50(s，3H+DMSO)，3.17(m，2H)，3.43(brs，1H)，3.83(brs，1H)，4.00(m，1H)，4.47(brs，1H)，5.40(septet，1H)，6.83(d，2H)，7.32(d，1H)，7.37(d，2H)，8.35(d，1H)，8.7(s，1H)；
19F NMR(500MHz MHz)-149.95(t，1F)；m/z 466.
Embodiment 131
2-(3-chloro-4-piperazine-1-yl) anilino-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) is phonetic
Thiamine hydrochloride
Under 85 ℃, with 2-[3-chloro-4-(4-ethanoyl piperazine-1-yl) anilino]-(embodiment 120 for pyrimidine for 4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 4.1g, 9.1mmol) in Virahol (41ml) and 33% hydrochloric acid (4.1ml), stir and heated 25 hours.With the reactant reduction vaporization, water (200ml) dilution then is with DCM (200ml) washing, with the saturated sodium bicarbonate aqueous solution alkalization, with chloroform (2 * 400ml) extractions.With the solution drying, reduction vaporization obtains amine, is dissolved in MeOH by making it: DCM (60ml, 1: 1) and handle with 1.0mol ether-HCl solution (9.1ml) is converted into hydrochloride with it.Solid is ground with ether (40ml), filter, obtain title compound (3.2g, 77%).
NMR：1.42(d，6H)，2.61(s，3H)，3.16(m，4H)，3.40(m，4H)，5.58(septet，1H)，7.10(d，1H)，7.14(d，1H)，7.48(dd，1H)，7.81(s，2H)，8.49(d，1H)，9.64(s，1H)；m/z 412.
Embodiment 132
2-[3-chloro-4-(hydroxyacetyl) piperazine-1-yl] anilino-4-(1-sec.-propyl-2-methyl isophthalic acid H-
Imidazoles-5-yl) pyrimidine
Under 0 ℃, (embodiment 131 for the pyrimidine hydrochloride to 2-(3-chloro-4-piperazine-1-yl) anilino-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 0.44g, add in DCM 1.0mmol): DMF (14ml, 6: the 1) solution oxyacetic acid (90mg, 1.2mmol), HOBt.H
2O (0.16g, 1.2mmol) and DIPEA (1.4ml, 8.0mmol).(0.23g 1.2mmol), stirred mixture 43 hours then at ambient temperature to add EDAC down at 0 ℃ then.With solution with DCM (40ml) dilution, then water (3 * 50ml), 1.0mol KOH solution (50ml), salt solution (50ml) and water (50ml) washs.With the organic extract liquid drying, concentrate.Residue is used MeOH: DCM (2.5: 97.5) chromatography purification on silica gel, obtain title compound, be light yellow solid (0.13g, 28%).
NMR：1.19(t，1H)，1.48(d，6H)，2.58(s，3H)，3.01(m，4H)，3.44(m，2H)，3.83(m，2H)，4.21(s，2H)，5.57(septet，1H)，6.90(d，1H)，6.95(d，1H)，7.37(m，3H)，7.74(s，1H)，8.34(d，1H)；m/z 470.
Embodiment 133
2-(3-chloro-4-piperazine-1-yl) anilino-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-5-
Fluorine pyrimidine hydrochloride
Press embodiment 131 methods, by 2-[3-chloro-4-(4-ethanoyl piperazine-1-yl) anilino]-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-(embodiment 117 for 5-fluorine pyrimidine for 4-; 4.1g 9.1mmol) the preparation title compound is separated into brown solid (1.5g, 94%).
NMR：1.40(d，6H)，3.09(m，4H)，3.15(s，3H)，3.18(m，4H)，3.29(m，1H)，5.37(septet，1H)，7.14(d，1H)，7.36(d，1H)，7.54(dd，1H)，7.78(d，1H)，8.54(d，1H)，9.58(s，1H)；m/z 430.
Embodiment 134
2-[3-chloro-4-(4-hydroxyacetyl piperazine-1-yl) anilino]-4-(1-sec.-propyl-2-methyl-
1H-imidazoles-5-yl)-5-fluorine pyrimidine
Press embodiment 132 methods, (1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-(embodiment 133 for 5-fluorine pyrimidine hydrochloride by 2-(3-chloro-4-piperazine-1-yl) anilino-4-; 0.40g 0.86mmol) the preparation title compound is used MeOH: DCM (5: 95) chromatography purification on silica gel, obtains yellow solid (0.25g, 60%).
NMR：1.47(d，6H)，2.61(s，3H)，3.01(m，4H)，3.44(m，2H)，3.84(m，2H)，4.22(s，2H)，5.55(septet，1H)，6.96(d，1H)，7.22(s，1H)，7.36(dd，1H)，7.57(d，1H)，7.65(d，1H)，8.26(d，1H)；m/z 488.
Embodiment 135
2-(3-chloro-4-{4-[(2S)-1-oxo propan-2-ol] piperazine-1-yl } aniline)-4-(1-sec.-propyl-2-
Methyl isophthalic acid H-imidazoles-5-yl)-5-fluorine pyrimidine
Press embodiment 38 methods, (1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-(embodiment 133 for 5-fluorine pyrimidine hydrochloride by 2-(3-chloro-4-piperazine-1-yl) anilino-4-; 0.40g, 0.86mmol) preparation title compound.With the reaction mixture reduction vaporization.With residue water (60ml) dilution, with DCM (3 * 50ml) extractions.With organic phase water (100ml) washing that merges, dry then, concentrate.Residue is used MeOH: DCM (5: 95) chromatography purification on silica gel, obtain title compound, be yellow solid (0.35g, 88%).
NMR：1.39(d，3H)，1.46(d，6H)，2.60(s，3H)，2.80(s，1H)，3.01(m，4H)，3.60(m，2H)，3.77(m，1H)，3.79(m，1H)，4.52(q，1H)，5.51(septet，1H)，6.96(d，1H)，7.37(dd，1H)，7.58(d，1H)，7.59(s，1H)，7.68(d，1H)，8.27(d，1H)；m/z 502.
Embodiment 136
2-[3-chloro-4-(4-methoxyl group ethanoyl) piperazine-1-yl] anilino-4-(1-sec.-propyl-2-methyl
-1H-imidazoles-5-yl)-5-fluorine pyrimidine
Press embodiment 38 methods, (1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-(embodiment 133 for 5-fluorine pyrimidine hydrochloride by 2-(3-chloro-4-piperazine-1-yl) anilino-4-; 0.40g, 0.86mmol) preparation title compound.With the reaction mixture reduction vaporization.With residue water (100ml) dilution, with chloroform (3 * 100ml) extractions.With the organic phase concentrating under reduced pressure that merges, use EtOAc (100ml) dilution then, water (150ml) washing, dry then, concentrate.Residue is ground with ether, solid is used MeOH: DCM (5: 95) chromatography purification on silica gel, obtain title compound, be yellow solid (0.27g, 62%).
NMR：1.40(d，6H)，2.70(s，3H)，2.81(m，4H)，3.22(s，3H)，3.46(m，4H)，4.03(s，2H)，5.17(septet，1H)，7.03(d，1H)，7.24(dd，1H)，7.72(d，1H)，7.95(s，1H)，8.69(s，1H)，9.78(s，1H)；m/z 502.
Embodiment 137
1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } benzene
Base) azetidin-3-alcohol
Under 130 ℃, under nitrogen, with (2Z)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 14,1.54g, 6.46mM) and N-[4-(3-hydroxy azetidine-1-yl) phenyl] guanidine supercarbonate (method 39; 2.3g, 9.7mM) stirring heating 24 hours in 2-methyl cellosolve (17ml).The solvent vacuum is removed, residue is distributed between DCM and water.With organic layer water, rare sodium bicarbonate, water, saturated sodium-chloride washing,, filter evaporation then through anhydrous sodium sulfate drying.Crude product through the silica gel column chromatography purifying, is used MeOH: DCM (5: 95) wash-out.To grind with ether from the effusive product of post, and filter, with the same solvent washing, drying obtains title compound, is brown solid (886mg, 18.3%).
NMR 1.35(d，6H)，2.5(s，3H+H
2O peak)3.4(t，2H)，4.0(t，2H)，4.5(q,1H)，5.42(m，1H)，5.53(d，1H)，6.37(d，2H)，7.28(m，3H)，8.4(d，1H)，9.07(s，1H)；m/z 383.
Embodiment 138
1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } benzene
Base) azetidine-3-base mesylate
(embodiment 137 for azetidin-3-alcohol to 1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } phenyl); 0.728g, 1.905mM) and triethylamine (153 μ l, add in the freezing solution of anhydrous DCM (22ml) 2.09mM) methylsulfonyl chloride (162 μ l, 2.09mM).Reactant was stirred 30 minutes down at 0 ℃, at room temperature stirred 20 hours.Again with the DCM dilution, water (twice), saturated sodium-chloride extraction through anhydrous sodium sulfate drying, are filtered successively with reaction mixture, and evaporation obtains title compound, is brown foam (717mg, 82%).
NMR 1.37(d，6H)，2.48(s，3H+DMSO)，3.25(s，3H)，3.82(m，2H)，4.2(m，2H)，5.4(m，2H)，6.45(d，2H)，7.35(m，3H)，8.42(d，1H)，9.13(s，1H)；m/z 461.
Embodiment 139
N-[4-(3-azido-azetidine-1-yl) phenyl]-5-fluoro-4-(1-sec.-propyl-2-methyl-
1H-imidazoles-5-yl) pyrimidine-2-amine
To 1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } phenyl) azetidine-(embodiment 138 for 3-base mesylate; 876mg, add in dry DMF 1.90mM) (7.3ml) solution sodiumazide (619mg, 9.5mM).Under nitrogen, under 80 ℃, with reactant stirring heating 18 hours.Reaction mixture is diluted with EtOAc,,, filter evaporation then through anhydrous sodium sulfate drying solution with water (twice), saturated sodium-chloride extraction.Make crude product through silica gel column chromatography, use MeOH: DCM (2: 98) wash-out purifying, obtain title compound, be brown foam (389mg, 50%).
NMR 1.4(d，6H)，2.53(s，3H+DMSO)，3.65(m，2H)，4.1(m，2H)，4.44(m，1H)，5.4(m，1H)，6.44(d，2H)，7.33(m，3H)，8.35(d，1H)；m/z 408.
Embodiment 140
N-[4-(the amino azetidine of 3--1-yl) phenyl]-5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-
Imidazoles-5-yl) pyrimidine-2-amine
To N-[4-(3-azido-azetidine-1-yl) phenyl]-(embodiment 139 for pyrimidine-2-amine for 5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 382mg, add in THF 938mM) (10ml) solution triphenyl phosphine (260mg, 0.984mM).Under nitrogen, reactant was at room temperature stirred 24 hours.Add entry (2.0ml) then, with mixture 65 ℃ of following heated and stirred 3 hours.(1M 1.5ml), removes the THF vacuum to add hydrochloric acid.And then add entry, solution is extracted with EtOAc.(1M 1.5ml) adds water layer, and solution is extracted with EtOAc with sodium hydroxide.Organic layer is merged, through anhydrous sodium sulfate drying, filter, evaporation obtains title compound, is yellow foam (324mg, 91%).
NMR(DMSO-d
6+d
4-acetic acid)1.38(d，6H)，2.5(s，3H)，3.73(m，2H)，4.05(m，3H)，5.43(m，1H)，6.45(d，2H)，7.33(s，1H)，7.4(d，2H)，8.4(d，1H)；m/z 382.
Embodiment 141
N-[1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] ammonia
Base } phenyl) azetidine-3-yl]-the 2-hydroxyl acetamide
To N-[4-(the amino azetidine of 3--1-yl) phenyl]-(embodiment 140 for pyrimidine-2-amine for 5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 107mg, 0.28mM), oxyacetic acid (26mg, 0.337mM) and the HOBt hydrate (46mg, 0.337mM) add in the mixture in anhydrous DCM (4.0ml) Diisopropylamine (56 μ l, 0.337mM) and EDAC (65mg, 0.337mM).Under nitrogen, reactant was at room temperature stirred 72 hours.The DCM vacuum is removed, residue is dissolved in EtOAc and water.Each liquid layer is distributed and separate.With organic layer water successively, rare sodium bicarbonate (twice), water, saturated sodium-chloride washing,, filter evaporation then through anhydrous sodium sulfate drying.Residue is dissolved in MeOH (2.0ml), adds 1.0mol sodium hydroxide (0.25ml).Solution was at room temperature stirred 1 hour.Reaction mixture with EtOAc and water dilution, is distributed each liquid layer, separate.With organic layer water, saturated sodium-chloride washing,, filter evaporation through anhydrous sodium sulfate drying.Crude product is ground with ether, filter, with the ether washing, drying obtains title compound, is yellow solid (79mg, 64%).
NMR 1.38(s，6H)，2.5(s，3H+DMSO)，3.64(t，2H)，3.8(d，2H)，4.03(t，2H)，4.63(m，1H)，5.37(t，1H)，5.45(m，1H)，6.4(d，2H)，7.33(m，3H)，8.28(d，1H)，8.4(d，1H)，9.08(s，1H)；m/z 440.
Embodiment 142
N-[1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] ammonia
Base } phenyl) azetidine-3-yl] ethanamide
Stir down, to N-[4-(the amino azetidine of 3--1-yl) phenyl]-(embodiment 140 for 5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine; 110mg, 0.29mM) and triethylamine (44 μ l, add in anhydrous DCM (4.0ml) solution 0.317mM) diacetyl oxide (30 μ l, 0.317mM).Under nitrogen, reactant was at room temperature stirred 2.5 hours.Add several MeOH, with solution stirring 10 minutes.Then reaction mixture is diluted with DCM again, with solution water successively (twice) and saturated sodium-chloride extraction.Then, organic layer filters through anhydrous sodium sulfate drying, evaporation.Crude product is ground with ether, filter, with the ether washing, drying obtains title compound, is yellow solid (99mg, 81%).
NMR 1.4(d，6H)，1.8(s，3H)，2.5(s，3H+DMSO)，3.5(t，2H)，4.05(t，2H)，4.53(m，1H)，5.43(m，1H)，6.4(d，2H)，7.33(m，3H)，8.42(m，2H)，9.08(s，1H)；m/z 424.
Embodiment 143
N-[1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] ammonia
Base } phenyl) azetidine-3-yl] Toluidrin
Stir down, to N-[4-(the amino azetidine of 3--1-yl) phenyl]-(embodiment 140 for 5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine; 110mg, 0.29mM) and triethylamine (44 μ l, add in anhydrous DCM (4.0ml) solution 0.317mM) methylsulfonyl chloride (25 μ l, 0.317mM).Under nitrogen, reactant was at room temperature stirred 24 hours.Reactant is filtered, will cross filter solid and wash with DCM.Be left this solid of pure products.Get filtrate and add DCM again.With solution water successively (twice), saturated sodium-chloride washing,, filter evaporation then through anhydrous sodium sulfate drying.The product and first product that so obtain are merged, both are ground with ether, filter, with the ether washing, drying obtains title compound, is yellow solid.
NMR 1.4(d，6H)，2.6(s，3H)，2.9(s，3H)，3.55(t，2H)，4.13(t，2H)，4.25(m，1H)，5.37(m，1H)，6.4(d，2H)，7.33(d，2H)，7.58(d，1H)，7.75(d，1H)，8.5(d，1H)，9.22(s，1H)；m/z460.
Embodiment 144
(3-chloro-4-morpholine-4-base-phenyl)-[4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine
-2-yl]-amine
Press method described in the embodiment 112, with carbonic acid N-(3-chloro-4-morpholine-4-base-phenyl)-guanidine (method 17; 500mg, 1.97mmol) and (2E)-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (WO 03/076436 method 24; 363mg, 1.64mmol) preparation title compound.Yield: 412mg, 61%, be white solid.
NMR：1.42(d，6H)，2.47(s，3H)，2.90(t，4H)，3.72(t，4H)，5.60(m，1H)，7.02(d，1H)，7.10(d，1H)，7.40(s，1H)，7.54(dd，1H)，7.78(d，1H)，8.37(d，1H)，9.43(s，1H)；m/z 413.
Embodiment 145
(3-chloro-4-morpholine-4-base-phenyl)-[5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazoles-4-
Base)-pyrimidine-2-base]-amine
Press method described in the embodiment 112, with carbonic acid N-(3-chloro-4-morpholine-4-base-phenyl)-guanidine (method 17; 500mg, 1.97mmol) and (2Z)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 14; 392mg, 1.64mmol) preparation title compound.Yield: 203mg, 30%, be white solid;
NMR：1.41(d，6H)，2.49(s，3H)，2.90(t，4H)，3.72(t，4H)，5.35(m，1H)，7.10(d，1H)，7.34(d，1H)，7.50(dd，1H)，7.73(d，1H)，8.52(d，1H)，9.51(s，1H)；m/z 431.
Embodiment 146
N-{4-[(2RS, 6SR)-2,6-thebaine-4-yl] phenyl }-5-fluoro-4-(1-sec.-propyl-2-
Methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine
Under 110 ℃, with (2E)-3-(dimethylamino)-1-(1-ethyl-2-methyl isophthalic acid H-imidazoles-5-yl)-2-fluorine third-2-alkene-1-ketone (method 15; 327mg, 1.37mmol) and N-[4-(cis-2,6-thebaine generation) phenyl] guanidine supercarbonate (method 20; 510mg, 2-methyl cellosolve 1.65mmol) (8ml) solution heating 17 hours.With the reaction mixture reduction vaporization, residue is used MeOH: DCM: EtOAc (4: 48: 48)-(10: 45: 45) chromatography purification on silica gel, obtain title compound, after grinding with isohexane, be solid (274mg, 47.2%).
NMR(CDCl
3)1.26(d，6H)，1.44(d，6H)，1.68(s，2H)，2.39(t，2H)，2.58(s，3H)，3.39(d，2H)，3.82(m，2H)，5.57(sept，1H)，6.82(s，1H)，6.89(d，2H)，7.37(d，2H)，7.57(d，1H)，8.22(d，1H)；m/z 425.
Embodiment 147
(R)-N-cyclopropyl-1-{4-[4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base
Amino]-phenyl }-tetramethyleneimine-2-methane amide
With (R)-N-cyclopropyl-1-(4-guanidine radicals-phenyl)-tetramethyleneimine-2-methane amide (method 63; 0.29g, 1.0mmol) with ((2E)-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (WO 03/076436 method 24; 0.15g, 0.68mmol) add 2-methyl cellosolve (4ml), in microwave, heated 2 hours down at 200 ℃.The solvent vacuum is removed,,, use the 3%MeOH/DCM wash-out at last, obtain yellow solid (110mg, 36%) with DCM, 1%MeOH/DCM, 2%MeOH/DCM with the careful chromatography of jelly.
NMR(299.954MHz，CDCl
3)8.28(d，1H)，7.39(d，1H)，7.34(s，1H)，6.85-6.82(m，2H)，6.60-6.57(m，3H)，5.61(septet，1H)，3.96-3.92(m，1H)，3.62(t，1H)，3.19(q，1H)，2.76-2.67(m，1H)，2.56(s，3H)，2.30-2.22(m，2H)，2.07-1.84(m，2H)，1.47(d，6H)，0.78-0.70(m，2H)，0.45-0.38(m，2H)；m/z 446.
Embodiment 148
N-(3-fluoro-4-morpholine-4-base phenyl)-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine
-2-amine
Under 100 ℃, with (2E)-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (WO 03/076436 method 24); (330mg, 1.5mmol) and N-(3-fluoro-4-morpholino phenyl) guanidine supercarbonate (method 23; 540mg, 2-methyl cellosolve 1.8mmol) (10ml) solution heating 49 hours.With the reaction mixture reduction vaporization, with residue on silica gel, use MeOH: DCM (2: 98-6: 94) chromatography purification, obtain title compound, after grinding with ether, be solid (296mg 50%).
NMR(CDCl
3)：1.51(d，6H)，2.59(s，3H)，3.06(t，4H)，3.89(t，4H)，5.68(sept，1H)，6.91(m，2H)，7.08(m，2H)，7.38(s，1H)，7.57(dd，1H)，8.32(d，1H)；m/z 397.
Embodiment 149
5-fluoro-N-(3-fluoro-4-morpholine-4-base phenyl)-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-
Base) pyrimidine-2-amine
Under 100 ℃, with (2E)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 14; 360mg, 1.5mmol) and N-(3-fluoro-4-morpholino phenyl) guanidine supercarbonate (method 23; 540mg, 2-methyl cellosolve 1.8mmol) (10ml) solution heating 45 hours.With the reaction mixture reduction vaporization, residue is used MeOH: DCM (3: 97) chromatography purification on silica gel, obtain title compound, after grinding with ether, be solid (298mg48%).
NMR(CDCl
3)1.50(d，6H)，2.60(s，3H)，3.05(t，4H)，3.88(t，4H)，5.58(sept，1H)，6.90(m，2H)，6.95(d，1H)，7.08(dd，1H)，7.49(dd，1H)，7.59(d，1H)，8.26(d，1H)；m/z 415.
Embodiment 150
(R)-N-cyclopropyl-1-{4-[5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine
-2-base is amino]-phenyl }-tetramethyleneimine-2-methane amide
With (R)-N-cyclopropyl-1-(4-guanidine radicals-phenyl)-tetramethyleneimine-2-methane amide (method 63) (0.36g, 1.25mmol) and (2Z)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 14; 0.15g, 0.63mmol) add 2-methyl cellosolve (4ml), in microwave, heated 2 hours down at 200 ℃.The solvent vacuum is removed, jelly carefully with DCM, 1%MeOH/DCM, 2%MeOH/DCM with use the 3%MeOH/DCM elution chromatography at last, is obtained yellow solid (180mg, 62%).
NMR(400.132MHz，CDCl
3)8.21(d，1H)，7.56(d，1H)，7.34(d，2H)，6.80(s，1H)，6.59(m，3H)，5.55(septet，1H)，3.62(t，1H)，3.21-3.15(m，1H)，2.74-2.68(m，1H)，2.58(s，3H)，2.28-2.22(m，2H)，2.05-1.98(m，1H)，1.96-1.86(m，1H)，1.45(d，6H)，0.79-0.72(m，2H)，0.44-0.37(m，2H)；m/z 464.
Embodiment 151
N-[(3R)-1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base]
Amino } phenyl) tetramethyleneimine-3-yl] ethanamide
Under nitrogen, with carbonic acid 4-((3R)-kharophen tetramethyleneimine-1-yl) guanidines (method 45; 1.25g, 4.28mmol) and (2Z)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 14; 0.79g 2-methyl cellosolve 3.3mmol) (20ml) solution heated 18 hours down at 115 ℃.Behind the reduction vaporization, and usefulness MeOH/DCM on silica gel (100-2.5: 97.5) chromatography, obtain title compound, after grinding with ether, be brown solid (612mg, 43%).
NMR：1.38(d，6H)，1.80(s，3H)，1.80-1.92(m，1H)，2.12-2.26(m，1H)，2.49(s，3H)，2.97-3.03(m，1H)，3.14-3.25(m，1H)，3.29-3.49(m，2H)，4.3-4.41(m，1H)，5.20-5.32(m，1H)，6.50(d，2H)，7.30(s，1H)，7.32(d，2H)，8.09(d，1H)，8.39(s，1H)，9.05(s，1H)；m/z 438.
Embodiment 152
N-[(3S)-1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base]
Amino } phenyl) tetramethyleneimine-3-yl] ethanamide
By the method identical, but prepare title compound with carbonic acid 4-((3S)-kharophen tetramethyleneimine-1-yl) guanidines (method 51) with above embodiment 151.
NMR：1.37(d，6H)，1.81(s，3H)，1.78-1.92(m，1H)，2.11-2.22(m，1H)，2.44(s，3H)，2.94-3.06(m，1H)，3.14-3.49(m，3H)，4.29-4.41(m，1H)，5.40-5.43(m，1H)，6.49(d，2H)，7.30(s，1H)，7.32(d，2H)，8.09(d，1H)，8.40(d，1H)，9.03(s，1H)；m/z 438.
Embodiment 153
N-{4-[(3S)-and 3-amino-pyrrolidine-1-yl] phenyl }-5-fluoro-4-(1-sec.-propyl-2-methyl-
1H-imidazoles-5-yl) pyrimidine-2-amine
Under nitrogen, with N-[(3S)-1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } phenyl) tetramethyleneimine-3-yl] (embodiment 152 for ethanamide; 0.49g, Virahol 1.12mmol) (20ml), water (5ml) and hydrochloric acid (2ml) vlil 18 hours.Behind the reduction vaporization,, transfer to pH 9 with ammonium hydroxide aqueous solution with mixture water-soluble (15ml).(3 * 15ml) extractions, drying behind the reduction vaporization, obtains title compound, is solid (0.42g, 95%) with DCM with solution.
NMR：1.38(d，6H)，1.61-1.73(m，1H)，2.00-2.13(m，1H)，2.44(s，3H)，2.80-2.88(m，1H)，3.12-3.20(m，1H)，3.20-3.42(m，2H)，3.49-3.60(m，1H)，5.40-5.51(m，1H)，6.46(d，2H)，7.30(d，2H)，7.33(s，1H)，8.40(s，1H)，9.00(s，1H)；m/z 396.
Embodiment 154
(2S)-N-[(3S)-1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-
The 2-yl] amino } phenyl) tetramethyleneimine-3-yl]-2-hydroxyl propionic acid amide
Under nitrogen, at room temperature, make N-{4-[(3S)-3-amino-pyrrolidine-1-yl] phenyl }-(embodiment 153 for pyrimidine-2-amine for 5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 220mg, 0.556mmol), L-lactic acid (61mg, 0.667mmol), the HOBt monohydrate (103mg, 0.667mmol) and HunigShi alkali (0.12ml, (128mg 0.667mmol) reacts 18 hours for (5ml) solution of DCM 0.667mmol) and EDAC.Mixture is diluted water (20ml), 1N potassium hydroxide aqueous solution (20ml) and saturated sodium-chloride water solution (15ml) washing with DCM (20ml).With the mixture drying, behind the reduction vaporization, on the Phenomenex post, through the HPLC purifying (the 0-50% acetonitrile/water, 0.2%TFA).With flow point water (20ml) dilution, with solid carbonic acid potashization, with EtOAc/DCM (20ml, 2: 1) extracting twice.Solution is washed with saturated sodium-chloride water solution (15ml), and drying behind the reduction vaporization, obtains title compound, is yellow solid (79mg, 30%).
NMR：1.20(d，3H)，1.37(d，6H)，1.90-2.04(m，1H)，2.11-2.27(m，1H)，2.47(s，3H)，3.00-3.09(m，1H)，3.20-3.47(m，3H)，3.91-4.00(m，1H)，4.32-4.47(m，1H)，5.38(s，1H)，5.40-5.49(m，1H)，6.49(d，2H)，7.30(s，1H)，7.32(d，2H)，7.76(d，1H)，8.40(d，1H)，9.06(s，1H)；m/z 468.
Embodiment 155
N-[(3S)-1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base]
Amino } phenyl) tetramethyleneimine-3-yl]-the 2-hydroxyl acetamide
With the method that is similar to embodiment 154, with N-{4-[(3S)-3-amino-pyrrolidine-1-yl] phenyl }-(embodiment 153 for pyrimidine-2-amine for 5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 220mg, 0.556mmol) and oxyacetic acid (51mg 0.667mmol) is feedstock production title compound (38mg, 15%).
NMR：1.39(d，6H)，1.91-2.04(m，1H)，2.13-2.25(m，1H)，2.44(s，3H)，3.04-3.12(m，1H)，3.18-3.47(m，3H)，3.80(d，2H)，4.38-4.47(m，1H)，5.32(t，1H)，5.40-5.52(m，1H)，6.50(d，2H)，7.30(s，1H)，7.35(d，2H)，7.82(d，1H)，8.40(d，1H)，9.04(s，1H)；m/z 454.
Embodiment 156
N-{4-[(3R)-and 3-amino-pyrrolidine-1-yl] phenyl }-5-fluoro-4-(1-sec.-propyl-2-methyl-
1H-imidazoles-5-yl) pyrimidine-2-amine
By the method identical with embodiment 153, with N-[(3R)-1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } phenyl) tetramethyleneimine-3-yl] ethanamide (embodiment 151) is feedstock production title compound (0.45g, 99%).
NMR：1.36(d，6H)，1.61-1.76(m，1H)，2.00-2.16(m，1H)，2.47(s，3H)，2.79-2.89(m，1H)，3.14-3.41(m，3H)，3.28(brs，2H)，3.50-3.60(m，1H)，5.40-5.52(m，1H)，6.44(d，2H)，7.31(d，2H)，7.35(s，1H)，8.39(d，1H)，9.00(s，1H)；m/z 396.
Embodiment 157
(2S)-N-[(3R)-1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-
The 2-yl] amino } phenyl) tetramethyleneimine-3-yl]-2-hydroxyl propionic acid amide
With the method that is similar to embodiment 154, with N-{4-[(3R)-3-amino-pyrrolidine-1-yl] phenyl }-(embodiment 156 for pyrimidine-2-amine for 5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 220mg, 0.556mmol) (61mg 0.667mmol) is feedstock production title compound (15mg, 6%) with L-lactic acid.
NMR：1.20(d，3H)，1.36(d，6H)，1.89-2.01(m，1H)，2.14-2.22(m，1H)，2.43(s，3H)，3.02-3.10(m，1H)，3.14-3.48(m，3H)，3.92-4.03(m，1H)，4.34-4.46(m，1H)，5.35(d，2H)，5.41-5.53(m，1H)，6.49(d，2H)，7.30(s，1H)，7.32(d，2H)，8.40(d，1H)，9.05(s，1H)；m/z 468.
Embodiment 158
N-[(3R)-1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base]
Amino } phenyl) tetramethyleneimine-3-yl]-the 2-hydroxyl acetamide
With the method that is similar to embodiment 155, with N-{4-[(3R)-3-amino-pyrrolidine-1-yl] phenyl }-(embodiment 156 for pyrimidine-2-amine for 5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl); 220mg, 0.556mmol) and oxyacetic acid (51mg 0.667mmol) is feedstock production title compound (38mg, 15%).
NMR：1.39(d，6H)，1.92-2.04(m，1H)，2.14-2.26(m，1H)，2.44(s，3H)，3.04-3.13(m，1H)，3.18-3.49(m，3H)，3.80(d，2H)，4.46-4.51(m，1H)，5.34(t，1H)，5.42-5.51(m，1H)，6.49(d，2H)，7.31(d，1H)，7.35(d，2H)，7.82(d，1H)，8.41(d，1H)，9.06(s，1H)；m/z 454.
Embodiment 159
(S)-and N, N-dimethyl-1-{4-[5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-phonetic
Pyridine-2-base is amino]-phenyl }-tetramethyleneimine-2-methane amide
With (S)-N, N-dimethyl-1-(4-guanidine radicals-phenyl)-tetramethyleneimine-2-methane amide (method 54; 0.5g, 1.82mmol) and (2Z)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 14; 0.2g 0.83mmol) reflux is spent the night in butanols (7ml).LCMS shows only 7% product.Reactant transfer to microwave tube, was heated 2 hours down at 200 ℃.LCMS shows 15% raw material and main product.The solvent vacuum is removed chromatography.Product by the HPLC purifying, with the flow point merging of needs, is used K
2CO
3(0.5g) alkalization, (2 * 50ml) extractions, drying is removed the solvent vacuum, obtains yellow solid (101mg, 31%) with DCM.
NMR(400.132MHz，CDCl
3)8.18(d，1H)，7.56(d，1H)，7.24(d，2H)，6.69(s，1H)，6.42(d，2H)，5.59(septet，1H)，4.51(dd，1H)，3.64(dt，1H)，3.41(q，1H)，3.16(s，3H)，2.98(s，3H)，2.56(s，3H)，2.38-2.28(m，1H)，2.25-2.14(m，1H)，2.08-1.98(m，2H)，1.39(t，6H)；m/z 452.
Embodiment 160
(R)-N-methyl isophthalic acid-{ 4-[5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-
Base is amino]-phenyl }-tetramethyleneimine-2-methane amide
With (R)-N-methyl isophthalic acid-(4-guanidine radicals-phenyl)-tetramethyleneimine-2-methane amide (method 59; 0.22g, 0.82mmol) and (2Z)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 14; 0.15g, 0.63mmol) add 2-methyl cellosolve (4ml), in microwave, heated 2 hours down at 200 ℃.The solvent vacuum is removed chromatography.Make product pass through the HPLC purifying,, use K the flow point merging of needs
2CO
3(0.5g) alkalization, (2 * 50ml) extractions, drying is removed the solvent vacuum, obtains yellow solid (110mg, 40%) with DCM.
NMR(400.132MHz，CDCl
3)8.21(d，1H)，7.56(d，1H)，7.34(d，2H)，6.79(s，1H)，6.60(d，2H)，6.56(s，1H)，5.56(septet，1H)，3.99(t，1H)，3.64(t，1H)，3.20(q，1H)，2.80(d，3H)，2.58(s，3H)，2.29-2.24(m，2H)，2.06-1.89(m，2H)，1.45(d，6H)；m/z 438.
Embodiment 161
(R)-N-methyl isophthalic acid-{ 4-[4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base ammonia
Base]-phenyl }-tetramethyleneimine-2-methane amide
With (R)-N-methyl isophthalic acid-(4-guanidine radicals-phenyl)-tetramethyleneimine-2-methane amide (method 59; 0.27g, 1.0mmol) and (2E)-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (WO 03/076436 method 24; 0.15g, 0.0.68mmol) add 2-methyl cellosolve (4ml), in microwave, heated 2 hours down at 200 ℃.The solvent vacuum is removed, jelly is carefully used DCM, 1%MeOH/DCM, 2%MeOH/DCM, use the 3%MeOH/DCM elution chromatography at last, obtain yellow solid (101mg, 35%).
NMR(400.132MHz，CDCl
3)8.28(d，1H)，7.39(d，2H)，7.34(s，1H)，6.89(s，1H)，6.83(d，1H)，6.61-6.57(m，3H)，5.62(septet，1H)，3.99(t，1H)，3.65(t，1H)，3.24-3.17(m，1H)，2.80(d，3H)，2.55(s，3H)，2.29-2.24(m，2H)，2.06-1.89(m，2H)，1.46(d，6H)；m/z420.
Embodiment 162
N-[(3R)-1-(4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino }
Phenyl) tetramethyleneimine-3-yl] ethanamide
Under nitrogen, with 4-((3R)-kharophen tetramethyleneimine-1-yl) guanidines trifluoroacetate (method 70; 1.79g, 4.55mmol), (2E)-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (WO 03/076436 method 24; 1.01g (1.74ml 10mmol) heated 20 hours down at 115 ℃ for (20ml) solution of 2-methyl cellosolve 4.55mmol) and DIPEA.Behind the reduction vaporization, and usefulness MeOH/DCM on silica gel (100-5: 95) chromatography, obtain title compound, after grinding with ether, be yellow solid (165mg, 9%).
NMR：1.39(d，6H)，1.75-1.90(m，1H)，1.80(s，3H)，2.11-2.22(m，1H)，2.44(s，3H)，2.98-3.02(m，1H)，3.16-3.48(m，3H)，4.28-4.37(m，1H)，5.64-5.75(m，1H)，6.50(d，2H)，6.89(d，1H)，7.35(s，1H)，7.37(d，1H)，8.09(d，H)，8.98(s，H)m/z：420.
Embodiment 163
N-[(3R)-1-(2-fluoro-4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base]
Amino-2-fluorine } phenyl) tetramethyleneimine-3-yl] ethanamide
By the route that is similar to embodiment 162, with carbonic acid 2-fluoro-4-((3R)-kharophen tetramethyleneimine-1-yl) guanidines (method 69,1.16g, 5.23mmol) and (2E)-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (WO 03/076436 method 24,2.43g, 7.84mmol) be feedstock production title compound (0.24g, 10%).
NMR：2.41(d，6H)，1.70-1.86(m，1H)，1.80(s，3H)，2.07-2.18(m，1H)，2.46(s，3H)，3.04-3.12(m，1H)，3.19-3.28(m，1H)，3.32-3.49(m，2H)，4.22-4.39(m，1H)，5.62-5.72(m，1H)，6.68(t，1H)，6.98(d，2H)，7.21(d，1H)，7.39(s，1H)，7.50(d，1H)，8.07(d，1H)，8.32(d，1H)，9.24(s，1H)；m/z 438.
The preparation raw material
Method 1
N-{4-[4-(methylsulfonyl) piperazine-1-yl] phenyl } guanidine
Under envrionment temperature and pressure, with 1-methylsulfonyl-4-(4-nitrophenyl) piperazine [J.Med.Chem.20 (8) 987-996 (1977)] EtOH (250ml) solution (24g) through 10% Pd/ carbon (2.4g) hydrogenation.Reactant is filtered, with catalyzer and insoluble solids MeOH: 2N hydrochloric acid (100: 100ml) wash.Reduction vaporization obtains anilinechloride, is orange solids (19.8g81%).M/z 256。
In EtOH (25ml) and 1, the mixture in the 4-diox (25ml) is 90 ℃-95 ℃ heating totally 19 hours down with aniline (4.7g 16.1mmol) and cyanamide (800mg 19.0mmol).5.5 after hour, add cyanamide (450mg) and EtOH (10ml) again.With the reaction mixture reduction vaporization.Water (100ml) is added residue, use 40% sodium hydroxide (pH＞11) alkalization then.The filtering solid is used a small amount of cold water washing, and is dry on filter, is transferred in the beaker then.Residue is ground with acetone (50ml), filter, dry, obtain title compound (3.2g 58%).NMR：2.89(s，3H)，3.08(m，4H)，3.21(m，4H)，3.30(b s，4H)，6.73(d，2H)，6.73(d，2H)；m/z298.
Method 2
N-[4-(4-ethanoyl piperazine-1-yl) phenyl] the guanidine supercarbonate
Under envrionment temperature and pressure, with 1-ethanoyl-4-(4-nitrophenyl) piperazine [J.Med.Chem.20 (8) 987-996 (1977)] EtOH (200ml) solution (20.8g) through 10%Pd/ carbon (2.1g) hydrogenation.Catalyzer is leached, and with EtOH (500ml) washing, reduction vaporization obtains aniline, is purple solid 22g (still moist).
Aniline (5.0g 22.8mmol) anhydrous 1, is stirred among 4-diox (55ml) and the EtOH (20ml).Add 4N HCl De dioxane solution (6.0ml 25mmol), then after 3-4 minute, add again cyanamide (1.6g, 38.1mmol) and EtOH (4ml).Reactant was heated 17.5 hours down at 95 ℃, and then add cyanamide (300mg) and 4N HCl/ diox (2ml).Reactant is continued heating 6 hours.Behind the reduction vaporization, (2 * 70ml) grind, and dry with ether with solid.With solid water-soluble (40ml).Stir down, slowly add saturated sodium bicarbonate solution (75ml).After 21 hours,, collect, with acetone (2 * 40ml) washings, vacuum-drying (5.7g, 77%) solid filtering.
NMR：2.01(s，3H)，2.98(t，2H)，3.05(t，2H)，2.9-3.8(v b s，exchangeables)，3.54(m，4H)，6.81(d，2H)，6.88(d，2H)；m/z 262.
Method 3
(2E)-2-chloro-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-
Alkene-1-ketone
Under room temperature, stirring, two chloriodic acid benzyltrimethylammon.um (2.6g 7.5mmol) are joined (2E)-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (WO 03/076436 method 24 in batches; 1.1g, in MeOH/DCM 5mmol) (15/30ml) solution.After 1 hour, add entry (10ml) and DCM (20ml), after 30 minutes, add saturated sodium bicarbonate solution (20ml) subsequently again.Organic liquor is separated, use DCM (25ml) aqueous phase extracted again.The organic liquor that merges is washed dry (Na with 5% (w/v) hypo solution (30-35ml) and salt solution (25ml)
2SO
4), evaporation obtains title compound, is oily matter (crude product, it is still wet to obtain 1.68g).M/z 256。
Method 4
N-[4-(morpholino) phenyl] the guanidine supercarbonate
With 4-morpholino aniline (1.78g, 10mmol) and cyanamide (420mg 10mmol) 1, stir in the 4-diox (17.5ml).Slowly add 1 of 7N HCl, 4-diox (2.5ml) solution heated 11 hours down at 95 ℃ then.With the reaction mixture reduction vaporization, solid is ground with ether, dry then and spend the night.This solid water (20ml) is handled, stirred down, slowly add saturated sodium bicarbonate aqueous solution (15ml).With solid filtering, collect, with acetone (15ml) washing, dry, obtain title compound 2.3g 80%.NMR 2.95 (4H, m), 3.39 (commutative, vbrs), 3.68 (4H, m), 6.68 (2H, d), 6.71 (2H, d); M/z 221.
Method 5
2-amino-5-chloro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine
Under nitrogen, under 65 ℃, with 2-amino-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine (WO 03/076436 method 39; 0.5g, 2.3mmol) and N-chloro-succinimide (0.4g, acetate 3mmol) (5ml) solution stirring 2 hours.Make reaction mixture be cooled to room temperature then, the solvent vacuum is removed.Crude product is dissolved in EtOAc and water, then under agitation, in this two phase liquid, adds solid carbonic acid potassium in batches until reaching pH 8-9.Two liquid layers are separated, with water layer once, then organic liquor is merged, use the salt water washing, drying with the EtOAc extraction.Solvent is removed, residual residue, with it on silica gel purifying (MeOH/DCM/EtOAc, 0/50/50-6/47/47).Foam is ground with ether, obtain white solid, it is leached (0.49g, 85%).
NMR(CDCl
3)：1.51(d，6H)，2.55(s，3H)，4.85(septuplet，1H)，5.01(b s，2H)，7.48(s，1H)，8.31(s，1H)；m/z 252(
35Cl)，254(
37Cl)；m/z 250(
35Cl)，252(
37Cl).
Method 6
4-[N-(propionyl)-N-(sec.-propyl) amino]-the 5-methyl-isoxazole
Under-3 ℃, in 45min, triethylamine (1.0 equivalent) is added drop-wise to N-sec.-propyl-5-methyl-isoxazole-4-amine (WO 03/76436 method 1; 258g, 1.0 equivalents) and in DCM (the 8.6 volume equivalent) solution of positive propionyl chloride (1.0 equivalent).Under 0 ℃, reactant is stirred 20min then, make it be warming up to ambient temperature overnight then.Add entry (10 volume equivalent), then mixture is stirred 30min.Organic layer is separated, water (2 * 10 volume equivalent), 2M HCl (3 * 10 volume equivalent), salt solution (10 volume equivalent) washing, drying is filtered, and then the solvent vacuum in the filtrate is removed, and the residue yellow oil is placed crystallization (330g, 91%).
NMR 0.91(3H，t)，0.95(6H，b s)，1.9(2H，q)，2.35(3H，s)，4.8(1H，septuplet)，8.61(1H，s).
Method 7
N-[(E)-1-ethanoyl-2-amido vinyl]-N-sec.-propyl propionic acid amide
Under hydrogen (1.0 equivalent), under 25 ℃, with 4-[N-(propionyl)-N-(sec.-propyl) amino]-5-methyl-isoxazole (method 6; 330g, 1.0 equivalents) and 10% palladium on carbon (0.1 equivalent) in EtOH (10 volume equivalent), stir and spend the night.Catalyzer is removed by filter, the EtOH vacuum is removed, residue pale solid (351g, 98%).Use this solid to be further purified.
Method 8
1-sec.-propyl-2-ethyl-5-acetyl imidazole
With N-[(E)-1-ethanoyl-2-amido vinyl]-N-sec.-propyl propionic acid amide (method 7; 373g, 1.0 equivalents) and EtOH (the 4 volume equivalent) solution stirring of sodium hydroxide (1.4 equivalent).Reactant is heated to backflow (85 ℃), and stirring is spent the night.Add ammonium chloride (2.0 equivalent) then, with this solution stirring 2 hours (thick reactant becomes thin precipitation).Make the reactant cooling then, solid is leached, discard, then the solvent vacuum is removed.Then acetone is added residue,, discard the solid filtering.Solvent removed in vacuo then.Be prepared chromatography then, use the 5%MeOH/DCM wash-out, residue brown oil (290g, 86%).
NMR 1.23(3H，t)，1.43(6H，d)，2.40(3H，s)，2.77(2H，q)，5.0(1H，b s)，7.87(1H，s).
Method 9
5-(3-dimethylamino third-2-alkene-1-acyl group)-1-sec.-propyl-2-ethyl imidazol(e)
With 1-sec.-propyl-2-ethyl-5-acetyl imidazole (method 8; 290g, 1.0 equivalents) and DMF (the 15 volume equivalent) solution stirring of DMFDMA (2.0 equivalent).Reactant is heated to 130 ℃, and stirring is spent the night.Make the reactant cooling, the solvent vacuum is removed.Residue is ground with ether, brown solid is leached,, repeat this process with the ether washing.Then filtrate is merged,,, obtain yellow solid (223g, 59%) with 5%MeOH/DCM wash-out purifying by preparative chromatography.
NMR 1.24(3H，t)1.46(6H，d)，2.73(2H，q)，2.96(6H，b s)，5.09(1H，septuplet)，5.56(1H，d)，7.51(1H，s)，7.53(1H，d).
Method 10
4-(N-butyryl radicals-N-ethylamino)-5-methyl-isoxazole
Stir down, to 4-ethylamino-5-methyl-isoxazole (WO 03/76436 method 5; 49.6g, 305mM) and triethylamine (77.0g, 763mM, slowly add in the freezing solution of DCM 107ml) (800ml) n-butyryl chloride (35.5,333mM, DCM 35ml) (100ml) solution.Gentle heat release appears.Make solution be warming up to envrionment temperature, stirred 1 hour.With reaction mixture water, 2N HCl, salt solution, saturated NaHCO
3With the salt water washing.With its drying, with solvent evaporation, obtain title compound, be oily matter, it crystallizes into waxy solid (45.1g, 75%).
NMR(300Mz，DMS0-d6)：0.78(t，3H)，0.96(t，3H)，1.44(sext，2H)，1.93(t，2H)，2.33(s，3H)，3.49(q，2H)，8.68(s，1H)；m/z 197.
Method 11
N-[(E)-1-ethanoyl-2-amido vinyl]-the N-ethyl butyramide
Under 4 bar pressures, make 4-(N-butyryl radicals-N-ethylamino)-5-methyl-isoxazole (method 10; 45g, EtOH 230mM) (1.51) solution is through 10%Pd/C (11.25g) hydrogenation.With the catalyzer filtering, with solution evaporation.Residue is ground with ether, crystallization of intermediate is leached (33.94g).Use this crystallization of intermediate to be further purified.
Method 12
1-ethyl-2-propyl group-5-acetyl imidazole
With N-[(E)-1-ethanoyl-2-amido vinyl]-N-ethyl butyramide (method 11; 33.9g, 171mM) and NaOH (8.2g, EtOH 205mM) (400ml) vlil 4 hours.With NH
4(11.9g 222mM) adds in this hot solution Cl, makes its cooling, stirs 48 hours.Reaction mixture is filtered, with solution evaporation.Residue is dissolved in ether, filters once more.With solution evaporation, obtain title compound, be yellow oil (30.55g, 74%).
NMR(300Mz，DMS0-d6)：0.92(t，3H)，1.17(t，3H)，1.70(sext，2H)，2.37(s，3H)，2.64(t，2H)，4.23(q，2H)，7.83(s，1H)；m/z 181.
Method 13
5-(3-dimethylamino third-2-alkene-1-acyl group)-1-ethyl-2-propyl imidazole
With 1-ethyl-2-propyl group-5-acetyl imidazole (method 12; 30.5g, 169mM) and DMFDMA (DMF 58ml) (100ml) solution stirred 18 hours down at 130 ℃ for 49.7g, 338mM, with the EtOH distillation that generates.When cooling, product is crystallization from reaction mixture, filters, with ether (20.94g) washing.With solvent evaporation, grind with ether, obtain second batch of product (8.8g) (29.74g, 75%).
NMR(300Mz，DMS0-d6)：0.92(t，3H)，1.18(t，3H)，1.70(sext，2H)，2.60(t，2H)，2.94(brs，6H)，4.30(q，2H)，5.56(d，1H)，7.50(d，1H)，7.56(s，1H)；m/z 236.
Method 14
(2Z)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-
Alkene-1-ketone
Stir down, at ambient temperature, in～5min, to (2E)-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (WO 03/076436 method 24; 5.53g, add in MeOH 25mmol) (100ml) solution in batches Selectfluor (14.16g, 40mmol).By cooling off a little temperature maintenance at 25-30 ℃.After stirring 90min, reaction mixture is cooled off in ice/acetone, filter.With filtrate evaporated under reduced pressure, residue is dissolved in DCM.It is used ammoniacal liquor, salt water washing, through anhydrous Na
2SO
4Drying, reduction vaporization.With two separator columns, through silica gel MPLC (10%EtOH/EtOAc, 3.5%EtOH/DCM then) title compound is separated, be golden yellow thickness oily matter, place several all post crystallizations.Yield=2.50g (42%).
NMR(300Mz)：1.40(d，6H)，2.38(s，3H)，3.05(s，6H)，4.70(septet，1H)，6.96(d，1H)，7.08(s，1H)；
19F NMR(376MHz)：-166.7(d)；m/z 240.
Method 15
(2Z)-3-(dimethylamino)-1-(1-ethyl-2-methyl isophthalic acid H-imidazoles-5-yl)-2-fluorine third-2-
Alkene-1-ketone
By the method for above method 14, with 46mM (2E)-3-(dimethylamino)-1-(1-ethyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (WO 02/20512 method 16) macro preparation title compound.With two separator columns, separate title compound through silica gel MPLC (5%EtOH/DCM, 10%EtOH/EtOAc then), crystallization easily after grinding with ether.Yield=3.93g (38%).
NMR(300Mz)：1.2(t，3H)，2.38(s，3H)，3.05(s，6H)，4.18(q，2H)，6.96(d，1H)，7.34(s，1H)；
19F NMR(376MHz)-168.2(d)；m/z 226.
Method 16
(2Z)-1-(1-cyclobutyl-2-methyl isophthalic acid H-imidazoles-5-yl)-3-(dimethylamino)-2-fluorine third-2-
Alkene-1-ketone
By the method for method 14, by (2E)-1-(1-cyclobutyl-2-methyl isophthalic acid H-imidazoles-5-yl)-3-(dimethylamino) third-2-alkene-1-ketone (WO 03/076435 method 37; 3.0g) the preparation title compound.By the silica gel column chromatography purifying, and usefulness EtOH/EtOAc (5: 95-10: 90) wash-out, obtain title compound, be yellow oil (1.64g, 51%).
NMR(CDCl
3)：1.73-1.88(m，2H)，2.47(s，3H)，2.45-2.55(m，4H)，3.10(s，6H)，5.00(quintet，1H)，6.87(d，1H)，7.23(d，1H)；m/z 252.
Method 17
N-(3-chloro-4-morpholine-4-base-phenyl)-guanidine supercarbonate
In order to method described in the last method 4, with N-(4-amino-2-chloro-phenyl-) morpholine (1.1g, 5.19mmol), cyanamide (273mg, 6.49mmol), the dioxane solution of 4.0M HCl (1.62ml, 6.49mmol) and diox (30ml) prepare title compound.Yield: 820mg, 50%.NMR：2.85(t，4H)，3.70(t，4H)，6.73(dd，1H)，6.81(d，1H)，7.00(d，1H).
Method 18
1-(cis-2,6-thebaine generation)-4-oil of mirbane
With 1-fluoro-4-oil of mirbane (4.9g 34.75mmol) adds cis-2, the 6-thebaine (44.4g, 38.26mmol) and Anhydrous potassium carbonate (2.5g is in acetonitrile 18.12mmol) (50ml) solution.With reactant reflux 19 hours, cooling was filtered, and solid is washed with acetonitrile.With the filtrate evaporation, obtain title compound, be yellow solid (8.1g, 99%).
NMR(CDCl
3)1.28(d，6H)，2.61(t，2H)，3.66(td，2H)，3.76(m，2H)，6.82(d，2H)，8.13(d，2H)；m/z 237.
Method 19
4-(cis-2,6-thebaine generation) aniline
Under 50 ℃, with 1-(cis-2,6-thebaine generation)-4-oil of mirbane (method 18; EtOH 8g) (100ml) solution is used hydrogen reduction through 10% palladium/carbon (800mg).After the catalyzer filtering, with the EtOH washing,, obtain title compound with the filtrate evaporation, be redness/brown oil, after several days, it begins to solidify (quantitative yield).
NMR(CDCl
3)1.23(d，6H)，2.33(t，2H)，3.25(d，2H)，3.81(m，2h)，6.65(d，2H)，6.79(d，2H)；m/z 207.
Method 20
N-[4-(cis-2,6-thebaine generation) phenyl] the guanidine supercarbonate
With 4-(cis-2,6-thebaine generation) aniline (method 19; 6g, 29.10mmol) and cyanamide (1.5g 35.71mmol) 1, stirs in the 4-diox (45ml).Slowly add 1 of 4N HCl, (8.8ml, 35.2mmol) solution heated 1.75 hours down at 100 ℃ the 4-diox then.With the reaction mixture reduction vaporization, residue is ground with ether.The jelly water (30ml) that obtains is handled, stirred down, slowly add saturated sodium bicarbonate aqueous solution (40ml).With solid filtering, collect, (2 * 25ml) washings are dried, and obtain title compound (6.4g 71%) with acetone.
NMR 1.15(d，6H)，2.21(t，2H)，3.48(td，2H)，3.68(m，2H)，6.85(d，2H)，6.89(brd，2H)；m/z 249.
Method 21
1-fluoro-2-morpholino-5-oil of mirbane
With 1,2-two fluoro-4-oil of mirbane (8.0g, 50mmol) add morpholine (4.85g, 55.7mmol) and Anhydrous potassium carbonate (3.85g is in acetonitrile 27.9mmol) (75ml) solution.Reactant was heated 3 hours down at 85 ℃, and cooling is filtered, with solid EtOAc (50ml) washing.With the filtrate evaporation, grind with isohexane, filter, obtain title compound, be solid (11.2g, 98%).
NMR(CDCl
3)：3.28(t，4H)，3.88(t，4H)，6.92(t，1H)，7.92(dd，1H)，8.00(m，1H)；m/z 227.
Method 22
3-fluoro-4-morpholino aniline
With 1-fluoro-2-morpholino-5-oil of mirbane (method 21; (50: 50ml) solution is used hydrogen reduction through 10% palladium/carbon (800mg) to EtOH 9g): EtOAc.After the catalyzer filtering, with the EtOH washing,, obtain title compound with the filtrate evaporation, be brown solid (quantitative yield).
NMR(CDCl
3)2.96(t，4H)，3.55(brs，2H)，3.84(t，4H)，6.41(d/s，2H)，6.79(t，1H)；m/z 197.
Method 23
N-(3-fluoro-4-morpholino phenyl) guanidine supercarbonate
With 3-fluoro-4-morpholino aniline (method 22; 7.8g, 39.8mmol) and cyanamide (2.1g, 50mmol) 1,4-diox: EtOH (75: stir 7.5ml).Slowly add 1 of 4N HCl, (11.9ml 47.6mmol), heated 6 hours down at 95 ℃ the 4-dioxane solution then.With the reaction mixture reduction vaporization, residue is ground with ether.The solid water (35ml) that obtains is handled, stirred down, slowly add saturated sodium bicarbonate aqueous solution (60ml).With solid filtering, collect, (2 * 25ml) washings are dried, and obtain title compound (10.9g, 91%) to use cold water (10ml), acetone successively.
NMR 2.90(t，4H)，3.72(t，4H)，5.24(brs，4H)，6.52(d/s，1H)，6.54(t，1H)，6.87(t，1H)；m/z239.
Method 24
1-ethanoyl-4-(2-chloro-4-nitrophenyl) piperazine
(10g, 57mmol) (14.6g is 114mmol) at 55 ℃ of following even heating 1h with 1-ethanoyl piperazine with 2-chloro-1-fluoro-4-oil of mirbane.Make reaction mixture be cooled to room temperature then.The viscosity orange solution is diluted with EtOAc and water.With organic liquor water (3 times), salt water washing, drying with solvent evaporation, obtains orange, and it is ground with isohexane.After solvent evaporation, obtain title compound, be yellow solid, with it under 50 ℃, dried overnight in vacuum drying oven (15.68g, 97%).It need not be further purified during use.
NMR(400.MHz)2.03(d，3H)，3.18(dt，4H)，3.62(tm，4H)，7.30(d，1H)，8.17(dd，1H)，8.26(d，1H)；m/z 284-286.
Method 25
1-ethanoyl-4-(2-methyl-4-nitrophenyl) piperazine
Stir down, (1.75g, (12g is 77.35mmol) with 1-ethanoyl piperazine (39.7g, acetonitrile 309.4mmol) (3ml) solution 7.74mmol) to be added to 1-fluoro-2-methyl-4-oil of mirbane with Tetrafluoroboric acid 1-butyl-3-Methylimidazole.Then with reaction mixture 95 ℃ of following heated overnight.Make reaction mixture be cooled to room temperature.Solution is diluted with EtOAc and water.The precipitation that forms is leached, obtain corresponding to the solid that needs product.With organic liquor water (4 times), salt water washing, drying with solvent evaporation, obtains solid.Twice solid is merged, after grinding and filter with isohexane/ether, obtains title compound, be yellow solid, with it in vacuum drying oven, 50 ℃ of following dried overnight.(19.61g，96％)。
NMR(400MHz)2.06(s，3H)，2.38(s，3H)，2.99(dt，4H)，3.61(m，4H)，7.14(d，1H)，8.04(dd，1H)，8.07(d，1H)；m/z264.
Method 26
1-ethanoyl-4-(2-fluoro-4-nitrophenyl) piperazine
Stir down, (15g, DCM 66.6mmol) (160ml) solution is cooled to 0 ℃ with 1-(2-fluoro-4-nitrophenyl) piperazine.Add then triethylamine (11.23ml, 79.92mmol), be added dropwise to subsequently Acetyl Chloride 98Min. (5.68ml, 79.92mmol).Make solution be warming up to envrionment temperature, stirred 1.5 hours.Reaction mixture is diluted water, saturated sodium bicarbonate and salt water washing with DCM.With its drying, with solvent evaporation, obtain title compound, be solid, with it under 50 ℃, dried overnight in vacuum drying oven (17.46g, 98%).
NMR(400MHz)2.05(s，3H)，3.30(dt，4H，under H
2Osignal)，3.61(m，4H)，7.18(t，1H)，8.02(d，1H)，8.02(dd，1H)；m/z 268.
Method 27
(3R, 5S)-3,5-dimethyl-1-(4-nitrophenyl) piperazine
Under 70 ℃, (10g is 70.87mmol) with (2R, 6S)-2, (17g 148.83mmol) heats 2h to the 6-lupetazin in acetonitrile (25ml) with 1-fluoro-4-oil of mirbane.With solution for vacuum concentration, residue is distributed between DCM and water+saturated sodium bicarbonate.With organic extract liquid water (4 times), salt water washing, drying concentrates, and obtains title compound, is yellow solid, with it in vacuum drying oven, at 50 ℃ of following dried overnight (16.13g, 97%).
NMR(400MHz)1.04(d，6H)，2.39(m，2H)，2.77(m，2H)，3.89(dd，2H)，7.02(d，2H)，8.03(d，2H)；m/z 236.
Method 28
(2S, 5R)-2,5-dimethyl-1-(4-nitrophenyl) piperazine
Under 100 ℃, (6g is 42.52mmol) with (2R, 5S)-2, (21.9g 191.34mmol) heats 11h to the 5-lupetazin in acetonitrile (20ml) with 1-fluoro-4-oil of mirbane.With solution for vacuum concentration, residue is distributed between DCM and water+saturated sodium bicarbonate.With organic extract liquid water (4 times), salt water washing, drying concentrates.On silica gel, use MeOH: DCM (1: 99-5: 95) chromatography, obtain title compound, be oily matter, its is placed the curing (8.32g, 83%) of spending the night.
NMR(400MHz)1.08(d，3H)，1.16(d，3H)，2.55(dd，1H)，3.18(m，2H)，3.34(m，2H)，3.95(m，1H)，6.91(d，2H)，8.03(d，2H)；m/z236.
Method 29
(2R, 6S)-1-ethanoyl-2,6-dimethyl-4-(4-nitrophenyl) piperazine
By method 26, by (3R, 5S)-3,5-dimethyl-1-(4-nitrophenyl) piperazine (method 27,16g, 68.027mmol) and Acetyl Chloride 98Min. (8.22ml 115.65mmol) prepares title compound.Obtain solid, with it under 50 ℃, dried overnight in vacuum drying oven (20.5g, 109%, contain solvent).
NMR(400MHz)1.19(brd，6H)，2.08(s，3H)，3.21(brd，2H)，4.00(d，2H)，4.34(v brs，2H)，7.08(d，2H)，8.06(d，2H)；m/z 278.
Method 30
(2R, 5S)-1-ethanoyl-2,5-dimethyl-4-(4-nitrophenyl) piperazine
By method 26, by (2S, 5R)-2,5-dimethyl-1-(4-nitrophenyl) piperazine (method 28,8.22g, 34.95mmol) and Acetyl Chloride 98Min. (4.5ml, 62.91) prepare title compound.Obtain oily matter, place the after fixing that spends the night (11.39g,＞100%, contain solvent)
NMR(400MHz)1.13(m，6H)，3.07(m，1H)，3.33(m，1H)，3.68(m，1H)，4.25(m，2H)，4.69(m，1H)，7.00(d，2H)，8.05(d，2H)；m/z 278.
Method 31
N-[4-(4-ethanoyl piperazine-1-yl)-3-aminomethyl phenyl] the guanidine supercarbonate
Under envrionment temperature and pressure, with 1-ethanoyl-4-(2-methyl-4-nitrophenyl) piperazine (method 25; 19.5g EtOH 74.06mmol) (400ml) solution is through 10%Pd/ carbon (2g) hydrogenation.With the catalyzer filtering, with EtOH (500ml) washing, reduction vaporization obtains aniline, is cream-coloured/purple solid, with it in vacuum drying oven, 50 ℃ of following dried overnight.(17g，98％)。
(15.5g 66.44mmol) anhydrous 1, stirs among 4-diox (120ml) and the EtOH (20ml) with this aniline.Add then 4N HCl De dioxane solution (19.93ml, 79.73mmol), add subsequently cyanamide (4.5g, 106.3mmol).Under nitrogen, with reactant 100 ℃ of down heating 2.5 hours, and then add cyanamide (838mg, 19.93mmol), with reactant reheat 5 hours.Behind the reduction vaporization, the solid jelly is ground with ether, with the solvent revaporization.With solid jelly water-soluble (small volume), stir down, slowly add excessive saturated sodium bicarbonate solution.After 1 hour,, collect, in vacuum drying oven,, obtain title compound (20.07g, 90%) 60 ℃ of following dried overnight with solid filtering.
NMR(400MHz)2.04(s，3H)，2.22(s，3H)，2.75(dt，4H)，3.30(brs，2H，underH
2O signal)，3.56(m，4H)，5.97(v brs，3H)，6.66(dd，1H)，6.70(d，1H)，6.90(d，1H)；m/z276.
Method 32-33
By method 31, with the suitable following compound of nitro-compound preparation.
| Method | R | NMR(400MHz) | m/z | SM |
| 32 1 | Cl | 2.05(s，3H)，2.85(dt，4H)，3.29(s，1H，under H 2O signal)， 3.57(m，4H)，5.13(s，3H)，6.68(dd，1H)，6.79(d，1H)， 6.98(d，1H) | 296- 298 | Method 24 |
| 33 2 | F | 2.03(s，3H)，2.87(dt，4H)，3.29(s，2H，under H 2O signal)， 3.56(m，4H)，5.15(brs，3H)，6.53(m，2H)，6.87(t，1H) | 280 | Method 26 |
1Only use 1.4 equivalent cyanamides, no longer add other cyanamide, only heat 5.5h.The preparation free alkali: salt is dissolved in less water, add subsequently the NaOH aqueous solution (2.5M) (～22ml).Leach the precipitation of formation, obtain the deep yellow solid, with it in vacuum drying oven, 50 ℃ of following dried overnight.(13.34g，100％)。
2Add other cyanamide and HCl, be heated and spend the night.(14.14g，68％)。
Method 34
N-[4-((3R, 5S)-4-ethanoyl-3,5-lupetazin-1-yl) phenyl] guanidine
By method 31, with (2R, 6S)-1-ethanoyl-2,6-dimethyl-4-(4-nitrophenyl) piperazine (method 29,16.44g, 66.5mmol) and cyanamide (5.03g 119.7mmol) is raw material, and 95 ℃ of following heated overnight, prepares title compound.With this supercarbonate in vacuum drying oven, 60 ℃ of following dried overnight.Because it is still moist, so it is dissolved in MeOH and acetone again,, obtain title compound with solvent evaporation, be brown solid (18.6g, 80%).
NMR(400MHz)1.3(brs，6H)，2.05(s，3H)，2.70(brd，2H)，3.35(m，4H under H
2O signal)，3.90-4.60(v brs，2H)，5.50-6.40(v brs，2H)，6.75(d，2H)，6.85(d，2H)；m/z 290.
Method 35
N-[4-((2S, 5R)-4-ethanoyl-2,5-lupetazin-1-yl) phenyl] guanidine
By method 31, with (2R, 5S)-1-ethanoyl-2,5-dimethyl-4-(4-nitrophenyl) piperazine (method 30,6.5g, 26.29mmol) and cyanamide (2.43g 57.84mmol) be raw material, and heats 10h at 95 ℃ times and prepare title compound.With this supercarbonate in vacuum drying oven, 60 ℃ of following dried overnight.Obtain solid (10.23g,＞100%, contain solvent).M/z 290。
Method 36
1-(4-nitrophenyl)-azetidin-3-alcohol
Stir down, with 4-fluoro-oil of mirbane (12.70g, 90mM), hydrochloric acid 3-hydroxyl (hydroxoy) azetidine (10.85g, 99mM) and the mixture heating up of Anhydrous potassium carbonate in acetonitrile (250ml) refluxed 6 hours.During cooling, some crystallizations appear.Reaction mixture is diluted with water to 1.41, crystalline material is leached, wash with water, drying.Title compound is yellow crystal solid (14.8g, 85%).
NMR：3.73(m，2H)，4.25(m，H)，4.60(m，1H)，5.77(d，1H)，6.43(d，2H)，8.00(d，2H)；m/z 195.
Method 37
1-(4-aminophenyl) azetidin-3-alcohol
Under normal pressure, stir down, 1-(4-nitrophenyl)-azetidin-3-alcohol (method 36; 15.15g EtOH 87mM) (250ml) solution was through 10%Pd/C (1.5g) hydrogenation 18 hours.Reaction mixture is filtered,, grind, obtain title compound, be grey crystalline solid with ether with the filtrate evaporation.The crystallization from reaction mixture of most of product is separated out, and leaches with catalyzer.These products and DMF (100ml) are stirred 15min, catalyzer is leached.With filtrate evaporation (high vacuum), grind with a small amount of EtOH.Second batch of product leached, with ether washing, drying.
NMR：3.35(m+water，2H)，3.90(t，2H)，4.32(s，2H)，4.45(m，1H)，5.41(d，1H)，6.20(d，2H)，6.45(d，2H)；m/z 165.
Method 38
((E)-{ [4-(3-hydroxy azetidine-1-yl) phenyl] amino } methylene radical
(methylylidene)) diamino acid di tert butyl carbonate
To [(Z)-the tert-butoxycarbonyl imino-]-trifyl-methyl }-t-butyl carbamate (13.62g, 34.8mM) and triethylamine (4.9ml adds 1-(4-aminophenyl) azetidin-3-alcohol (method 37 in anhydrous DCM (183ml) solution 34.8mM); 6.0g, 36.5mM).Under nitrogen, at room temperature, with solution stirring 48 hours.Again with the DCM dilution, water (twice), saturated sodium bicarbonate solution (twice), water and saturated sodium-chloride wash with reaction mixture.Solution filters through anhydrous sodium sulfate drying then, evaporation.Crude product is ground with ether/isohexane (2: 1), filter, with the same solvent washing, drying obtains title compound, is yellow solid (11.77g, 83%).
NMR 1.4(s，9H)，1.5(s，9H)，3.47(t，1H)，4.02(t，2H)，4.5(m，1H)，5.55(d，1H)，6.38(d，2H)，7.23(d，2H)，9.75(s，1H)，11.46(m，1H)；m/z407.
Method 39
N-[4-(3-hydroxy azetidine-1-yl) phenyl] the guanidine supercarbonate
With ((E)-{ [4-(3-hydroxy azetidine-1-yl) phenyl] amino } methylene radical) diamino acid di tert butyl carbonate (method 38; 250mg, TFA 0.62mM) (4.5ml) and water (0.52ml) solution at room temperature stir and spend the night.Water and excessive TFA vacuum are removed.Crude salt is dissolved in MeOH (5ml), and (the 3.0m.equ/g capacity, 0.49g) support agent is with mixture mild stirring 4 hours at room temperature to add the macroporous polystyrene carbonate resin.With the resin filtering, with the MeOH washing,, obtain title compound with the filtrate evaporation, be brown glass shape thing (45mg, 77%).
NMR 3.47(t，2H)，4.05(t，2H)，4.54(m，1H)，6.42(d，2H)，7.0(d，2H)；m/z207.
Method 40
[(3R)-and 1-(4-nitrophenyl) tetramethyleneimine-3-yl] t-butyl carbamate
With (3R)-tetramethyleneimine-3-aminocarbamic acid tert-butyl ester (4.54g, 24.4mmol), the 4-fluoronitrobenzene (3.78g, 24mmol) and acetonitrile (70ml) vlil of salt of wormwood (3.54g 25.6mmol) 18 hours.Behind the reduction vaporization, mixture is dissolved in DCM (200ml), water (100ml), saturated nacl aqueous solution (25ml) washing.With the solution drying, filter.Behind the reduction vaporization, on silica gel, use the DCM elution chromatography, obtain title compound (7.19g, 97%).
NMR：1.39(s，9H)，1.87-1.98(m，1H)，2.09-2.21(m，1H)，3.15-3.23(m，1H)，3.32-3.44(m，1H)，3.45-3.51(m，1H)，3.53-3.61(m，1H)，4.09-4.21(m，1H)，6.57(d，2H)，7.21(s，1H)，8.01(d，2H)；m/z(MH
+-C
4H
8)252.
Method 41
(3R)-1-(4-nitrophenyl) tetramethyleneimine-3-amine trifluoroacetate
At room temperature, make [(3R)-and 1-(4-nitrophenyl) tetramethyleneimine-3-yl] t-butyl carbamate (method 40; 1.0g, (15ml) solution of DCM 3.26mmol) and TFA (7.5ml) reaction 18 hours.After the filtration, impouring cold diethyl ether (200ml) obtains title compound (0.97g, 93%).
NMR：2.03-2.17(m，1H)，2.22-2.44(m，1H)，3.40-3.60(m，3H)，3.68-3.74(m，1H)，3.95-4.08(m，1H)，6.66(d，2H)，8.08(d，2H)，8.14(s，2H).
Method 42
N-[(3R)-and 1-(4-nitrophenyl) tetramethyleneimine-3-yl] ethanamide
At room temperature, make (3R)-1-(4-nitrophenyl) tetramethyleneimine-3-amine trifluoroacetate (method 41; 0.96g, 3mmol) and sodium acetate (0.245g, (10ml) solution of acetate 3mmol) and diacetyl oxide (0.57ml, 6mmol) reaction 18 hours.After the filtration,, obtain title compound, be yellow solid (0.63g, 84%) with the ether washing.
NMR：1.79(s，3H)，1.85-1.98(m，1H)，2.09-2.23(m，1H)，3.19-3.30(m，1H)，3.39-3.52(m，2H)，3.55-3.67(m，1H)，4.30-4.43(m，1H)，6.60(d，2H)，8.04(d，2H)，8.15(d，1H)；m/z 250.
Method 43
N-[(3R)-and 1-(4-aminophenyl) tetramethyleneimine-3-yl] ethanamide one hydrochloride
At room temperature, under 1 normal atmosphere, in dehydrated alcohol (200ml), make N-[(3R)-1-(4-nitrophenyl) tetramethyleneimine-3-yl] ethanamide (method 42; 4.5g, 18mmol) through 10% palladium/hydrocarbonize.After the catalyzer filtration, reduction vaporization obtains N-[(3R)-1-(4-aminophenyl) tetramethyleneimine-3-yl] ethanamide, be red oil (3.75g, 95%).
NMR(CDCl
3)：1.97(s，3H)，1.89-2.03(m，1H)，2.22-2.34(m，1H)，2.54(s，2H)，3.06-3.27(m，2H)，3.34-3.48(m，2H)，4.52-4.68(m，1H)，5.79(brs，1H)，6.48(d，2H)，6.69(d，2H)；m/z220.
With 1 of 4M hydrogenchloride, the 4-dioxane solution is handled, and obtains title compound (4.21g, 96%).LCMS：m/z 220。
Method 44
[(E)-(4-[(3R)-3-(kharophen) tetramethyleneimine-1-yl] phenyl } amino) methylene radical] diamino
Base formic acid di tert butyl carbonate
At room temperature, make N-[(3R)-1-(4-aminophenyl) tetramethyleneimine-3-yl] ethanamide one hydrochloride (method 43; 2.47g, 9.67mmol) and Hunigs alkali (2.02ml is 1.16mmol) with [(Z)-1H-pyrazol-1-yl methylene radical] diamino acid di tert butyl carbonate (2.95g, THF 9.5mmol) (50ml) solution reaction 72 hours.Behind the reduction vaporization, and usefulness EtOAc/ isohexane on silica gel (50: 50-100) chromatography, obtain title compound, be yellow oil (3.06g, 69%).
NMR：1.39(s，9H)，1.52(s，9H)，1.81(s，3H)，1.82-1.93(m，1H)，2.11-2.24(m，1H)，3.00-3.08(m，1H)，3.21-3.51(m，3H)，4.29-4.40(m，1H)，6.50(d，2H)，7.29(d，2H)，8.12(d，1H)，9.74(s，1H)，11.49(s，1H)；m/z 462.
Method 45
Carbonic acid 4-((3R)-kharophen tetramethyleneimine-1-yl) guanidines
At room temperature, under nitrogen, make [(E)-(4-[(3R)-3-(acetylamino) tetramethyleneimine-1-yl] phenyl } amino) methylene radical] diurethanes (method 44; 3.06g, 6.6mmol) with DCM (100ml) solution reaction of TFA (20ml) 18 hours.Behind the reduction vaporization, make residue be dissolved in MeOH (40ml), (the 3.0m.equ/g capacity, 0.49g) (6g) handles, and stirs 4 hours with the macroporous polystyrene carbonate resin.Mixture is filtered, wash with MeOH.Behind the reduction vaporization, obtain title compound, be gray solid (1.25g, 65%).
NMR：1.80-1.94(m，1H)，1.83(s，3H)，2.09-2.22(m，1H)，2.96-3.09(m，1H)，3.19-3.29(m，1H)，3.30-3.39(m，1H)，3.40-3.52(m，1H)，4.28-4.41(m，1H)，6.52(d，2H)，6.91(d，2H)，7.32(brs，4H)，8.13(d，1H)；m/z 262.
Method 46
[(3S)-and 1-(4-nitrophenyl) tetramethyleneimine-3-yl] t-butyl carbamate
By method 40, be feedstock production title compound (6.11g, 74%) with (3S)-tetramethyleneimine-3-aminocarbamic acid tert-butyl ester.
NMR：1.36(s，9H)，1.83-1.98(m，1H)，2.08-2.20(m，1H)，3.12-3.24(m，1H)，3.31-3.51(m，2H)，3.52-3.65(m，1H)，4.09-4.23(m，1H)，6.58(d，2H)，7.20(s，1H)，8.01(d，2H)；m/z 198(MH
+-C
4H
8).
Method 47
(3S)-1-(4-nitrophenyl) tetramethyleneimine-3-amine trifluoroacetate
By method 41, be feedstock production title compound (6.6g, 100%) with [(3S)-1-(4-nitrophenyl) tetramethyleneimine-3-yl] t-butyl carbamate (method 46).
NMR：2.03-2.19(m，1H)，2.20-2.40(m，1H)，3.25-3.75(m，3H)，3.94-4.04(m，1H)，4.38(brs，2H)，6.64(d，2H)，8.08(d，2H)，8.24(s，3H)：m/z 208.
Method 48
N-[(3S)-and 1-(4-nitrophenyl) tetramethyleneimine-3-yl] ethanamide
By method 42, be feedstock production title compound (4.2g, 93%) with (3S)-1-(4-nitrophenyl) tetramethyleneimine-3-amine trifluoroacetate (method 47).
NMR：1.80(s，3H)，1.86-1.98(m，1H)，2.11-2.24(m，1H)，3.15-3.28(m，1H)，3.37-3.55(m，2H)，3.64-3.70(m，1H)，4.32-4.44(m，1H)，6.61(d，2H)，8.04(d，2H)，8.15(d，1H)：m/z 250.
Method 49
N-[(3S)-and 1-(4-aminophenyl) tetramethyleneimine-3-yl] ethanamide
By method 43, with N-[(3S)-1-(4-nitrophenyl) tetramethyleneimine-3-yl] ethanamide (method 48) is the feedstock production title compound.
NMR：1.79(s，3H)，1.69-1.88(m，1H)，2.07-2.20(m，1H)，2.82-2.93(m，1H)，3.01-3.14(m，1H)，3.16-3.38(m，2H)，4.25-4.36(m，1H)，6.31(d，2H)，6.51(d，2H)，8.08(d，1H)+EtOH.
Method 50
[(E)-(4-[(3R)-3-(acetylamino) tetramethyleneimine-1-yl] phenyl } amino) methylene radical] two
The carboxylamine di tert butyl carbonate
By method 44, with N-[(3S)-1-(4-aminophenyl) tetramethyleneimine-3-yl] ethanamide (method 49) is feedstock production title compound (4.16g, 45%).
NMR：1.31-1.56(brs，18H)，1.80(s，3H)，1.82-1.93(m，1H)，2.07-2.21(m，1H)，3.00-3.08(m，1H)，3.19-3.40(m，2H)，3.43-3.49(m，1H)，4.30-4.41(m，1H)，6.50(d，2H)，7.26(d，2H)，7.57(s，2H)，8.10(d，1H)；m/z 462.
Method 51
Carbonic acid 4-((3S)-kharophen tetramethyleneimine-1-yl) guanidines
By method 45, with [(E)-({ 4-[(3R)-3-(acetylamino) tetramethyleneimine-1-yl] phenyl } amino) methylene radical] diamino acid di tert butyl carbonate (method 50) is feedstock production title compound (2.26g, 86%).
NMR：1.79(s，3H)，1.79-1.89(m，1H)，2.09-2.21(m，1H)，2.97-3.02(m，1H)，3.16-3.23(m，1H)，3.27-3.44(m，3H)，4.26-4.37(m，1H)，6.20-6.25(m，1H)，6.46(d，2H)，6.79(d，2H)，7.57(d，2H)，8.09(d，1H)；m/z 262.
Method 52
(R)-and N, N-dimethyl-1-(4-nitro-phenyl)-tetramethyleneimine-2-methane amide
With the 4-fluoronitrobenzene (0.47g, 3.34mmol), salt of wormwood (1.39,10mmol) and (R)-N, N-dimethyl-tetramethyleneimine-2-methane amide (0.50,3.52mmol) pre-mixing in acetonitrile (40ml), reflux 36 hours.(40ml) will react quencher with saturated ammonium chloride, and (2 * 100ml) extractions, drying is removed the solvent vacuum, obtains title compound, is yellow solid with DCM.Add ether, stir solids is filtered, dry (0.85g, 96%).M/z 264。
Method 53
(S)-and N, N-dimethyl-1-(4-amino-phenyl)-tetramethyleneimine-2-methane amide
With (R)-N, N-dimethyl-1-(4-nitro-phenyl)-tetramethyleneimine-2-methane amide (method 52; 0.85g) be dissolved in MeOH (50ml), in this solution, add ammonium formiate (1.0g, 16mmol) and palladium (0.1g).With reactant reflux 60 minutes (reactant fades).The MeOH vacuum is removed, add saturated ammonium chloride (50ml).(2 * 100ml) extractions, drying with solvent vacuum-evaporation, obtains title compound, is brown jelly (0.67g, 87%) with DCM with system.Product is exposed to blackening rapidly in the air.Use this product immediately, need not any purifying.
Method 54
(S)-and N, N-dimethyl-1-(4-guanidine radicals-phenyl)-tetramethyleneimine-2-methane amide
To (S)-N, N-dimethyl-1-(4-amino-phenyl)-tetramethyleneimine-2-methane amide (method 53; 0.67g) middle acetonitrile (20ml) and the EtOH (2ml) of adding.(0.86ml 3.48mmol), stirs reactant 10 minutes, and HCl salt precipitation is separated out to add HCl De dioxane solution.(0.2g 4.9mmol), spends weekend with the reactant reflux to add cyanamide.The black reaction thing is filtered,, use NaHCO black HCl salt water-soluble (5ml)
3(20ml) solution alkalization.Do not find solid; The aqueous solution is alkalized to pH 14 with KOH again, and (2 * 100ml) extractions, drying is removed the solvent vacuum, obtains title compound, is black jelly (0.50g, 63%) with DCM.M/z276。
Method 55
(R)-1-(4-nitro-phenyl)-tetramethyleneimine-2-formic acid
With proline(Pro) (3.5g, 30.4mmol), the 4-iodonitrobenzene (7.2g, 28.9mmol), Pd (PPh
3)
4(1.7g, 5mol%), cuprous iodide (0.3g, 5mol%), benzyltriethylammonium chloride (11.9g, 52mmol), triethylamine (8.3ml, 60mmol) and salt of wormwood (4.2g, 30mmol) pre-mixing in DMF (60ml)/water (6ml).Reactant was heated 8 hours down at 80 ℃.The DMF vacuum is removed, will remain the black jelly and be dissolved in DCM, with 2.0N HCl (50ml) acidifying, (3 * 100ml) extractions, drying is removed the solvent vacuum, obtains black tar with DCM.Tar is dissolved in minute quantity DCM (7ml), installs on the 50g silicagel column, system is used 20%EtOAc/ isohexane, 60%EtOAc/ isohexane and 100%EtOAc wash-out successively.Obtain title compound, be orange jelly.
NMR(299.954MHz，CDCl
3)8.13(d，2H)，6.52(d，2H)，4.41(d，1H)，3.66(t，1H)，3.49(q，1H)，2.47-2.29(m，2H)，2.25-2.12(m，2H)；m/z 237.
Method 56
(R)-N-methyl isophthalic acid-(4-nitro-phenyl)-tetramethyleneimine-2-methane amide
To (R)-1-(4-nitro-phenyl)-tetramethyleneimine-2-formic acid (method 55; 1.8g, add in DCM 7.6mmol) (50ml) solution HATU (3.2g, 8.4mmol) and DIPEA (2.0ml, 11.4mmol).Reactant was stirred 10 minutes, add then methylamine (the THF solution of 2.0N, 5.0ml, 15mmol); Reactant was stirred 1 hour water (50ml) quencher then.(3 * 100ml) extractions, drying is removed the solvent vacuum, obtains yellow jelly with DCM with reactant.By column chromatography,, finish purifying with the 100%EtOAc wash-out at last with 20%EtOAc/ isohexane, 60%EtOAc/ isohexane.Obtain title compound, be orange jelly; (1.4g, 74%).
NMR(299.954MHz，CDCl
3)8.10(d，2H)，6.56(d，2H)，6.24(s，1H)，4.20(t，1H)，3.75(t，1H)，3.40(q，1H)，2.80(d，3H)，2.36-2.29(m，2H)，2.13-2.05(m，2H)；m/z 250.
Method 57
(R)-N-methyl isophthalic acid-(4-amino-phenyl)-tetramethyleneimine-2-methane amide
With (R)-N-methyl isophthalic acid-(4-nitro-phenyl)-tetramethyleneimine-2-methane amide (method 56; 1.2g, 4.8mmol) be dissolved in MeOH (50ml), in this solution, add ammonium formiate (1.5g, 24mmol) and palladium (0.1g).With reactant reflux 60 minutes; Reactant fades.The MeOH vacuum is removed, add saturated ammonium chloride (50ml), (2 * 100ml) extractions, drying is removed the solvent vacuum, obtains title compound, is brown jelly (1.0g, 95%) with DCM with system.Product is exposed to blackening rapidly in the air.Use this product immediately, need not any purifying.
Method 58
1-[4-({ (E)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } ammonia
Base) phenyl]-N-methyl D-prolineamide (prolinamide)
To (R)-N-methyl isophthalic acid-(4-amino-phenyl)-tetramethyleneimine-2-methane amide (method 57; 1.0g, disposable adding in DCM 4.5mmol) (60ml) solution [(Z)-1H-pyrazol-1-yl methylene radical] the diamino acid di tert butyl carbonate (1.7g, 5.5mmol).The reactant stirring is spent the night, then the solvent vacuum is removed.Make residue by column chromatography 20%EtOAc/ isohexane, 50%EtOAc/ isohexane, use 100%EtOAc wash-out purifying at last.Obtain title compound, be white foam shape thing (1.9g, 91%).
Method 59
(R)-N-methyl isophthalic acid-(4-guanidine radicals-phenyl)-tetramethyleneimine-2-methane amide
To 1-[4-({ (E)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl]-N-methyl D-prolineamide (method 58; 1.9g) middle DCM (60ml) and the TFA (20ml) of adding.Reactant was stirred 4 hours, then the solvent vacuum is removed.With the reactant alkalization, (2 * 50ml) extract with DCM with 2.0N KOH (20ml).Fail product is extracted to DCM, the aqueous solution is reduced to 90% of original volume, (3 * 200ml) extractions again, drying is removed the solvent vacuum, obtains title compound, is brown solid (0.84g, 78%) with DCM.
NMR(299.955MHz)7.79(q，1H)，7.57(s，1H)，7.18(s，2H)，7.03(d，2H)，6.48(d，2H)，3.91(d，1H)，3.58-3.54(m，1H)，3.17(q，1H)，2.56(d，3H)，2.19-2.09(m，2H)，2.01-1.89(m，2H)；m/z 261.
Method 60
(R)-N-cyclopropyl-1-(4-nitro-phenyl)-tetramethyleneimine-2-methane amide
To (R)-1-(4-nitro-phenyl)-tetramethyleneimine-2-formic acid (method 55; 1.8g, add in DCM 7.6mmol) (50ml) solution HATU (3.2g, 8.4mmol) and DIPEA (2.0ml, 11.4mmol).Reactant was stirred 10 minutes, add then methylamine (0.84g, 15mmol); Reactant was stirred 1 hour water (50ml) quencher then.(3 * 100ml) extractions, drying is removed the solvent vacuum, obtains yellow jelly with DCM with reactant.With 20%EtOAc/ isohexane, 60%EtOAc/ isohexane, finish purifying with 100% EtOAc wash-out by column chromatography at last.Obtain title compound, be yellow solid (1.4g, 74%).
NMR(299.954MHz，CDCl
3)δ8.13(d，2H)，6.55(d，2H)，6.06(s，1H)，4.14(t，1H)，3.70(t，1H)，3.38(q，1H)，2.75-2.66(m，1H)，2.36-2.29(m，2H)，2.17-1.95(m，2H)，0.82-0.73(m，2H)，0.46-0.35(m，2H)；m/z 276.
Method 61
(R)-N-cyclopropyl-1-(4-amino-phenyl)-tetramethyleneimine-2-methane amide
With (R)-N-cyclopropyl-1-(4-nitro-phenyl)-tetramethyleneimine-2-methane amide (method 60; 142g 5.1mmol) is dissolved in MeOH (50ml), in this solution, add ammonium formiate (1.6g, 26mmol) and palladium (0.1g).With reactant reflux 60 minutes; Reactant fades.The MeOH vacuum is removed, add saturated ammonium chloride (50ml), (2 * 100ml) extractions, drying is removed the solvent vacuum, obtains title compound, is brown jelly (1.20g, 96%) with DCM with system.Product is exposed to blackening rapidly in the air.Use this product immediately, need not any purifying; M/z246.
Method 62
1-[4-({ (E)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } ammonia
Base) phenyl]-N-cyclopropyl-D-prolineamide
With (R)-N-cyclopropyl-1-(4-amino-phenyl)-tetramethyleneimine-2-methane amide (method 61; 1.2g, the disposable adding of DCM 4.9mmol) (60ml) solution [(Z)-1H-pyrazol-1-yl methylene radical] diamino acid di tert butyl carbonate (1.9g, 6.1mmol) in.The reactant stirring is spent the night, then the solvent vacuum is removed.Make residue pass through column chromatography,, use 100%EtOAc wash-out purifying at last with 20% ethyl acetate/isohexane, 50%EtOAc/ isohexane.Obtain title compound, be white foam shape thing (2.0g, 81%).
NMR(299.954MHz，CDCl
3)11.63(s，1H)，10.09(s，1H)，7.60(s，1H)，7.40(d，2H)，6.45(m，3H)，3.92(t，1H)，3.59(t，1H)，3.19(q，1H)，2.69(m，1H)，2.29-2.22(m，2H)，2.03-1.84(m，2H)，1.53(s，9H)，1.49(s，9H)，0.80-0.68(m，2H)，0.44-0.32(m，2H)；m/z 488.
Method 63
(R)-N-cyclopropyl-1-(4-guanidine radicals-phenyl)-tetramethyleneimine-2-methane amide
To 1-[4-({ (E)-[(tert-butoxycarbonyl) amino] [(tert-butoxycarbonyl) imino-] methyl } amino) phenyl]-N-cyclopropyl-D-prolineamide (method 62; 2.0g) middle DCM (60ml) and the TFA (20ml) of adding.Reactant was stirred 4 hours, then the solvent vacuum is removed.(3.0m.equ/g capacity, 0.49g) support agent (20g) are spent the night slow stirring of reactant to add DCM (75ml) and macroporous polystyrene carbonate resin in jelly.Reactant is filtered, the solvent vacuum is removed, obtain the minute quantity product.There is white solid in the filter bowl, this solid is dissolved in MeOH, resin is also added among this MeOH, system was stirred 10 minutes, filter then, the solvent vacuum is removed, obtain title compound, be white solid (0.90g, 75%).NMR(299.954 MHz，CDCl
3)δ7.26(s，3H)，6.85(d，2H)，6.49(d，2H)，3.93(d，1H)，3.62-3.60(m，1H)，3.17(q，1H)，2.70-2.62(m，1H)，2.32-2.14(m，2H)，2.00-1.92(m，2H)，0.76-0.63(m，2H)，0.42(q，2H)；m/z 287.
Method 64
[(3R)-and 1-(2-fluoro-4-nitrophenyl) tetramethyleneimine-3-yl] t-butyl carbamate
By the route that is similar to method 40, be feedstock production title compound (5.40g, 74%) with (3R)-tetramethyleneimine-3-aminocarbamic acid tert-butyl ester.
NMR：1.36(s，9H)，1.81-1.94(m，1H)，2.02-2.16(m，1H)，3.30-3.42(m，1H)，3.48-3.59(m，1H)，3.69-3.79(m，H)，4.02-4.17(m，1H)，6.72(t，1H)，7.18(brs，1H)，7.92(d，2H)；m/z 270(MH
+-C
4H
8).
Method 65
(3R)-1-(2-fluoro-4-nitrophenyl) tetramethyleneimine-3-amine trifluoroacetate
By the route that is similar to method 41, be feedstock production title compound (5.12g, 94%) with [(3R)-1-(2-fluoro-4-nitrophenyl) tetramethyleneimine-3-yl] t-butyl carbamate (method 64).
NMR：2.01-2.14(m，1H)，2.20-2.36(m，1H)，3.53-4.01(m，4H)，6.80(t，1H)，7.96(d，2H)，8.18(s，3H)；m/z 226.
Method 66
N-[(3R)-and 1-(2-fluoro-4-nitrophenyl) tetramethyleneimine-3-yl] ethanamide
By the route that is similar to method 42, so that (3R)-1-(2-fluoro-4-nitrophenyl) tetramethyleneimine-3-amine trifluoroacetate (method 65) is feedstock production title compound (3.78g, 90%).
NMR：1.80(s，3H)，1.85-1.94(m，1H)，2.05-2.19(m，1H)，3.32-3.42(m，1H)，3.51-3.71(m，2H)，3.73-3.82(m，H)，4.28-4.36(m，1H)，6.72(t，1H)，7.38-7.92(n，2H)，8.11(d，1H)；m/z 268.
Method 67
N-[(3R)-and 1-(4-amino-2-fluorophenyl) tetramethyleneimine-3-yl] ethanamide
By the route that is similar to method 43, with N-[(3R)-1-(2-fluoro-4-nitrophenyl) tetramethyleneimine-3-yl] ethanamide (method 66) is feedstock production title compound (2.62g, 76%).
NMR：1.64-1.76(m，1H)，1.79(s，3H)，2.02-2.16(m，1H)，2.87-2.92(m，H)，2.99-3.05(m，1H)，3.16-3.32(m，2H)，4.16-4.28(m，1H)，4.68(brs，2H)，6.22-6.33(m，1H)，6.35(d，2H)，6.73(d，1H)，8.02(d，H)；m/z238.
Method 68
[(E)-(2-fluoro-4-[(3R)-3-(acetylamino) tetramethyleneimine-1-yl] phenyl } amino) methylene
Base] the diamino acid di tert butyl carbonate
By the route that is similar to method 44, with N-[(3R)-1-(4-amino-2-fluorophenyl) tetramethyleneimine-3-yl] ethanamide (method 67) is the feedstock production title compound.
NMR：1.39(brs，9H)，1.46(brs，9H)，1.79(s，3H)，1.70-1.87(m，1H)，2.02-2.16(m，1H)，3.09-3.16(m，1H)，3.22-3.34(m，1H)，3.38-3.47(m，1H)，3.51-3.56(m，1H)，4.25-4.32(m，1H)，6.68(t，1H)，7.08(d，1H)，7.41(d，1H)，8.08(d，1H)，8.89(brs，1H)，9.83(brs，1H)，11.41(brs，1H)；m/z480.
Method 69
Carbonic acid 2-fluoro-4-((3R)-kharophen tetramethyleneimine-1-yl) guanidines
By the route that is similar to method 45, with [(E)-({ 2-fluoro-4-[(3R)-3-(acetylamino) tetramethyleneimine-1-yl] phenyl } amino) methylene radical] diamino acid di tert butyl carbonate (method 68) is feedstock production title compound (2.43g, 86%).
NMR：1.75-1.86(m，1H)，1.80(s，3H)，2.06-2.18(m，1H)，3.21-3.38(m，2H)，3.50-3.60(m，1H)，4.21-4.34(m，1H)，6.72(t，1H)，6.89(d，1H)，7.00(d，1H)，7.29(brs，3H)，8.08(d，1H)，9.50(s，1H).
Method 70
4-((3R)-kharophen tetramethyleneimine-1-yl) guanidines trifluoroacetate
With N-[(3R)-1-(4-aminophenyl) tetramethyleneimine-3-yl] ethanamide one hydrochloride (method 44,3.31g, 15mmol), [(Z)-and 1H-pyrazol-1-yl methylene radical] diamino acid di tert butyl carbonate (5.91g, 15mmol) and triethylamine (4.17ml, DCM 30mmol) (50ml) solution is 40 ℃ of down heating 18 hours.Behind the reduction vaporization; on silica gel, use ethyl acetate/isohexane (50: 50-100) chromatography; obtain [(E)-(4-[(3R)-3-(acetylamino) tetramethyleneimine-1-yl] phenyl } amino) methylene radical] the diamino acid di tert butyl carbonate; it is dissolved in DCM (80ml); under nitrogen, use TFA (15ml) to handle at ambient temperature 18 hours.Behind the reduction vaporization, residue is dissolved in MeOH (20ml), dilutes with ether.Title compound is filtered, collect, be pale solid (1.79g, two step yields 30%).
NMR：1.80(s，3H)，1.81-1.93(m，1H)，2.10-2.27(m，1H)，2.99-3.06(m，1H)，3.19-3.51(m，3H)，4.27-4.39(m，1H)，6.52(d，2H)，7.03(d，2H)，7.16(s，3H)，8.10(d，1H)，9.36(s，1H).
Embodiment 164
Below illustrate the treatment that is used for the people or the representative drugs formulation of preventive use, these formulations contain hydrolyzable ester (hereinafter claiming compounds X) in formula (I) compound or its pharmacy acceptable salt or the body :-
| (a): tablet I | The mg/ sheet |
| Compounds X | 100 |
| Lactose-European Pharmacopoeia | 182.75 |
| Croscarmellose sodium | 12.0 |
| Corn starch liquid (5%w/v slurry) | 2.25 |
| Magnesium Stearate | 3.0 |
| (b): tablet II | The mg/ sheet |
| Compounds X | 50 |
| Lactose-European Pharmacopoeia | 223.75 |
| Croscarmellose sodium | 6.0 |
| W-Gum | 15.0 |
| Polyvinylpyrrolidone (5%w/v slurry) | 2.25 |
| Magnesium Stearate | 3.0 |
| (c): tablet III | The mg/ sheet |
| Compounds X | 1.0 |
| Lactose-European Pharmacopoeia | 93.25 |
| Croscarmellose sodium | 4.0 |
| Corn starch liquid (5%w/v slurry) | 0.75 |
| Magnesium Stearate | 1.0 |
| (d): capsule | The mg/ capsule |
| Compounds X | 10 |
| Lactose-European Pharmacopoeia | 488.5 |
| Magnesium Stearate | 1.5 |
| (e): injection I | (50mg/ml) |
| Compounds X | 5.0％w/v |
| The 1M sodium hydroxide solution | 15.0％v/v |
| 0.1M hydrochloric acid | (pH is transferred to 7.6) |
| Poly(oxyethylene glycol) 400 | 4.5％w/v |
| Water for injection | To 100% |
| (f): injection II | 10mg/ml |
| Compounds X | 1.0％w/v |
| Sodium phosphate BP | 3.6％w/v |
| 0.1M sodium hydroxide solution | 15.0％v/v |
| Water for injection | To 100% |
| (g): injection III | (1mg/ml is buffered to pH6) |
| Compounds X | 0.1％w/v |
| Sodium phosphate BP | 2.26％w/v |
| Citric acid | 0.38％w/v |
| Poly(oxyethylene glycol) 400 | 3.5％w/v |
| Water for injection | To 100% |
Explanation
Can obtain above preparation by the ordinary method of knowing in the pharmaceutical field.Can pass through ordinary method, for example provide the Cellacefate dressing can tablet (a)-(c) is enteric coated.
Claims (15)
1. formula (I) compound or its pharmacy acceptable salt:
Wherein:
The optional 4-7 unit saturated rings that contains other nitrogen or Sauerstoffatom that the A ring connects for nitrogen;
If wherein the A ring contains other nitrogen-atoms, then this nitrogen can be chosen wantonly by R
7Replace,
R wherein
7Be selected from C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
2-6Thiazolinyl alkylsulfonyl, carbocylic radical-R
18-or heterocyclic radical-R
19-; R wherein
7Can be independently optional selected on carbon from R
20Group replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly by R
21Replace;
R
18And R
19Be-C (O)-;
R
20Be selected from halogen, cyano group, hydroxyl, C
1-6Alkoxyl group, C
2-6Alkynyloxy group, C
1-6Alkyloyl oxygen base, N, N-(C
1-6Alkyl)
2Amino, wherein a is 2 C
1-6Alkyl S (O)
aOr heterocyclic radical, wherein R
20Can be independently optional by one or more R on carbon
26Replace;
R
21Be C
1-6Alkyl;
R
26It is hydroxyl;
R
1Be halogen or C
1-6Alkyl;
P is 0 or 1;
R
2Be selected from hydroxyl, amino, azido-, C
1-6Alkyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, carbocylic radical-R
34-,-NHR
9Or-O-R
12
R
9And R
12Independently be selected from C
1-6Alkyloyl or C
1-6Alkyl sulphonyl; R wherein
9And R
12Can be independently optional selected on carbon from R
20Group replace;
R
20It is hydroxyl;
R
34Be-N (R
29) C (O)-, R wherein
29Be hydrogen; Q is 0-2; R wherein
2Can be identical or different;
R
3Be halogen;
N is 0 or 1;
R
4Be C
1-6Alkyl or carbocylic radical; R wherein
4Can choose wantonly on carbon by one or more R
14Replace, wherein R
14Be carbocylic radical;
R
5And R
6Independently be selected from hydrogen or C
1-6Alkyl; R wherein
5And R
6Independently of one another, can choose wantonly on carbon by one or more R
16Replace, wherein R
16Be methoxyl group;
Wherein above-mentioned carbocylic radical is saturated, fractional saturation or unsaturated monocycle or the bicyclic carbocyclic that contains 3-12 atom; And
Wherein above-mentioned heterocyclic radical is saturated, fractional saturation or unsaturated monocycle or the dicyclo that contains 4-12 atom, and wherein at least one atom is selected from nitrogen, sulphur or oxygen.
2. the formula of claim 1 (I) compound or its pharmacy acceptable salt, wherein:
The A ring is piperazine-1-base, morpholino, tetramethyleneimine-1-base or azetidine-1-base; Wherein said piperazine-1-base can be chosen wantonly by R on nitrogen
7Replace; Wherein
R
7Be selected from ethanoyl, propionyl, 2,2-dimethyl propylene acyl group, 3-methylbutyryl base, butyryl radicals, isobutyryl, methylsulfonyl, ethylsulfonyl, vinylsulfonyl, cyclopropyl-R
18-, tetrahydrofuran base-R
19-or pyrrolidyl-R
19-; R wherein
7Can be independently optional selected on carbon from R
20Group replace; If wherein described heterocyclic radical contains-the NH-part, then this nitrogen can be chosen wantonly by R
21Replace;
R
18And R
19For-C (O)-;
R
20Be selected from fluorine, chlorine, cyano group, hydroxyl, methoxyl group, third-2-alkynes-1-base oxygen base, acetoxyl group, dimethylamino, diethylin, methylsulfonyl, tetrazyl, pyrrolidyl, morpholino, azetidinyl; R wherein
20Can on carbon, choose wantonly by one or more R
26Replace;
R
21Be methyl; With
R
26Be hydroxyl.
3. the formula of claim 1 (I) compound or its pharmacy acceptable salt, wherein R
1Be chlorine, fluorine or methyl.
4. the formula of claim 1 (I) compound or its pharmacy acceptable salt, wherein:
R
2Be selected from hydroxyl, amino, azido-, methyl, N-methylamino formyl radical, N, N-formyl-dimethylamino, carbocylic radical-R
34-,-NHR
9Or-O-R
12
R
9And R
12Independently be selected from ethanoyl, propionyl or methylsulfonyl; R wherein
9And R
12Can be independently optional selected on carbon from R
20Group replace;
R
20Be hydroxyl; With
R
34For-N (R
29) C (O)-; R wherein
29Be hydrogen.
5. the formula of claim 1 (I) compound or its pharmacy acceptable salt, wherein R
3Be chlorine or fluorine.
6. the formula of claim 1 (I) compound or its pharmacy acceptable salt, wherein:
R
4Be ethyl, sec.-propyl, isobutyl-, cyclobutyl or cyclopropyl methyl.
7. the formula of claim (I) compound or its pharmacy acceptable salt, wherein:
R
5Be methyl, ethyl, propyl group or methoxymethyl; With
R
6Be hydrogen.
8. formula (I) compound or its pharmacy acceptable salt described of claim 1, wherein:
Ring A, R
2Form together with q:
1) piperazine-1-base,
2) morpholino,
3) 4-methylsulfonyl piperazine-1-base,
4) 4-ethanoyl piperazine-1-base,
5) 4-(2-acetoxyl group ethanoyl) piperazine-1-base,
6) 4-(2-hydroxyacetyl) piperazine-1-base,
7) 4-(2-chloracetyl) piperazine-1-base,
8) 4-(2-methoxyl group ethanoyl) piperazine-1-base,
9) (3-methoxy propyl acyl group) piperazine-1-base,
10) (3-hydroxy-3-methyl butyryl radicals) piperazine-1-base,
11) (3-hydroxyl-2,2-dimethyl propylene acyl group) piperazine-1-base,
12) ((R)-3-methyl-2-maloyl group) piperazine-1-base,
13) ((S)-3-methyl-2-maloyl group) piperazine-1-base,
14) 4-(2-dimethylamino ethanoyl) piperazine-1-base,
15) 4-[2-(dimethylamino) ethylsulfonyl] piperazine-1-base,
16) 4-[2-(methoxyl group) ethylsulfonyl] piperazine-1-base,
17) 4-[2-(hydroxyl) ethylsulfonyl] piperazine-1-base,
18) 4-(cyclopropyl carbonyl) piperazine-1-base,
19) 4-(1-hydroxyl cyclopropyl carbonyl) piperazine-1-base,
20) 4-(1-cyano group cyclopropyl carbonyl) piperazine-1-base,
21) 4-(2-hydroxy-2-methyl propionyl) piperazine-1-base,
22) 4-((R)-2-hydroxyl propionyl) piperazine-1-base,
23) 4-((S)-2-hydroxyl propionyl) piperazine-1-base,
24) 4-((R)-2-methoxy propyl acyl group) piperazine-1-base,
25) 4-((S)-2-methoxy propyl acyl group) piperazine-1-base,
26) 4-((R)-tetrahydrofuran (THF)-2-base carbonyl) piperazine-1-base,
27) 4-((S)-tetrahydrofuran (THF)-2-base carbonyl) piperazine-1-base,
28) 4-(isobutyryl) piperazine-1-base,
29) 4-((R)-2-maloyl group) piperazine-1-base,
30) 4-((S)-2-maloyl group) piperazine-1-base,
31) (R)-3-acetylamino tetramethyleneimine-1-base,
32) (S)-3-acetylamino tetramethyleneimine-1-base,
33) (R)-2-(cyclopropyl aminocarboxyl) tetramethyleneimine-1-base,
34) (R)-2-(N-methylamino formyl radical) tetramethyleneimine-1-base,
35) (S)-2-(N, N-formyl-dimethylamino) tetramethyleneimine-1-base,
36) 4-(vinylsulfonyl) piperazine-1-base,
37) 4-[2-(2-propine-1-base oxygen base) ethanoyl] piperazine-1-base,
38) 4-(tetrahydrofuran (THF)-3-base carbonyl) piperazine-1-base,
39) 4-(3-dimethylamino propionyl) piperazine-1-base,
40) 4-[2-(N-methyl-N-hydroxyl methylamino-) ethanoyl] piperazine-1-base,
41) 4-[3-hydroxyl-2-(methylol) propionyl] piperazine-1-base,
42) 4-[2-(pyrrotriazole-1-yl) ethanoyl] piperazine-1-base,
43) 4-[2-(pyrrotriazole-5-yl) ethanoyl] piperazine-1-base,
44) 4-(1-methyl-L-prolyl) piperazine-1-base,
45) 4-[2-(methylsulfonyl) ethanoyl] piperazine-1-base,
46) 4-(2,2-difluoro ethanoyl) piperazine-1-base,
47) 4-[2-(tetramethyleneimine-1-yl) ethanoyl] piperazine-1-base,
48) 4-[2-(morpholino) ethanoyl] piperazine-1-base,
49) 4-[2-(diethylin) ethanoyl] piperazine-1-base,
50) 4-(propionyl) piperazine-1-base,
51) 4-(3-hydroxyl propionyl) piperazine-1-base,
52) 4-[2-(azetidine-1-yl) ethanoyl] piperazine-1-base,
53) (R)-3-amino-pyrrolidine-1-base,
54) (S)-3-amino-pyrrolidine-1-base,
55) (3R, 5S)-4-ethanoyl-3,5-lupetazin-1-base,
56) (2S, 5R)-4-ethanoyl-2,5-lupetazin-1-base,
57) (2RS, 6SR)-2,6-thebaine-4-yl] phenyl,
58) 3-hydroxy azetidine-1-base,
59) 3-acetylamino azetidine-1-base,
60) 3-(2-glycoloyl amino) azetidine-1-base,
61) the amino azetidine of 3-methylsulfonyl-1-base,
62) 3-methylsulfonyl oxygen base azetidine-1-base,
63) 3-azido-azetidine-1-base,
64) the amino azetidine of 3--1-base,
65) (3R)-3-{[(2S)-and 2-hydroxyl propionyl] amino } tetramethyleneimine-1-base,
66) (3S)-3-{[(2S)-and 2-hydroxyl propionyl] amino } tetramethyleneimine-1-base,
67) (3S)-3-(glycoloyl amino) tetramethyleneimine-1-base and
68) (3R)-3-(glycoloyl amino) tetramethyleneimine-1-base;
R
1Be fluorine, chlorine or methyl;
P is 0 or 1;
R
2Be selected from hydroxyl, amino, azido-, methyl, N-methylamino formyl radical, N; N-formyl-dimethylamino, kharophen, { [(2S)-2-hydroxyl propionyl] amino }, glycoloyl amino, methanesulfonamido, 2-glycoloyl amino, mesyloxy or N-cyclopropyl formamyl
Q is 0-2; R wherein
2Can be identical or different;
R
3Be 5-fluorine or 5-chlorine;
N or 0 or 1;
R
4Be ethyl, sec.-propyl, isobutyl-, cyclobutyl or cyclopropyl methyl;
R
5And R
6Independently be selected from hydrogen, methyl, ethyl, methoxymethyl, propyl group.
9. formula (I) compound or its pharmacy acceptable salt of describing in the claim 1, described compound is selected from:
1) 2-{4-[4-(2-hydroxyacetyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-5-fluorine pyrimidine hydrochloride;
2) 2-{4-[4-(2-hydroxyacetyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine;
3) (2S)-1-[4-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } phenyl) piperazine-1-yl]-1-oxo propan-2-ol;
4) 2-[4-(morpholino) anilino]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-5-fluorine pyrimidine;
5) 2-{4-[4-(ethanoyl) piperazine-1-yl] anilino }-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-5-fluorine pyrimidine;
6) 2-[4-(4-ethanoyl piperazine-1-yl) anilino]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine;
7) 5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-N-{4-[4-(methoxyl group ethanoyl) piperazine-1-yl] phenyl } pyrimidine-2-amine;
8) N-[4-(4-ethanoyl piperazine-1-yl)-3-fluorophenyl]-5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine;
9) N-[4-(4-ethanoyl piperazine-1-yl)-3-fluorophenyl]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine; With
10) (2R)-1-[4-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } phenyl) piperazine-1-yl]-1-oxo propan-2-ol.
10. one kind prepares among the claim 1-9 each formula (I) compound or the method for its pharmacy acceptable salt, and wherein except that referring else, the group variable-definition is with claim 1, and described method comprises:
Method a) makes formula (II) pyrimidine:
Wherein L is a displaceable group; With formula (III) aniline reaction:
Or
Method b) make formula (IV) compound:
React with the formula V compound:
Wherein T is O or S; R
XCan be identical or different, and be selected from C
1-6Alkyl; Or
Method C) make formula (VI) pyrimidine:
Wherein X is a displaceable group; React with formula (VII) heterocyclyl compounds:
Or
Method d) for obtaining formula (I) compound; Make formula (VIII) pyrimidine
React with formula (IX) compound:
Wherein Y is a displaceable group;
Thereafter method a), b), c) or d) after any one, as needs:
I) formula (I) compound is converted into another kind of formula (I) compound;
Ii) remove any blocking group;
Iii) form pharmacy acceptable salt.
11. a medicinal compositions, described composition comprise among the claim 1-9 each formula (I) compound or its pharmacy acceptable salt, and the pharmaceutically acceptable diluent or carrier of applied in any combination.
12. each formula (I) compound or its pharmacy acceptable salt purposes in the preparation medicine among the claim 1-9, described medicine is used for producing warm-blooded animal the effect of cell cycle inhibition, inhibition of cell proliferation.
13. each formula (I) compound or its pharmacy acceptable salt are used for the treatment of purposes in the medicine of cancer in preparation among the claim 1-9.
14. the purposes of claim 13, wherein said cancer is selected from leukemia, mammary cancer, lung cancer, colorectal carcinoma, the rectum cancer, cancer of the stomach, prostate cancer, bladder cancer, carcinoma of the pancreas, ovarian cancer, liver cancer, kidney, skin carcinoma and carcinoma vulvae.
15. each formula (I) compound or its pharmacy acceptable salt are used for producing the purposes of the inhibiting medicine of CDK among the claim 1-9 in preparation.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0402277A GB0402277D0 (en) | 2004-02-03 | 2004-02-03 | Chemical compounds |
| GB0402277.8 | 2004-02-03 | ||
| GB0411998.8 | 2004-05-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1938295A CN1938295A (en) | 2007-03-28 |
| CN100528865C true CN100528865C (en) | 2009-08-19 |
Family
ID=31985506
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005800100579A Expired - Fee Related CN100528865C (en) | 2004-02-03 | 2005-01-31 | Imidazolo-5-yl-anilinopyrimidines as agents for the inhibition of cell proliferation |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN100528865C (en) |
| GB (1) | GB0402277D0 (en) |
-
2004
- 2004-02-03 GB GB0402277A patent/GB0402277D0/en not_active Ceased
-
2005
- 2005-01-31 CN CNB2005800100579A patent/CN100528865C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| GB0402277D0 (en) | 2004-03-10 |
| CN1938295A (en) | 2007-03-28 |
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