CN1894243A

CN1894243A - 4-(pyrazol-3-ylamino) pyrimidine derivatives for use in the treatment of cancer

Info

Publication number: CN1894243A
Application number: CN 200480037801
Authority: CN
Inventors: T·诺瓦克; A·P·托马斯
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2003-10-17
Filing date: 2004-10-11
Publication date: 2007-01-10
Also published as: GB0324335D0; ZA200603037B

Abstract

A compound of Formula (I); wherein the substituents are as defined in the text for use in modulating insulin-like growth factor 1 receptor activity in a warm blooded animal such as man.

Description

4-(pyrazoles-3-base is amino) the pyrimidine derivative that is used for the treatment of cancer

The pharmaceutical composition that the present invention relates to novel poyrimidine derivatives, its preparation method, comprises it with and application in treatment.

Insulin-like growth factor (IGF) axle is by part, acceptor, form in conjunction with albumen and protease. Its two kinds of parts, IGF-I and IGF-II, be by with a kind of assorted tetramer cell surface receptor---the mitogenetic peptide that 1 type IGF-1 (IGF-1R) interacts and to signal. All can stimulate the activation of regional tyrosine kinase domain in the beta chain cell with any a kind of combination in these two kinds of parts and cause the phosphorylation of some tyrosine residues, so that various signalling molecule is raised and activated. Having shown that this cell intracellular domain can transmit causes mitosis, survival, conversion and differentiation signal in the cell. The people such as Adams (Cellular and Molecular Life Sciences, 57,1050-1093,2000) summarize the 26S Proteasome Structure and Function of IGF-1R. IGF-IIR (being also referred to as mannose 6-phosphate receptor) does not have such kinase domain, therefore can not send out and cause the mitosis signal, but it can regulate the utilization rate of this cell surface ligand, thereby offset the effect of IGF-1R. This igf binding protein (IGFBP) is being controlled the utilization rate of circulation IGF, and can regulate the release of IGF from these materials by molten albumen cracking. Collett-Solberg and Cohen (Endocrine, 12,121-136,2000) summarize these other components of this IGF axle.

There are many signs to show that IGF signal and cell transform and beginning and the development of tumour are related. IGF has been confirmed as protecting the main survival factors (people such as Harrington, EMBO J, 13,3286-3295,1994) that the cell death that oncogene induces do not occur. Shown the cell that lacks IGF-1R to some can effectively transform corresponding wild-type cell different oncogene (comprising SV40T antigen and ras) conversion should (people such as Sell., Mol.Cell Biol., 14,3604-12,1994). The rise that IGF axle component has occured in many tumor cell lines and tissue has been described, the said particularly breast (Surmacz that organizes, Journal of Mammary Gland Biology ﹠ Neoplasia, 5,95-105,2000), the prostate (people such as Djavan, World J.Urol., 19,225-233,2001, and the people such as O ' Brien, Urology, 58,1-7,2001) and colon (people such as Guo, Gastroenterology, 102,1101-1108,1992) tumour. On the contrary, to be inferred to be tumour inhibitor and deleted in certain cancers (people such as DaCosta, Journal of Mammary Gland Biology ﹠ Neoplasia, 5,85-94,2000) to IGF-IIR. More and more epidemiological studies increases circulation IGF (perhaps the ratio of IGF-1 and IGFBP3 increases) and links up with risk of cancer (Yu and Rohan, J.Natl.Cancer Inst., 92,1472-1489,2000). The little mouse model of transgenosis also hints and relate to IGF signalling (Lamm and Christofori, Cancer Res.58,801-807 in the beginning of tumor cell proliferation, the people such as 1998, Foster, Cancer Metas. Rev., 17,317-324,1998, and the people such as DiGiovanni, Proc.Natl.Acad.Sci., 97,3455-3460,2000).

The material evidence that some are external and the interior strategy of body provides inhibition IGF-1R to signal and reversed this phenotype that is converted and suppressed the tumour cell growth. During these evidences comprise and antibody (the people Cancer Res. such as Kalebic, 54,5531-5534,1994), the ASON (people such as Resnicoff, Cancer Res., 54,2218-2222,1994), become three spiral oligonucleotides (triple-helix forming the oligonucleotides) (people such as Rinninsland, Proc.Natl.Acad. Sci., 94,5854-5859,1997), the antisense mRNA (people such as Nakamura, Cancer Res., 60,760-765,2000) and dominant acceptor (dominant negative receptors) (D ' people such as Ambrosio., Cancer Res., 56,4013-4020,1996). ASON has shown that suppressing IGF-1R expresses the cell apoptosis of having induced cell in the body (people such as Resnicoff, Cancer Res., 55,2463-2469,1995) consider that and it also is applicable to the people (people such as Resnicoff, Proc. Amer.Assoc.Cancer Res., 40 Abs 4816,1999). But, for the treatment of main solid tumor disease, without any method special attraction is arranged in these methods.

Because signaling, hint IGF in the growth of tumour cell and survival increases, and the increase of this kind of blocking-up IGF-1R function reversible, be a kind of suitable therapy for the treatment of cancer so suppress the IGF-1R tyrosine kinase domain. Use the interior research of external and body of dominant IGF-1R modification to support this kind viewpoint. Particularly the proof ATP that blocked receptor tyrosine kinase activity has effectively stoped tumour cell growth people such as (, Mol.Cell.Biol., 17,1595-1606,1997) Kulik in conjunction with the point mutation in the position. Some signs show that sporadicly normal cell relatively is not easy to be suppressed the signal impact of the cell apoptosis that causes of IGF, and this shows may have certain treatment boundary (Baserga, Trends Biotechnol., 14,150-2,1996) to such treatment.

The report that seldom relevant selective IGF-1R tyrosine-kinase enzyme inhibitor is arranged. The people such as Parrizas described some in vitro and in vivo effectively the tyrosine phosphatase inhibitor (people such as Parrizas., Endocrinology, 138:1427-33 (1997)). These compounds have the effect of appropriateness and the insulin acceptor are had selectively. But Telik Inc. has had selective to some to the insulin acceptor has been described (disclosed PCT patent application WO 00/35455) in external effectiveness to tumour cell still not high assorted aryl-aryl urea.

In WO 03/048133, the pyrimidine derivative in the substituted amino replacement of 2-and 4-position with IGF-IR tyrosine-kinase enzyme inhibition activity is described. But the nitrogen-atoms that does not wherein disclose said amino substituting group has formed the compound of a heterocycle part.

The pyrimidine derivative that WO 02/50065 discloses some pyrazoles base-amino replacement has protein kinase inhibiting activity, it especially can be used as the inhibitor of Aurora-2 and glycogen synthase kinase-3 (GSK-3), and can be used for treating disorders such as cancers, diabetes and Alzheimer's. Its disclosed compound has the amino substituting group of replacement in the 2-position of this pyrimidine ring, but it does not still have the open wherein nitrogen-atoms of amino substituting group to form the compound of the part of heterocycle.

The heterocyclic substituted that the general 2-position that discloses pyrimidine ring is wherein connected by N-at WO 02/22601, WO 02/22602, WO 02/22603, WO 02/22604, WO 02/22605, WO 02/22606, WO 02/22607 and during WO is connected have a pyrimidine derivative that Aurora-2 and glycogen synthase kinase-3 (GSK-3) suppress active pyrazoles base-amino replacement. In the most compounds in more than 400 cited compound, this pyrimidine ring is that the form that condenses the part of ring system exists, but, in cited compound, be the heterocyclic substituent that is replaced by another kind ring substituents on this kind position at itself without any compound.

WO 01/60816 discloses some substituted pyrimidine derivative and has had protein kinase inhibiting activity. The 2-position that the 4-position that is not disclosed in the pyrimidine ring in WO 01/60816 has pyrazoles base-amino substituting group and a pyrimidine ring that is connected has the pyrimidine derivative of the saturated monocycle that substituted N-connects.

The invention provides compound or its pharmaceutically useful salt of formula (I):

Wherein:

R ¹Represent three methyl fluorides or (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each group can choose wantonly by one or more be independently selected from halogen and (C1-C6) substituting group of alkoxyl replace;

R ²Expression hydrogen, halogen or three methyl fluorides;

R ³Expression hydrogen, hydroxyl or halogen or (C1-C6) alkyl, (C2-C6) alkene base, (C2-C6) alkynes base, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxyl, (C3-C8) cycloalkyl (C1-C6) alkoxyl, (C1-C6) alkyl-carbonyl, (C3-C8) naphthene base carbonyl, (C3-C8) cycloalkyl (C1-C6) alkyl-carbonyl, (C1-C6) alkoxy carbonyl, amino, (C1-C6) alkyl amino, two-[(C1-C6) alkyl] amino, (C3-C8) cycloalkyl amino, (C3-C8) cycloalkyl (C1-C6) alkyl amino, (C1-C6) alkoxy amino, carbamoyl, (C1-C6) alkyl-carbamoyl, two-[(C1-C6) alkyl] carbamoyl ,-C (O) R^3b、-OR ^3b、-SR ^3b、-NHR ^3bThe alkyl of ,-N[(C1-C6)] R^3b、-S(O) _mR ^3aOr-N (R^3c)C(O)R ^3a, R wherein^3aExpression (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxyl, m are 0,1 or 2, R^3bExpression comprises the heteroatomic saturated 4-of at least one ring that is selected from nitrogen, oxygen and sulphur, 5-or 6-person's monocyclic heterocycles and R^3cExpression hydrogen or (C1-C6) alkyl,

Or R³Expression comprises the saturated monocyclic heterocycles of heteroatomic 5-to the 6-member of at least one ring that is selected from nitrogen, oxygen and sulphur,

Or R³Expression comprises heteroatomic 5-to the 6-member of at least one ring that is selected from nitrogen, oxygen and sulphur heteroaromatic rings,

Or R³Expression 2,7-diazaspiracyclic [3.5] nonane base,

R ³In each group or ring can choose wantonly by one or more being independently selected from (C1-C6) alkyl; (C1-C6) alkoxyl; (C1-C6) alkoxyl (C1-C6) alkyl; (C1-C6) alkoxyl (C1-C6) alkoxyl; halogen; hydroxyl; three methyl fluorides; three-[(C1-C4) alkyl] monosilane bases; cyano group; amino; (C1-C6) alkyl amino; two-[(C1-C6) alkyl] amino; (C3-C8) cycloalkyl amino; (C3-C6) cycloalkyl (C1-C3) alkyl amino; amino (C1-C6) alkyl; (C1-C6) alkyl amino (C1-C6) alkyl; two-[(C1-C6) alkyl] amino (C1-C6) alkyl; (C3-C8) cycloalkyl amino (C1-C6) alkyl; (C3-C6) cycloalkyl (C1-C3) alkyl amino (C1-C6) alkyl; (C1-C6) alkoxy carbonyl; carbamoyl; (C1-C6) alkyl-carbamoyl; two-[(C1-C6) alkyl] carbamoyls; (C1-C6) alkylthio group; (C1-C6) alkyl sulphonyl; (C1-C6) alkyl sulphinyl; (C1-C6) alkane acyl group; R wherein^3aAnd R^3cAs defined above described alkanoylamino-N (R^3c)C(O)R ^3a, or optionally comprise one or more substituting groups that are selected from heteroatomic saturated 3-, 4-, 5-, 6-or 7-person's monocycle of nitrogen, oxygen and sulphur and replace, any a kind of in these substituting groups optionally replaced by one or more (C1-C4) alkyl, hydroxyl or cyano group;

-NQ ¹Expression comprises a nitrogen heteroatom and comprises one or more nitrogen, oxygen and sulphur of being selected from optionally is connected the saturated monocycle of 5-to 6-member of the heteroatomic N-of other ring connection;

Q ²Expression comprises heteroatomic 5-to the 6-member of at least one ring that is selected from nitrogen, oxygen and sulphur heteroaromatic rings, and this encircles by Q³Replace and any obtainable ring atom take up an official post selection of land by one or more being independently selected from (C1-C6) alkyl or (C1-C6) alkoxyl (it can be replaced by one or more substituting groups that are independently selected from halogen, amino, hydroxyl and three methyl fluorides separately with choosing wantonly), halogen, nitro, cyano group ,-NR⁴R ⁵, carboxyl, hydroxyl, (C2-C6) alkene base, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxy carbonyl, (C1-C4) alkyl-carbonyl, (C1-C4) alkyl-carbonyl-amino, phenylcarbonyl group ,-S (O)_p(C1-C4) alkyl ,-C (O) NR⁶R ⁷With-SO₂NR ⁸R ⁹Other substituting group replace R wherein⁴、R ⁵、R ⁶、R ⁷、R ⁸And R⁹Represent independently of one another hydrogen or (C1-C6) alkyl, or when when nitrogen-atoms that it is attached thereto connects together, R⁴And R⁵, or R⁶And R⁷, or R⁸And R⁹Can form independently of one another saturated heterocyclic and p is 0,1 or 2;

Q ³Expression (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl maybe can comprise heteroatomic saturated or undersaturated 5-to the 6-member monocycle of at least one ring that is selected from nitrogen, oxygen and sulphur, and Q wherein³Optionally by one or more being independently selected from (C1-C6) alkyl or (C1-C6) alkoxyl (it is optionally replaced by one or more substituting groups that are independently selected from halogen, amino, hydroxyl and three methyl fluorides separately), halogen, nitro, cyano group ,-NR¹⁰R ¹¹, carboxyl, hydroxyl, (C2-C6) alkene base, (C3-C8) cycloalkyl, (C1-C6) alkoxy carbonyl, (C1-C6) alkyl-carbonyl, (C1-C6) alkyl-carbonyl-amino, phenylcarbonyl group ,-S (O)_n(C1-C6) alkyl ,-C (O) NR¹²R ¹³With-SO₂NR ¹⁴R ¹⁵Substituting group replace R wherein¹⁰、R ¹¹、R ¹²、 R ¹³、R ¹⁴And R¹⁵Represent independently of one another hydrogen or (C1-C6) alkyl, or when when nitrogen-atoms that it is attached thereto connects together, R¹⁰And R¹¹, or R¹²And R¹³, or R¹⁴And R¹⁵Can form independently of one another saturated heterocyclic and n is 0,1 or 2;

And wherein any saturated monocycle optionally with 1 or 2 oxo or sulphur for substituting group.

According to another aspect of the present invention, it provides compound or its pharmaceutically useful salt of formula (I), wherein:

R ¹Represent three methyl fluorides or (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each group optionally by one or more be independently selected from halogen and (C1-C6) substituting group of alkoxyl replace;

R ²Expression hydrogen, halogen or three methyl fluorides;

R ³The expression hydrogen or halogen or (C1-C6) alkyl, (C2-C6) alkene base, (C2-C6) alkynes base, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxyl, (C3-C8) cycloalkyl (C1-C6) alkoxyl, (C1-C6) alkyl-carbonyl, (C3-C8) naphthene base carbonyl, (C3-C8) cycloalkyl (C1-C6) alkyl-carbonyl, (C1-C6) alkoxy carbonyl, amino, (C1-C6) alkyl amino, two-[(C1-C6) alkyl] amino, (C3-C8) cycloalkyl amino, (C3-C8) cycloalkyl (C1-C6) alkyl amino, (C1-C6) alkoxy amino, carbamoyl, (C2-C6) alkanoylamino ,-C (O) R^3b、 -OR ^3b、-SR ^3b、-NHR ^3bThe alkyl of ,-N[(C1-C6)] R^3bOr-S (O)_mR ^3aBase, wherein R^3aExpression (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxyl, m is 0,1 or 2, and R^3bExpression comprises one or more saturated monocycles of heteroatomic 5-to 6-member that are selected from nitrogen, oxygen and sulphur,

R ³In each group or ring optionally by one or more being independently selected from (C1-C6) alkyl, (C1-C6) alkoxyl, (C1-C6) alkoxyl (C1-C6) alkoxyl, halogen, hydroxyl, three methyl fluorides, cyano group, amino, (C1-C6) alkyl amino, two-[(C1-C6) alkyl] amino, (C3-C8) cycloalkyl amino, (C3-C6) cycloalkyl (C1-C3) alkyl amino, (C1-C6) alkoxy carbonyl, carbamoyl, (C1-C6) alkyl-carbamoyl, two-[(C1-C6) alkyl] carbamoyl, (C1-C6) alkylthio group, (C1-C6) alkyl sulphonyl, (C1-C6) alkyl sulphinyl, (C1-6) alkanoylamino or optionally comprise one or more substituting groups that are selected from heteroatomic 4-, 5-, 6-or the saturated monocycle of 7-person of nitrogen, oxygen and sulphur and replace

Q ²Expression comprises heteroatomic 5-to the 6-member of at least one ring that is selected from nitrogen, oxygen and sulphur heteroaromatic rings, and this ring can be by Q³Replace and optional ground on any obtainable ring atom by one or more being independently selected from (C1-C6) alkyl or (C1-C6) alkoxyl (it is optionally replaced by one or more substituting groups that are independently selected from halogen, amino, hydroxyl and three methyl fluorides separately), halogen, nitro, cyano group ,-NR⁴R ⁵, carboxyl, hydroxyl, (C2-C6) alkene base, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxy carbonyl, (C1-C4) alkyl-carbonyl, (C1-C4) alkyl-carbonyl-amino, phenylcarbonyl group ,-S (O)_p(C1-C4) alkyl ,-C (O) NR⁶R ⁷With-SO₂NR ⁸R ⁹Other substituting group replace R wherein⁴、R ⁵、R ⁶、R ⁷、R ⁸And R⁹Represent independently of one another hydrogen or (C1-C6) alkyl, or when when nitrogen-atoms that it is attached thereto connects together, R⁴And R⁵, or R⁶And R⁷, or R⁸And R⁹Can form independently of one another saturated heterocyclic and p is 0,1 or 2;

Q ³Expression (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl maybe can comprise heteroatomic saturated or undersaturated 5-to the 6-member monocycle of at least one ring that is selected from nitrogen, oxygen and sulphur, and Q wherein³Optionally by one or more being independently selected from (C1-C6) alkyl or (C1-C6) alkoxyl (it is optionally replaced by one or more substituting groups that are independently selected from halogen, amino, hydroxyl and three methyl fluorides separately), halogen, nitro, cyano group ,-NR¹⁰R ¹¹, carboxyl, hydroxyl, (C2-C6) alkene base, (C3-C8) cycloalkyl, (C1-C6) alkoxy carbonyl, (C1-C6) alkyl-carbonyl, (C1-C6) alkyl-carbonyl-amino, phenylcarbonyl group ,-S (O)_n(C1-C6) alkyl ,-C (O) NR¹²R ¹³With-SO₂NR ¹⁴R ¹⁵Substituting group replace R wherein¹⁰、R ¹¹、R ¹²、 R ¹³、R ¹⁴And R¹⁵Represent independently of one another hydrogen or (C1-C6) alkyl, or when when nitrogen-atoms that it is attached thereto connects together, R¹⁰And R¹¹, or R¹²And R¹³, or R¹⁴And R¹⁵Can form independently of one another saturated heterocyclic and n is 0,1 or 2.

According to another aspect of the present invention, provide compound or its pharmaceutically useful salt of formula (I), wherein:

R ¹Represent three methyl fluorides or (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each group optionally by halogen or (C1-C6) alkoxyl replace;

R ²Expression hydrogen, halogen or three methyl fluorides;

R ³Expression hydrogen or (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxyl, (C1-C6) alkyl-carbonyl, (C3-C8) naphthene base carbonyl, (C3-C8) cycloalkyl (C1-C6) alkyl-carbonyl, (C1-C6) alkoxy carbonyl, (C1-C6) alkyl amino, (C3-C8) cycloalkyl amino, (C3-C8) cycloalkyl (C1-C6) alkyl amino, (C1-C6) alkoxy amino or-S (O)_mR ^3aBase, R³In each group optionally be selected from (C1-C6) alkoxyl, (C1-C6) alkoxyl (C1-C6) alkoxyl, halogen, hydroxyl, three methyl fluorides by at least one or optionally comprise one or more substituting groups that are selected from heteroatomic 4-, 5-, 6-or the saturated monocycle of 7-person of nitrogen, oxygen and sulphur and replace, R wherein^3aExpression (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxyl and m are 0,1 or 2;

Q ²Expression comprises heteroatomic 5-to the 6-member of at least one ring that is selected from nitrogen, oxygen and sulphur heteroaromatic rings, and this encircles by Q³Replace and replaced by one or more other substituting groups that can be identical or different in any obtainable ring atom selection of land of taking up an official post, said substituting group be selected from (C1-C6) alkyl or (C1-C6) alkoxyl (it is optionally replaced by at least one substituting group that is selected from halogen, amino, hydroxyl and three methyl fluorides separately), halogen, nitro, cyano group ,-NR⁴R ⁵, carboxyl, hydroxyl, (C2-C6) alkene base, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxy carbonyl, (C1-C4) alkyl-carbonyl, (C1-C4) alkyl-carbonyl-amino, phenylcarbonyl group ,-S (O)_p(C1-C4) alkyl ,-C (O) NR⁶R ⁷With-SO₂NR ⁸R ⁹, R wherein⁴、R ⁵、R ⁶、 R ⁷、R ⁸And R⁹Represent independently of one another hydrogen or (C1-C6) alkyl, or when when nitrogen-atoms that it is attached thereto connects together, R⁴And R⁵, or R⁶And R⁷, or R⁸And R⁹Can form independently of one another saturated heterocyclic and p is 0,1 or 2;

Q ³Expression (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl maybe can comprise heteroatomic saturated or undersaturated 5-to the 6-member monocycle of at least one ring that is selected from nitrogen, oxygen and sulphur, and Q wherein³Optional ground be selected from by at least one (C1-C6) alkyl or (C1-C6) alkoxyl (it is optionally replaced by at least one substituting group that is selected from halogen, amino, hydroxyl and three methyl fluorides separately), halogen, nitro, cyano group ,-NR¹⁰R ¹¹, carboxyl, hydroxyl, (C2-C6) alkene base, (C3-C8) cycloalkyl, (C1-C6) alkoxy carbonyl, (C1-C6) alkyl-carbonyl, (C1-C6) alkyl-carbonyl-amino, phenylcarbonyl group ,-S (O)_n(C1-C6) alkyl ,-C (O) NR¹²R ¹³With-SO₂NR ¹⁴R ¹⁵Substituting group replace R wherein¹⁰、R ¹¹、R ¹⁴、R ¹³、R ¹⁴And R¹⁵Represent independently of one another hydrogen or (C1-C6) alkyl, or when when nitrogen-atoms that it is attached thereto connects together, R¹⁰And R¹¹, or R¹²And R¹³, or R¹⁴And R¹⁵Can form independently of one another saturated heterocyclic and n is 0,1 or 2.

Unless stated otherwise, otherwise when using separately or during coupling, term ' alkyl ' refers to the straight or branched moieties. (C1-C6) alkyl has one to six carbon atom, comprise methyl, ethyl, just-propyl group, isopropyl,Uncle-Butyl, just-amyl group, just-oneself base etc. When relating to ' (C1-C4) alkyl ', it will be interpreted as correspondingly that finger has the straight or branched moieties of 1 to 4 carbon atom. Specific ground only refers to the straight chain version when relating to each alkyl such as " propyl group ", refers to the side chain version when relating to each side chain alkyl such as " isopropyl " only specificly.

Similarly, when being used alone or in combination, term ' (C1-C6) alkoxyl ' and ' (C1-C4) alkoxyl ' will be understood to refer to have respectively the straight or branched group of 1 to 6 or 1 to 4 carbon atom, and comprise the group such as first oxygen base, second oxygen base, propoxyl group, different propoxyl group and butoxy.

' (C2-C6) alkene base ' refers to have straight or branched group such as vinyl, isopropenyl, pi-allyl and the but-2-ene base of 2 to 6 carbon atoms. Similarly, ' (C2-C6) alkynes base ' refers to have straight or branched group such as acetylene base, 2-propynyl and the fourth-2-alkynes base of 2 to 6 carbon atoms.

When independent or coupling, term ' cycloalkyl ' refers to have the saturated fat ring family part of 3 to 8 carbon atoms and comprise, for example, and cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl. To be interpreted as mutually referring to having the saturated fat ring family part of 3 to 6 carbon atoms when relating to (C3-C6) cycloalkyl, have been listed its representative instance in the above.

Here used term ' halogen ' comprises fluorine, chlorine, bromine and iodine.

Here used term ' optionally substituted ' refers on any suitable obtainable position by group or the optional replacement of some groups.

Here any substituting group, for example ' R ' base (R¹To R¹⁵、R ^3a、R ^3bOr R^3c) suitable value or-NQ¹、Q ²Or Q³The suitable value of various groups comprises in the base :-

For halogen: fluorine, chlorine, bromine and iodine;

For C1-C6) for the alkyl: methyl, ethyl, propyl group, isopropyl,Uncle-Butyl, just-

Amyl group and just-oneself base;

For (C2-C6) alkene base: vinyl, isopropenyl, pi-allyl and but-2-ene base;

For (C2-C6) alkynes base: acetylene base, 2-propynyl and fourth-2-alkynes base;

For (C1-C6) alkoxyl: first oxygen base, second oxygen base, propoxyl group, different propoxyl group and fourth oxygen

Base;

For (C1-C6) alkoxyl

(C1-C6) alkoxyl: methoxymethoxy, methoxy ethoxy, (ethoxymethyl) oxygen

Base, propoxyl group first oxygen base and butoxy first oxygen base;

For (C1-C6) alkoxyl

(C1-C6) alkyl: methoxy, methoxy ethyl, ethoxyl methyl, third

Oxygen base methyl and butoxymethyl;

For three-[(C1-C4) alkyl]

Monosilane base trimethyl silyl, triethylsilyl, dimethyl-

Ethyl monosilane base and methyl-diethylsilane base;

For (C1-C6) alkylthio group: first sulphur base, ethylmercapto group and rosickyite base;

For (C1-C6) alkyl amino: methyl amino, ethylamino, amino, the isopropyl ammonia of propyl group

Base and butyl are amino;

For two-[(C1-C6) alkyl]

Amino: dimethylamino, diethylamino,N-ethyl-N-methyl ammonia

Base and diisopropylaminoethyl;

For amino (C1-C6) alkyl: amino methyl, amino-ethyl, aminopropyl and aminobutyl;

For (C1-C6) alkyl amino

(C1-C6) alkyl: methyl amino methyl, methyl amino-ethyl, methyl aminopropan

Base, ethylamino methyl, ethylamino ethyl, propyl group ammonia

Base methyl, isopropyl amino-ethyl and butyl amino methyl;

For two-[(C1-C6) alkyl]

Amino (C1-C6) alkyl: dimethylaminomethyl, dimethyl aminoethyl, dimethyl

Aminobutyl, diethylamino methyl, diethylamino second

Base, diethylamino propyl group,N-ethyl-NThe amino first of-methyl

Base,N-ethyl-N-methyl amino methyl and diisopropylaminoethyl

Ethyl;

For (C1-C6) alkyl oxycarbonyl

Base: methyl carbonyl, ethyl carbonyl, propyl group carbonyl andUncle-The butyl carbonyl

Base;

For (C1-C6) alkoxyl carbonyl

Base: methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl andUncle-

Butoxy carbonyl;

ForN-(C1-C6) alkyl

Carbamoyl:N-methyl carbamoyl,N-ethylamino formyl base and

N-propyl group carbamoyl;

ForN， N-two-

[(C1-C6) alkyl] amino

The formyl base:N， N-formyl-dimethylamino,N-ethyl-N-methyl is amino

The formyl base andN， N-diethylacbamazine acyl group;

For (C3-C8) cycloalkyl: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl;

For (C3-C8) cycloalkyl

(C1-C6) alkyl: cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl, ring

Hexyl methyl and suberyl methyl;

For (C3-C8) cycloalkyl

(C1-C6) alkoxyl: cyclo propyl methoxy, cyclobutylmethyl oxygen base, cyclopenta first oxygen

Base, cyclohexyl first oxygen base and suberyl first oxygen base;

For (C3-C8) cycloalkyl carbonyl

Base: cyclopropyl carbonyl, cyclobutyl carbonyl, cyclopentylcarbonyl, ring

Own basic carbonyl and suberyl carbonyl;

For (C3-C8) cycloalkyl

(C1-C6) alkyl-carbonyl: cyclopropyl methyl carbonyl, cyclobutylmethyl carbonyl, cyclopenta

Methyl carbonyl and cyclohexyl methyl carbonyl;

For (C3-C8) cycloalkyl ammonia

Base: cyclopropyl is amino, cyclobutyl is amino, cyclopenta is amino, ring

Oneself is amino base and suberyl is amino;

For (C3-C8) cycloalkyl ammonia

Base (C1-C6) alkyl: cyclopropyl amino methyl, cyclopropyl amino-ethyl, cyclopropyl

Aminopropyl, cyclobutyl amino methyl, the amino second of cyclopenta

The base, cyclopenta aminopropyl cyclohexyl amino-ethyl and the ring heptan

The base amino-ethyl;

For (C3-C8) cycloalkyl

(C1-C6) alkyl amino: cyclopropyl methyl amino, cyclopropyl ethylamino, cyclopenta

Methyl is amino and cyclohexyl methyl is amino;

For (C3-C8) cycloalkyl

(C1-C6) alkyl amino

(C1-C6) alkyl: cyclopropyl methyl amino methyl, the amino second of cyclopropyl methyl

Base, cyclopropyl methyl aminopropyl, cyclopropyl ethylamino

Ethyl, cyclopropyl ethylamino butyl, cyclopentyl-methyl ammonia

Base ethyl, cyclopentyl-methyl aminobutyl and cyclohexyl methyl

Amino-ethyl;

For (C1-C6) alkoxyl ammonia

Base: first oxygen base is amino, second oxygen base is amino, propoxyl group is amino and fourth

The oxygen base is amino;

For (C1-C6) alkane acyl group: formyl base, acetyl group, propiono, bytyry and different butyryl

Base;

For (C2-C6) alkane acyl group ammonia

Base: acetyl amino and propionamido;

For (C1-C6) alkyl sulfonyl

Base: methyl sulphonyl and ethylsulfonyl; With

For (C1-C6) alkyl

Inferior sulphonyl base: the inferior sulphonyl base of methylsulfinyl and ethyl.

' hetero atom ' is nitrogen, sulphur or oxygen atom. Comprise in the situation of nitrogen-atoms that at ring one-tenth key needs or said ring that these atoms can be substituted to satisfy nitrogen as required can be connected on the residue part of this structure by this nitrogen-atoms. Nitrogen-atoms can also be the form of N-oxide. The sulphur atom can be S, S (O) or SO₂Form.

' optionally comprising one or more saturated monocycles of heteroatomic 3-, 4-, 5-, 6-or 7-person that are selected from nitrogen, oxygen and sulphur ' can be carbocyclic ring (the alicyclic ring that namely only has ring carbon atom) or can be that wherein at least one atom is that be selected from nitrogen, oxygen and sulphur heteroatomic comprises the heterocycle of 3 to 7 atoms and unless stated otherwise, otherwise this ring is connected by carbon or nitrogen. When ' optionally comprising one or more saturated monocycles of heteroatomic 3-, 4-, 5-, 6-or 7-person that are selected from nitrogen, oxygen and sulphur ' when being heterocycle, this heterocycle preferably comprises 1 to 4, more preferably comprise 1 to 3, more preferably comprise 1 to 2 hetero atom that is independently selected from nitrogen, oxygen and sulphur. Unless stated otherwise, otherwise this heterocycle can be carbon or nitrogen connects. The example of suitable carbocyclic ring comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl. The saturated monocyclic heterocycles of 3-, 4-, 5-, 6-or 7-person can be selected from Oxyranyle, azetidinyl, two  alkyl, three  alkyl, oxepanyl, dithiane base, trithiane base (trithianyl), thioxane base, thio-morpholinyl, pyrroles's alkyl, piperidines base, imidazoles alkyl, morpholine base, tetrahydrofuran base, THP trtrahydropyranyl and piperazine base (particularly azetidinyl, pyrroles's alkyl, piperidines base, morpholine base, tetrahydrofuran base, THP trtrahydropyranyl and piperazine base) suitablely. For example can be that 2-oxo-pyrrolidine base, 2-sulphur are for pyrroles's alkyl, 2-oxo-imidazole alkyl, 2-thiocarbamoyl imidazole alkyl, 2-oxo-piperidine base, 2 with 1 or 2 oxo or sulphur for the saturated heterocyclic of substituting group, 5-dioxo pyrroles alkyl, 2,5-dioxo alkyl imidazole base or 2,6-dioxopiperidine base.

In the situation that relates to ' the saturated monocycle of 5-to 6-member ' or ' the saturated monocyclic heterocycles of 5-to 6-member ', should be understood that it refers to comprise the ring of 5 or 6 ring atoms, has listed its representative instance in the above. In the situation that relates to ' the saturated monocycle of 4-, 5-or 6-person ' or ' the saturated monocyclic heterocycles of 4-, 5-or 6-person ', should be understood that said ring comprises 4,5 or 6 ring atoms, has listed its representative instance in the above.

' comprise a nitrogen heteroatom and comprise one or more nitrogen, oxygen and sulphur of being selected from optionally and be connected the saturated monocycle of 5-to 6-member that the heteroatomic N-of other ring connects ' is to comprise 5 or 6 saturated monocyclic heterocycles that encircle atoms, said ring atom except this ring by comprise the hetero atom that at least one is selected from nitrogen, oxygen and sulphur the nitrogen-atoms of its residue that is connected to this structure on partly also optionally. The said saturated monocyclic heterocycles that comprises 5 or 6 ring atoms except this ring by also preferably comprising 1 to 3 the nitrogen-atoms of its residue that is connected to this structure on partly, more preferably comprise 1 to 2 hetero atom that is independently selected from nitrogen, oxygen and sulphur. The specific example of such ring system comprises pyrroles's alkyl, piperidines base, morpholine base and piperazine base.

' comprising heteroatomic 5-to the 6-member of at least one ring that is selected from nitrogen, oxygen and sulphur heteroaromatic rings ' is to comprise 5 or 6 atoms wherein at least one is the heteroatomic fully saturated aromatic monocyclic that is selected from nitrogen, oxygen and sulphur, unless stated otherwise, otherwise this ring can be carbon or nitrogen connects. This 5-to 6-member heteroaromatic rings preferably comprises 1 to 4 hetero atom that is independently selected from nitrogen, oxygen and sulphur. The specific example of such ring system comprises pyridine radicals, imidazole radicals, different  azoles base, pyrazoles base, furyl, pyrazine base, pyridazine base, pyrimidine radicals, pyrrole radicals, thiazolyl,  azoles base,  di azoly, isothiazolyl, triazole base, tetrazole radical or thiophene base.

' can comprise heteroatomic saturated or undersaturated 5-to the 6-member monocycle of at least one ring that is selected from nitrogen, oxygen and sulphur ' be comprise 5 or 6 atoms wherein optional ground at least one be to be selected from the heteroatomic saturated of nitrogen, oxygen and sulphur or undersaturated monocycle wholly or in part, unless stated otherwise, otherwise this ring can be carbon or nitrogen connects. This ring can have alicyclic family or aromatics character. Aromatic monocyclic can be aryl (such as phenyl) or heteroaromatic group, has listed its representative instance in the above.

Here used term ' heterocycle ' refers to have the saturated monocycle ring system that hetero atom that 3 to 8 ring atoms and wherein one or more ring carbon is selected from nitrogen, oxygen and sulphur replaces. This heterocycle preferably comprises 1 to 4, more preferably comprises 1 to 3, more preferably comprises 1 to 2 hetero atom that is independently selected from nitrogen, oxygen and sulphur. The example comprises pyrroles's alkyl and piperidines base.

Work as R³When being 2,7-diazaspiracyclic [3.5] nonane base, it preferably by nitrogen-atoms, particularly is connected on the pyrimidine ring by the nitrogen-atoms on the 7-position. When this 2, when 7-diazaspiracyclic [3.5] nonane base band had substituting group, its substituting group can be positioned on any obtainable carbon or the nitrogen-atoms, for example can be positioned at any not with nitrogen-atoms that the pyrimidine ring links to each other on. 2 of a kind of specific replacement, 7-diazaspiracyclic [3.5] nonane base can be for example 2-(Uncle-Butoxy carbonyl)-2,7-diazaspiracyclic [3.5] nonane.

At R⁴And R⁵, or R⁶And R⁷, or R⁸And R⁹, or R¹⁰And R¹¹, or R¹²And R¹³, or R¹⁴And R¹⁵Form in the situation of saturated heterocyclic, unique hetero atom of existence is R⁴And R⁵, or R⁶And R⁷, or R⁸And R⁹, or R¹⁰And R¹¹, or R¹²And R¹³, or R¹⁴And R¹⁵The nitrogen-atoms that is attached thereto. This saturated heterocyclic preferably comprises R⁴And R⁵, or R⁶And R⁷, or R⁸And R⁹, or R¹⁰And R¹¹, or R¹²And R¹³, or R¹⁴And R¹⁵4-to the 7-member ring of the nitrogen-atoms that is attached thereto.

R ¹It is optional substituted (C3-C8) cycloalkyl (C1-C6) alkyl (such as cyclopropyl methyl, cyclopentyl-methyl, cyclohexyl methyl) suitablely, but preferably optionally substituted (C1-C6) alkyl ((C1-C4) alkyl particularly, for example methyl, ethyl, propyl group, isopropyl,Uncle-Butyl) or optionallyly substituted (C3-C8) cycloalkyl (particularly (C3-C6) cycloalkyl, such as cyclopropyl, cyclopenta, cyclohexyl). R¹Particularly not substituted (C1-C6) (preferably (C1-C4)) alkyl or not substituted (C3-C8) (preferably (C3-C6)) cycloalkyl.

In embodiments of the invention, R¹Expression (C1-C4) alkyl, especially methyl, ethyl orUncle-Butyl, more preferably be methyl orUncle-Butyl more preferably is methyl.

In another embodiment, R¹Expression (C3-C6) cycloalkyl, especially cyclopropyl.

R ²Can be hydrogen or three methyl fluorides, but halogen (such as fluorine, chlorine, bromine or iodine) preferably.

In a preferred embodiment, R²Expression chlorine or fluorine (particularly chlorine). In another preferred embodiment, R²Hydrogen.

In one embodiment, R³Expression hydrogen, hydroxyl or halogen or (C1-C6) alkyl, (C2-C6) alkene base, (C2-C6) alkynes base, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxyl, (C3-C8) cycloalkyl (C1-C6) alkoxyl, (C1-C6) alkyl-carbonyl, (C1-C6) alkoxy carbonyl, amino, (C1-C6) alkyl amino, two-[(C1-C6) alkyl] amino, (C3-C8) cycloalkyl amino, (C3-C8) cycloalkyl (C1-C6) alkyl amino, (C1-C6) alkoxy amino, carbamoyl, (C1-C6) alkyl-carbamoyl, two-[(C1-C6) alkyl] carbamoyl ,-C (O) R^3b、-OR ^3b、-NHR ^3b,-N[(C 1-C6) and alkyl] R^3b、-S(O) _mR ^3aOr-N (R^3c)C(O)R ^3aBase, wherein R^3aExpression (C1-C6) alkyl or (C1-C6) alkoxyl, m are 0,1 or 2, R^3bExpression comprises the heteroatomic saturated 4-of at least one ring that is selected from nitrogen, oxygen and sulphur, 5-or 6-person's monocyclic heterocycles and R^3cExpression hydrogen or (C1-C6) alkyl or R³Expression comprises the saturated monocyclic heterocycles of heteroatomic 5-to the 6-member of at least one ring that is selected from nitrogen, oxygen and sulphur, or R³Expression comprises heteroatomic 5-to the 6-member of at least one ring that is selected from nitrogen, oxygen and sulphur heteroaromatic rings, or R³Expression 2,7-diazaspiracyclic [3.5] nonane base. R³In these groups or ring optionally be independently selected from (C1-C6) alkyl by one or more (for example one or two, particularly one) separately; (C1-C6) alkoxyl; (C1-C6) alkoxyl (C1-C6) alkyl; (C1-C6) alkoxyl (C1-C6) alkoxyl; halogen; hydroxyl; three methyl fluorides; three-[(C1-C4) alkyl] monosilane bases; cyano group; amino; (C1-C6) alkyl amino; two-[(C1-C6) alkyl] amino; amino (C1-C6) alkyl; (C1-C6) alkyl amino (C1-C6) alkyl; two-[(C1-C6) alkyl] amino (C1-C6) alkyl; (C1-C6) alkoxy carbonyl; carbamoyl; (C1-C6) alkyl-carbamoyl; two-[(C1-C6) alkyl] carbamoyls; (C1-C6) alkylthio group; (C1-C6) alkyl sulphonyl; (C1-C6) alkyl sulphinyl; (C1-C6) alkane acyl group; R wherein^3aAnd R^3cAs defined above described alkanoylamino-N (R^3c)C(O)R ^3a, or optionally comprise one or more substituting groups that are selected from heteroatomic 3-, 4-, 5-, 6-or the saturated monocycle of 7-person of nitrogen, oxygen and sulphur and replace, any a kind of in these substituting groups can choose wantonly (C1-C4) alkyl, hydroxyl or cyano group replace by one or more (for example one or two, particularly one). R³In any saturated monocycle optionally with 1 or 2 oxo or sulphur for substituting group.

In another embodiment, R³Expression hydrogen, hydroxyl or halogen or (C1-C6) alkyl, (C2-C6) alkene base, (C2-C6) alkynes base, (C3-C8) cycloalkyl, (C1-C6) alkoxyl, (C1-C6) alkoxy carbonyl, amino, (C1-C6) alkyl amino, two-[(C1-C6) alkyl] amino, (C3-C8) cycloalkyl amino, carbamoyl, (C1-C6) alkyl-carbamoyl, two-[(C1-C6) alkyl] carbamoyl ,-C (O) R^3b、-OR ^3b、-NHR ^3bOr-S (O)_mR ^3aBase, wherein R^3aExpression (C1-C6) alkyl, m is 0 and R^3bExpression comprises the heteroatomic 4-of at least one ring that is selected from nitrogen, oxygen and sulphur, 5-or the saturated monocyclic heterocycles of 6-person, or R³Expression comprises the saturated monocyclic heterocycles of heteroatomic 5-to the 6-member of at least one ring that is selected from nitrogen and oxygen, or R³Expression comprises heteroatomic 5-to the 6-member of at least one ring that is selected from nitrogen and oxygen heteroaromatic rings, or R³Expression 2,7-diazaspiracyclic [3.5] nonane base. R³In these groups or ring optionally be independently selected from (C1-C6) alkyl, (C1-C6) alkoxyl, (C1-C6) alkoxyl (C1-C6) alkyl, (C1-C6) alkoxyl (C1-C6) alkoxyl, halogen, hydroxyl, three methyl fluorides, three-[(C1-C4) alkyl] monosilane base, amino, amino, amino (C1-C6) alkyl of (C1-C6) alkyl amino, two-[(C1-C6) alkyl], (C1-C6) alkoxy carbonyl, carbamoyl, (C1-C6) alkyl-carbamoyl, (C1-C6) alkylthio group, (C1-C6) alkyl sulphonyl, (C1-C6) alkane acyl group, R wherein by one or more (for example one or two, particularly one) separately^3aExpression (C1-C6) alkyl or (C1-C6) alkoxyl and R^3cExpression hydrogen or (C1-C6) alkanoylamino-N (R of alkyl^3c)C(O)R ^3a, or optionally comprise one or more substituting groups that are selected from heteroatomic 3-, 4-, 5-or the saturated monocycle of 6-person of nitrogen, oxygen and sulphur and replace, optionally (C1-C4) alkyl, hydroxyl or cyano group replace by one or more (for example one or two, particularly one) for any a kind of in these substituting groups. R³In the optional ground of any saturated monocycle with 1 or 2 oxo substituting group.

In another embodiment, R³Expression hydrogen, hydroxyl or halogen or (C1-C4) alkyl, (C2-C4) alkene base, (C2-C4) alkynes base, (C1-C3) alkoxyl, amino, (C1-C3) alkyl amino, two-[(C1-C3) alkyl] amino, (C3-C6) cycloalkyl amino, carbamoyl, (C1-C3) alkyl-carbamoyl, two-[(C1-C3) alkyl] carbamoyl ,-C (O) R^3b、-OR ^3b、-NHR ^3bOr-S (O)_mR ^3aBase, wherein R^3aExpression (C1-C3) alkyl, m is 0 and R^3bExpression comprises the heteroatomic 4-of at least one ring that is selected from nitrogen, oxygen and sulphur, 5-or the saturated monocyclic heterocycles of 6-person, or R³Expression comprises the saturated monocyclic heterocycles of heteroatomic 5-to the 6-member of at least one ring that is selected from nitrogen and oxygen, or R³Expression comprises heteroatomic 5-to the 6-member of at least one ring that is selected from nitrogen and oxygen heteroaromatic rings. R³In these groups or the ring optionally replaced by one or more substituting group as defined above separately; particularly be independently selected from (C1-C3) alkyl, (C1-C3) alkoxyl, (C1-C3) alkoxyl (C1-C3) alkyl, (C1-C3) alkoxyl (C1-C3) alkoxyl, halogen, hydroxyl, three methyl fluorides, amino, amino, amino (C1-C3) alkyl of (C1-C3) alkyl amino, two-[(C1-C3) alkyl], carbamoyl, (C1-C3) alkyl-carbamoyl, (C1-C3) alkylthio group, (C1-C3) alkyl sulphonyl, (C1-C3) alkane acyl group, R wherein by one or more (for example one or two, particularly one)^3aExpression (C1-C3) alkyl or (C1-C3) alkoxyl and R^3cExpression hydrogen or (C1-C3) alkanoylamino-N (R of alkyl^3c)C(O)R ^3a, or optionally comprise one or more substituting groups that are selected from heteroatomic 3-, 4-, 5-or the saturated monocycle of 6-person of nitrogen, oxygen and sulphur and replace, all optionally (C1-C2) alkyl, hydroxyl or cyano group replace by one or more (for example one or two, particularly one) for any a kind of in these substituting groups. R³In the optional ground of any saturated monocycle with 1 oxo substituting group.

In another embodiment, R³Expression hydrogen or (C1-C4) alkyl, (C1-C3) alkoxyl or (C3-C5) cycloalkyl or R³Expression comprises the saturated monocyclic heterocycles of heteroatomic 5-to the 6-member of at least one ring that is selected from nitrogen and oxygen. R³In these groups or the ring separately optionally by one or more (for example one or two, particularly one) substituting group as defined above replaces, particularly by one or more be independently selected from hydroxyl and (C1-C3) substituting group of alkoxyl replace.

R ³Suitable value for example comprise hydrogen, hydroxyl, chlorine, fluorine or iodine or methyl, ethyl, just-propyl group, different-propyl group, just-butyl,Uncle-Butyl, vinyl, acrylic, cyclobutenyl, amylene base, acetylene base, propinyl, butynyl, first oxygen base, second oxygen base, propoxyl group,Uncle-Butoxy, cyclopropyl, cyclobutyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl,Uncle-Butoxy carbonyl, methyl amino, ethylamino, propyl group amino, dimethylamino, diethylamino, cyclobutyl are amino, cyclohexyl is amino, carbamoyl, N-methyl carbamoyl, N-ethylamino formyl base, N-propyl group carbamoyl, N-butyl carbamoyl, N; N-formyl-dimethylamino, N-ethyl-N-methyl carbamoyl, pyrroles's alkyl-carbonyl, morpholinyl carbonyl, azetidinyl carbonyl, first sulphur base, ethylmercapto group, piperidines base are amino, THP trtrahydropyranyl is amino, tetrahydro-pyran oxy, pyrroles's alkyl, morpholine base; piperazine base,  di azoly or 2,7-diazaspiracyclic [3.5] ninth of the ten Heavenly Stems-7-base group. These groups or ring are optionally replaced by one or more (for example one or two, particularly one) substituting group as defined above separately.

R ³Suitable value for example particularly comprise hydrogen, hydroxyl, chlorine, fluorine, bromine, iodine, methyl, ethyl, propyl group, different-propyl group, butyl,Uncle-Butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, three methyl fluorides, hydroxyl methyl, methoxy, ethoxyl methyl, (2-methoxy ethoxy) methyl, amino methyl, methyl amino methyl, ethylamino methyl, morpholine be for methyl, piperazine-1-base methyl, 4-methyl piperazine-1-base methyl, pyrrolidines-1-base methyl, 2-hydroxyl ethyl, 2-methoxy ethyl, 2-ethoxyethyl group, 2-(ethoxy carbonyl) ethyl, 2-(N-methyl carbamoyl) ethyl, 3-hydroxyl propyl group, 3-methoxy-propyl, 3-ethoxycarbonyl propyl, 3-aminopropan-1-base, 3-N, N-dimethylaminopropyl, 3-(Uncle-Butoxy carbonyl is amino) third-1-base; 3-pyrrolidines-1-base propyl group; vinyl; acrylic; cyclobutenyl; the amylene base; 3-hydroxyl third-1-alkene-1-base; 3-aminopropan-1-alkene-1-base; 2-(methoxycarbonyl) ethene-1-base; 3-(uncle-butoxy carbonyl is amino) third-1-alkene-1-base; the acetylene base; propinyl; butynyl; pentynyl; 3-hydroxyl third-1-alkynes-1-base; 3-methoxy propyl-1-alkynes-1-base; 2-(trimethyl silyl) acetylene base; 3-aminopropan-1-alkynes-1-base; 3-methyl aminopropan-1-alkynes-1-base; 3-(dimethylamino) third-1-alkynes-1-base; 3-(N-methyl acetyl is amino) third-1-alkynes-1-base; 3-acetyl aminopropan-1-alkynes-1-base; first oxygen base; second oxygen base; propoxyl group; butoxy; amoxy; (5-oxo-pyrrolidine-2-yl) first oxygen base; oxolane-3-base first oxygen base; 2-hydroxyl base oxethyl; the 2-ethoxy ethoxy; 2-(2-hydroxyl base oxethyl) second oxygen base; the 2-methoxy ethoxy; (2-methoxy ethoxy) second oxygen base; 2-{N-[2-hydroxyl ethyl]-N-methyl-amino } second oxygen base; 2-morpholine second oxygen base; 2-(2-oxo-pyrrolidine-1-yl) second oxygen base; 2-(imidazoles alkane-2-ketone-1-yl) second oxygen base; 3-hydroxyl propoxyl group; 2-hydroxyl third-1-base oxygen base; 3-methoxy propyl-1-base oxygen base; 2-methoxy propyl-1-base oxygen base; 3-morpholine third-1-base oxygen base; 3-(first sulphur base) third-1-base oxygen base; 3-(methyl sulphonyl) propyl group-1-oxygen base; methoxycarbonyl;Uncle-Butoxy carbonyl, N-(Uncle-Butoxy carbonyl) amino; methyl is amino; the 2-methoxy ethyl is amino; the 2-aminoethylamino; 2-(dimethylamino) ethylamino; (N-2-methoxy ethyl)-N-methyl is amino; the different propoxyl group third-1-base of 3-is amino; 2-(2-hydroxyl base oxethyl) ethylamino; 2-(acetyl is amino) ethylamino; 2-(morpholine-4-yl) ethylamino; 2-methyl-prop-1-base is amino; 2-hydroxyl third-1-base is amino; the 3-methoxy-propyl is amino; the 3-ethoxycarbonyl propyl is amino; the different propoxyl group ethylamino of 2-; oxolane-2-base methyl is amino; dimethylamino; N-(2-hydroxyl ethyl)-N-ethylamino; cyclopropyl is amino; cyclobutyl is amino; cyclopenta is amino; 4-methyl cyclohexane base is amino; 4-hydroxyl cyclohexyl is amino; carbamoyl; N-hydroxyl amino formyl base; N-cyclopropyl carbamoyl; N-cyclopenta carbamoyl; the amino carbamoyl of N-; N-(acetyl-amino) carbamoyl; N-methyl carbamoyl; 2-hydroxyl ethylamino formyl base; N-(2-hydroxyl propyl group) carbamoyl; N-(2; the 3-dihydroxypropyl) carbamoyl; N-(4-hydroxybutyl) carbamoyl; N-(2-methoxy ethyl) carbamoyl; N-(2-(acetyl-amino) ethyl) carbamoyl; N-[2-(2-hydroxyl base oxethyl) ethyl] carbamoyl; N-(carbamoyl methyl) carbamoyl; N-[2-(first sulphur base) ethyl] carbamoyl; N-(2-methoxy ethyl)-N-methyl carbamoyl; pyrrolidines-1-base carbonyl; morpholino carbonyl; azetidine-1-base carbonyl; (3-hydroxyl pyrrolidines-1-yl) carbonyl; first sulphur base; ethylmercapto group; the rosickyite base; 2; 2; 6,6-tetramethyl piperidine-4-base is amino; the 4-THP trtrahydropyranyl is amino; oxinane-4-oxygen base; pyrrolidines-1-base; morpholine generation (morpholino); piperazine-1-base; 4-methyl piperazine-1-base; 4-ethyl piperazidine-1-base; 4-isopropyl piperazine-1-base; 4-(2-hydroxyl ethyl) piperazine-1-base; 4-(3-hydroxyl propyl group) piperazine-1-base; 4-(2-methoxy ethyl) piperazine-1-base; 4-(2-amino-ethyl) piperazine-1-base; 4-[2-(2-hydroxyl base oxethyl) ethyl] piperazine-1-base; 4-(2-cyano ethyl) piperazine-1-base; 4-(Uncle-Butoxy carbonyl) piperazine-1-base, 1-formyl base-piperazine-4-base, 4-acetyl group piperazine-1-base, 4-(ethylsulfonyl) piperazine-1-base, 4-amino piperidine-1-base, 4-(N-Uncle-Butoxy carbonyl is amino) piperidines-1-is basic, 3-hydroxyl pyrrolidines-1-is basic, 3-dimethylamino-pyrrolidines-1-base, suitable-3,4-dihydroxy pyrrolidine-1-base, 5-methyl-[1,3,4]- diazole-2-base, 2,7-diazaspiracyclic [3.5] ninth of the ten Heavenly Stems-7-base and (Uncle-Butoxy carbonyl)-2,7-diazaspiracyclic [3.5] ninth of the ten Heavenly Stems-7-base.

R ³Suitable value for example more particularly comprise hydrogen, hydroxyl, chlorine, iodine, methyl, ethyl, propyl group, cyclopropyl, three methyl fluorides, hydroxyl methyl, methoxy, ethoxyl methyl, (2-methoxy ethoxy) methyl, amino methyl, methyl amino methyl, morpholine for methyl, 4-methyl piperazine-1-base methyl, pyrrolidines-1-base methyl, 2-methoxy ethyl, 2-(ethoxy carbonyl) ethyl, 2-(N-methyl carbamoyl) ethyl, 3-hydroxyl propyl group, 3-methoxy-propyl, 3-aminopropan-1-base, 3-N, N-dimethylaminopropyl, 3-(Uncle-Butoxy carbonyl is amino) third-1-base, 3-pyrrolidines-1-base propyl group, vinyl, penta-3-alkene-1-base, 3-hydroxyl third-1-alkene-1-base, 3-aminopropan-1-alkene-1-base, 2-(methoxycarbonyl) ethene-1-base, 3-(uncle-butoxy carbonyl is amino) third-1-alkene-1-base, the acetylene base, 3-hydroxyl third-1-alkynes-1-base, 3-methoxy propyl-1-alkynes-1-base, 2-(trimethyl silyl) acetylene base, 3-aminopropan-1-alkynes-1-base, 3-methyl aminopropan-1-alkynes-1-base, 3-(dimethylamino) third-1-alkynes-1-base, 3-(N-methyl acetyl is amino) third-1-alkynes-1-base, 3-acetyl aminopropan-1-alkynes-1-base, first oxygen base, second oxygen base, (5-oxo-pyrrolidine-2-yl) first oxygen base (for example (2S)-(5-oxo-pyrrolidine-2-yl) first oxygen base or (2R)-(5-oxo-pyrrolidine-2-yl) first oxygen base), oxolane-3-base first oxygen base, 2-hydroxyl base oxethyl, the 2-ethoxy ethoxy, 2-(2-hydroxyl base oxethyl) second oxygen base, the 2-methoxy ethoxy, (2-methoxy ethoxy) second oxygen base, 2-{N-[2-hydroxyl ethyl]-N-methyl-amino } second oxygen base, 2-morpholine second oxygen base, 2-(2-oxo-pyrrolidine-1-yl) second oxygen base, 2-(imidazoles alkane-2-ketone-1-yl) second oxygen base, 3-hydroxyl propoxyl group, 2-hydroxyl third-1-base oxygen base (for example (2R)-2-hydroxyl third-1-base oxygen base), 3-methoxy propyl-1-oxygen base, 2-methoxy propyl-1-base oxygen base (for example (2S)-2-methoxy propyl-1-base oxygen base), 3-morpholine third-1-base oxygen base, 3-(first sulphur base) third-1-base oxygen base, 3-(methyl sulphonyl) propyl group-1-oxygen base, methoxycarbonyl, N-(Uncle-Butoxy carbonyl) amino; methyl is amino; the 2-methoxy ethyl is amino; the 2-aminoethylamino; 2-(dimethylamino) ethylamino; (N-2-methoxy ethyl)-N-methyl is amino; the different propoxyl group third-1-base of 3-is amino; 2-(2-hydroxyl base oxethyl) ethylamino; 2-(acetyl is amino) ethylamino; 2-(morpholine-4-yl) ethylamino; 2-methyl-prop-1-base is amino; 2-hydroxyl third-1-base amino (for example (2R)-2-hydroxyl third-1-base amino or (2S)-2-hydroxyl third-1-base is amino); the 3-methoxy-propyl is amino; the 3-ethoxycarbonyl propyl is amino; the different propoxyl group ethylamino of 2-; oxolane-2-base methyl amino (for example (2R)-oxolane-2-base methyl is amino); dimethylamino; N-(2-hydroxyl ethyl)-N-ethylamino; cyclobutyl is amino; 4-methyl cyclohexane base is amino; 4-hydroxyl cyclohexyl is amino; carbamoyl; N-hydroxyl amino formyl base; N-cyclopropyl carbamoyl; N-cyclopenta carbamoyl; the amino carbamoyl of N-; N-(acetyl-amino) carbamoyl; N-methyl carbamoyl; 2-hydroxyl ethylamino formyl base; N-(2-hydroxyl propyl group) carbamoyl (for example N-((R)-2-hydroxyl propyl group) carbamoyl); N-(2; the 3-dihydroxypropyl) carbamoyl (N-((2R)-2 for example; the 3-dihydroxypropyl) carbamoyl); N-(4-hydroxybutyl) carbamoyl; N-(2-methoxy ethyl) carbamoyl; N-(2-(acetyl-amino) ethyl) carbamoyl; N-[2-(2-hydroxyl base oxethyl) ethyl] carbamoyl; N-(carbamoyl methyl) carbamoyl; N-[2-(first sulphur base) ethyl] carbamoyl; N-(2-methoxy ethyl)-N-methyl carbamoyl; pyrrolidines-1-base carbonyl; morpholino carbonyl; azetidine-1-base carbonyl; (3-hydroxyl pyrrolidines-1-yl) carbonyl (for example (3R)-3-hydroxyl pyrrolidines-1-base carbonyl); first sulphur base; 2; 2; 6,6-tetramethyl piperidine-4-base is amino; the 4-THP trtrahydropyranyl is amino; tetrahydropyran-4-base oxygen base; pyrrolidines-1-base; morpholine generation; piperazine-1-base; 4-methyl piperazine-1-base; 4-ethyl piperazidine-1-base; 4-isopropyl piperazine-1-base; 4-(2-hydroxyl ethyl) piperazine-1-base; 4-(3-hydroxyl propyl group) piperazine-1-base; 4-(2-methoxy ethyl) piperazine-1-base; 4-(2-amino-ethyl) piperazine-1-base; 4-[2-(2-hydroxyl base oxethyl) ethyl] piperazine-1-base; 4-(2-cyano ethyl) piperazine-1-base; 4-(Uncle-Butoxy carbonyl) piperazine-1-base, 1-formyl base-piperazine-4-base, 4-acetyl group piperazine-1-base, 4-(ethylsulfonyl) piperazine-1-base, 4-amino piperidine-1-base, 4-(N-Uncle-Butoxy carbonyl is amino) piperidines-1-is basic, 3-hydroxyl pyrrolidines-1-base (for example (3R)-3-hydroxyl pyrrolidines-1-yl), 3-dimethylamino-pyrrolidines-1-base (for example (3R)-3-dimethylamino-pyrrolidines-1-yl), suitable-3,4-dihydroxy pyrrolidine-1-base, 5-methyl-[1,3,4]- diazole-2-base, 2,7-diazaspiracyclic [3.5] ninth of the ten Heavenly Stems-7-base and (Uncle-Butoxy carbonyl)-2,7-diazaspiracyclic [3.5] ninth of the ten Heavenly Stems-7-base.

R ³Suitable value more particularly comprise for example hydrogen; chlorine; iodine; methyl; ethyl; three methyl fluorides; the hydroxyl methyl; methoxy; ethoxyl methyl; (2-methoxy ethoxy) methyl; morpholine is for methyl; 3-hydroxyl propyl group; the 3-methoxy-propyl; 3-N; the N-dimethylaminopropyl; vinyl; 3-hydroxyl third-1-alkene-1-base; the acetylene base; 3-hydroxyl third-1-alkynes-1-base; 3-methoxy propyl-1-alkynes-1-base; 3-aminopropan-1-alkynes-1-base; 3-methyl aminopropan-1-alkynes-1-base; 3-(dimethylamino) third-1-alkynes-1-base; 3-(N-methyl acetyl is amino) third-1-alkynes-1-base; 3-acetyl aminopropan-1-alkynes-1-base; first oxygen base; second oxygen base; (5-oxo-pyrrolidine-2-yl) first oxygen base (for example (2S)-(5-oxo-pyrrolidine-2-yl) first oxygen base or (2R)-(5-oxo-pyrrolidine-2-yl) first oxygen base); oxolane-3-base first oxygen base; 2-hydroxyl base oxethyl; the 2-ethoxy ethoxy; 2-(2-hydroxyl base oxethyl) second oxygen base; the 2-methoxy ethoxy; (2-methoxy ethoxy) second oxygen base; 2-{N-[2-hydroxyl ethyl]-N-methyl-amino } second oxygen base; 2-morpholine second oxygen base; 2-(2-oxo-pyrrolidine-1-yl) second oxygen base; 2-(imidazoles alkane-2-ketone-1-yl) second oxygen base; 3-hydroxyl propoxyl group; 2-hydroxyl third-1-base oxygen base (for example (2R)-2-hydroxyl third-1-base oxygen base); 3-methoxy propyl-1-base oxygen base; 2-methoxy propyl-1-base oxygen base (for example (2S)-2-methoxy propyl-1-base oxygen base); 3-morpholine third-1-base oxygen base; 3-(first sulphur base) third-1-base oxygen base; 3-(methyl sulphonyl) propyl group-1-oxygen base; methyl is amino; the 2-methoxy ethyl is amino; 2-(methoxy ethyl) amino; 2-(2-hydroxyl base oxethyl) ethylamino; 2-(morpholine-4-yl) ethylamino; 2-methyl-prop-1-base is amino; 2-hydroxyl third-1-base amino (for example (2R)-2-hydroxyl third-1-base amino or (2S)-2-hydroxyl third-1-base is amino); the 3-methoxy-propyl is amino; the 3-ethoxycarbonyl propyl is amino; the different propoxyl group ethylamino of 2-; oxolane-2-base methyl amino (for example (2R)-oxolane-2-base methyl is amino), dimethylamino; N-(2-hydroxyl ethyl)-N-ethylamino; cyclobutyl is amino; carbamoyl; N-cyclopropyl carbamoyl; N-methyl carbamoyl; 2-hydroxyl ethylamino formyl base; N-(2-hydroxyl propyl group) carbamoyl (for example N-((R)-2-hydroxyl propyl group) carbamoyl); N-(2-methoxy ethyl) carbamoyl; N-[2-(first sulphur base) ethyl] carbamoyl; pyrrolidines-1-base carbonyl; azetidine-1-base carbonyl; first sulphur base; the 4-THP trtrahydropyranyl is amino; tetrahydropyran-4-base oxygen base; pyrrolidines-1-base; morpholine generation; piperazine-1-base; 4-methyl piperazine-1-base; 4-ethyl piperazidine-1-base; 4-isopropyl piperazine-1-base; 4-(2-hydroxyl ethyl) piperazine-1-base; 4-(3-hydroxyl propyl group) piperazine-1-base; 4-(2-methoxy ethyl) piperazine-1-base; 4-(2-cyano ethyl) piperazine-1-base; 4-acetyl group piperazine-1-base; 4-(ethylsulfonyl) piperazine-1-base; 3-hydroxyl pyrrolidines-1-base (for example (3R)-3-hydroxyl pyrrolidines-1-yl); 3-dimethylamino-pyrrolidines-1-base (for example (3R)-3-dimethylamino-pyrrolidines-1-yl) and 1-formyl base-piperazine-4-base.

In one embodiment, R³Be selected from suitablely hydrogen or halogen or (C1-C6) alkyl, (C2-C6) alkene base, (C2-C6) alkynes base, (C1-C6) alkoxyl, (C1-C6) alkyl-carbonyl, (C1-C6) alkoxy carbonyl, amino, (C1-C6) alkyl amino, two-[(C1-C6) alkyl] amino, carbamoyl ,-C (O) R^3b、-OR ^3b、-SR ^3b、-NHR ^3bThe alkyl of ,-N[(C1-C6)] R3b or-S (O)_mR ^3aBase (R wherein^3aAnd R^3bDescribed as defined above) or comprise the heteroatomic 5-of at least one ring that is selected from nitrogen, oxygen and sulphur or the saturated monocyclic heterocycles of 6-person, each ring or group optionally by one or more (for example one or two, particularly one) above defined substituting group replace.

In another embodiment, R³Be selected from suitablely hydrogen or substituted or unsubstituted being selected from (C1-C6) alkyl (preferred (C1-C4) alkyl) as methyl, ethyl, propyl group, isopropyl,Uncle-Butyl, (C3-C8) cycloalkyl (preferred (C3-C6) cycloalkyl) as cyclopropyl, cyclopenta, cyclohexyl, (C3-C8) cycloalkyl (C1-C6) alkyl (preferred (C3-C6) cycloalkyl (C1-C4) alkyl) as cyclopropyl methyl, (C1-C6) alkoxyl (preferred (C1-C4) alkoxyl) as first oxygen base, second oxygen base, propoxyl group, different propoxyl group and butoxy, (C1-C6) alkyl-carbonyl such as methyl carbonyl, (C3-C8) naphthene base carbonyl such as cyclopropyl carbonyl, (C3-C8) cycloalkyl (C1-C6) alkyl-carbonyl such as cyclopropyl methyl carbonyl, (C1-C6) alkoxy carbonyl, (C1-C6) alkyl amino such as methyl amino or ethylamino, (C3-C8) cycloalkyl amino, (C3-C8) cycloalkyl (C1-C6) alkyl amino, (C1-C6) alkoxy amino or-S (O)_mR ^3aGroup.

R ³On suitable substituting group comprise one or more (for example, one, two or three, particularly one or two, more particularly one) be independently selected from (C1-C6) alkoxyl (such as methoxy or ethoxy), (C1-C6) alkoxyl (C1-C6) alkoxyl (such as methoxy ethoxy) or optional comprise one or more substituting groups that are selected from heteroatomic 3-, 4-, 5-, a 6-or 7-member (for example 4-to 7-member) the saturated monocycle (such as cyclopenta, cyclohexyl, pyrroles's alkyl, piperidines base, two  alkyl, morpholine base, tetrahydrofuran base, piperazine base) of nitrogen, oxygen and sulphur.

When being substituted, R³Specified substituent comprise that for example one or more (for example one or two, particularly one) are independently selected from (C1-C6) alkyl, (C1-C6) alkoxyl, halogen, hydroxyl, three methyl fluorides, amino, (C1-C6) alkyl amino and two-[(C1-C6) alkyl] is amino or optionally comprise one or more substituting groups that are selected from the saturated monocycle of heteroatomic 3-, 4-, 5-, a 6-or 7-member (for example individual member of 4-to 7-) of nitrogen, oxygen and sulphur.

Work as R³What carry is that this ring preferably comprises nitrogen and also comprises the other hetero atom that one or two is selected from nitrogen, oxygen and sulphur optionally when optionally comprising the substituting group of the saturated monocycle of one or more heteroatomic 3-, 4-, 5-, 6-or 7-member that are selected from nitrogen, oxygen and sulphur (for example 4-to 7-member). For example, R³On 3-, 4-, 5-, a 6-or 7-member (for example 4-to 7-member) saturated mono ring substituents can comprise pyrrolidines.

In one embodiment, R³Expression hydrogen.

-NQ ¹Preferably expression comprises a nitrogen heteroatom and (for example comprises at least one other ring hetero atom that is selected from nitrogen, oxygen and sulphur optionally, one, two, three or four ring hetero atoms, these ring hetero atoms can be identical or different) 5 or 6 Yuans saturated monocycles.

In one embodiment, this N-connects comprises one-NQ¹The saturated monocycle of 5-to 6-member of nitrogen heteroatom comprise one or two other ring hetero atom that is selected from nitrogen, oxygen and sulphur (it can be identical or different) optionally.

In another embodiment ,-NQ¹Expression comprises 5 or 6 Yuans saturated monocycles of a nitrogen heteroatom.

In an especially preferred embodiment ,-NQ¹Expression pyrroles's alkyl or piperidines base (being most preferably pyrroles's alkyl).

Ring NQ¹Can be set up by ring Q in any desirable the subrogating of this ring²Replace. NQ¹Preferably with general-NQ¹Be connected on the ring atom that the nitrogen-atoms of the compounds of this invention pyrimidine ring adjoins mutually by Q²Replace.

Q ²Represent to comprise 5-to the 6-member heteroaromatic rings of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur (for example,, two, three or four can be identical or different ring hetero atom) suitablely and can be for example thiophene base, pyrazoles base,  azoles base, different  azoles base, thiadiazolyl group, pyrrole radicals, furyl, thiazolyl, triazole base, tetrazole radical, imidazole radicals, pyrazine base, pyridazine base, pyrimidine radicals or pyridine radicals.

Q ²Preferably expression comprises the heteroatomic 5 or 6 Yuans heteroaromatic rings of the ring that is selected from nitrogen and oxygen that one or two can be identical or different, such as pyridine radicals, pyrimidine radicals, pyrazine base, pyridazine base, imidazole radicals,  azoles base, tetrazole radical or different  azoles base (particularly tetrazole radical or different  azoles base).

In another embodiment, Q²Represent that 5 or 6 Yuans comprise nitrogen and the heteroatomic heteroaromatic rings of oxygen ring.

In an especially preferred embodiment, Q²Represent different  azoles base ring.

In another embodiment, Q²Expression comprises one to four heteroatomic 5 or 6 Yuans heteroaromatic rings of azo-cycle, for example, and Q²Can represent pyrrole radicals, pyrazoles base, triazole base, tetrazole radical, imidazole radicals, pyrazine base, pyridazine base, pyrimidine radicals or pyridine radicals.

Q ²Can be connected to ring NQ by any obtainable ring atom with suiting¹On, for example it can be connected by ring carbon or nitrogen-atoms. At Q²Comprise at least one and encircle in the heteroatomic situation, then Q²Preferably be connected to ring NQ by the ring carbon atom that adjoins with hetero atom¹On.

Remove by Q³Outside the replacement, Q²Also optional ground by at least one (for example, one, two, three or four can be identical or different substituting group) substituting group that is independently selected from following group replaces: (C1-C6) alkyl, particularly (C1-C4) alkyl (such as methyl, ethyl, just-propyl group, isopropyl, just-butyl, isobutyl group,Uncle-Butyl, just-amyl group or just-oneself base), (C1-C6) alkoxyl, particularly (C1-C4) alkoxyl (such as first oxygen base, second oxygen base, just-propoxyl group, just-butoxy,Uncle-Butoxy, just-amoxy or just-own oxygen base) ((C1-C6) alkyl and (C1-C6) alkoxy substituent optional ground is by at least one substituting group separately, for example one, two, three or four substituting groups that are independently selected from halogen (such as fluorine, chlorine, bromine or iodine), amino, hydroxyl and three methyl fluorides replace), halogen (such as fluorine, chlorine, bromine or iodine), nitro, cyano group ,-NR⁴R ⁵, carboxyl, hydroxyl, (C2-C6) alkene base, particularly (C2-C4) alkene base (such as vinyl), (C3-C8) cycloalkyl are (for example, cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl), (C3-C8) cycloalkyl (C1-C6) alkyl (such as the cyclopropyl methyl), (C1-C4) alkoxy carbonyl, particularly (C1-C3) alkoxy carbonyl (such as methoxycarbonyl or ethoxy carbonyl), (C1-C4) alkyl-carbonyl, particularly (C1-C3) alkyl-carbonyl (such as methyl carbonyl, ethyl carbonyl, just-propyl group carbonyl, isopropyl carbonyl or just-butyl carbonyl), (C1-C4) alkyl-carbonyl-amino, particularly (C1-C3) alkyl-carbonyl-amino (amino such as methyl carbonyl amino or ethyl carbonyl), phenylcarbonyl group ,-S (O)_p(C1-C4), particularly (C1-C2) alkyl (such as the inferior sulphonyl base of first sulphur base, ethylmercapto group, methylsulfinyl, ethyl, first sulphonyl base and ethylsulfonyl) ,-C (O) NR⁶R ⁷With-SO₂NR ⁸R ⁹(wherein p, R⁶、R ⁷、R ⁸And R⁹Described as defined above)

R ⁴、R ⁵、R ⁶、R ⁷、R ⁸And R⁹Suitablely represent independently separately hydrogen or (C1-C6) alkyl, preferred (C1-C4) alkyl such as methyl, ethyl, propyl group or butyl, or when when nitrogen-atoms that it is attached thereto connects together, R⁴And R⁵, or R⁶And R⁷, or R⁸And R⁹Can form independently of one another saturated heterocyclic such as pyrroles's alkyl or piperidines base.

In one embodiment, Q²Optional ground be independently selected from by at least one (C1-C6) alkyl, (C1-C6) alkoxyl, halogen and (C3-C8) substituting group of cycloalkyl replace.

Q ³Suitably is a substituted or unsubstituted (C1-C6) alkyl (preferably (C1-C4) alkyl) such as methyl, ethyl, propyl or butyl group, (C3-C8) cycloalkyl group (preferably (C3-C6) cycloalkyl group) such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, (C3-C8) cycloalkyl (C1-C6) alkyl group such as cyclopropyl group or optionally containing at least one heteroatom selected from nitrogen, oxygen and sulfur ring heteroatom (e.g. one, two, three or four heteroatoms) saturated or unsaturated 5 - to 6 - membered monocyclic such as phenyl, pyridyl , imidazolyl, iso  oxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, thiazolyl,  oxazolyl, isothiazolyl, triazolyl, tetrahydrofuranyl or thienyl (especially pyridyl, pyrazinyl, thiazolyl, tetrahydrofuranyl or pyrimidinyl group)....

In one embodiment, Q³Represent substituted or unsubstituted being selected from (C1-C6) alkyl, (C3-C8) cycloalkyl or optional the group that comprises heteroatomic substituted or unsubstituted saturated or undersaturated 5-to the 6-member monocycle of at least one ring that is selected from nitrogen, oxygen and sulphur. For example, Q³Can represent the substituted or unsubstituted group that is selected from methyl, cyclopropyl, pyridine radicals, pyrazine base, thiazolyl, tetrahydrofuran base or pyrimidine radicals.

In another embodiment, Q³Preferably substituted or unsubstituted being selected from (C1-C4) alkyl (especially methyl), (C3-C6) cycloalkyl (especially cyclopropyl) or comprise the unsaturated monocycle of heteroatomic optionally substituted 5-to the 6-member of the ring that is selected from nitrogen, oxygen and sulphur that one or two can be identical or different, such as imidazole radicals, different  azoles base, pyrazoles base, furyl, pyrazine base (especially pyrazine-2-yl), pyridazine base, pyrimidine radicals (especially pyrimidine-2-base), pyrrole radicals,  azoles base, isothiazolyl, triazole base, tetrahydrofuran base or thiophene base, especially pyridine radicals (preferred pyridine-2-base or pyridine-3-yl) or thiazolyl (especially thiazole-2-base or thiazole-4-yl) or tetrahydrofuran base (especially oxolane-3-yl).

For Q³; suitable optional substituting group be one or more (for example; one, two, three or four) be independently selected from the substituting group of following group: (C1-C6) alkyl or (C1-C6) alkoxyl (it separately optionally by at least one (for example; one, two, three or four substituting groups) be independently selected from halogen, the substituting group of amino, hydroxyl and three methyl fluorides replaces), halogen, nitro, cyano group ,-NR¹⁰R ¹¹, carboxyl, hydroxyl, (C2-C6) alkene base, (C3-C8) cycloalkyl, (C1-C6) alkoxy carbonyl, (C1-C6) alkyl-carbonyl, (C1-C6) alkyl-carbonyl-amino, phenylcarbonyl group ,-S (O)_n(C1-C6) alkyl ,-C (O) NR¹²R ¹³With-SO₂NR ¹⁴R ¹⁵(wherein n, R¹⁰、R ¹¹、 R ¹²、R ¹³、R ¹⁴And R¹⁵Described as defined above).

R ¹⁰、R ¹¹、R ¹²、R ¹³、R ¹⁴And R¹⁵Suitable ground represents hydrogen or (C1-C6) alkyl such as methyl independently of one another, or R¹⁰And R¹¹, or R¹²And R¹³, or R¹⁴And R¹⁵, when when nitrogen-atoms that it is attached thereto connects together, can form saturated heterocyclic such as pyrroles's alkyl or piperidines base separately suitablely.

Should recognize number and character to the upper substituting group of ring in the compounds of this invention are selected to avoid undesirable spatial chemistry combination.

In the compound of one group of preferred formula of the present invention (I), R¹Expression (C1-C4) alkyl or (C3-C6) cycloalkyl; R²The expression halogen; R³Expression hydrogen;-NQ¹Expression comprises a nitrogen heteroatom and comprises at least one the heteroatomic 5-of other ring that is selected from nitrogen, oxygen and sulphur or the saturated monocycle of 6-person optionally; Q²Represent the substituted heteroatomic 5-of the ring that is selected from nitrogen and oxygen or the 6-person's heteroaromatic rings that comprises one or two can be identical or different; And Q³Expression (C1-C4) alkyl or (C3-C6) the substituted unsaturated monocycle of heteroatomic 5-to the 6-member of the ring that is selected from nitrogen, oxygen and sulphur that comprises one or two can be identical or different of cycloalkyl or optional ground.

In this group particularly preferred compound be those wherein-NQ¹Expression pyrroles's alkyl or piperidines base (particularly pyrroles's alkyl); Q²Represent different  azoles base or tetrazole radical (particularly different  azoles base); And Q³The compound of expression methyl, cyclopropyl, tetrahydrofuran base, pyrazine base, thiazolyl, pyrimidine radicals or pyridine radicals.

This group in other particularly preferred compound be those wherein-NQ¹Expression pyrroles's alkyl or piperidines base; Q²Represent different  azoles base or tetrazole radical; And Q³The compound of expression methyl, cyclopropyl, thiazolyl, tetrahydrofuran base or pyridine radicals.

This group in other particularly preferred compound be those wherein-NQ¹Expression pyrroles's alkyl or piperidines base; Q²Represent different  azoles base; And Q³The compound of expression methyl, cyclopropyl, thiazolyl or pyridine radicals.

This group in other particularly preferred compound be those wherein-NQ¹Expression pyrroles alkyl; Q²Represent different  azoles base; And Q³The compound of representative ring propyl group, thiazolyl, pyrazine base, pyrimidine radicals or pyridine radicals.

The suitable value of minor (i) (it is connected on the 2-position of formula (I) pyrimidine ring) group:

Comprise for example different  azoles of 2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-base, 2-(the different  azoles of 3-methyl-5-yl] pyrrolidines-1-base, the different  azoles of 3-cyclopropyl-5-yl] pyrrolidines-1-base, the different  azoles of 2-[3-(thiazole-2-yl)-5-yl] pyrrolidines-1-base, the different  azoles of 2-[3-(thiazole-4-yl)-5-yl] pyrrolidines-1-base, the different  azoles of 2-[3-(pyridine-3-yl)-5-yl] pyrrolidines-1-base, 2-(the different  azoles of 3-(pyridine-2-yl)-5-yl) piperidines-1-base, 2-(3-{ oxolane-3-yl } different  azoles-5-yl] pyrrolidines-1-base, 2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-base, 2-(2-methyl-2H-tetrazolium-5-yl) pyrrolidines-1-base, the different  azoles of 2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-base, the different  azoles of 2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-base, 2-{3-(3-first oxygen base pyrazine-2-yl) different  azoles-5-yl } pyrrolidines-1-base and the different  azoles of 2-{3-(3-hydroxyl pyrazine-2-yl)-5-yl } pyrrolidines-the 1-base is (wherein, in order to avoid any doubt, it is to be connected to pyrrolidines on the 2-position of pyrimidine ring in the formula (I)-1-base or piperidines-1-yl).

Suitably is a substituted or unsubstituted (C1-C6) alkyl (preferably (C1-C4) alkyl) such as methyl, ethyl, propyl or butyl group, (C3-C8) cycloalkyl group (preferably (C3-C6) cycloalkyl group) such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, (C3-C8) cycloalkyl (C1-C6) alkyl group such as cyclopropyl group or optionally containing at least one heteroatom selected from nitrogen, oxygen and sulfur ring heteroatom (e.g. one, two, three or four heteroatoms) saturated or unsaturated 5 - to 6 - membered monocyclic such as phenyl, pyridyl , imidazolyl, iso  oxazolyl, pyrazolyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, thiazolyl,  oxazolyl, isothiazolyl, triazolyl, tetrahydrofuranyl or thienyl (especially pyridyl, pyrazinyl, thiazolyl, tetrahydrofuranyl or pyrimidinyl group)....

The compound that a particular of the present invention is formula (Ia) or its pharmaceutically useful salt:

Wherein:

R ²Expression hydrogen, halogen or three methyl fluorides;

Or R³Expression 2,7-diazaspiracyclic [3.5] nonane base,

R ³In each group or the ring optionally by one or more being independently selected from (C1-C6) alkyl; (C1-C6) alkoxyl; (C1-C6) alkoxyl (C1-C6) alkyl; (C1-C6) alkoxyl (C1-C6) alkoxyl; halogen; hydroxyl; three methyl fluorides; three-[(C1-C4) alkyl] monosilane bases; cyano group; amino; (C1-C6) alkyl amino; two-[(C1-C6) alkyl] amino; (C3-C8) cycloalkyl amino; (C3-C6) cycloalkyl (C1-C3) alkyl amino; amino (C1-C6) alkyl; (C1-C6) alkyl amino (C1-C6) alkyl; two-[(C1-C6) alkyl] amino (C1-C6) alkyl; (C3-C8) cycloalkyl amino (C1-C6) alkyl; (C3-C6) cycloalkyl (C1-C3) alkyl amino (C1-C6) alkyl; (C1-C6) alkoxy carbonyl; carbamoyl; (C1-C6) alkyl-carbamoyl; two-[(C1-C6) alkyl] carbamoyls; (C1-C6) alkylthio group; (C1-C6) alkyl sulphonyl; (C1-C6) alkyl sulphinyl; (C1-C6) alkane acyl group; R wherein^3aAnd R^3cAs defined above described alkanoylamino-N (R^3c)C(O)R ^3a, or optionally comprise one or more substituting groups that are selected from heteroatomic 3-, 4-, 5-, 6-or the saturated monocycle of 7-person of nitrogen, oxygen and sulphur and replace, any a kind of in these substituting groups optionally replaced by one or more (C1-C4) alkyl, hydroxyl or cyano group;

Q ²Expression comprises heteroatomic 5-to the 6-member of at least one ring that is selected from nitrogen, oxygen and sulphur heteroaromatic rings, and this encircles by Q³Replace and optional ground on any obtainable ring atom by one or more being independently selected from (C1-C6) alkyl or (C1-C6) alkoxyl (it is optionally replaced by one or more substituting groups that are independently selected from halogen, amino, hydroxyl and three methyl fluorides separately), halogen, nitro, cyano group ,-NR⁴R ⁵, carboxyl, hydroxyl, (C2-C6) alkene base, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxy carbonyl, (C1-C4) alkyl-carbonyl, (C1-C4) alkyl-carbonyl-amino, phenylcarbonyl group ,-S (O)_p(C1-C4) alkyl ,-C (O) NR⁶R ⁷With-SO₂NR ⁸R ⁹(R wherein⁴、R ⁵、R ⁶、R ⁷、R ⁸And R⁹Represent independently of one another hydrogen or (C1-C6) alkyl, or when when nitrogen-atoms that it is attached thereto connects together, R⁴And R⁵, or R⁶And R⁷, or R⁸And R⁹Can form independently of one another saturated heterocyclic and p is 0,1 or 2) other substituting group replace;

According to another embodiment of the invention, it provides compound or its pharmaceutically useful salt of formula (Ia), wherein:

R ²Expression hydrogen, halogen or three methyl fluorides;

R ³The expression hydrogen or halogen or (C1-C6) alkyl, (C2-C6) alkene base, (C2-C6) alkynes base, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxyl, (C3-C8) cycloalkyl (C1-C6) alkoxyl, (C1-C6) alkyl-carbonyl, (C3-C8) naphthene base carbonyl, (C3-C8) cycloalkyl (C1-C6) alkyl-carbonyl, (C1-C6) alkoxy carbonyl, amino, (C1-C6) alkyl amino, two-[(C1-C6) alkyl] amino, (C3-C8) cycloalkyl amino, (C3-C8) cycloalkyl (C1-C6) alkyl amino, (C1-C6) alkoxy amino, carbamoyl, (C2-C6) alkanoylamino ,-C (O) R^3b、 -OR ^3b、-SR ^3b、-NHR ^3bThe alkyl of ,-N[(C1-C6)] R^3bOr-S (O)_mR ^3a, R wherein^3aExpression (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxyl, m is 0,1 or 2, and R^3bExpression comprises one or more saturated monocycles of heteroatomic 5-to 6-member that are selected from nitrogen, oxygen and sulphur,

R ³In each group or ring optionally by one or more being independently selected from (C1-C6) alkyl, (C1-C6) alkoxyl, (C1-C6) alkoxyl (C1-C6) alkoxyl, halogen, hydroxyl, three methyl fluorides, cyano group, amino, (C1-C6) alkyl amino, two-[(C1-C6) alkyl] amino, (C3-C8) cycloalkyl amino, (C3-C6) cycloalkyl (C1-C3) alkyl amino, (C1-C6) alkoxy carbonyl, carbamoyl, (C1-C6) alkyl-carbamoyl, two-[(C1-C6) alkyl] carbamoyl, (C1-C6) alkylthio group, (C1-C6) alkyl sulphonyl, (C1-C6) alkyl sulphinyl, (C1-6) alkanoylamino or optionally comprise one or more substituting groups that are selected from heteroatomic 4-, 5-, 6-or the saturated monocycle of 7-person of nitrogen, oxygen and sulphur and replace;

Q ²Expression comprises heteroatomic 5-to the 6-member of at least one ring that is selected from nitrogen, oxygen and sulphur heteroaromatic rings, and this encircles by Q³Replace and optional ground on any obtainable ring atom by one or more being independently selected from (C1-C6) alkyl or (C1-C6) alkoxyl (it is optionally replaced by one or more substituting groups that are independently selected from halogen, amino, hydroxyl and three methyl fluorides separately), halogen, nitro, cyano group ,-NR⁴R ⁵, carboxyl, hydroxyl, (C2-C6) alkene base, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxy carbonyl, (C1-C4) alkyl-carbonyl, (C1-C4) alkyl-carbonyl-amino, phenylcarbonyl group ,-S (O)_p(C1-C4) alkyl ,-C (O) NR⁶R ⁷With-SO₂NR ⁸R ⁹Other substituting group replace R wherein⁴、R ⁵、R ⁶、R ⁷、R ⁸And R⁹Represent independently of one another hydrogen or (C1-C6) alkyl, or when when nitrogen-atoms that it is attached thereto connects together, R⁴And R⁵, or R⁶And R⁷, or R⁸And R⁹Can form independently of one another saturated heterocyclic and p is 0,1 or 2;

In this kind embodiment, Q²Particularly represent to comprise at least one ring nitrogen and be selected from heteroatomic 5-to the 6-member of the other ring heteroaromatic rings of nitrogen, oxygen and sulphur with optional at least one. Q²More particularly represent to comprise at least one ring nitrogen and be selected from heteroatomic 5-to the 6-member of the other ring heteroaromatic rings of nitrogen and oxygen with optional at least one. For example, Q²Can represent different  azoles base (particularly different  azoles-5-yl) or tetrazole radical (particularly tetrazolium-5-yl). Q²Different  azoles base (for example different  azoles-5-yl) particularly. This encircles Q²By defined Q above³Replace, and optional ground is further replaced by one or more above defined other substituting groups on any obtainable ring atom.

Another particularly preferred embodiment of the present invention is compound or its pharmaceutically useful salt of formula (Ib):

Wherein:

R ²Expression hydrogen, halogen or three methyl fluorides;

Or R³Expression 2,7-diazaspiracyclic [3.5] nonane base,

According to another embodiment of the invention, compound or its pharmaceutically useful salt of formula (Ib) is provided, wherein:

R ²Expression hydrogen, halogen or three methyl fluorides;

R ³The expression hydrogen or halogen or (C1-C6) alkyl, (C2-C6) alkene base, (C2-C6) alkynes base, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxyl, (C3-C8) cycloalkyl (C1-C6) alkoxyl, (C1-C6) alkyl-carbonyl, (C3-C8) naphthene base carbonyl, (C3-C8) cycloalkyl (C1-C6) alkyl-carbonyl, (C1-C6) alkoxy carbonyl, amino, (C1-C6) alkyl amino, two-[(C1-C6) alkyl] amino, (C3-C8) cycloalkyl amino, (C3-C8) cycloalkyl (C1-C6) alkyl amino, (C1-C6) alkoxy amino, carbamoyl, (C2-C6) alkanoylamino ,-C (O) R^3b、 -OR ^3b、-SR ^3b、-NHR ^3bThe alkyl of ,-N[(C1-C6)] R^3bOr-S (O)_mR ^3a, R wherein^3aExpression (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxyl, m is 0,1 or 2, and R^3bExpression comprises one or more saturated monocycles of heteroatomic 5-to 6-member that are selected from nitrogen, oxygen and sulphur;

Or R³Expression comprises the heteroatomic 5-of at least one ring that is selected from nitrogen, oxygen and sulphur or the saturated monocycle of 6-person,

In this kind embodiment, Q³Particularly be selected from (C1-C6) alkyl or (C3-C6) cycloalkyl, maybe can comprise heteroatomic saturated or undersaturated 5-to the 6-member monocycle of at least one ring that is selected from nitrogen, oxygen and sulphur, and Q wherein³Optional ground is replaced by one or more above defined substituting groups.

The compound that specific embodiment of the present invention is formula (Ic):

Or its pharmaceutically useful salt,

Wherein:

R ²Expression hydrogen, halogen or three methyl fluorides;

R ³Expression hydrogen, hydroxyl or halogen or (C1-C6) alkyl, (C2-C6) alkene base, (C2-C6) alkynes base, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxyl, (C3-C8) cycloalkyl (C1-C6) alkoxyl, (C1-C6) alkyl-carbonyl, (C3-C8) naphthene base carbonyl, (C3-C8) cycloalkyl (C1-C6) alkyl-carbonyl, (C1-C6) alkoxy carbonyl, amino, (C1-C6) alkyl amino, two-[(C1-C6) alkyl] amino, (C3-C8) cycloalkyl amino, (C3-C8) cycloalkyl (C1-C6) alkyl amino, (C1-C6) alkoxy amino, carbamoyl, (C1-C6) alkyl-carbamoyl, two-[(C1-C6) alkyl] carbamoyl ,-C (O) R^3b、-OR ^3b、-SR ^3b、-NHR ^3bThe alkyl of ,-N[(C1-C6)] R^3b、-S(O) _mR ^3aOr-N (R^3c)C(O)R ^3a, R wherein^3aExpression (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxyl, m are 0,1 or 2, R^3bExpression comprises the heteroatomic saturated 4-of at least one ring that is selected from nitrogen, oxygen and sulphur, 5-or 6-person's monocyclic heterocycles and R^3cThe expression hydrogen or (C1-C6) alkyl,

Or R³Expression 2,7-diazaspiracyclic [3.5] nonane base,

According to another embodiment of the invention, it provides compound or its pharmaceutically useful salt of formula (Ic), wherein:

R ²Expression hydrogen, halogen or three methyl fluorides;

R ³In each group or ring optionally by one or more being independently selected from (C1-C6) alkyl, (C1-C6) alkoxyl, (C1-C6) alkoxyl (C1-C6) alkoxyl, halogen, hydroxyl, three methyl fluorides, cyano group, amino, (C1-C6) alkyl amino, two-[(C1-C6) alkyl] amino, (C3-C8) cycloalkyl amino, (C3-C6) cycloalkyl (C1-C3) alkyl amino, (C1-C6) alkoxy carbonyl, carbamoyl, (C1-C6) alkyl-carbamoyl, two-[(C1-C6) alkyl] carbamoyl, (C1-C6) alkylthio group, (C1-C6) alkyl sulphonyl, (C1-C6) alkyl sulphinyl, (C1-6) alkanoylamino or optionally comprise one or more substituting groups that are selected from the saturated monocycle of heteroatomic 4-to 7-member of nitrogen, oxygen and sulphur and replace;

In this kind embodiment, Q²Particularly expression comprises at least one ring nitrogen and comprises heteroatomic 5-to the 6-member of the other ring heteroaromatic rings that at least one is selected from nitrogen, oxygen and sulphur optionally. Q²More particularly expression comprises at least one ring nitrogen and comprises heteroatomic 5-to the 6-member of the other ring heteroaromatic rings that at least one is selected from nitrogen and oxygen optionally. For example, Q²Can represent different  azoles base (particularly different  azoles-5-yl). This encircles Q²By Q³Replace, and optional ground is further replaced by one or more above defined other substituting groups on any obtainable ring atom.

Another particular of the present invention is the compound of formula (Id):

Or its pharmaceutically useful salt,

Wherein:

R ²Expression hydrogen, halogen or three methyl fluorides;

Or R³Expression 2,7-diazaspiracyclic [3.5] nonane base,

R ³In each group or the ring optionally by one or more being independently selected from (C1-C6) alkyl; (C1-C6) alkoxyl; (C1-C6) alkoxyl (C1-C6) alkyl; (C1-C6) alkoxyl (C1-C6) alkoxyl; halogen; hydroxyl; three methyl fluorides; three-[(C1-C4) alkyl] monosilane bases; cyano group; amino; (C1-C6) alkyl amino; two-[(C1-C6) alkyl] amino; (C3-C8) cycloalkyl amino; (C3-C6) cycloalkyl (C1-C3) alkyl amino; amino (C1-C6) alkyl; (C1-C6) alkyl amino (C1-C6) alkyl; two-[(C1-C6) alkyl] amino (C1-C6) alkyl; (C3-C8) cycloalkyl amino (C1-C6) alkyl; (C3-C6) cycloalkyl (C1-C3) alkyl amino (C1-C6) alkyl; (C1-C6) alkoxy carbonyl; carbamoyl; (C1-C6) alkyl-carbamoyl; two-[(C1-C6) alkyl] carbamoyls; (C1-C6) alkylthio group; (C1-C6) alkyl sulphonyl; (C1-C6) alkyl sulphinyl; (C1-C6) alkane acyl group; R wherein^3aAnd R^3cAs defined above described alkanoylamino--N (R^3c)C(O)R ^3a, or optionally comprise one or more substituting groups that are selected from heteroatomic 3-, 4-, 5-, 6-or the saturated monocycle of 7-person of nitrogen, oxygen and sulphur and replace, any a kind of in these substituting groups optionally replaced by one or more (C1-C4) alkyl, hydroxyl or cyano group;

According to another embodiment of the invention, compound or its pharmaceutically useful salt of formula (Id) is provided, wherein:

R ²Expression hydrogen, halogen or three methyl fluorides;

Particular compound of the present invention comprises that for example any one or more are selected from the compound of the formula (I) of following compound :-

The different  azoles of 5-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

5-chloro-2-[2-(the different  azoles of 3-methyl-5-yl] pyrrolidines-1-yl]-4-(5-Uncle-Butyl-1H-pyrazoles-3-base is amino) pyrimidine;

5-chloro-2-[2-(the different  azoles of 3-methyl-5-yl] pyrrolidines-1-yl]-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine;

5-chloro-2-[2-(the different  azoles of 3-cyclopropyl-5-yl] pyrrolidines-1-yl]-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine;

5-chloro-2-[2-(the different  azoles of 3-cyclopropyl-5-yl] pyrrolidines-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

5-chloro-2-[2-(the different  azoles of 3-methyl-5-yl] pyrrolidines-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of 5-chloro-2-{2-[3-(thiazole-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of 5-chloro-2-{2-[3-(thiazole-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of 5-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of 5-chloro-2-{2-[3-(pyridine-3-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of 5-chloro-2-{2-[3-(pyridine-3-yl)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine;

2-[2-(the different  azoles of 3-cyclopropyl-5-yl) pyrrolidines-1-yl]-6-methoxy-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine;

2-[2-(the different  azoles of 3-cyclopropyl-5-yl) pyrrolidines-1-yl]-6-methoxy-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine;

5-chloro-2-(2-(the different  azoles of 3-(pyridine-2-yl)-5-yl) piperidines-1-yl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

5-chloro-2-[2-(3-{ oxolane-3-yl } different  azoles-5-yl] pyrrolidines-1-yl]-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine;

5-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-2-[2-(3-{ oxolane-3-yl } different  azoles-5-yl] pyrrolidines-1-yl]-pyrimidine;

6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

5-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] piperidines-1-yl } pyrimidine;

5-chloro-2-{2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

5-fluoro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-pyrimidine;

4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 5-fluoro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

The different  azoles of S-5-chloro-2-{2-[3-methyl-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine;

4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 6-methyl-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 6-methyl-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-6-methyl-2-[2-(the different  azoles of 3-methyl-5-yl) pyrrolidines-1-yl] pyrimidine

6-ethyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

6-(3-methoxy-propyl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

6-methoxy-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 6-methoxy-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

6-methoxy-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(thiazole-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

6-methoxy-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-3-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(penta-3-alkene-1-the yl)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-I-yl] pyrimidine;

4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-the 6-trifluoromethyl pyrimidine:

4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-the 6-trifluoromethyl pyrimidine;

S-6-ethyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

The different  azoles of S-5-chloro-2-{2-[3-(thiazole-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of S-5-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 6-methyl-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

The different  azoles of S-5-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-5-chloro-2-{2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl } pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

6-(3-N, N-dimethylaminopropyl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

6-(3-pyrrolidines-1-base propyl group)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

6-methoxycarbonyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

6-(2-hydroxyl ethylamino formyl base)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-6-(pyrrolidines-1-base carbonyl) pyrimidine;

6-first oxygen base-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-{2-[3-(pyridine-2-yl)) different  azoles-5-yl] pyrrolidines-1-yl } pyrimidine;

5-chloro-4-(3-cyclopropyl-1H-pyrazoles-5-base is amino)-2-[2-(2-methyl-2H-tetrazolium-5-yl) pyrrolidines-1-yl] pyrimidine;

6-N-ethyl piperazidine base-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl } pyrimidine;

The different  azoles of 6-N-methyl piperazine base (piperazyl)-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

6-morpholine generation (morpholino)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

6-(3-(N, N-dimethylamino) propine-1-yl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-(2-(the different  azoles of 3-(pyridine-2-yl)-5-yl) pyrrolidines-1-yl) pyrimidine;

6-methyl amino-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-(the 3-pyridine-different  azoles of 2-base-5-yl) pyrrolidines-1-yl] pyrimidine;

6-(2-methoxy ethyl) amino-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

The different  azoles of 6-methoxycarbonyl-2-{2-[3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

6-(N-methyl the carbamoyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of 6-morpholino carbonyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

6-(N-(2-methoxy ethyl) the carbamoyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

6-(N-hydroxyl amino formyl the base)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of 6-carbamoyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of S-6-methoxycarbonyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-(N-(2-methoxy ethyl) the carbamoyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-[N-(2-methoxy ethyl)-N-methyl carbamoyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-[N-(2-(acetyl-amino) ethyl) carbamoyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-{N-[2-(2-hydroxyl base oxethyl) ethyl] carbamoyl }-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-[N-((R)-2-hydroxyl propyl group) carbamoyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-[N-(4-hydroxybutyl) carbamoyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-[N-((2R)-2,3-dihydroxypropyl) carbamoyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-[N-(carbamoyl methyl) carbamoyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-((3R)-3-hydroxyl pyrrolidines-1-base the carbonyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-{N-[2-(first sulphur base) ethyl] carbamoyl }-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-(N-cyclopropyl the carbamoyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-(N-cyclopenta the carbamoyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-(azetidine-1-base the carbonyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-(N-methyl the carbamoyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

6-(the amino carbamoyl of the N-)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

6-[N-(acetyl-amino) carbamoyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

6-(5-methyl-[1,3,4]- diazole-2-yl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of 6-hydroxyl methyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of 6-(morpholine is for methyl)-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

6-(4-methyl piperazine-1-base the methyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of 6-(methyl amino methyl)-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

6-(pyrrolidines-1-base the methyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of 6-amino methyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of S-6-hydroxyl methyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of S-6-ethoxyl methyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The S-6-[(2-methoxy ethoxy) methyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of S-5-chloro-2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine;

S-6-methyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

S-6-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyrazine-2-yl)-5-yl } pyrrolidines-1-yl } pyrimidine;

S-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl }-6-(the 2-methoxy ethyl is amino) pyrimidine;

S-6-methyl amino-and the different  azoles of 2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine;

S-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-6-first oxygen base-and the different  azoles of 2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

The different  azoles of 6-pyrrolidines-1-base-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-(2,2,6,6-tetramethyl piperidine-4-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-iodo-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-E-6-[3-( Uncle-Butoxy carbonyl is amino) third-1-alkene-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-vinyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-E-6-(3-hydroxyl third-1-alkene-1-yl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[3-( Uncle-Butoxy carbonyl is amino) third-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[3-aminopropan-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-E-6-[3-aminopropan-1-alkene-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[3-methyl aminopropan-1-alkynes-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[3-methoxy propyl-1-alkynes-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[3-hydroxyl third-1-alkynes-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[2-(trimethyl silyl) acetylene base]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[the different  azoles of 2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[3-(N-methyl acetyl is amino) third-1-alkynes-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[3-(dimethylamino) third-1-alkynes-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[the different  azoles of 2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[3-acetyl aminopropan-1-alkynes-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[2-(ethoxy carbonyl) ethyl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-E-6-[2-(methoxycarbonyl) ethene-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[the different  azoles of 2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-acetylene base-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

6-methoxy-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-methoxy-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-methoxy-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[3-aminopropan-1-alkynes-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[2-(N-methyl carbamoyl) ethyl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[the different  azoles of 2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-ethyl-1H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine;

S-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine;

6-(N- Uncle-Butoxy carbonyl) the different  azoles of amino-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of 6-(4-amino piperidine-1-yl) 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

6-(4-(N- Uncle-Butoxy carbonyl is amino) piperidines-1-yl)-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of 6-piperazine-1-base-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-{4-[2-(2-hydroxyl base oxethyl) ethyl] piperazine-1-yl }-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-(1-formyl base-piperazine-4-the yl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of S-6-piperazine-1-base-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-(4-isopropyl piperazine-1 the base)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-[(4-(2-hydroxyl ethyl) piperazine-1-yl)]-and the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-[(3R)-3-hydroxyl pyrrolidines-1-yl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-[(3R)-3-dimethylamino-pyrrolidines-1-yl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-(the 4-THP trtrahydropyranyl the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of S-6-morpholine generation-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of S-6-(2-methoxy ethyl) amino-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The S-6-[(N-2-methoxy ethyl)-the N-methyl is amino]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-((2R)-2-hydroxyl third-1-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

S-6-[N-(2-hydroxyl ethyl)-N-ethylamino]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of S-6-dimethylamino-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of S-6-methyl amino-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of S-6-chloro-2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of 6-morpholine generation (Mopholino)-2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine;

The different  azoles of 6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine;

6-(2-hydroxyl the base oxethyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine;

6-[4-( Uncle-Butoxy carbonyl) piperazine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

6-(4-acetyl group piperazine-1-yl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

6-[2-( Uncle-Butoxy carbonyl)-2,7-diazaspiracyclic [3.5] ninth of the ten Heavenly Stems-7-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

6-(2,7-diazaspiracyclic [3.5] ninth of the ten Heavenly Stems-7-yl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[4-(2-amino-ethyl) piperazine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[4-(3-hydroxyl propyl group) piperazine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[4-(2-cyano ethyl) piperazine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[4-(2-methoxy ethyl) piperazine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[the different  azoles of 2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-(4-acetyl group piperazine-1-yl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[4-(ethylsulfonyl) piperazine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[2-(2-hydroxyl base oxethyl) ethylamino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[the different  azoles of 2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[2-(acetyl is amino) ethylamino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

The S-6-[2-aminoethylamino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[4-methyl cyclohexane base is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[4-hydroxyl cyclohexyl is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[is suitable-3,4-dihydroxy pyrrolidine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{3-(3-first oxygen base pyrazine-2-yl) different  azoles-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-morpholine generation-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-morpholine generation-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{3-(3-first oxygen base pyrazine-2-yl) different  azoles-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-morpholine generation-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(3-hydroxyl pyrazine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[4-methyl piperazine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

The S-6-[cyclobutyl is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

The different propoxyl group third-1-base of S-6-[3-is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[2-(morpholine-4-yl) ethylamino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[2-(dimethylamino) ethylamino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[(2S)-2-hydroxyl third-1-base is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[2-methyl-prop-1-base is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

The S-6-[3-methoxy-propyl is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[4-ethyl piperazidine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

The S-6-[3-ethoxycarbonyl propyl is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[(2R)-oxolane-2-base methyl is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-(the different propoxyl group ethylamino of 2-)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-morpholine generation-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-methyl amino-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-methyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{3-(3-first oxygen base pyrazine-2-yl) different  azoles-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-first oxygen base-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-(2-methoxy ethoxy)-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

S-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

S-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 5-fluoro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

S-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 5-fluoro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 6-methyl-2-{2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines-1-yl } pyrimidine;

4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 6-methyl-2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 6-methyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

6-(3-hydroxyl propyl group)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

S-6-(3-hydroxyl propyl group)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine;

The different  azoles of S-6-propyl group-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine;

S-6-chloro-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-(2-hydroxyl base oxethyl)-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-(2-methoxy ethoxy)-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-morpholine generation-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-(4-methyl piperazine-1-yl)-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-chloro-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(2-pyrazine base)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-first oxygen base-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-(2-methoxy ethoxy)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-pyrrolidines-1-base-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-morpholino carbonyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-carbamoyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-5-fluoro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(2-hydroxyl the base oxethyl)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-azoles-3-base is amino)-6-(2-{N-[2-hydroxyl ethyl]-N-methyl-amino } second oxygen base)-the different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(the 2-morpholine is for second oxygen the base)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(first sulphur the base)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(oxolane-3-base first oxygen the base)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(2-(2-hydroxyl base oxethyl) second oxygen base)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 6-(2-methoxy ethoxy)-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(3-hydroxyl the propoxyl group)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-[2-(2-methoxy ethoxy) second oxygen base]-2-[the different  azoles of 2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 6-(2-ethoxy ethoxy)-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(3-morpholine generation third-1-base oxygen base)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(3-methoxy propyl-1-base oxygen the base)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-[2-(2-oxo-pyrrolidine-1-yl) second oxygen base]-the different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-[(2S)-2-methoxy propyl-1-base oxygen base]-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-[3-(first sulphur base) third-1-base oxygen base]-the different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-[(2S)-5-oxo-pyrrolidine-2-yl) first oxygen base]-the different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-[(2R)-5-oxo-pyrrolidine-2-yl) first oxygen base]-the different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-[2-(imidazoles alkane-2-ketone-1-yl) second oxygen base]-2-[the different  azoles of 2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 6-second oxygen base-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 6-hydroxyl-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 6-(2-methoxy ethoxy)-2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(2-hydroxyl the base oxethyl)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-[(2R)-2-hydroxyl third-1-base oxygen base]-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 6-(2-methoxy ethoxy)-2-[2-{3-(pyrazine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 6-first oxygen base-2-[2-{3-(pyrazine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-6-(2-hydroxyl the base oxethyl)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(tetrahydropyran-4-base oxygen the base)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-5-fluoro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-5-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-4-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-5-fluoro-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 5-fluoro-2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-morpholine generation-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-morpholine generation-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrazine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-(the 2-methoxy ethyl is amino)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-methyl amino-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-(4-methyl piperazine-1 base)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-methyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-[3-(methyl sulphonyl) propyl group-1-oxygen base]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[the different  azoles of 2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 6-(2-methoxy ethoxy)-2-[2-{3-(pyrazine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-methyl-4-(5-ethyl-1H-pyrazoles-3-base is amino)-2-[2-{3-(3-first oxygen base pyrazine-2-yl) different  azoles-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-chloro-4-(5-ethyl-1H-pyrazoles-3-base is amino)-2-[2-{3-(3-first oxygen base pyrazine-2-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine;

S-6-chloro-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-first oxygen base-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-ethyl-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-methyl amino-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-ethyl-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-cyclopropyl-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-cyclopropyl-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-(2-methoxy ethoxy)-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-methyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine;

S-5-fluoro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine;

S-5-fluoro-4-(5-ethyl-1H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine;

S-6-(2-hydroxyl base oxethyl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine;

S-6-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine;

S-6-chloro-4-(5-ethyl-1H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine;

S-6-(2-hydroxyl base oxethyl)-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine;

S-5-fluoro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine;

S-6-(2-hydroxyl base oxethyl)-4-(5-ethyl-1H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine;

S-6-methyl-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-2-[2-{3-(3-first oxygen base pyrazine-2-yl) different  azoles-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-morpholine generation-4-(5-ethyl-1H-pyrazoles-3-base is amino)-2-[2-{3-(3-first oxygen base pyrazine-2-yl) different  azoles-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine;

S-6-methyl-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-methyl-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

S-6-morpholine generation-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(3-hydroxyl pyrazine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine; With

S-6-(3-methoxy-propyl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine;

With and pharmaceutically useful salt.

Compound of the present invention comprise one or more by the situation of the carbon atom of Asymmetrical substitute in, the present invention includes they all stereoisomers that comprise enantiomter and diastereoisomer and comprise the mixture of its racemic mixture. Also comprise its change isomers and mixture.

Can the racemic body be separated into each enantiomter with known method (referring to Advanced Organic Chemistry: the 3rd edition: author J March, 104-107 page or leaf). A kind of suitable method comprises by this racemic material and chirality auxiliary agent are reacted to form diastereoisomeric derivative, then this diastereoisomer is separated, and for example separates with chromatogram, then this auxiliary agent cracking is got off.

The compound that should be understood that some formula (I) can be with solvation and solvation form not, and for example hydrated form exists. Should be understood that all such solvation forms that the present invention includes to regulate and control insulin-like growth factor 1 receptor active in the human or animal body.

The compound that also should be understood that some formula (I) may show polymorphic, the present invention includes all such forms that can regulate and control insulin-like growth factor 1 receptor active in the human or animal body.

Compound of the present invention can be provided with the form of officinal salt. Suitable pharmaceutically useful salt comprises for example sodium salt, alkali salt for example triethylamine, morpholine, N-methyl piperidines, N-ethylpiperidine, procaine, dibenzylamine of calcium salt or magnesium salt, organic amine salt for example of alkali salt such as alkali metal salt, N, the salt of N-DBHA or amino acid is lysine salt for example. On the other hand, have in the situation of enough alkalescence at this compound, suitable salt comprises acid-addition salts such as first sulfonate, fumarate, hydrochloric acid salt, hydrobromic acid salt, citric acid salt, maleic acid salt and the salt that forms with phosphoric acid and sulfuric acid.

The present invention also provides a kind of method for preparing formula as defined above (I) compound or its pharmaceutically useful salt, and it comprises:

(i) compound of formula (II) and the compound of formula (III) are reacted,

L wherein¹Represent to leave away group (for example halogen or sulfonyloxy such as first sulfonyloxy or toluene-4-sulfonyloxy) and R¹、R ²And R³Definition described suc as formula (I), just can protect any functional group if necessary,

Q wherein¹And Q²Definition described suc as formula (I), just any protective group can be got up if necessary;

Perhaps

(ii) compound of formula (IV) and the compound of formula (V) are reacted,

L wherein²Represent to leave away group (for example halogen or sulfonyloxy such as first sulfonyloxy or toluene-4-sulfonyloxy) and R²、R ³、Q ¹And Q²Definition described suc as formula (I), just any protective group can be got up if necessary,

R wherein¹Definition described suc as formula (I), just any protective group can be got up if necessary;

Perhaps

(iii) compound of formula (VI) and the compound of formula (VII) are reacted,

Q wherein¹And Q²Definition described suc as formula (I), just any protective group can be got up if necessary,

Wherein X represent oxygen atom and q be 1 or X represent that nitrogen-atoms and q are 2, R²¹Represent independently (C1-C6) alkyl and R²And R³Definition described suc as formula (I), just any protective group can be got up if necessary;

Perhaps

(iv) compound and the hydrazine with formula (VIII) reacts,

R wherein¹、R ²、R ³、NQ ¹And Q²Definition described suc as formula (I), just any protective group can be got up if necessary;

Perhaps

(v) for R wherein³Be (C1-C6) alkoxyl, amino, (C1-C6) alkyl amino, two-[(C1-C6) alkyl] amino, amino ,-OR^3b、-SR ^3b、-NHR ^3bThe alkyl of ,-N[(C1-C6)] R^3bOr-S (O)_mR ^3a(wherein m is 0 and R^3aAnd R^3bAs defined above described (and radicals R³Optional ground is replaced by at least one group as defined above) the compound of formula (I), L wherein³Represent to leave away group (for example halogen or sulfonyloxy such as first sulfonyloxy or toluene-4-sulfonyloxy) and R¹、R ²、Q ¹And Q²Definition described suc as formula (I), the compound of the formula (IX) that just any protective group can be got up if necessary

React with the compound of formula H-Xa, wherein Xa is selected from OR²²、NH ₂、NHR ²²、 N(R ²²) ₂、NH ₂、OR ^3b、SR ^3b、NHR ^3b, N[(C1-C6) alkyl] R^3bAnd SR^3a, R wherein²²Optionally substituted (C1-C6) alkyl and R^3aAnd R^3bSeparately described as defined above just can get up any protective group if necessary;

Perhaps

(vi) for R wherein³Optional substituted at least one ring nitrogen and optional the compound that comprises the formula (I) of one or more other heteroatomic 5-that are selected from nitrogen, oxygen and sulphur or 6-person's saturated heterocyclic of comprising, the compound of formula (IX) and the compound of formula (Xb) are reacted

Q wherein⁴Except the nitrogen-atoms shown in top, to comprise one or more heteroatomic 5-or saturated monocyclic heterocycles of 6-person that are selected from nitrogen, oxygen and sulphur also optionally, this ring is optionally replaced by at least one group as defined above, perhaps have optionally substituted 2,7-diazaspiracyclic [3.5] nonane base;

Perhaps

(vii) for R³(C2-C6) alkene base or (C2-C6) alkynes base, and radicals R³Optional ground is by the compound of the formula (I) that at least one group as defined above replaced, the compound of the compound of formula (IX) and formula (Xc) or formula (Xc ') reacted,

H-C≡C-R ²³ (Xc)

R wherein²³Be selected from hydrogen and optionally substituted (1-4C) alkyl or (C1-C4) alkoxy carbonyl;

Perhaps

(viii) for R wherein³Be connected to the compound of the formula (I) on the pyrimidine ring by carbon atom, with compound and the formula M-R of formula (IX)³Compound react R wherein³Be selected from R as defined above suitablely³Group and M are a kind of metal groups, such as ZnBr, B (OH)₂, CuCN or SnBu₃；

(ix) for R wherein³It is (C1-C6) alkoxy carbonyl (and radicals R³Optional ground is replaced by at least one group as defined above) the compound of formula (I), R wherein¹、R ²、Q ¹And Q²Definition described suc as formula (I), the compound of the formula (X) that just any protective group can be got up if necessary

React with the compound of formula H-O-(C1-C6) alkyl, wherein the optional ground of (C1-C6) alkyl is replaced by at least one group as defined above and if necessary can be with any protective group; Perhaps

(x) for R wherein³To comprise heteroatomic 5-person's heteroaromatic rings (and radicals R that at least one is selected from nitrogen, oxygen and sulphur³Optional ground is replaced by at least one group as defined above) the compound of formula (I), carry out inner condensation reaction with suitable initial material and suitable dehydrating agent. For example, for R wherein³Be the compound of the formula (I) of 1,3,4- di azoly, with the compound of formula (XI) and suitable dehydrating agent dehydrating agent, react such as hydroxide (methoxycarbonyl sulfamoyl (sulphamoyl)) triethyl ammonium,

Wherein Z represents R as defined above³Any suitable substituting group and R¹、R ²、Q ¹And Q²Definition described suc as formula (I), just any protective group can be got up if necessary; Perhaps

(xi) for R wherein³By (C1-C6) alkyl that at least one group as defined above replaced, (C3-C6) alkene base, (C3-C6) alkynes base or (C1-C6) compound of the formula of alkoxyl (I), with the compound of formula (XII) and formula H-Xa as defined above, (Xb), (Xc), (Xc ') or M-R³Compound react,

L wherein³Represent the group of leaving away as defined above, W represents optionally substituted (C1-C6) alkyl, (C3-C6) alkene base, (C3-C6) alkynes base or (C1-C6) alkoxyl and R¹、R ²、Q ¹And Q²Definition described suc as formula (I), just any protective group can be got up if necessary;

With optionally carry out at (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x) or (xi) below step or a multistep in the process:

The compound of gained is changed into another kind compound of the present invention

Form the pharmaceutically useful salt of this compound.

Process (i) can be easily exist suitable atent solvent or diluent for example ketone such as acetone or alcohol such as ethanol, butanols or just-situation of own alcohol or aromatic hydrocarbon such as toluene or NMP under, with the alkali that optionally suits in existence, for example in the situation of organic amine alkali such as diisopropyl ethyl amine, in 0 ℃ of temperature scope that extremely refluxes, preferably under reflux temperature, carry out.

Process (ii) can be easily exist suitable atent solvent or diluent for example ketone such as acetone or alcohol such as ethanol, butanols or just-situation of own alcohol or aromatic hydrocarbon such as toluene or NMP under, with optionally exist suitable acid for example in the situation of inorganic acid such as anhydrous chlorides of rase hydrogen and 0 ℃ to the temperature scope that refluxes, preferably under reflux temperature, carry out.

Process (i) and (ii) or can (for example see J. Am.Chem.Soc., 118,7215 in standard Buchwald condition easily separately; J.Am.Chem.Soc., 119,8451; J.Org.Chem., 62,1568 and 6066) for example exist in the situation of palladium under, at suitable atent solvent or diluent for example in arsol such as toluene, benzene or the dimethylbenzene, for example inorganic alkali such as carbonic acid caesium or organic alkali such as uncle-butanols-potassium exist suitable part such as 2 with suitable alkali, 2 '-two (diphenylphosphino)-1,1 '-under 25 to 80 ℃ temperature scope, react in the situation of binaphthyl.

Process (iii) can be easily in suitable atent solvent or diluent such as 1-METHYLPYRROLIDONE or butanols at 100 to 200 ℃, particularly carry out under 150 to 170 ℃ the temperature. This reaction preferably existing suitable alkali as for example, is carried out in the situation of methyl alcohol sodium or potash.

Process (iv) can be at suitable atent solvent or diluent, for example, alcohol as in ethanol or the butanols at 50 to 120 ℃, particularly carry out under 70 to 100 ℃ the temperature.

Process (v) and (vi) can be easily existing suitable atent solvent or diluent for example in the situation of ketone such as acetone or alcohol as methyl alcohol, ethanol, butanols or just-own alcohol or aromatic hydrocarbon such as toluene or NMP, optionally in the situation that has the alkali that suits, carry out. Suitable alkali has hydrogenation sodium or organic amine alkali such as diisopropyl ethyl amine. Suitable alkali in addition has the alkali metal alcohol compound, for example methyl alcohol sodium or ethanol sodium. Process (v) and (vi) can be easily 0 ℃ to reflux temperature, particularly carry out under the reflux temperature. These processes also can be easily by heating to carry out to reactant in the sealing container with suitable heating device such as heating using microwave device.

Process (vii) can be easily exists suitable atent solvent or diluent for example in the situation of acetonitrile, THF or two  alkane, carries out in the situation that has suitable alkali and suitable catalyst. Suitable alkali has organic amine alkali for example triethylamine or diisopropyl ethyl amine. Suitable catalyst has for example cupric iodide/chlorination palladium (II)-two (triphenyl) phosphine. Process (vii) can easily in 0 ℃ of temperature scope that extremely refluxes, particularly be carried out under the reflux temperature. This kind process can also be easily by heating to carry out to reactant in the sealing container with suitable heating device such as heating using microwave device.

Process (viii) can be easily existing suitable atent solvent or diluent for example in the situation of THF or two  alkane, in the situation that has suitable catalyst, carry out. Suitable catalyst has palladium (O) catalyst, for example four (triphenyl) phosphine palladium (O). As those skilled in the art recognize, this palladium (O) catalyst can be prepared in original position. Process (viii) can easily in 0 ℃ of temperature scope that extremely refluxes, particularly be carried out under the reflux temperature.

Process (ix) can easily in the situation that does not have atent solvent or diluent and in the temperature scope that room temperature extremely refluxes, particularly be carried out under the reflux temperature. Process (ix) is the acid that suits in existence easily, for example carries out in the situation of the concentrated sulfuric acid.

Process (x) can easily having suitable atent solvent or diluent, for example be carried out in the situation of carrene, THF or two  alkane. Process (x) can easily in 0 ℃ of temperature scope that extremely refluxes, be carried out under the preferred reflux temperature.

Carry out under the condition of the process (v) that process (xi) can be discussed easily in the above.

Formula (II), (III), (IV), (V), (VI), (VII), (VIII), Hxa, (Xb), (Xc), (Xc ') and M-R³Compound or can obtain by commercial sources, be known in the literature or can be prepared with known technology, for example can be prepared with the method similar to method described in the WO 03/048133. Formula (IX), (X), (XI) and compound (XII) can be with top processes (i) and (ii) are prepared. Provided the example for the preparation of the method for some compound in these compounds among the embodiment hereinafter.

Can the compound of formula (I) be changed into standard technique of the prior art the compound of other formula (I).

The example of the conversion reaction type that can use comprises with aromatics substitution reaction or nucleophilic displacement of fluorine reaction introduces substituting group, the reduction of substituting group, the alkylation of substituting group and the oxidation of substituting group. The reagent and the reaction condition that are used for such method are well-known at chemical field.

The specific example of aromatics substitution reaction comprises with red fuming nitric acid (RFNA) introduces nitro; Under Friedel Crafts condition, introduce acyl group with for example carboxylic acid halides and lewis acid (such as tri-chlorination aluminium); Under Friedel Crafts condition, introduce alkyl with alkyl halide and lewis acid (such as tri-chlorination aluminium); With the introducing halogen group. The specific example of nucleophilic displacement of fluorine reaction comprises with standard conditions to be introduced alkoxyl or alkyl amino, dialkyl amido or comprises the heterocycle of N. The specific example of reduction reaction comprises with sodium borohydride and carbonyl is reduced into hydroxyl or by carrying out catalytic hydrogenation with Raney nickel or by nitro being reduced into amino existing in the situation of hydrochloric acid in heating to process with iron; Comprise with the specific example of oxidation reaction alkylthio group (alkylthio) is oxidized to alkyl sulphinyl or alkyl sulphonyl. Other that can use transforms reaction and comprises acid catalyzed esterification with the pure carboxylic acid that carries out.

A suitable example that transforms reaction is with R wherein³The compound that is the formula (I) of (C1-C6) alkene base changes into wherein R³The compound of the formula (I) of (C1-C6) alkyl that is replaced by two-[(C1-C6) alkyl] amino or involved nitrogen and one or more saturated monocycle of heteroatomic 4-to 7-member that is independently selected from nitrogen, oxygen and sulphur. Can carry out such with standard method and transform, for example can the alkene base be changed into the dihydroxy alkyl, with suitable oxidant (for example periodic acid sodium) it is oxidized to corresponding ketone and by reacting in the situation that has suitable reducing agent (for example cyano group sodium borohydride) with the amine that suits ketone group be changed into required substituting group as defined above with four oxidation osmiums.

Suitable another example that transforms reaction is with R wherein³The compound that is the optionally formula (I) of substituted (C1-C6) alkoxy carbonyl changes into wherein R³Optionally substituted carbamoyl, (C1-C6) alkyl-carbamoyl or two-[(C1-C6) alkyl] carbamoyl or the substituted-C in optional ground (O) R^3bThe compound of the formula (I) of base, wherein R^3bDescribed as defined above. Such conversion can be carried out with standard method, for example can pass through wherein R³The compound of the optionally formula (I) of substituted (C1-C6) alkoxy carbonyl and ammonia, optional substituted primary, second month in a season or tertiary amine or the substituted H-R in optional ground^3bBase reacts to carry out. Such just as skilled in the art will be aware of, this kind conversion can begin and prepares active ester from carboxylic acid, for example use chlorination 4-(4,6-dimethoxy [1,3,5] triazine-2-yl)-and 4-methyl-morpholine  (morpholinium) is prepared, then reacts to carry out with required amine.

Suitable another example that transforms reaction is with R wherein³The compound that is the formula (I) of (C1-C6) alkoxy carbonyl changes into wherein R³It is the compound of the formula of alkyl (I) of hydroxyl-(C1-C6). Such conversion can be carried out with standard method, for example can be by also originally transforming with boron hydrogenation lithium or aluminum hydride lithium.

Should recognize that the preparation of formula (I) compound can comprise in each stage and adds and remove one or more blocking groups. ' Protective Groups in Organic Synthesis ', the 2nd edition, T.W. Greene and P.G.M.Wuts, among the Wiley-Interscience (1991) to the protection of functional group with go protection to be described.

When the pharmaceutically useful salt of needs formula (I) compound, for example during acid-addition salts, this salt can be by for example reacting said compound and suitable acid to obtain with conventional method.

Described such as mentioned, compound of the present invention can comprise one or more chiralitys center and therefore can exist with the form of stereoisomer. Can use routine techniques, for example chromatography or fractional crystallization come these stereoisomers are separated. Can by the separation of racemic body, for example separate to come with fractional crystallization, fractionation or HPLC enantiomter is separated. Can separate by utilizing the different physical property of diastereoisomer, for example come diastereoisomer is separated with fractional crystallization, HPLC or hurried chromatography. Perhaps, specific stereoisomer can begin in the situation that can not cause racemic or epimerization synthetic or synthetic by coming with deriving of chiral reagent by chirality by the initial material of chirality. When specific stereoisomer was separated, it is separated into suitablely did not have other stereoisomer substantially, for example comprises and is less than 20%, particularly was less than 10% and more particularly be less than other stereoisomer of 5% weight.

In the part on relevant with the preparation of formula (I) compound, the expression of " atent solvent " refers to not the solvent that can react in the mode with the required product yield of adverse effect with initial material, reagent, intermediate or product.

Those skilled in the art will recognize that, in order otherwise and in some cases to obtain compound of the present invention in mode more easily, the step of each method mentioned above can be carried out with different orders, and/or each reaction can be carried out in the different phase of whole approach (namely can different intermediates be chemically converted into above these phase related substances with specific reaction).

The compound of formula (I) has the activity as medicine, particularly have as the conditioning agent of insulin-like growth factor-i acceptor (IGF-1R) activity or the activity of inhibitor, and can be used for treating hyperplasia and excessive hyperplasia disease/condition, the example comprises following cancer:

(1) cancer comprises carcinoma of urinary bladder, the cancer of the brain, breast cancer, colon cancer, kidney, liver cancer, lung cancer, ovary cancer, pancreas cancer, prostate cancer, cancer of the stomach, uterine neck cancer, colon cancer, thyroid gland cancer and cutaneum carcinoma;

(2) the hematopoietic tumour of Lymphatic System (hematopoietic tumouts) comprises acute lymphocytic leukaemia, B-cell lymphoma and Burketts lymthoma;

(3) the hematopoietic tumour of myeloid lineage comprises acute and chronic myeloid leukaemia and promyelocyte leukaemia;

(4) tumour of matter origin comprises fibrosarcoma and band muscle knurl between; With

(5) other tumour comprises melanoma, spermatogonium knurl, tetratocarcinoma, neuroblastoma and neuroglia knurl.

Compound of the present invention especially can be used for treating the tumour of breast and prostate.

Therefore, according to another aspect, the invention provides compound or its pharmaceutically useful salt for the formula as defined above (I) that human or animal body is treated.

The present invention particularly provides compound or the application of its pharmaceutically useful salt in regulation and control human or animal's insulin-like growth factor-i acceptor (IGF-1R) activity of formula as defined above (I).

The present invention also provides the compound of defined formula (I) above or its pharmaceutically useful salt at preparation medicine for treatment thing, especially for the application in the active medicine of the insulin-like growth factor-i acceptor (IGF-1R) in the regulation and control human or animal body.

Unless stated otherwise, otherwise should recognize that " treatment " also comprises " prevention ". Term " treatment " and " therapeutic " also had corresponding understanding.

The present invention provides a kind of method for the treatment of cancer on the other hand, and it comprises to its effective above compound or its pharmaceutically useful salt of defined formula (I) of amount of patient's administering therapeutic of needs.

The present invention also provides a kind of regulation and control insulin-like growth factor-i acceptor (IGF-1R) active method, and it comprises to its effective above compound or its pharmaceutically useful salt of defined formula (I) of amount of patient's administering therapeutic of needs.

The compound of formula (I) with and pharmaceutically useful salt can be used with himself form, but usually will be with the form of pharmaceutical composition by administration, in said composition, compound/salt (active component) of formula (I) is combined with pharmaceutically useful auxiliary agent, diluent or carrier. According to administering mode, said pharmaceutical composition will preferably comprise 0.05 to 99%w (weight percentage), more preferably 0.05 to 80%w, more preferably 0.10 to 70%w, and more preferably 0.10 to 50%w active component, all weight percentage are all take total composition as the basis.

The present invention also provides the pharmaceutical composition of the compound that comprises defined formula (I) above or its pharmaceutically useful salt and pharmaceutically useful auxiliary agent, diluent or carrier.

The present invention also provides the method for preparing pharmaceutical composition of the present invention, and it comprises above compound or its pharmaceutically useful salt of defined formula (I) mix with pharmaceutically useful auxiliary agent, diluent or carrier.

This pharmaceutical composition can be with the form of for example emulsifiable paste, solution, suspension, seven fluorine alkane aerosols and dry powder formulations by topical (for example being delivered medicine to skin or lung and/or air flue); Perhaps for example can pass through with the oral administration of form of tablet, capsule, syrup agent, powder or particle by the whole body administration; Perhaps can be with the form of solution or suspension by parenteral; Perhaps can be by subcutaneous administration; With the form of suppository by the rectum administration; Perhaps can be by percutaneous dosing.

Composition of the present invention can obtain by conventional method with conventional excipients well-known in the prior art. Therefore, the composition for oral application can comprise for example one or more colouring agents, sweetener, flavoring agent and/or anticorrisive agent.

But the suitable pharmaceutical excipient that is used for tablet formulation comprises for example inert diluent such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulation agent and disintegrant such as corn starch or alginic acid (algenic acid); Adhesive such as starch; Lubricant such as stearic acid magnesium, stearic acid or talcum powder; Anticorrisive agent such as ethyl p-hydroxybenzoate or propyl ester, and antioxidant are such as ascorbic acid. Tablet formulation can be not by dressing or by dressing to change its disintegration and the subsequently absorption of active component in intestines and stomach, perhaps improve its stability and/or outward appearance, in any a kind of situation, all use method well-known in conventional coating agent and the prior art.

The composition that is used for oral application can be hard gelatin capsule or soft gelatin capsule form, in hard gelatin capsule, with active component and inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin mix, in soft gelatin capsule, active component is mixed such as peanut oil, liquid paraffin or olive oil with water or oil.

Aqueous suspension comprises active component and one or more supensoid agents of fine powder form usually, such as carboxymethyl cellulose sodium, methylcellulose, hydroxypropyl methyl fiber element, alginic acid sodium, polyvinylpyrrolidone, yellow alpine yarrow glue and Arabic gum; The condensation product of dispersant or wetting agent such as lecithin or oxidation alkene and aliphatic acid (for example polyoxygenated ethene stearic acid ester (polyoxethylene stearate)) or oxidation ethene and long-chain fatty alcohol, for example the condensation product of 17 inferior ethoxyl spermaceti alcohol (heptadecaethyleneoxycetanol) or oxidation ethene and the condensation product such as polyoxyethylene sorbitol monoleate or oxidation ethene and the long-chain fatty alcohol that derive from the inclined to one side ester of aliphatic acid and own sugar alcohol, for example condensation product such as polyoxyethylene sorbitol monoleate or the oxidation ethene and the condensation product such as the polyoxygenated ethene sorb glycan monoleate that derive from the inclined to one side ester of aliphatic acid and own sugar alcohol acid anhydride of the condensation product of 17 inferior ethoxyl spermaceti alcohol or oxidation ethene and the inclined to one side ester that derives from aliphatic acid and own sugar alcohol. Said aqueous suspension also can comprise one or more anticorrisive agents (such as ethyl p-hydroxybenzoate or propyl ester), antioxidant (such as ascorbic acid), colouring agent, flavoring agent and/or sweetener (such as sucrose, asccharin or aspartame).

Oil-based suspension can be prepared by active component being suspended in vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or the mineral oil (such as liquid paraffin). This oil-based suspension also can comprise thickener such as beeswax, solid paraffin or spermaceti alcohol. Can add sweetener such as these above-mentioned substances and flavoring agent a kind of agreeable to the taste oral formulations is provided. Can come these compositions anticorrosion by adding antioxidant such as ascorbic acid.

The powder that disperses and the particle that are applicable to prepare by adding entry aqueous suspension comprise active component and dispersant or wetting agent, supensoid agent and one or more anticorrisive agents usually. With these above-mentioned materials suitable dispersant or wetting agent and supensoid agent are illustrated. Can also there be other excipient such as sweetener, flavoring agent and colouring agent.

Pharmaceutical composition of the present invention can also be the form of water bag oil emu. Its oil phase can be that vegetable oil such as olive oil or peanut oil or mineral oil are such as the mixture of any material in for example liquid paraffin or these materials. Suitable emulsifying agent can be condensation product such as the polyoxygenated ethene dehydration sorb glycan monoleate of for example naturally occurring natural gum such as Arabic gum or yellow alpine yarrow glue, naturally occurring phosphatide such as soybean lecithin, lecithin, the ester that derives from aliphatic acid and own sugar alcohol acid anhydride or inclined to one side ester (sorb glycan monoleate for example dewaters) and said inclined to one side ester and oxidation ethene. This emulsion also can comprise sweetener, flavoring agent and anticorrisive agent.

Syrup agent and elixir can be prepared with sweetener such as glycerine, propane diols, sorb alcohol, aspartame or sucrose, and can comprise moderator, anticorrisive agent, flavoring agent and/or colouring agent.

This pharmaceutical composition can also be sterile aqueous or the oil-based suspension form that can inject, and can be prepared with the suitable dispersion of having mentioned above one or more or wetting agent and supensoid agent according to known method. What can inject can also be aseptic solution or the suspension injected that is arranged in the outer acceptable nontoxic diluent of stomach and intestine or solvent without bacteria preparation, for example is arranged in the solution of 1,3-BDO.

Suppository formulations can be by being solid under the typical temperature but being that the non-irritating excipient of liquid mixes to be prepared that with suitable therefore, it will melt the release medicine in rectum with active component under the rectum temperature. Suitable excipient comprises for example cocoa fat and polyethylene glycol.

Topical formulations usually can be by use conventional method well-known in the art such as emulsifiable paste, ointment, gel and water-based or oiliness solution or suspension, with routine can local usefulness excipient or diluent active component is prepared to be prepared.

Can be the very thin powder type of cutting apart to get of 30u for example or lower particle by insufflation for comprising average diameter by the composition of administration, this powder itself only comprises active component or also has one or more physiology acceptable carrier such as lactose. Then, the powder that is used for insufflation can be maintained at easily and comprise for example capsule of 1 to 50mg active component, suck device (turbo-inhaler) device with turbine and use this capsule, for example it is used to the insufflation of known material Cromoglycic acid sodium.

Be used for to be the pressurised aerosol form of routine by the composition of inhalation that said aerosol is arranged to active component is cut apart very carefully solid or the form of the aerosol of liquid droplets is distributed to comprise. Can and can arrange easily to distribute the active component of institute's metered amounts with this aerosol device with conventional aerosol propellant such as volatility fluorinated hydrocarbons or hydrocarbon class.

Should recognize dosage will along with used compound, administering mode, required treatment and shown in illness change. The typical day dosage scope of accepting is every kg body weight 0.5 mg to 75mg active component, if necessary, this day, dosage can be with the form of fractionated dose by administration, according to principle well-known in the art, use the exact magnitude of compound and the specific situation (condition) that method of administration depends on body weight, age, the sex that is treated the patient and is treated.

Above defined anti-hyperplasia treatment can be employed with the form of monotherapy, perhaps except compound of the present invention, also can comprise conventional operation or radiotherapy or chemotherapy. This based chemotherapy can comprise antitumor dose of type below one or more :-

(i) in the oncology used anti-hyperplasia/antineoplastic with and combination, such as alkanisation agent (for example along platinum, card platinum, endoxan, mustargen, American and French logical sequence, Chlorambucil, busulfan and nitroso ureas); Anti-metabolism medicine (for example anti-folic acid agent such as 5-FU class such as 5 FU 5 fluorouracil and for adding fluorine, thunder for Qu Sai, first aminopterin, cytarabine and hydroxyl urea); Antitumor activity antibiotic (for example anthracene nucleus class antibiotic such as adriamycin, bleomycin, Doxorubicin, daunorubicin, epirubicin, Yi Da are than star, mitomycin-C, dactinomycin D and mithramycin); Anti-mitosis agent (for example catharanthus alkaloid such as vincristine, vincaleukoblastinum, eldisine and vinorelbine and Japanese yew alkane class (taxoids) are such as Japanese yew phenol (taxol) and safe rope Supreme Being (taxotere)); And topoisomerase enzyme inhibitor (for example Podophyllum emodi var chinense ethylidene glucoside (epipodophyllotoxins) is as relying on the pool glycosides and mooring glycosides, amsacrine, holder pool for health and camplotheca acuminata alkali for the Buddhist nun);

(ii) cell inhibitor such as antiestrogenic medicine (for example he not former times fragrant, hold in the palm auspicious ground rice, thunder Lip river former times fragrant, bend Lip river former times sweet smell and iodoxyfene), adjust (for example fluorine is tieed up this group), antiandrogen medicine (for example Bicalutamide, Flutamide, Ni Lumite and cyproterone acetate), lhrh antagonist or LHRH activator (for example dagger-axe house Rayleigh, bright the third Rayleigh and Buserelin), progestational hormone class (for example megestrol acetate), aromatase inhibitor (for example Anastrozole, come bent azoles, vorazole and Yi Ximeitan) and 5α-reductase inhibitor such as Finasteride under the ERs;

(iii) the inhibition cancer cell material of invading (for example metal protease inhibitors such as horse are immediately taken charge of the inhibitor of he and urokinase plasminogen activator function of receptors);

(iv) inhibitor of growth factor function, for example such inhibitor comprises that growth factor antibodies, growth factor receptor antibody (for example resist-the bent appropriate monoclonal antibody [Herceptin of erbB2 antibody^TM] and anti--erbB1 antibody west appropriate former times monoclonal antibody [C225]), Farnesyltransferase inhibitor, tyrosine-kinase enzyme inhibitor and serine/threonine kinase inhibitor, for example other inhibitor of epidermal growth factor family (for example EGFR family tyrosine-kinase enzyme inhibitor asN-(3-chloro-4-fluorophenyl)-7-first oxygen base-6-(the 3-morpholine is for propoxyl group) quinazoline-4-amine (gefitinib, AZD1839),N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy) quinazoline-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(the 3-morpholine is for propoxyl group) quinazoline-4-amine (CI 1033)), for example inhibitor of platelet-derived growth factor family and for example inhibitor of the hepatic cell growth factor;

(v) material of anti-angiogenic generation (antiangiogenic) agent such as these inhibition vascular endothelial growth factor effects (for example resists-vascular endothelial cell growth factor antibody bevacizumab [Avastin^TM], compound such as these disclosed compound in International Patent Application WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and the compound that works by other mechanism (for example the inhibitor of sharp promise amine, beta 2 integrin alpha v β 3 functions and blood vessel he fourth (angiostatin));

(vi) blood vessel infringement agent such as Bu Kaotating A4 and disclosed compound in International Patent Application WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapy for example relates to these materials of target listed above, as ISIS 2503, antisense anti--ras (anti-ras antisense);

(viii) gene therapy comprises and for example replaces aberrant gene (aberrant genes) such as the method for method, GDEPT (the enzyme prodrug therapy that gene instructs) method such as these use cytimidine deaminizating enzymes, thymidine nucleosides kinases or the bacterium nitro reduction enzyme of unusual p53 or unusual BRCA1 or BRCA2 with for increasing method such as the multi-drug resistant gene therapy of patient to the tolerance of chemotherapy or radiotherapy; With

(ix) immunotherapy, for example comprise for increasing the immune originality of patient tumors cell from body with at body method, as with the cell factor such as interleukin-22, IL-4 or the transfection of granulocyte-macrophage colony stimulating factor, reduce the T-cell without the method for the dendron shape cell of the method for efficiency, the immune cell that uses transfection such as cytokine transfection, use cytokine transfection tumor cell line method and use the method for anti-idiotype antibody.

Can be by simultaneously, in succession or each component of independently treating finish such therapeutic alliance. Such combination product uses the compound of the present invention that is arranged in dosage scope mentioned above and is arranged in other pharmaceutically active substances that it ratifies the dosage scope.

According to this aspect of the present invention, the invention provides compound or its pharmaceutically useful salt that comprises defined formula (I) above and be used for the above defined antitumor dose other pharmaceutical composition of said associating anticancer therapy.

The activity and selectivity of the compounds of this invention can with for example described in the WO 03/048133 and below the suitable test of detailed description determine.

Embodiment

To the present invention further be described with following illustrative example now, wherein, unless stated otherwise, otherwise:

(i) temperature take degree centigrade (℃) provide as unit; Operation is carried out under room temperature or environment temperature, that is, be to carry out under 18 to 25 ℃ temperature;

(ii) with anhydrous slufuric acid magnesium organic solution is carried out drying; The solvent evaporation is decompression (600-4000 Pascal with the rotation evaporimeter; 4.5-30mmHg) carry out with the highest 60 ℃ bath temperature down;

(iii) chromatography refers to use the hurried chromatography of silica gel; Thin-layered chromatography (TLC) is carried out with the silica gel plate;

(iv) the common back of course of reaction is TLC, and the reaction time only provides as example;

(v) end-product has gratifying proton magnetic resonance (PMR) (NMR) spectrum and/or mass spectrum data;

(vi) providing the receipts rate only is in order to describe, and might not be that those process the receipts rate that obtains by diligent processing; If need more material, then repeat preparation;

(vii) unless stated otherwise, otherwise when being presented, the NMR data are for mainly distinguishing the form of the δ value of proton, and it is to provide as unit with respect to per 1,000,000 umber (ppm) for interior target tetramethyl silane (TMS), under 300MHz, at DMSO-d₆Middle mensuration. Abbreviation below using: s, unimodal; D, bimodal; T, triple peaks; Q, the quadruple peak; M, multiplet; B, wide peak;

(viii) chemical symbol has its implication commonly used; Use SI unit and symbol;

(ix) solvent ratios is with volume: volume (v/v) provides; With

(x) mass spectrum is to use in chemi-ionization (CI) mode with 70 electron-volts electron energy directly to expose the probe operation; Right when indicating, ionization is finished by electronics bombardment (EI), fast atom bombardment (FAB) or electron spray (ESP); Provided the value of m/z; Usually only report the ion of indication parent quality; And unless stated otherwise, otherwise the quality ion of quoting (mass ion) is (MH)⁺；

(xi) use following abbreviation:

The THF oxolane;

EtOAc ethyl acetate;

The DCM carrene;

The DMSO dimethyl sulfoxide (DMSO);

The DIPEA diisopropyl ethyl amine;

The NMP NMP;

tBuOH Uncle-Butanols;

TFA three fluorine acetic acid;

The DMF DMF; With

The DMA DMA.

Embodiment 1

The different  azoles of 5-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With 2,5-two chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (method 10 of WO 03/048133) (158mg, 0.648mmol), the different  azoles of 2-[3-(pyridine-2-yl)-5-yl] pyrrolidines (method 12) (212mg, 0.972mmol) and the mixture of two-isopropyl ethyl amine (282 μ L, 1.62mmol) under nitrogen just-under 140 ℃, stir in oneself alcohol (7.0ml) and heated 9 hours. Then remove oneself alcohol of great majority by evaporation and residue distributed between ethyl acetate and water. Ethyl acetate layer is separated, and with 1.0 mole of phosphoric acid salt buffer pH 4 (x2), water then, last salt solution washs. With the dry (Na of organic layer₂SO ₄), filter and evaporation, crude product is absorbed on the 10g isolute SCX2 ion exchange column. With this post with DCM/ methyl alcohol (4: 1) wash-out to remove neutral thing, then use carrene/2M methyl alcohol ammoniacal liquor (4: 1) that product is carried out wash-out. This product that has carried out purifying is dissolved among the minimum DCM and in this solution that is carrying out stirring, adds slightly excessive 1.0M ether hydrogen chloride processed. To wherein adding some ether and by the solid collected by filtration product, carrying out drying with the ether washing and to it, obtain the hydrochloric acid salt (300mg, 100%) of title compound again.

NMR(DMSO-d6 ₊d ₄Acetic acid is under 100 ℃): 2.13 (m, 3H), 2.4 (m, 1H), 3.7 (m, 1H), 3.86 (m, 1H), 3.86 (m, 1H), 5.45 (d, 1H), 6.12 (s, 1H) 6.75 (s, 1H), (7.45 t, 1H), 7.9 (m, 2H), (8.07 s, 1H), 8.65 (d, 1H); M/z 423[MH]⁺。

Embodiment 2 to 11 uses the method identical with the method for embodiment 1 to be prepared :-

Embodiment number	Initial material	The compound title	Q ³	R ¹	NMR DMSO-d ₆+d ₄Acetic acid is in 100 ℃	m/z(MH) ⁺
Embodiment number	Initial material	The compound title	Q ³	R ¹	NMR DMSO-d ₆+d ₄Acetic acid is in 100 ℃	m/z(MH) ⁺	2	Following method 13 and A	5-chloro-2-[2-(the different  azoles of 3-methyl-5-yl] pyrrolidines-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine	Methyl	Methyl	1.93-2.0(m，2H)， 2.15(s，3H)，2.20- 2.36(m，3H)，3.46- 3.55(m，1H)，3.66- 3.78(m，1H)，5.19- 5.22(m，1H)，5.80(s， 1H)，6.02(s，1H)， 8.0(s，3H)，8.50(s， 1H)。	360
3	Following method 13 and B	5-chloro-2-[2-(the different  azoles of 3-methyl-5-yl] pyrrolidines-1-yl]-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine	Methyl	Ring-propyl group	0.68(d，2H)，0.92(d， 2H)，1 80-2.05(m， 4H)，2.15(s，3H)， 2.22-2.35(m，1H)， 3.44-3.58(m，1H)， 3.62-3.79(m，1H)， 5.22(d，1H)，5.82(s， 1H)，6.0(s，1H)， 7.98(s，1H)，12.4(s， 1H)	386	2	Following method 13 and A		Methyl	Methyl		360
3	Following method 13 and B		Methyl	Ring-propyl group		386	4	Following method 13 and C	5-chloro-2-[2-(the different  azoles of 3-methyl-5-yl] pyrrolidines-1-yl]-4-(5-tert-butyl-1H-pyrazoles-3-base is amino) pyrimidine	Methyl	Uncle-Butyl	1.35(s，9H)，2 30- 2.40(m，1H)，1.98- 2.10(m，3H)，2.14(s， 3H)，3.65-3.75(m， 2H)，5.32(d，1H)， 5.99(s，1H)，6.35(s， 1H)，7.99(s，1H)， 8.10(s，1H)，11.75(s， 1H)。	402

Embodiment number	Initial material	The compound title	Q ³	R ¹	NMR DMSO-d ₆+d ₄Acetic acid is in 100 ℃	m/z(MH) ⁺
Embodiment number	Initial material	The compound title	Q ³	R ¹	NMR DMSO-d ₆+d ₄Acetic acid is in 100 ℃	m/z(MH) ⁺	5	Following method 14 and B	5-chloro-2-[2-(the different  azoles of 3-cyclopropyl-5-yl] pyrrolidines-1-yl]-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine	Ring-propyl group	Ring-propyl group	0.65(m，4H)，0.90(m， 4H)，1.97(m，5H)， 2.28(m，1H)，3.62(m， 2H)，5.25(d，1H)， 5.80(s，1H)，6.06(s， 1H)，7.93(s，1H)	412
6	Following method 14 and A	5-chloro-2-[2-(the different  azoles of 3-cyclopropyl-5-yl] pyrrolidines-1-yl]-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine	Ring-propyl group	Methyl	0.65(m，2H)，0.87(m， 2H)，1.95(m，4H)， 2 18(s，3H)，2.25(m， 1H)，3.66(m，2H)， 5.22(d，1H)，5.81(s， 1H)，6.13(s，1H)， 7.95(s，1H)	386	5	Following method 14 and B		Ring-propyl group	Ring-propyl group		412
6	Following method 14 and A		Ring-propyl group	Methyl		386	7	Following method 15 and A	The different  azoles of 5-chloro-2-{2-[3-(thiazole-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine	The 2-thiazole	Methyl	2.1(m，3H)，2.28(s， 3H)，2.47(m，1H)， 3.65(m，1H)，3.76(m， 1H)，5.36(d，1H)， 6.22(s，1H)，6.61(s， 1H)，7.77(d，1H)， 7.94(d，1H)，7.96(s， 1H)	429

Embodiment number	Initial material	The compound title	Q ³	R ¹	NMR DMSO-d ₆+d ₄Acetic acid is in 100 ℃	m/z(MH) ⁺
Embodiment number	Initial material	The compound title	Q ³	R ¹	NMR DMSO-d ₆+d ₄Acetic acid is in 100 ℃	m/z(MH) ⁺	8	Following method 15 and B	The different  azoles of 5-chloro-2-{2-[3-(thiazole-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine-	The 2-thiazole	Ring-propyl group	0.7(m，2H)，0.9(m， 2H)，1.87(m，1H)， 2.21(m，3H)，24(m， 1H)，3.65(m，1H)， 3.79(m，1H)，5.4(d， 1H)，6.11(s，1H)， 6.65(s，1H)，7.85(d， 1H)，7.99(d，1H)， 8.01(s，1H)	455
9	Following method 12 and B	The different  azoles of 5-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine	The 2-pyridine	Ring-propyl group	0.66(m，2H)，0.88(m， 2H)，1.82(m，1H)， 2.1(m，3H)，2.36(m， 1H)，3.67(m，1H)， 3.77(m，1H)，5.4(d， 1H)，6.1(s，1H)， 6.61(s，1H)，7.41(t， 1H)，7.87(t，1H)， 7.92(d，1H)，7.99(s， 1H)，8.63(d，1H)	449	8	Following method 15 and B		The 2-thiazole	Ring-propyl group		455
9	Following method 12 and B		The 2-pyridine	Ring-propyl group		449	10	Following method 16 and A	The different  azoles of 5-chloro-2-{2-[3-(pyridine-3-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine	The 3-pyridine	Methyl	2.1(m，3H)，2.2(s， 3H)，2.4(m，1H)， 3.68(m，1H)，3.8(m， 1H)，3.57(d，1H)， 6.12(s，1H)，6.73(s， 1H)，7.45(t，1H)， 8.0(s，2H)，8.15(d， 1H)，8.65(d，1H)， 8.97(s，1H)，11.7(s， 1H)。	423

Embodiment number	Initial material	The compound title	Q ³	R ¹	NMR DMSO-d ₆+d ₄Acetic acid is in 100 ℃	m/z(MH) ⁺
Embodiment number	Initial material	The compound title	Q ³	R ¹	NMR DMSO-d ₆+d ₄Acetic acid is in 100 ℃	m/z(MH) ⁺	11	Following method 16 and B	The different  azoles of 5-chloro-2-{2-[3-(pyridine-3-yl)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine	The 3-pyridine	Ring-propyl group	0.66(m，2H)，0.90(m， 2H)，1.90(m，1H)， 2.1(m，3H)，2.38(m， 1H)，3.67(m，1H)， 3.80(m，1H)，5.38(d， 1H)，6.12(s，1H)， 6.70(s，1H)，7.45(t， 1H)，7.97(s，1H)， 8.10(d，1H)，8.62(d， 1H)，8.95(s，1H)	449

A:2,5-two chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

B:2,5-two chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

C:2,5-two chloro-4-(5-Uncle-Butyl-1H-pyrazoles-3-base is amino) pyrimidine

In WO 03/048133, the preparation of compound A-C is described.

Embodiment 12

2-[2-(the different  azoles of 3-cyclopropyl-5-yl) pyrrolidines-1-yl]-6-methoxy-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With 4-chloro-2-[2-(the different  azoles of 3-cyclopropyl-5-yl] pyrrolidines-1-yl]-6-methoxy methyl yl pyrimidines (method 19) (250mg, 0.746mmol), 3-amino-5-methyl isophthalic acid H-pyrazoles (109mg, 1.2mmol) and hydrogen chloride (the 4M two  alkane solution of 0.56ml, 2.24mmol) mixture in NMP (5ml) was 120 ℃ of lower heating 18 hours. Allow this mixture cooling, then it is applied directly on the isolute SCX2 ion exchange column. With this post with DCM/ methyl alcohol (4: 1) wash-out to remove neutral thing (neutrals), then use 7M methyl alcohol ammoniacal liquor (methanolic ammonia) that product is carried out wash-out. Then with silica gel chromatography this is carried out purifying by partially purified product, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 95: 5). Product ground with ether/DCM and by the solid collected by filtration product, obtain the title compound (100mg, 34%) of white solid form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 0.65 (m, 2H), 0.88 (m, 2H), (1.97 m, 4H), 2.17 (s, 3H), (2.25 m, 1H), 3.35 (s, 3H), (3.63 m, 2H), 4.13 (dd, 2H), (5.28 d, 1H), 5.85 (s, 1H), (6.00 s, 1H), 6.33 (s, 1H); M/z 396[MH]+.

Embodiment 13

2-[2-(the different  azoles of 3-cyclopropyl-5-yl) pyrrolidines-1-yl]-6-methoxy-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

Title compound is to use the method identical with embodiment 12 described methods, (130mg, 41 %) that begun to be prepared by 3-amino-5-cyclopropyl-1H-pyrazoles (method 7 of WO 03/048133).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 0.65 (m, 4H), 0.86 (m, 4H), (1.85 m, 2H), 2.00 (m, 3H), (2.25 m, 1H), 3.32 (s, 3H), (3.63 m, 2H), 4.12 (dd, 2H), (5.30 d, 1H), 5.86 (s, 1H), (5.95 s, 1H), 6.32 (s, 1H); M/z 422[MH]+.

Embodiment 14

The different  azoles of 5-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] piperidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With the different  azoles of 2-[3-(pyridine-2-yl)-5-yl] piperidines (method 16 (a)) (137mg, 0.6mmol) process like that as described in Example 1, just reactant mixture was heated 18 hours under 140 ℃, then process for the cleanser on basis in order to ethylene aminopropyl silica (ethylene diaminopropyl silica), then carry out like that as described in Example 1 post processing, obtain title compound (35mg, 16%).

NMR(DMSOd6，100℃，400MHz)：1.53(m，2H)，1.75(m，2H)，1.93(m， 1H)，2.2(s，3H)，2.25(m，1H)，2.9(m，1H)，4.6(d，1H)，6.13(s，2H)，6.7(s，1H)， 7.4(t，1H)，7.85(m，2H)，8.05(s，1H)，8.17(s，1H)，8.68(d，1H)，11.75(s，1H)； m/z 437[MH]+。

Embodiment 15 to 24

Embodiment 15 to 24 is that the method with embodiment 1 is prepared:

The embodiment sequence number	Initial material	The compound title	R ¹	R ²	R ³	Q ¹	Q ²	Q ³	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺
The embodiment sequence number	Initial material	The compound title	R ¹	R ²	R ³	Q ¹	Q ²	Q ³	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺	15	A and following method 24	5-chloro-2-[2-(3-{ oxolane-3-yl } different  azoles-5-yl] pyrrolidines-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine	Me	Cl	H	Pyrrolidines-1-base	Different  azoles-5-base	Oxolane-3-base	2.02(m，4H)，2.21(m，1H)， 2.32(m，1H)，3.41(m，1H)， 3.6(m，2H)，3.72(m，2H)， 3.8(m，1H)，3.92(t，1H)， 5.38(d，1H)，6.05(s，1H)， 6.1(s，1H)，7.96(s，1H)	416
16	B and following method 24	5-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-2-[2-(3-{ oxolane-3-yl } different  azoles-5-yl] pyrrolidines-1-yl]-pyrimidine	Ring-propyl group	Cl	H	Pyrrolidines-1-base	Different  azoles-5-base	Oxolane-3-base	0.69(m，2H)，0.89(m，2H)， 1.9-2.1(m，5H)，2.21(m， 1H)，2.3(m，1H)，3.4(m， 1H)，3.6(M，2H)，3.65- 3.83(m，3H)，3.94(t，1H)， 5.3(d，1H)，6.05(s，1H)， 6.09(s，1H)，7.96(s，1H)	442	15	A and following method 24		Me	Cl	H	Pyrrolidines-1-base	Different  azoles-5-base	Oxolane-3-base		416
16	B and following method 24		Ring-propyl group	Cl	H	Pyrrolidines-1-base	Different  azoles-5-base	Oxolane-3-base		442	17	Following method 29 and method 12	6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-{2-[the different  azoles of 3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine	Me	H	Cl	Pyrrolidines-1-base	Different  azoles-5-base	Pyridine-2-base	(2.08 m, 2H), 2.18 (m, 4H), (3.74 m, 2H), 5.47 (d, 1H), (5.98 s, 1H), 6.4 (s, 1H), (6.67 s, 1H), 7.43 (m, 1H), (7.9 m, 2H), 8.65 (d, 1H), (8.88 br s, 1H), 11.44 (br s, 1H) (not by deuterate)	423

The embodiment sequence number	Initial material	The compound title	R ¹	R ²	R ³	Q ¹	Q ²	Q ³	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺
The embodiment sequence number	Initial material	The compound title	R ¹	R ²	R ³	Q ¹	Q ²	Q ³	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺	18	B and following method 16 (a)	5-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-2-{2-[the different  azoles of 3-(pyridine-2-yl)-5-yl] piperidines-1-yl } pyrimidine	Ring-propyl group	Cl	H	Piperidines-1-base	Different  azoles-5-base	Pyridine-2-base	0.6(m，2H)，0.87(m，2H)， 1.53(m，2H)，1.73(m，2H)， 1.85(m，1H)，1.95(m，1H)， 2.26(m，1H)，3.0(d，1H)， 4.6(d，1H)，6.05(s，1H)， 6.13(d，1H)，6.66(s，1H)， 7.4(t，1H)，7.87(t，1H)， 7.94(d，1H)，8.03(s，1H)， 8.62(d，1H)。	463
19	A and following method 25	5-chloro-2-{2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine	Me	Cl	H	Pyrrolidines-1-base	Different  azoles-5-base	2-first oxygen base-pyridine-3-base	2.06(m，3H)，2.2(s，3H)， 2.37(m，1H)，3.65(m，1H)， 3.75(m，1H)，3.9(s，3H)， 5.37(d，1H)，6.15(s，1H)， 6.55(s，1H)，7.03(t，1H)， 8.0(s，1H)，8.07(d，1H)， 8.25(d，1H)	453	18	B and following method 16 (a)		Ring-propyl group	Cl	H	Piperidines-1-base	Different  azoles-5-base	Pyridine-2-base		463
19	A and following method 25		Me	Cl	H	Pyrrolidines-1-base	Different  azoles-5-base	2-first oxygen base-pyridine-3-base		453	20	Following method 27 (b) and method 12	5-fluoro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-{2-[the different  azoles of 3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-pyrimidine	Me	F	H	Pyrrolidines-1-base	Different  azoles-5-base	Pyridine-2-base	2.1(m，3H)，2.2(s，3H)， 2.4(m，1H)，3.6(m，1H)， 3.77(m，1H)，5.35(d，1H)， 6.15(s，1H)，6.63(s，1H)， 7.42(t，1H)，7.9(m，3H)， 8.63(s，1H)，8.83(s，1H)， 11.53(s，1H)。	407

The embodiment sequence number	Initial material	The compound title	R ¹	R ²	R ³	Q ¹	Q ²	Q ³	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺
The embodiment sequence number	Initial material	The compound title	R ¹	R ²	R ³	Q ¹	Q ²	Q ³	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺	21	Following method 27 and method 12	4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-5-fluoro-2-the different  azoles of 2-[3-(pyridine-2-yl)-5-yl] and pyrrolidines-1-yl } pyrimidine	Ring-propyl group	F	H	Pyrrolidines-1-base	Different  azoles-5-base	Pyridine-2-base	0.7(2H，m)，0.9(2H，m)， 1.9(m，1H)，2.12(m，3H)， 2.38(m，1H)，3.63(m，1H)， 3.74(m，1H)，5.4(d，1H)， 6.1(s，1H)，6.63(s，1H)， 7.43(t，1H)，7.88(m，3H)， 8.62(d，1H)，8.83(s，1H)， 11.63(s，1H)。	433
221	B and following method 40	The different  azoles of S-5-chloro-2-{2-[3-methyl-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine	Ring-propyl group	Cl	H	Pyrrolidines-1-base	Different  azoles-5-base	Methyl	0.68(d，2H)，0.92(d，2H)， 1.80-2.05(m，4H)，2.15(s， 3H)，2.22-2.35(m，1H)， 3.44-3.58(m，1H)，3.62- 3.79(m，1H)，5.22(d，1H)， 5.82(s，1H)，6.0(s，1H)， 7.98(s，1H)，12.4(s，1H)	386	21	Following method 27 and method 12		Ring-propyl group	F	H	Pyrrolidines-1-base	Different  azoles-5-base	Pyridine-2-base		433
221	B and following method 40		Ring-propyl group	Cl	H	Pyrrolidines-1-base	Different  azoles-5-base	Methyl		386	23	Following method 26 and method 42	4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine	Me	H	H	Pyrrolidines-1-base	Different  azoles-5-base	Pyridine-2-base	2.00(m，3H)，2.15(s，3H)， 2.32(m，1H)，3.54(m，1H)， 3.80(m，1H)，5.38(d，1H)， 6.20(m，1H)，6.66(s，1H)， 7.45(m，1H)，7.90(m，4H)， 8.62(d，1H)，9.38(br s，1H)， 11.76(br s，1H)	389

The embodiment sequence number	Initial material	The compound title	R ¹	R ²	R ³	Q ¹	Q ²	Q ³	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺
The embodiment sequence number	Initial material	The compound title	R ¹	R ²	R ³	Q ¹	Q ²	Q ³	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺	24	Following method 28 and method 12	4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine	Ring-propyl group	H	H	Pyrrolidines-1-base	Different  azoles-5-base	Pyridine-2-base	0.60(m，2H)，0.85(m，2H)， 1.80(m，1H)，2.00(m，3H)， 2.30(m，1H)，3.56(m，1H)， 3.80(m，1H)，5.40(d，1H)， 6.20(br s，1H)，6.64(s，1H)， 7.45(m，1H)，7.90(m，3H)， 8.62(d，1H)，9.40(br s，1H)， 11.84(br s，1H)	415

B:2,5-two chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

The preparation of compound A and B is as described in the WO 03/048133.

¹Carry out purifying with silica gel chromatograph, carry out wash-out with DCM/ methyl alcohol (98: 2 to polarity increase to 95: 5).

Embodiment 25

4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 6-methyl-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With the different  azoles of 4-hydroxyl-6-methyl-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] mixture of pyrimidine (method 30) (200mg, 0.62mmol) in phosphoryl chloride phosphorus oxychloride (7ml) under 70 ℃ under nitrogen the heating 30 minutes. Remove volatile materials and residue is dissolved among the DCM by evaporation, with the saturated sodium bicarbonate solution washing, dry (MgSO₄) and by the evaporation desolventizing. Then as embodiment 12 is described, with 3-amino-5-cyclopropyl-1H-pyrazoles (method 7 of WO-03/048133) (120mg, 0.98mmol) and two  alkane solution (0.65ml) of 4M hydrogen chloride in NMP (5ml), this crude product is processed, obtain title compound (100mg, 37%).

NMR(DMSO)：0.64(m，2H)，0.84(m，2H)，1.76-1.82(m，1H)，1.96- 2.15(m，7H)，2.25-2.36(m，1H)，3.45-3.55(m，1H)，3.72-3.80(m，1H)，5.40(d， 1H)，5.87(s，1H)，6.08(s，1H)，6.61(s，1H)，7.44(dd，1H)，7.86-7.95(m，2H)， 8.60(d，1H)，9.30(s，1H)；m/z 429[MH]+。

Embodiment 26 to 36

Embodiment 26 to 36 uses the method preparation similar to embodiment 25 described methods.

Embodiment 26

4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 6-methyl-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: the different  azoles of 4-hydroxyl-6-methyl-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (method 30) and 3-amino-5-methyl isophthalic acid H-pyrazoles.

Carry out purifying with silica gel chromatograph, carry out wash-out with methyl alcohol/DCM (8: 92), obtain title compound (42mg, 22%).

NMR(DMSO)：1.99-2.15(m，10H)，2.25-2.38(m，1H)，3.52-3.60(m， 1H)，3.72-3.80(m，1H)，5.39(d，1H)，6.10(s，1H)，6.64(s，1H)，7.45(dd，1H)， 7.86-7.98(m，2H)，8.62(d，1H)，9.22(s，1H)；m/z 403[MH]+。

Embodiment 27

Initial material: the different  azoles of 4-hydroxyl-6-methyl-2-[2-{3-(methyl)-5-yl } pyrrolidines-1-yl] pyrimidine (method 31) and 3-amino-5-cyclopropyl-1H-pyrazoles (method 7 of WO-03/048133).

Receipts rate: 70mg, 25%.

NMR(DMSO)：0.62(m，2H)，0.89(d，2H)，1.84-1.78(m，1H)，2.0- 1.94(m，3H)，2.08(s，3H)，2.12(s，3H)，3.48-3.55(m，1H)，3.63-3.73(m，1H)， 5.30(d，1H)，6.0(s，1H)，6.08(s，1H)，9.21(s，1H)，11.8(s，1H)；m/z 364 [MH]-。

Embodiment 28

6-ethyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: the different  azoles of 4-hydroxyl-6-ethyl-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (method 32) and 3-amino-5-methyl isophthalic acid H-pyrazoles.

Receipts rate: 150mg, 38%.

NMR(DMSO)：1.02-1.15(m，3H)，1.99-2.09(m，3H)，2.14(s，3H)，2.28- 2.41(m，3H)，3.58-3.62(m，1H)，3.75-3.80(m，1H)，5.38(d，1H)，6.14(s，1H)， 6.68(s，1H)，7.45(dd，1H)，7.87-7.95(m，2H)，8.62(d，1H)，9.22(s，1H)；m/z 417[MH]+。

Embodiment 29

6-(3-methoxy-propyl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: the different  azoles of 4-hydroxyl-6-(3-methoxy-propyl)-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (method 33) and 3-amino-5-methyl isophthalic acid H-pyrazoles.

Receipts rate: 56mg, 14%.

NMR(DMSO)：1.78-1.82(m，1H)，2.0-2.12(m，3H)，2.18(s，3H)，2.28- 2.40(m，2H)，2.58-2.64(m，2H)，3.04-3.20(m，2H)，3.30(s，3H)，3.58-3.62(m， 1H)，3.73-3.82(m，1H)，5.38(d，1H)，5.90(s，1H)，6.10(s，1H)，6.65(s，1H)， 7.48(dd，1H)，7.87-7.98(m，2H)，8.62(d，1H)，9.24(s，1H)；m/z 461 [MH]+。

Embodiment 30

6-methoxy-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: the different  azoles of 4-hydroxyl-6-methoxy-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (method 34) and 3-amino-5-methyl isophthalic acid H-pyrazoles.

Receipts rate: 260mg, 49%.

NMR(DMSO)：2.0-2.15(m，3H)，2.20(s，3H)，3.30(s，3H)，3.65-3.8(m， 2H)，4.15(q，2H)，5.45(d，1H)，6.04(s，1H)，6.38(s，1H)，6.64(s，1H)，7.44(dd， 1H)，7.88-7.90(m，2H)，8.65(d，1H)，8.90(s，1H)。

Embodiment 31

4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 6-methoxy-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: the different  azoles of 4-hydroxyl-6-methoxy-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (method 34) and 3-amino-5-cyclopropyl-1H-pyrazoles (method 7 of WO-03/048133).

Receipts rate: 245mg, 48%.

NMR(DMSO)：0.63-0.65(m，2H)，0.84-0.9(m，3H)，1.80-1.89(m，1H)， 2.04-2.10(m，2H)，2.11-2.18(m，1H)，2.32-2.40(m，1H)，3.35(s，3H)，3.68- 3.80(m，2H)，4.18(q，2H)，5.45(d，1H)，6.0(s，1H)，6.38(s，1H)，6.65(s，1H)， 7.44(dd，1H)，7.78-7.97(m，2H)，8.65(d，1H)，8.92(s，1H)；m/z 459 [MH]+。

Embodiment 32

6-methoxy-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(thiazole-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

Initial material: the different  azoles of 4-hydroxyl-6-methoxy-2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (method 36) and 3-amino-5-methyl isophthalic acid H-pyrazoles.

Receipts rate: 32mg, 12%.

NMR(DMSO)：2.0-2.15(m，3H)，2.16(s，3H)，2.37(m，1H)，3.33(s，3H)， 3.65-3.79(m，2H)，4.14(m，2H)，5.44(d，1H)，6.0(s，1H)，6.37(s，1H)，6.63(s， 1H)，7.79(d，1H)，7.95(d，1H)；m/z 439[MH]+。

Embodiment 33

6-methoxy-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-3-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: the different  azoles of 4-hydroxyl-6-methoxy-2-[2-{3-(pyridine-3-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (method 35 (a)) and 3-amino-5-methyl isophthalic acid H-pyrazoles.

Receipts rate: 30mg, 21%.

NMR(DMSO)：2.07(m，3H)，2.17(s，3H)，2.36(m，1H)，3.33(s，3H)， 3.7(m，2H)，4.16(t，2H)，5.43(d，1H)，6.03(s，1H)，6.37(s，1H)，6.77(s，1H)， 7.47(t，1H)，8.13(d，1H)，8.65(d，1H)，8.87(s，1H)，8.98(s，1H)，11.5(s，1H)； m/z 433[MH]+。

Embodiment 34

4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(penta-3-alkene-1-the yl)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: 4-hydroxyl-6-(penta-3-alkene-1-the yl)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (method 35) and 3-amino-5-methyl isophthalic acid H-pyrazoles.

Receipts rate: 341mg, 56%.

NMR(DMSO)：1.55(d，3H)，2.02-2.18(m，3H)，2.18(s，3H)，2.23- 2.28(m，1H)，2.32-2.45(m，3H)，3.68-3.8(m，2H)，5.34-5.40(m，3H)，6.05(s， 1H)，6.18(s，1H)，6.65(s，1H)，7.43(dd，1H)，7.88-7.96(m，2H)，8.65(d，1H)， 8.75(s，1H)，11.50(s，1H)；m/z 457[MH]+。

Embodiment 35

4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-the 6-trifluoromethyl pyrimidine

Initial material: the different  azoles of 4-hydroxyl-6-three methyl fluorides-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (method 37) and 3-amino-5-methyl isophthalic acid H-pyrazoles.

Receipts rate: 115mg, 38%.

NMR(DMSO)：2.20(m，7H)，3.70(br m，2H)，5.42(br d，1H)，5.95(br s，1H)，6.62(br m，1H)，6.80(br s，1H)，7.50(m，1H)，7.95(m，2H)，8.64(m， 1H)；m/z 457[MH]+。

Embodiment 36

4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-the 6-trifluoromethyl pyrimidine

Initial material: the different  azoles of 4-hydroxyl-6-three methyl fluorides-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (method 37) and 3-amino-5-cyclopropyl-1H-pyrazoles (method 7 of WO-03/048133).

Receipts rate: 60mg, 17%.

NMR(DMSO)：0.70(m，2H)，0.90(m，2H)，1.90(m，1H)，2.15(m，4H)， 3.78(m，2H)，5.50(d，1H)，6.05(s，1H)，6.70(s，1H)，7.45(m，1H)，7.95(m，2H)， 8.68(d，1H)，9.58(br s，1H)，11.78(br s，1H)；m/z 483[MH]+.

Embodiment 37 to 42

The single enantiomter of following embodiment 37 to 42 makes by separating with the external racemization compound of chirality HPLC, and this separate to use Chiralpak AD post, with methyl alcohol or methanol/ethanol mixture as the wash-out agent.

Embodiment 37

S-6-ethyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Title compound is by separating to be prepared (embodiment 28) to this racemic compound.

Embodiment 38

The different  azoles of S-5-chloro-2-{2-[3-(thiazole-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Title compound is by separating to be prepared (embodiment 7) to this racemic compound.

Embodiment 39

The different  azoles of S-5-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

Title compound is by separating to be prepared (embodiment 9) to this racemic compound.

Embodiment 40

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 6-methyl-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Title compound is by separating to be prepared (embodiment 26) to this racemic compound.

Embodiment 41

The different  azoles of S-5-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Title compound is by separating to be prepared (embodiment 1) to this racemic compound.

Embodiment 42

S-5-chloro-2-{2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Title compound is by separating to be prepared (embodiment 19) to this racemic compound.

Embodiment 43

6-(3-N, N-dimethylaminopropyl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Under nitrogen, with four oxidation osmiums (0.070ml 2.5% weight is arranged in the solution of tBuOH), then water (0.38ml) is joined and carrying out the 4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) that stirs-6-(penta-3-alkene-1-the yl)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl pyrrolidines-1-yl] in the solution of pyrimidine (embodiment 34) (100mg, 2.2mmol) in THF (2ml). To wherein adding periodic acid sodium (150mg, 6.5mmol) and this mixture being stirred 1 hour. Extract with this mixture water dilution with ethyl acetate. To extract thing and merge, dry (MgSO₄) and remove volatile materials by evaporation. Be dissolved in residue in methyl alcohol and the acetic acid (0.066ml) and to wherein adding the solution of 2M dimethylamine in THF (0.55ml). Rapidly to wherein adding cyano group sodium borohydride (28mg) and this mixture being stirred 18 hours at ambient temperature. Then, remove volatile materials by evaporation, residue is dissolved in the ethyl acetate, then wash with salt solution with the saturated aqueous sodium carbonate washing. Remove volatile materials by evaporation, and residue is carried out purifying with silica gel chromatograph, carry out wash-out with DCM/ methyl alcohol/ammoniacal liquor (100: 0: 0 to polarity increase to 85: 15: 0.3), obtain title compound (8mg, 11%).

NMR(DMSO)：1.28-1.35(m，2H)，1.70-1.78(m，2H)，2.07-2.10(m2H)， 2.1(s，6H)，2.20(s，3H)，2.30-2.45(m，4H)，3.70-3.82(m，2H)，5.47(d，1H)， 6.08(s，1H)，6.20(s，1H)，6.65(s，1H)，7.45(dd，1H)，7.87-7.99(m，2H)，8.68(d， 1H)；m/z 472[MH]-。

Embodiment 44

6-(3-pyrrolidines-1-base propyl group)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Embodiment 44 uses the method similar to embodiment 43 described methods, by 4-(5-methyl isophthalic acid H-pyrazoles-3-base amino)-6-(penta-3-alkene-1-the yl)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 34) and pyrrolidines begin to be prepared.

Receipts rate: 6mg, 18%.

NMR(DMSO)：1.55-1.68(m，4H)，1.68-1.78(m，2H)，2.0-2.17(m，4H)， 2.18(s，3H)，2.28-2.45(m，8H)，3.65-3.80(m，2H)，5.43(d，1H)，6.04(s，1H)， 6.18(s，1H)，6.64(s，1H)，742(dd，1H)，7.85-7.97(m，2H)，8.63(d，1H)，8.74(s， 1H)；m/z 500[MH]+。

Embodiment 45

6-methoxycarbonyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

With the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-mixture of 4-(5-methyl isophthalic acid H-pyrazoles-3-base amino) pyrimidine-6-base formic acid (method 43) (100mg 0.21mmol), methyl alcohol (10ml) and 1 98% sulfuric acid heated 18 hours under refluxing. Remove volatile materials and residue is dissolved in the water by evaporation. By careful adding 10M sodium hydrate aqueous solution the pH of gained solution is transferred to 12, then with DCM it is extracted. To extract the thing merging and remove volatile materials by evaporation. Residue is carried out purifying with silica gel chromatograph, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 95: 5). This product that has carried out purifying is ground and passes through to filter the solid of collection gained with ether, obtain title compound (10mg, 8.8%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.05 (m, 3H), 2.15 (s, 3H), (2.35 m, 1H), 3.75 (m, 5H), (5.50 dd, 1H), 6.05 (s, 1H), (6.70 S, 1H), 6.88 (s, 1H), (7.40 m, 1H), 7.88 (t, 1H), (7.95 d, 1H), 8.65 (d, 1H); M/z 447[MH]+.

Embodiment 46

6-(2-hydroxyl ethylamino formyl base)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

With 6-methoxycarbonyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine (embodiment 45) (49.5mg, 0.11mmol) and the mixture of ethanol amine (2.0ml, 33.7mmol) in methyl alcohol (4ml) 88 ℃ of lower heating 2 hours. Remove volatile materials and residue is carried out purifying with the reversed-phase HPLC that uses the C18 post by evaporation, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out, and the fraction that will comprise product merges and makes it pass through 50g isolute SCX-2 ion exchange column. With methyl alcohol this post is carried out wash-out so that any neutral impurity is eluted, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, residue with the ether grinding and by filtering the solid of collecting gained, is obtained title compound (27mg, 57%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.10 (m, 3H), 2.20 (s, 3H), 2.40 (m, 1H), 3.35 (m, 2H), 3.55 (t, 2H), (3.75 m, 1H), 3.85 (m, 1H), 5.50 (dd, 1H), 6.10 (s, 1H), 6.72 (s, 1H), (6.88 s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.62 (d, 1H); M/z 476[MH]+.

Embodiment 47

4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-6-(pyrrolidines-1-base carbonyl) pyrimidine

Embodiment 47 uses the method similar to the method for embodiment 46 to be prepared, just initial material is processed with pure pyrrolidines and product is carried out purifying with silica gel chromatograph, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 90: 10), obtain title compound (10mg, 2.8%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.75 (m, 4H), 2.10 (m, 3H), 2.20 (s, 3H), 2.40 (m, 1H), 3.45 (m, 4H), (3.70 m, 1H), 3.85 (m, 1H), 5.40 (dd, 1H), 6.10 (s, 1H), 6.55 (S, 1H), (6.65 s, 1H), 7.40 (m, 1H), 7.88 (t, 1H), 7.95 (d, 1H), 8.65 (d, 1H); M/z 486[MH]+.

Embodiment 48

6-first oxygen base-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-{2-[3-(pyridine-2-yl)) different  azoles-5-yl] pyrrolidines-1-yl } pyrimidine

With 6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine (embodiment 17) (200mg, 0.47mmol), the mixture of 25% NaOMe/MeOH solution (0.54ml, 2.3mmol) in methyl alcohol (3ml) under air-proof condition 140 ℃ of lower heating 1 hour. Make this mixture cooling, then by the careful 2M ether hydrogen chloride processed (ethereal hydrogen chloride) that adds its pH is transferred to 7. Then, extract with DCM with this mixture water dilution and with aqueous mixture, will extract thing and merge, dry (MgSO₄) and by the evaporation desolventizing. Residue is ground with ether, collect product by filtering, obtain the title compound (98mg, 50%) of white solid form.

NMR(DMSO)：2.14-2.2(m，6H)，2.38(m，1H)，3.75(m，5H)，5.44(d， 1H)，5.75(s，1H)，5.94(s，1H)，6.66(s，1H)，7.4(m，1H)，7.88(m，1H)，7.91(m， 1H)，8.63(m，1H)；m/z 419[MH]+。

Embodiment 49

5-chloro-4-(3-cyclopropyl-1H-pyrazoles-5-base is amino)-2-[2-(2-methyl-2H-tetrazolium-5-yl) pyrrolidines-1-yl] pyrimidine

Uncle 1--butoxy-2-(2-methyl-2H-tetrazolium-5-yl) pyrrolidines (method 46) (160mg, 0.63mmol) was stirred 1 hour in TFA (2ml) at ambient temperature. Remove TFA and the product of gained is joined 2 by evaporation, 5-two chloro-4 (3-cyclopropyl-1H-pyrazoles-5-base is amino) pyrimidine (method 20 of WO 03/048133) (152mg, 0.57mmol) and two-isopropyl ethyl amine (330 μ L, 1.9mmol) just-oneself alcohol (4.0ml) mixture in. The mixture of gained is stirred and descends to heat 12 hours at 120 ℃ under nitrogen. To the silica gel (40mg, 0.11mmol) that wherein adds 3-(1,2-diamino ethyl) propyl group functionalization, then this mixture was heated 12 hours under 140 ℃. Make this mixture cooling, filter and this filtrate is applied directly on the isolute SCX2 ion exchange column. With this post with DCM/ methyl alcohol (4: 1) wash-out to remove neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. This product ground with ether and by the solid collected by filtration product, carry out drying with the ether washing and to it, obtain title compound (82mg, 38%).

NMR(DMSO-d ₆, under 100 ℃): 0.72 (m, 2H), 093 (m, 2H), 1.87 (m, 1H), 2.06 (m, 3H), 2.41 (m, 1H), (3.71 m, 2H), 4.27 (s, 3H) 5.47 (dd, 1H), 6.11 (br s, 1H), 7.92 (s, 1H); M/z 387[MH]+.

Embodiment 50

6-N-ethyl piperazidine base-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

With the different  azoles of 6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine (embodiment 17) (250mg, 0.59mmol) and NEP (674mg, 5.9mmol) mixture in anhydrous Isosorbide-5-Nitrae-two  alkane (5ml) is in heating 40 minutes under the microwave radiation in the container of sealing under 150 ℃. Remove volatile materials and residue is carried out purifying with the reversed-phase HPLC that uses the C18 post by evaporation, water/acetonitrile/three fluorine acetic acid (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing and again it is carried out purifying with silica gel chromatograph, carry out wash-out with DCM/ methyl alcohol/ammoniacal liquor (100: 0: 0 to polarity increase to 89: 20: 1), obtain title compound (200mg, 68%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.08 (t, 3H), 2.05 (m, 3H), 2.18 (s, 3H), 2.87 (m 6H), 2.35 (m, 1H), 2.87 (m, 6H), (3.57 s, 4H), 3.65 (m, 1H), 3.75 (m, 1H), (5.35 d, 1H), 5.55 (s, 1H), 5.95 (s, 1H), (6.60 s, 1H), 7.40 (m, 1H), 7.85 (m, 1H), 7.95 (d, 1H), 8.60 (d, 1H); M/z 501[MH]+.

Embodiment 51 and 52

Embodiment 51 and 52 uses the method similar to embodiment 50 described methods to be prepared, and still, does not need the normal-phase chromatography method, and by grinding with ether/DCM compound is separated and by filtering it collected.

Embodiment 51

The different  azoles of 6-N-methyl piperazine base (piperazyl)-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Initial material: the different  azoles of 6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 17) and N methyl piperazine.

Receipts rate: 201mg, 70%.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.00-2.15 (m, 3H), 2.20 (s, 3H), 2.35 (m, 1H), 2.60 (s, 3H), 2.95 (m, 4H), (3.6 m, 4H), 3.70 (m, 1H), 3.75 (m, 1H), 5.35 (d, 1H), 5.95 (s, 1H), (6.65 s, 1H), 7.40 (m, 1H), 7.85 (m, 1H), 7.95 (d, 1H), 8.60 (d, 1H); M/z 487[MH]+.

Embodiment 52

6-morpholine generation-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

Initial material: the different  azoles of 6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 17) and morpholine.

Receipts rate: 239mg, 85%.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.00-2.20 (m, 3H), 2.25 (s, 3H), 2.35 (m, 1H), 3.35 (m, 4H), 3.55 (m, 4H), (3.60-3.75 m, 2H), 5.35 (d, 1H), 5.60 (s, 1H), 5.70 (s, 1H), 5.95 (s, 1H), (6.67 s, 1H), 7.40 (m, 1H), 7.85 (m, 1H), 7.95 (d, 1H), 8.60 (d, 1H); M/z 474[MH]+.

Embodiment 53

6-(3-(N, N-dimethylamino) propine-1-yl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-(2-(the different  azoles of 3-(pyridine-2-yl)-5-yl) pyrrolidines-1-yl) pyrimidine

With 6-bromo-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-(2-(the different  azoles of 3-(pyridine-2-yl)-5-yl) pyrrolidines) pyrimidine (method 49) (200mg, 0.43mmol), chlorination palladium (II)-two (triphenyl phosphine) (12mg, 0.02mmole), cuprous iodide (I) (2mg, 0.02mmol), triethylamine (0.300ml, 2.1mmol), 3-(N, the N-dimethylamino) mixture of propine (0.070ml, 0.64mmol) in acetonitrile (2ml) heating 15 minutes under the microwave radiation in the sealing container under 75 ℃. This mixture is dissolved in the ethyl acetate, this solution is poured out from the insoluble matter updip, with this solution with water washing, dry (MgSO₄), and by the evaporation desolventizing. Residue is carried out purifying with silica gel chromatograph (chromatography on silica gel), carry out wash-out with DCM/ methyl alcohol (90: 10 to polarity increase to 85: 15). This product that has carried out purifying is ground with ether and by filtering it is collected, obtain title compound (44mg, 25%).

NMR(DMSO)：2.10(m，3H)，2.20(s，3H)，2.29(s，6H)，2.32-2.45(m， 1H)，3.45(s，2H)，3.66-3.80(m，2H)，5.45(d，1H)，6.08(s，1H)，6.47(s，1H)， 6.68(s，1H)，7.46(d，1H)，7.88-7.98(m，2H)，8.66(d，1H)，9.04(s，1H)，11.55(s， 1H)；m/z 470[MH]+。

Embodiment 54

6-methyl amino-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-(the 3-pyridine-different  azoles of 2-base-5-yl) pyrrolidines-1-yl] pyrimidine

With the different  azoles of 6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine (embodiment 17) (250mg, 0.59mmol) and first amine (4ml 2M methanol solution, mixture 8.0mmol) under 130 ℃ the sealing container under the microwave radiation heating 90 minutes. Remove volatile materials and residue is carried out purifying with the reversed-phase HPLC that uses the C18 post by evaporation, water/acetonitrile/three fluorine acetic acid (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain the title compound (126mg, 50%) of yellow solid form.

NMR(DMSO-d ₆, under 100 ℃): 2.05 (m, 3H), 2.15 (s, 3H). (2.35 m, 1H), 2.74 (s, 3H), 3.70 (m, 2H), 5.43 (d, 1H), 5.51 (br s, 1H), (5.91 br s, 2H), 6.60 (s, 1H), (7.40 m, 1H), 7.85 (m, 1H), (7.95 d, 1H), 8.04 (br s, 1H), (8.60 d, 1H), 11.33 (br s, 1H); M/z 418[MH]+.

Embodiment 55

6-(2-methoxy ethyl) amino-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

With the different  azoles of 6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine (embodiment 17) (250mg, 0.59mmol) and 2-methoxy ethyl amine (443mg, 5.9mmol) mixture in anhydrous Isosorbide-5-Nitrae-two  alkane (5ml) is in heating 40 minutes under the microwave radiation in the sealing container under 150 ℃. Should react and as described in the embodiment 54, carry out post processing, obtain the title compound (108mg, 40%) of cream-colored solid form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.00-2.15 (m, 3H), 2.18 (s, 3H), 2.35 (m, 1H), 3.15 (s, 1H), 3.20-3.40 (m, 4H), (3.65 m, 1H), 3.75 (m, 1H), 5.35 (d, 1H), 5.55 (s, 1H), 5.85 (s, 1H), (6.55 s, 1H), 7.40 (m, 1H), 7.85 (m, 1H), 7.95 (d, 1H), 8.60 (d, 1H); M/z 462[MH]+.

Embodiment 56

The different  azoles of 6-methoxycarbonyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine

With the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-mixture of 4-(5-methyl isophthalic acid H-pyrazoles-3-base amino) pyrimidine-6-base formic acid (method 43) (1.73g, 4.0mmol), methyl alcohol (300ml) and 98 % sulfuric acid (1ml) heated 18 hours under refluxing. Remove volatile materials by evaporation, residue is dissolved in the water and with 10M NaOH the pH of gained solution is transferred to 12. This aqueous solution is extracted with DCM and with silica gel chromatograph it is carried out purifying, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 90: 10), obtain title compound (904mg, 51%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.05 (m, 3H), 2.15 (s, 3H), (2.35 m, 1H), 3.75 (m, 5H), (5.50 dd, 1H), 6.05 (s, 1H), 6.70s, 1H), 6.88 (s, 1H), (7.40 m, 1H), 7.88 (t, 1H), (7.95 d, 1H), 8.65 (d, 1H); M/z 447[MH]+.

Embodiment 57

6-(N-methyl the carbamoyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With the different  azoles of 6-methoxycarbonyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 56) (62.5mg, 0.14mmol), the mixture of the methanol solution (2.0ml, 4.00mmol) of 2N first amine and methyl alcohol (3.0ml) is in heating 1 hour under the microwave radiation under 65 ℃. Remove volatile materials and residue is dissolved among the DCM by evaporation, carry out purifying with silica gel chromatograph, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 90: 10). This product that has carried out purifying is ground and passes through to filter the solid of collection gained with ether, obtain title compound (21mg, 34%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.10 (m, 3H), 2.20 (s, 3H), (2.40 m, 1H), 3.75 (m, 1H), 3.85 (m, 1H), 5.50 (dd, 1H), 6.10 (s, 1H), (6.70 s, 1H), 6.90 (s, 1H), (7.40 m, 1H), 7.87 (t, 1H), (7.93 d, 1H), 8.65 (d, 1H); M/z 446[MH]+.

Embodiment 58

The different  azoles of 6-morpholino carbonyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine

With the different  azoles of 6-methoxycarbonyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 56) (200mg, 0.45mmol) and the mixture of morpholine (0.5ml, 5.73mmol) in anhydrous methyl alcohol (5.0ml) 120 ℃ of lower heating 18 hours. Remove volatile materials and residue is carried out purifying with the reversed-phase HPLC that uses the C18 post by evaporation, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. Grind with ether by the evaporation desolventizing and with residue. By filtering the solid of collecting gained, obtain title compound (120mg, 52%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.10 (m, 3H), 2.20 (s, 3H), (2.40 m, 1H), 3.47 (m, 8H), 3.65 (m, 1H), 3.76 (m, 1H), 5.42 (dd, 1H), (6.07 s, 1H), 6.45 (s, 1H), 6.65 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), (7.95 d, 1H), 8.60 (d, 1H); M/z 502[MH]+.

Embodiment 59

6-(N-(2-methoxy ethyl) the carbamoyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With the different  azoles of 6-methoxycarbonyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 56) (200mg, 0.45mmol) and the heating 18 hours under refluxing of the mixture of 2-methoxy ethyl amine (5ml, 57.2mmol). With the evaporation of this reactant mixture, be dissolved in residue in the methyl alcohol and make it pass through the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By evaporation desolventizing and this residue is carried out purifying with silica gel chromatograph, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 90: 10). This product that has carried out purifying is ground and passes through to filter the solid of collection gained with ether, obtain title compound (78mg, 36%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.10 (m, 3H), 2.20 (s, 3H), 2.40 (m, 1H), 3.25 (s, 3H), 3.40 (m, 4H), (3.75 m, 1H), 3.85 (m, 1H), 5.45 (dd, 1H), 6.10 (s, 1H), 6.70 (s, 1H), (6.90 s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.92 (d, 1H), 8.65 (d, 1H); M/z 490[MH]+.

Embodiment 60

6-(N-hydroxyl amino formyl the base)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With the different  azoles of 6-methoxycarbonyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 56) (200mg, 0.45mmol), single hydroxylamine hydrochloride (340mg, 4.86mmol) and the heating 18 hours under refluxing of the mixture of triethylamine (0.80ml, 5.40mmol) in anhydrous methyl alcohol (5ml). Remove volatile materials and residue is carried out purifying with the reversed-phase HPLC that uses the C18 post by evaporation, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain the title compound (40mg, 20%) of form of foam.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.08 (m, 3H), 2.15 (s, 3H), (2.37 m, 1H), 3.74 (m, 1H), 3.80 (m, 1H), 5.54 (dd, 1H), 6.08 (s, 1H), (6.70 s, 1H), 6.85 (s, 1H), (7.40 m, 1H), 7.85 (t, 1H), (7.92 d, 1H), 8.63 (d, 1H); M/z 448[MH]+.

Embodiment 61

The different  azoles of 6-carbamoyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine

With the different  azoles of 6-methoxycarbonyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 56) (200mg, 0.45mmol) and 7N be arranged in methyl alcohol ammonia spirit (7ml, 49mmol) mixture under 65 ℃ the sealing container under the microwave radiation, heating 1 hour. With the evaporation of this reactant mixture, be dissolved in the methyl alcohol and make it pass through the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. Grind with ether by the evaporation desolventizing and with residue. By filtering the solid of collecting gained, obtain title compound (180.0mg, 93%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.10 (m, 3H), 2.18 (s, 3H), (2.40 m, 1H), 3.78 (m, 1H), 3.84 (m, 1H), 5.48 (dd, 1H), 6.10 (s, 1H), (6.70 s, 1H), 6.90 (s, 1H), (7.40 m, 1H), 7.85 (t, 1H), (7.92 d, 1H), 8.62 (d, 1H); M/z 432[MH]+.

Embodiment 62

The different  azoles of S-6-methoxycarbonyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With the different  azoles of S-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-mixture of 4-(5-methyl isophthalic acid H-pyrazoles-3-base amino) pyrimidine-6-base formic acid (method 50) (1.73g, 4.0mmol), methyl alcohol (300ml) and 98 % sulfuric acid (1ml) heated 18 hours under refluxing. Remove volatile materials by evaporation, residue is dissolved in the water and with 10M NaOH the pH of gained solution is transferred to 12. This aqueous solution is extracted with DCM and with silica gel chromatograph it is carried out purifying, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 90: 10), obtain title compound (904.0mg, 51%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.05 (m, 3H), 2.15 (s, 3H), (2.35 m, 1H), 3.75 (m, 5H), (5.50 dd, 1H), 6.05 (s, 1H), 6.70 s, 1H), 6.88 (s, 1H), (7.40 m, 1H), 7.88 (t, 1H), (7.95 d, 1H), 8.65 (d, 1H); M/z 447[MH]+.

Embodiment 63

S-6-(N-(2-methoxy ethyl) the carbamoyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With chlorination 4-(4,6-dimethoxy [1,3,5] triazine-2-yl)-4-methyl-morpholine  (149.3mg, 0.54mmol) join the different  azoles of S-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl-also this reactant mixture was stirred 0.5 hour at ambient temperature until form a kind of solution (show and successfully formed active ester) of clarification in the mixture of 4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine-6-base formic acid (method 50) (200mg, 0.46mmol) and dry DMF (10ml). To wherein adding 2-methoxy ethyl amine (0.50ml, 5.75mmol) and this this reaction being stirred 2 hours at ambient temperature again. Then, make this reactant mixture by the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing and residue carried out purifying with silica gel chromatograph, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 90: 10). This product that has carried out purifying is ground and passes through to filter the solid of collection gained with ether, obtain title compound (136mg, 58%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.10 (m, 3H), 2.18 (s, 3H), 2.40 (m, 1H), 3.25 (s, 3H), 3.42 (m, 4H), (3.75 m, 1H), 3.83 (m, 1H), 5.46 (dd, 1H), 6.10 (s, 1H), 6.70 (s, 1H), (6.90 s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.92 (d, 1H), 8.62 (d, 1H); M/z 490[MH]+.

Embodiment 64

S-6-[N-(2-methoxy ethyl)-N-methyl carbamoyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With chlorination 4-(4,6-dimethoxy [1,3,5] triazine-2-yl)-4-methyl-morpholine  (149.3mg, 0.54mmol) join the different  azoles of S-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl-also this reactant mixture was stirred 0.5 hour at ambient temperature until form a kind of solution of clarification in the mixture of 4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine-6-base formic acid (method 50) (200mg, 0.46mmol) and dry DMF (10ml). To wherein adding N-(2-methoxy ethyl)-N-first amine (0.5ml) and this this reaction being stirred 2 hours at ambient temperature again. Then, make this reactant mixture by the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing and residue carried out purifying with silica gel chromatograph, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 90: 10). Then, with the reversed-phase HPLC that uses the C18 post product that this has carried out purifying is carried out purifying again, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain title compound (90mg, 37 %).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.08 (m, 3H), 2.18 (s, 3H), 2.37 (m, 1H), 2.95 (s, 2H), 3.18 (s, 3H), 3.40 (m, 3H), 3.50 (m, 1H), 3.69 (m, 1H), 3.76 (m, 1H), 5.45 (dd, 1H), 6.38 (s, 1H), (6.60 s, 1H), 7.38 (m, 1H), 7.85 (t, 1H), 7.88 (d, 1H), 8.58 (d, 1H); M/z 504[MH]+.

Embodiment 65

S-6-[N-(2-(acetyl-amino) ethyl) carbamoyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With chlorination 4-(4,6-dimethoxy [1,3,5] triazine-2-yl)-4-methyl-morpholine  (149.3mg, 0.54mmol) join the different  azoles of S-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl-also this reactant mixture was at room temperature stirred 0.5 hour until form a kind of solution of clarification in the mixture of 4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine-6-base formic acid (method 50) (200mg, 0.46mmol) and dry DMF (5ml). To wherein adding N-acetyl group-1,2-ethylenediamine (0.22ml, 2.29mmol) also should react and at room temperature stir 2 hours again. This reactant mixture is filtered, remove volatile materials and residue is carried out purifying with the reversed-phase HPLC of use C18 post from filtrate by evaporation, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, residue is ground with ether and by filtering it is collected, obtain title compound (115.7mg, 49%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.80 (s, 3H), 2.10 (m, 3H), 2.19 (s, 3H), 2.40 (m, 1H), 3.25 (m, 2H) 3.35 (m, 2H), (3.77 m, 1H), 3.85 (m, 1H), 5.53 (dd, 1H), 6.10 (s, 1H), 6.71 (s, 1H), (6.88 s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.93 (d, 1H), 8.61 (d, 1H); M/z 517[MH]+.

Embodiment 66 to 76

Embodiment 66 to 76 uses the method similar to embodiment 65 described methods to use S-2-{ the different  azoles of 2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base amino) basic formic acid (method 50) of pyrimidine-6-and the amine that suits is prepared.

Embodiment 66

S-6-{N-[2-hydroxyl base oxethyl) ethyl] carbamoyl }-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Amine-initiated material: 2-(2-hydroxyl base oxethyl) ethyl amine. Receipts rate: 123mg, 49%.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.10 (m, 3H), 2.19 (s, 3H), 2.40 (m, 1H), 3.40 (m, 2H) 3.45 (m, 2H), 3.55 (m, 2H), (3.75 m, 1H), 3.85 (m, 1H), 5.47 (dd, 1H), 6.10 (s, 1H), 6.71 (s, 1H), (6.90 s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.93 (d, 1H), 8.62 (d, 1H); M/z 520[MH]+.

Embodiment 67

S-6-[N-((R)-2-hydroxyl propyl group) carbamoyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Amine-initiated material: (R)-2-hydroxyl propyl group amine. Receipts rate: 137mg, 61%.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.05 (d, 3H), 2.10 (m, 3H), 2.19 (s, 3H), 2.40 (m, 1H), 3.46 (m, 2H), 3.75 (m, 1H), 3.85 (m, 1H), 3.90 (m, 1H), 5.44 (dd, 1H), 6.12 (s, 1H), 6.71 (s, 1H), (6.90 s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.93 (d, 1H), 8.62 (d, 1H); M/z 490[MH]+.

Embodiment 68

S-6-[N-(4-hydroxybutyl) carbamoyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Amine-initiated material: 4-hydroxybutyl amine. In the situation of not grinding, this kind product is separated (153mg, 66%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.45 (m, 2H), 1.55 (m, 2H), 2.10 (m, 3H), 2.19 (s, 3H), 2.40 (m, 1H), 3.25 (m, 2H), 3.40 (t, 2H), 3.76 (m, 1H), 3.84 (m, 1H), 5.44 (dd, 1H), 6.12 (s, 1H), 6.70 (s, 1H), 6.88 (s, 1H), 7.39 (m, 1H), 7.85 (t, 1H), 7.93 (d, 1H), 8.61 (d, 1H); M/z 504[MH]+.

Embodiment 69

S-6-[N-((2R)-2,3-dihydroxypropyl) carbamoyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Amine-initiated material: (2R)-2,3-dihydroxypropyl amine. In the situation that water does not grind, this kind product is separated (135mg, 58%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.15 (m, 3H), 2.19 (s, 3H), 2.43 (m, 1H), 3.25 (m, 1H), 3.43 (m, 3H), 3.65 (m, 1H), 3.76 (m, 1H), 3.85 (m, 1H), 5.50 (dd, 1H), 6.11 (s, 1H), 6.76 (s, 1H), (6.92 s, 1H), 7.42 (m, 1H), 7.87 (t, 1H), 7.95 (d, 1H), 8.65 (d, 1H); M/z 506[MH]+.

Embodiment 70

S-6-[N-(carbamoyl methyl) carbamoyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

This kind product is with hydrochloric acid glycinimide and triethylamine (7.0 equivalent) is preparation and separated in the situation of not grinding (141mg, 62%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.10 (m, 3H), 2.18 (s, 3H), (2.40 m, 1H), 3.80 (m, 2H), 3.85 (m, 2H), 5.50 (dd, 1H), 6.08 (s, 1H), (6.74 s, 1H), 6.90 (s, 1H), (7.40 m, 1H), 7.85 (t, 1H), (7.93 d, 1H), 8.62 (d, 1H); M/z 506[MH]+.

Embodiment 71

S-6-((3R)-3-hydroxyl pyrrolidines-1-base the carbonyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Amine-initiated material: (2R)-3-hydroxyl pyrrolidines. With grinding this kind product is separated (129mg, 56%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.70 (m, 2H), 2.10 (m, 3H), 2.18 (s, 3H), 2.38 (m, 1H), 3.50 (m, 2H), 3.65 (m, 2H), 3.81 (m, 2H), 4.23 (s, 1H), 5.40 (dd, 1H), 6.07 (s, 1H), 6.56 (s, 1H), (6.65 s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.93 (d, 1H), 8.62 (d, 1H); M/z 502[MH]+.

Embodiment 72

S-6-{N-[2-(first sulphur base) ethyl] carbamoyl }-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Amine-initiated material: 2-(first sulphur base) ethyl amine. With grinding this kind product is separated (147mg, 63%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.02 (s, 3H), 2.10 (m, 3H), 2.17 (s, 3H), 2.38 (m, 1H), 2.60 (t, 2H), 3.45 (m, 2H), 3.75 (m, 1H), 3.83 (m, 1H), 5.46 (dd, 1H), 6.07 (s, 1H), 6.70 (s, 1H), (6.89 s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.61 (d, 1H); M/z 506[MH]+.

Embodiment 73

S-6-(N-cyclopropyl the carbamoyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Amine-initiated material: cyclopropylamine. With grinding this kind product is separated (113mg, 52 %).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 0.50 (m, 1H), 0.60 (m, 1H), 0.67 (m, 2H), 2.10 (m, 3H), 2.19 (s, 3H), 2.40 (m, 1H), 2.77 (m, 1H), 3.75 (m, 1H), 3.83 (m, 1H), 5.43 (dd, 1H), 6.12 (s, 1H), 6.70 (s, 1H), 6.88 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.92 (d, 1H), 8.62 (d, 1H); M/z 472[MH]+.

Embodiment 74

S-6-(N-cyclopenta the carbamoyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Amine-initiated material: cyclopenta amine. With grinding this kind product is separated (162mg, 70 %).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.30-1.91 (m, 8H), 2.12 (m, 3H), 2.19 (s, 3H), 2.43 (m, 1H), 3.75 (m, 1H), (3.85 m, 1H), 4.11 (m, 1H), 5.43 (dd, 1H), 6.15 (s, 1H), 6.70 (s, 1H), (6.88 s, 1H), 7.40 (m, 1H), 7.86 (t, 1H), 7.92 (d, 1H), 8.63 (d, 1H); M/z 500[MH]+.

Embodiment 75

S-6-(azetidine-1-base the carbonyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Amine-initiated material: azetidine. With grinding this kind product is separated (153mg, 70 %).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.08 (m, 3H), 2.10 (s, 5H), 2.40 (m, 1H), 3.70 (m, 1H), 3.85 (m, 1H), 4.02 (m, 2H), 4.40 (m, 1H), 4.57 (m, 1H), 5.45 (dd, 1H), 6.10 (s, 1H), 6.65 (s, 1H), (6.80 s, 1H), 7.44 (m, 1H), 7.78 (t, 1H), 7.95 (d, 1H), 8.65 (d, 1H); M/z 472[MH]+.

Embodiment 76

The different  azoles of S-6-(N-methyl carbamoyl) 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

This kind product is and under the situation of not grinding separated (145mg, 70%) preparation with the THF solution of 2N first amine (10.0 equivalent).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.08 (m, 3H), 2.18 (s, 3H), (2.38 m, 1H), 2.77 (s, 3H), 3.75 (m, 1H), 3.85 (m, 1H), 5.47 (dd, 1H), (6.08 s, 1H), 6.67 (s, 1H), 6.85 (s, 1H), 7.38 (m, 1H), 7.82 (t, 1H), (7.90 d, 1H), 8.58 (d, 1H); M/z 446[MH]+.

Embodiment 77

6-(the amino carbamoyl of the N-)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

At room temperature, with single hydration hydrazine (1.6ml, 20.6mmol) join in 6-methoxycarbonyl-2-{ the different  azoles of 2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino) mixture of pyrimidine (embodiment 56) (1.54g, 3.45mmol) in methyl alcohol (20.0ml). The reactant mixture of gained was heated 1 hour under refluxing, then make it cooling. By the solid of filtration collection gained and with methyl alcohol it is washed, obtain title compound (1.05g, 68.3%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.10 (m, 3H), 2.17 (s, 3H), (2.38 m, 1H), 3.75 (m, 1H), 3.82 (m, 1H), 5.50 (dd, 1H), 6.06 (s, 1H), (6.68 s, 1H), 6.86 (s, 1H), (7.38 m, 1H), 7.85 (t, 1H), (7.95 d, 1H), 8.61 (d, 1H); M/z 447[MH]+.

Embodiment 78

6-[N-(acetyl-amino) carbamoyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With 6-[N-(acetyl-amino) carbamoyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(2-acetyl group-5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (method 51) (170mg; 0.32mmol) solution in methyl alcohol (10ml) and 2N NaOH (0.5ml, 1.0mmol) at room temperature stirred 0.5 hour. By filtering the precipitation of collecting gained, obtain title compound (150mg, 96%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.88 (s, 3H), 2.08 (m, 3H), (2.18 s, 3H), 2.40 (m, 1H), 3.75 (m, 1H), 3.84 (m, 1H), 5.55 (dd, 1H), (6.10 s, 1H), 6.70 (s, 1H), 6.90 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), (7.93 d, 1H), 8.62 (d, 1H); M/z 489[MH]+.

Embodiment 79

6-(5-methyl-[1,3,4]- diazole-2-yl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With hydroxide (methoxycarbonyl sulfamoyl) triethyl ammonium (inner salt) (90mg; 3.76mmol) join 6-[N-(acetyl-amino) carbamoyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl-4-(2-acetyl group-5-methyl isophthalic acid H-pyrazoles-3-base the is amino) solution of pyrimidine (method 51) (500mg, 0.94mmol) in anhydrous THF (20ml) in and should react under backflow and heat 18 hours. Remove volatile materials and residue is dissolved in methyl alcohol (5ml) and the 2N sodium hydrate aqueous solution (1.0ml) and with it by evaporation and stirred at ambient temperature 15 minutes. Remove methyl alcohol and with 1N hydrochloric acid the pH of gained solution is transferred to 7 by evaporation. Evaporation is removed volatile materials and residue is carried out purifying with silica gel chromatograph, carries out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 90: 10). Then, this product that has carried out purifying is ground and by filtering it is collected with ether, obtain title compound (200mg, 52%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.08 (m, 3H), 2.18 (s, 3H), (2.38 m, 1H), 2.53 (s, 3H), 3.76 (m, 1H), 3.84 (m, 1H), 5.50 (dd, 1H), (6.08 s, 1H), 6.72 (s, 1H), 7.02 (s, 1H), 7.39 (m, 1H), 7.85 (t, 1H), (7.92 d, 1H), 8.61 (d, 1H); M/z 471[MH]+.

Embodiment 80

The different  azoles of 6-hydroxyl methyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With 2M boron hydrogenation lithium at THF (22.4ml, 44.8mmol) in solution join the different  azoles of 6-methoxycarbonyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl-4-(5-methyl isophthalic acid H-pyrazoles-3-base amino) mixture of pyrimidine (embodiment 56) (4.0mg, 8.96mmol) in anhydrous THF (200ml) in. This reactant mixture was at room temperature stirred 3 hours, then it was at room temperature refluxed 1 hour. Make the cooling of this mixture and to wherein adding methyl alcohol until stop effervesce, then to the two  alkane solution (30ml) that wherein add 4M hydrogen chloride and with the heating 1 hour under refluxing of this mixture. Remove volatile materials by evaporation, residue is dissolved in the water and by careful adding 10M sodium hydrate aqueous solution the pH of gained solution is transferred to 9. This aqueous mixture is extracted and with silica gel chromatograph it is carried out purifying with DCM, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 90: 10), obtain title compound (3.4g, 91%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.10 (m, 3H), 2.18 (s, 3H), (2.35 m, 1H), 3.70 (m, 1H), 3.77 (m, 1H), 4.23 (dd, 2H), 5.45 (dd, 1H), (6.01 s, 1H), 6.41 (s, 1H), 6.65 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), (7.95 d, 1H), 8.62 (d, 1H); M/z 419[MH]+.

Embodiment 81

The different  azoles of 6-(morpholine is for methyl)-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine

With 6-[(4-aminomethyl phenyl sulfonyloxy) methyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-2-N-[4-aminomethyl phenyl sulphonyl base]-1H-pyrazoles-3-base is amino) pyrimidine (method 52) (214mg; 0.295mmol) and the heating 2 hours under refluxing of the mixture of morpholine (5ml, 83.2mmol). Remove volatile materials and residue is dissolved in methyl alcohol (10ml) and the 10M sodium hydrate aqueous solution (3ml) by evaporation. This mixture was heated 1 hour under 60 ℃. Remove volatile materials and residue is dissolved in the water by evaporation, with carrene it is extracted. To extract the thing merging and pass through the evaporation desolventizing. Residue is carried out purifying with silica gel chromatograph, with carrene (100%), then use ether (100%) to carry out wash-out. This product that has carried out purifying is ground with ether and by filtering it is collected, obtain title compound (125mg).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.05 (m, 3H), 2.18 (s, 3H), 2.35 (m, 1H), 2.57 (m, 4H), 3.40 (m, 2H), 3.55 (m, 4H), 3.68 (m, 1H), 3.78 (m, 1H), 545 (dd, 1H), 6.05 (s, 1H), 6.38 (s, 1H), (6.64 s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.93 (d, 1H), 8.62 (d, 1H); M/z 488[MH]+.

Embodiment 82

6-(4-methyl piperazine-1-base the methyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With 6-[(4-aminomethyl phenyl sulfonyloxy) methyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-2-N-[4-aminomethyl phenyl sulphonyl base]-1H-pyrazoles-3-base is amino) pyrimidine (method 52) (214mg; 0.295mmol) and the heating 4 hours under refluxing of the mixture of 1-methyl piperazine (3.0ml, 27.1mmol). Remove volatile materials and residue is carried out purifying with the reversed-phase HPLC that uses the C18 post by evaporation, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain title compound (107mg, 71%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.08 (m, 3H), 2.18 (s, 3H), 2.35 (m, 4H), 2.60 (m, 8H), 3.34 (d, 2H), (3.67 m, 1H), 3.77 (m, 1H), 5.43 (dd, 1H), 6.06 (s, 1H), 6.33 (s, 1H), (6.62 s, 1H), 7.40 (m, 1H), 7.86 (t, 1H), 7.92 (d, 1H), 8.63 (d, 1H); M/z 501[MH]+.

Embodiment 83

The different  azoles of 6-(methyl amino methyl)-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With 6-[(4-aminomethyl phenyl sulfonyloxy) methyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-2-N-[4-aminomethyl phenyl sulphonyl base]-1H-pyrazoles-3-base is amino) pyrimidine (method 52) (190mg; 0.26mmol) and the mixture of the solution (5ml, 10mmol) of 2N first amine in THF in the sealing container under the microwave radiation 90 ℃ of lower heating 1 hour. Remove volatile materials and residue is carried out purifying with the reversed-phase HPLC that uses the C18 post by evaporation, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain title compound (87.1mg, 77%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.08 (m, 3H), 2.18 (s, 3H), 2.35 (m, 1H), 2.60 (s, 3H), 3.75 (m, 1H), (3.82 m, 1H), 3.92 (dd, 2H), 5.53 (dd, 1H), 6.06 (s, 1H), 6.30 (s, 1H), (6.67 s, 1H), 7.40 (m, 1H), 7.86 (t, 1H), 7.93 (d, 1H), 8.62 (d, 1H); M/z 432[MH]+.

Embodiment 84

6-(pyrrolidines-1-base the methyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With 6-[(4-aminomethyl phenyl sulfonyloxy) methyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-2-N-[4-aminomethyl phenyl sulphonyl base]-1H-pyrazoles-3-base is amino) pyrimidine (method 52) (214mg; 0.295mmol) and the mixture of pyrrolidines (3.0ml, 27mmol) 95 ℃ of lower heating 24 hours. Remove volatile materials and residue is carried out purifying with the reversed-phase HPLC that uses the C18 post by evaporation, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain title compound (77.6mg, 52%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.08 (m, 3H), 2.18 (s, 3H), 2.36 (m, 1H), 3.22 (m, 4H), 3.70 (m, 1H), (3.80 m, 1H), 4.05 (dd, 2H), 5.49 (dd, 1H), 6.07 (s, 1H), 6.35 (s, 1H), (6.67 s, 1H), 7.40 (m, 1H), 7.86 (t, 1H), 7.93 (d, 1H), 8.62 (d, 1H); M/z 472[MH]+.

Embodiment 85

The different  azoles of 6-amino methyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With sodium azide (44mg; 0.68mmol) join 6-[(4-aminomethyl phenyl sulfonyloxy) methyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl-4-(5-methyl isophthalic acid-N-[4-aminomethyl phenyl sulphonyl base]-1H-pyrazoles-3-base the is amino) solution of pyrimidine (method 52) (159mg, 0.22mmol) in dry DMF (2.0ml) in and with this mixture 110 ℃ of lower heating 1.5 hours. Then, to wherein adding triphenyl phosphine (282.0mg, 1.08mmol) and water (0.10ml) and this reactant mixture being heated 1 hour under 100 ℃. Make this mixture cooling, then make it pass through the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. Remove volatile materials and residue is dissolved in methyl alcohol (5ml) and 10M sodium hydrate aqueous solution (0.5ml) and it was stirred 1 hour by evaporation. Remove volatile materials and residue is dissolved in the water by evaporation, then, with DCM it is extracted. To extract thing merges, by the evaporation desolventizing and with silica gel chromatograph residue is carried out purifying, carry out wash-out with DCM/ methyl alcohol/ammoniacal liquor (100: 0: 0 to polarity increase to 80: 20: 1), obtain the title compound (48.5mg, 53%) of solid form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.08 (m, 3H), 2.19 (s, 3H), (2.35 m, 1H), 3.75 (m, 1H), 3.82 (m, 3H), 5.55 (dd, 1H), 6.05 (s, 1H), (6.32 s, 1H), 6.69 (s, 1H), (7.42 m, 1H), 7.87 (t, 1H), (7.95 d, 1H), 8.63 (d, 1H); M/z 418[MH]+.

Embodiment 86

The different  azoles of S-6-hydroxyl methyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine

With the different  azoles of S-6-methoxycarbonyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base amino) pyrimidine (embodiment 62) processes with embodiment 80 described methods, obtains title compound.

Embodiment 87

The different  azoles of S-6-ethoxyl methyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With 1M two (trimethyl silyl) lithium amide at THF (5.0ml; 5.0mmol) in solution join the different  azoles of S-6-chloromethyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl-4-(5-methyl-2-N-[4-aminomethyl phenyl sulfuryl amino]-1H-pyrazoles-3-base is amino) pyrimidine (method 53) (240mg, 0.41mmol) is in without the mixture in the water-ethanol (30ml). Then, this reactant mixture was heated 48 hours down and makes it cooling at 100 ℃. Add a small amount of water, remove volatile materials by evaporation. Residue is carried out purifying with silica gel chromatograph, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 90: 10), obtain title compound (29mg, 16%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.15 (t, 3H), 2.05 (m, 3H), 2.18 (s, 3H), 2.35 (s, 1H), 3.52 (q, 2H), 3.67 (m, 1H), 3.76 (m, 1H), 4.20 (dd, 2H), 5.42 (dd, 1H), 6.02 (s, 1H), 6.38 (s, 1H), (6.62 s, 1H), 7.40 (m, 1H), 7.86 (t, 1H), 7.92 (m, 1H), 8.62 (d, 1H); M/z 447[MH]+.

Embodiment 88

The S-6-[(2-methoxy ethoxy) methyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With 1M two (trimethyl silyl) lithium amide at THF (5.0ml; 5.0mmol) in solution join the different  azoles of S-6-chloromethyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl-4-(5-methyl-2-N-[4-aminomethyl phenyl sulfuryl amino]-1H-pyrazoles-3-base the is amino) mixture of pyrimidine (method 53) (240mg, 0.41mmol) in anhydrous 2-methyl cellosolve (30ml) in. Then, this reactant mixture is being sealed in the container the lower heating of microwave radiation 1.5 hours at 150 ℃. Add a small amount of water, remove volatile materials by evaporation. Residue is carried out purifying with silica gel chromatograph, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 90: 10), obtain title compound (69.0mg, 43%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.05 (m, 3H), 2.18 (s, 3H), 2.35 (s, 1H), 3.25 (s, 2H), 3.48 (t, 2H), 3.60 (t, 2H), 3.68 (m, 1H), 3.76 (m, 1H), 4.25 (dd, 2H), 5.42 (dd, 1H), 6.05 (s, 1H), 6.38 (s, 1H), 6.65 (s, 1H), 7.42 (m, 1H), 7.86 (t, 1H), 7.92 (m, 1H), 8.63 (d, 1H); M/z 477[MH]+.

Embodiment 89

The different  azoles of S-5-chloro-2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

With 2,5-two chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine (method 20 of WO 03/04133) (195mg, 0.72mmol), the different  azoles of S-2-[3-(2-pyrazine base)-5-yl] pyrrolidines (method 55) (171.5mg, 0.79mmol), N, N-diisopropyl ethyl amine (0.28ml, 1.58mmol) and mixture just-oneself pure (10.0ml) were 125 ℃ of lower heating 18 hours. Then, to wherein adding the functionalized silica gel (500mg) of 3-(2-aminoethylamino) propyl group and this reactant mixture being heated under 140 ℃ 2 hours again. Make this reactant mixture by the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing and residue carried out purifying with silica gel chromatograph, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 90: 10). This product that has carried out purifying is ground with ether and by filtering it is collected, obtain title compound (100mg, 31%)

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.28 (m, 2H), 1.48 (m, 2H), (2.68 m, 2H), 2.78 (m, 1H), (3.01 m, 1H), 4.27 (m, 1H), (4.41 m, 1H), 6.05 (d, 1H), (7.29 s, 1H), 8.60 (s, 1H), (9.25 m, 2H), 9.73 (s, 1H); M/z 450[MH]+.

Embodiment 90

S-6-methyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

With S-2-chloro-6-methyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (method 56) (250mg, 1.12mmol), the different  azoles of S-2-[3-(2-pyrazine base)-5-yl] pyrrolidines (method 55) (266mg, 1.23mmol) and N, the mixture of N-diisopropyl ethyl amine (0.22ml, 2.52mmol) in just-oneself pure (5ml) heating 6 hours under the microwave radiation in the sealing container under 150 ℃. Be dissolved in the methyl alcohol by the evaporation desolventizing and with residue, it is poured on the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out to elute any neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain title compound (319.6mg, 71%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.05 (m, 3H), 2.12 (s, 3H), (2.17 s, 3H), 2.36 (m, 1H), (3.69 m, 1H), 3.78 (m, 1H), (5.45 dd, 1H), 5.98 (s, 1H), (6.18 s, 1H), 6.71 (s, 1H), (8.68 m, 2H), 9.12 (s, 1H); M/z 404[MH]+.

Embodiment 91

S-6-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

With S-2,6-two chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine (method 57) (1.5g, 5.55mmol), the different  azoles of S-2-[3-(2-pyrazine base)-5-yl] pyrrolidines (method 55) (1.32g, 6.11mmol) and N, N-diisopropyl ethyl amine (0.92ml, 6.66mmol) just-mixture in the butanols (25ml) is 80 ℃ of lower heating 4 hours. By the evaporation desolventizing and residue carried out purifying with silica gel chromatograph, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 90: 10), obtain title compound (750mg, 30%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 0.63 (m, 2H), 0.85 (m, 2H), (1.82 m, 1H), 2.05 (m, 2H), 2.15 (m, 1H), 2.38 (m, 1H), 3.67 (m, 1H), (3.77 m, 1H), 5.43 (dd, 1H), 5.92 (s, 1H), 6.35 (s, 1H), 6.72 (s, 1H), (8.68 m, 2H), 9.12 (s, 1H); M/z 450[MH]+.

Embodiment 92

S-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl }-6-(the 2-methoxy ethyl is amino) pyrimidine

With S-6-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine (embodiment 91) (215mg, 0.48mmol) and 2-methoxy ethyl amine (4.0ml, 46.1mmol)) mixture under 150 ℃ the sealing container under the microwave radiation heating 2 hours. Carry out purifying by the evaporation desolventizing and with residue with the reversed-phase HPLC of use C18 post, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain title compound (78mg, 33%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 0.63 (m, 2H), 0.85 (m, 2H), 1.80 (m, 1H), 2.10 (m, 3H), 2.35 (m, 1H), (3.20 s, 3H), 3.35 (m, 4H), 3.65 (m, 1H), 3.77 (m, 1H), 5.43 (dd, 1H), (5.52 s, 1H), 5.80 (s, 1H), 6.72 (s, 1H), 8.68 (m, 2H), 9.12 (s, 1H); M/z 489 [MH]+.

Embodiment 93

S-6-methyl amino-and the different  azoles of 2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

With S-6-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-the base amino)-different  azoles of 2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl } mixture of THF solution (5.0ml) of pyrimidine (embodiment 91) (215mg, 0.48mmol) and 2M first amine heated 1.5 hours under the microwave radiation sealing in the container under 150 ℃. Carry out purifying by the evaporation desolventizing and with residue with the reversed-phase HPLC of use C18 post, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain title compound (100mg, 50%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 0.63 (m, 2H), 0.85 (m, 2H), (1.82 m, 1H), 2.10 (m, 3H), 2.36 (m, 1H), 2.68 (s, 3H), 3.67 (m, 1H), (3.75 m, 1H), 5.44 (dd, 1H), 5.60 (s, 1H), 5.80 (s, 1H), 6.72 (s, 1H), (8.68 m, 2H), 9.13 (s, 1H); M/z 445[MH]+.

Embodiment 94

S-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-6-first oxygen base-and the different  azoles of 2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

With the solution (3.0ml of 1.33M methyl alcohol sodium in anhydrous methyl alcohol, 2.25mmol) join S-6-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-the base amino)-different  azoles of 2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl also this reactant mixture was heated 1.5 hours under the microwave radiation sealing in the container under 120 ℃ in the mixture of pyrimidine (embodiment 91) (200mg, 0.45mmol) in anhydrous methyl alcohol (2.0ml). By the evaporation desolventizing and residue is carried out purifying water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) with the reversed-phase HPLC of use C18 post carry out wash-out. To comprise the fraction merging of product and make it pass through the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain title compound (87.5mg, 44%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 0.64 (m, 2H), 0.85 (m, 2H), (1.82 m, 1H), 2.10 (m, 3H), 2.40 (m, 1H), 3.71 (m, 4H), 3.78 (m, 1H), (5.45 dd, 1H), 5.72 (s, 1H), (5.89 s, 1H), 6.72 (s, 1H), (8.68 m, 2H), 9.15 (s, 1H); M/z 446[MH]+.

Embodiment 95

The different  azoles of 6-pyrrolidines-1-base-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine

With 6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine (embodiment 17) (250mg, 0.59mmol), pyrrolidines (0.5ml, 5.98mmol) and the mixture of anhydrous Isosorbide-5-Nitrae-two  alkane (5.0ml) in heating 1 hour under the microwave radiation in the sealing container under 100 ℃. Remove volatile materials and residue is carried out purifying water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) with the reversed-phase HPLC that uses C1 8 posts carry out wash-out by evaporation. To comprise the fraction merging of product and make it pass through the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. It is collected with the ether grinding and by filtering by the evaporation desolventizing and with residue, obtain title compound (145mg, 54%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.85 (s, 4H), 2.08 (m, 3H), (2.17 s, 3H), 2.35 (m, 1H), 3.25 (m, 2H) 3.33 (m, 2H), 3.69 (m, 1H), 3.80 (m, 1H), 5.40 (dd, 1H), 5.85 (s, 1H), (6.71 s, 1H), 7.38 (m, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.61 (d, 1H); M/z 458[MH]+.

Embodiment 96

S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With 2,6-two chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (method 29) (14.36g, 59mmol), the different  azoles of S-2-[3-(pyridine-2-yl)-5-yl] pyrrolidines (method 42) (12.69g, 59mmol) and N, the mixture of N-diisopropyl ethyl amine (14.5ml, 83mmol) in dimethylbenzene (380ml) was 80 ℃ of lower heating 2 days. By the evaporation desolventizing. With ether and water ground and passed through to filter the collection gained to this residue solid crude product, water washs it and it is carried out drying. From filtrate, evaporate ether and in this aqueous mixture, add DCM. By removing by filter insoluble material, the DCM layer is separated and it is carried out drying (MgSO₄). The solid crude product of separating at first is dissolved among the DCM and with it joins in this kind solution. By evaporating this solution is concentrated and it being left standstill 2 days. By filter collecting the solid of gained, with minimum DCM it to be washed, drying obtains the title compound (13.3g, 53%) of white crystal form.

NMR(DMSO)：2.08(m，2H)，2.18(m，4H)，3.74(m，2H)，5.47(d，1H)， 5.98(s，1H)，6.4(s，1H)，6.67(s，1H)，7.43(m，1H)，7.9(m，2H)，8.65(d，1H)， 8.88(br s，1H)，11.44(br s，1H)；m/z 423[MH]+。

Embodiment 97

S-6-(2,2,6,6-tetramethyl piperidine-4-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With the different  azoles of S-6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine (embodiment 96) (200mg, 0.47mmol), 4-amino-2,2,6, the mixture of 6-tetramethyl piperidine (0.4ml, 2.33mmol) and anhydrous Isosorbide-5-Nitrae-two  alkane (5.0ml) was heating 4 hours under the microwave radiation in the sealing container under 150 ℃. Remove volatile materials and residue is carried out purifying with the reversed-phase HPLC that uses the C18 post by evaporation, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain title compound (122mg, 47%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.25-1.45 (m, 12H), 2.01 (m, 3H), (2.17 s, 3H), 2.35 (m, 1H), 3.65 (m, 1H), 3.75 (m, 1H), 4.23 (m, 1H), (5.40 dd, 1H), 5.89 (s, 1H), 6.60 (s, 1H), 7.40 (m, 1H), 7.87 (t, 1H), (7.93 d, 1H), 8.63 (d, 1H); M/z 543[MH]+.

Embodiment 98

S-6-iodo-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With the S-6-chloro-4-in hydroiodic acid (25ml) (5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) (2.0g, 4.7mmol), sodium iodide (3.9g, 26mmol) is 50 ℃ of lower heating 3 days. Make the cooling of this reactant mixture and it is poured on ice, alkalize and extract with DCM with 20% sodium hydrate aqueous solution. To extract thing and merge, dry (MgSO₄) and solvent evaporated, obtain title compound (2g, 83 %).

NMR(DMSO)：1.9-2.1(m，3H)，2.16(s，3H)，2.28-2.40(m，1H)，3.45- 3.60(m，1H)，3.68-3.80(m，1H)，5.35(d，1H)，5.75(s，1H)，5.84(s，1H)，6.75(s， 1H)，7.45(dd，1H)，7.86-8.0(m，2H)，8.63(d，1H)，9.52(s，1H)；m/z 515 [MH]+

Embodiment 99

S-E-6-[3-(uncle-butoxy carbonyl is amino) third-1-alkene-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With 3-(Uncle-Butoxy carbonyl is amino) third-1-alkene-1-ylboronic acid [2,3-dihydroxy-2, the 3-dimethylbutane] ester (method 58) (938mg, 3.5mmol) join S-6-iodo-4-(5-methyl isophthalic acid H-pyrazoles-3-the base amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl pyrrolidines-1-yl] pyrimidine (embodiment 98) (300mg, 0.6mmol), in tetrakis triphenylphosphine palladium (O) (27mg, 0.02mmol) and the mixture of 2M aqueous sodium carbonate (1.5ml) in toluene (8ml) and ethanol (4ml) and with this mixture in heating 15 minutes under the microwave radiation in the sealing container under 140 ℃. This mixture is extracted and will extract thing merge with EtOAc, water washs it and it is carried out drying (MgSO₄). By the evaporation desolventizing and with silica gel column chromatography residue is carried out purifying, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 96: 4), obtain title compound (188mg, 60%).

NMR(DMSO)：1.45(s，9H)，2.05-2.18(m，2H)，2.20(s，3H)，2.35- 2.46(m，1H)，2.95-3.0(m，2H)，3.74-3.9(m，4H)，5.5(d，1H)，6.10(s，1H)， 6.22(d，1H)，6，30(s，1H)，6.58-6.71(m，3H)，7.45(dd，1H)，7.90-8.0(dd，2H)， 8.65(d，1H)，8.90(s，1H)，11.55(s，1H)；m/z 544[MH]+

Embodiment 100 and 101

Embodiment 100 and 101 uses the method similar to embodiment 99 described methods to be prepared.

Embodiment 100

S-6-vinyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-iodo-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 98) and vinyl boric acid [2,3-dihydroxy-2, the 3-dimethylbutane] ester. This product is ground with ether/DCM/ hexane, obtain title compound (82mg, 47%).

NMR(DMSO)：2.02-2.12(m，3H)，2.21(s，3H)，2.35-2.40(m，1H)，3.69- 3.80(m，2H)，5.40(d，1H)，5.49(dd，1H)，6.08(s，1H)，6.15(d，1H)，6.29(s，1H)， 6.40-6.50(m，1H)，6.66(s，1H)，7.44(dd，1H)，7.95(m，2H)，8.61(s，1H)， 8.90(s，1H)，11.50(s，1H)；m/z 415[MH]+

Embodiment 101

S-E-6-(3-hydroxyl third-1-alkene-1-yl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-iodo-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 98) and 3-second acyloxy third-1-alkene-1-ylboronic acid [2,3-dihydroxy-2, the 3-dimethylbutane] ester. With the reversed-phase HPLC that uses the C18 post product is carried out purifying, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out, obtains title compound (19mg, 7%).

NMR(DMSO)：2.05-2.16(m，3H)，2.19(s，3H)，2.34-2.42(m，1H)，3.70- 3.85(m，2H)，4.16(dd，2H)，4.50(t，1H)，5.49(d，1H)，6.08(s，1H)，6.25- 6.32(m，2H)，6.69(s，1H)，6.75-6.82(m，1H)，7.45(dd，1H)，7.88-7.96(m，2H)， 8.67(d，1H)，8.88(s，1H)，11.52(s，1H)；m/z 445[MH]+。

Embodiment 102

S-6-[3-(uncle-butoxy carbonyl is amino) third-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[the different  azoles of 2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With S-E-6-[3-(Uncle-Butoxy carbonyl is amino) third-1-alkene-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 99) (84mg, 0.15mmol), p-toluene sulfonyl hydrazide (259mg, 1.4mmol) heat to refluxing and in 2 hours, also this mixture being heated 18 hours under backflow to wherein adding the sodium acetate (240mg, 2.9mmol) that is arranged in water (5ml) at the solution of dimethyl ethyl ether (5ml). This mixture is diluted with EtOAc, and then water uses the salt water washing, dry (MgSO₄) and by the evaporation desolventizing. Residue is dissolved in the methyl alcohol and with it is poured on SCX2 (10g) ion exchange column. Fall impurity with methanol-eluted fractions, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain title compound (80mg, 95%).

NMR(DMSO)：1.38(s，9H)，1.68-1.78(m，2H)，2.04-2.18(m，3H)， 2.20(s，3H)，2.30-2.40(m，3H)，3.65-3.80(m，2H)，5.45(d，1H)，6.02(s，1H)， 6.20(s，1H)，6.28(s，1H)，6.68(s，1H)，7.45(dd，1H)，7.88-7.98(m，2H)，8.68(d， 1H)，8.76(s，1H)，11.5(s，1H)；m/z 546[MH]+。

Embodiment 103

S-6-[3-aminopropan-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With the S-6-[3-in DCM (Uncle-Butoxy carbonyl is amino) third-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 102) (80mg, 0.15mmol) is cooled to about 0 to 5 ℃. To wherein adding three fluorine acetic acid (TFA) (1ml) and this mixture being stirred 1 hour under 5 ℃, then it was stirred 1.5 hours at ambient temperature. Remove volatile materials and residue is dissolved in the methyl alcohol by evaporation, it is poured on SCX2 (10g) ion exchange column. Fall impurity with methanol-eluted fractions, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain title compound (40mg, 63%).

NMR(DMSO)：1.62-1.70(m，2H)，2.04-2.15(m，2H)，2.19(s，3H)，2.32- 2.48(m，3H)，2.50-2.60(m，2H)，3.68-3.80(m，2H)，5.49(d，1H)，6.05(s，1H)， 6.20(s，1H)，6.65(s，1H)，7.45(dd，1H)，7.85-7.95(m，2H)，8.66(d，1H)，8.73(s， 1H)；m/z 446[MH]+。

Embodiment 104

S-E-6-[3-aminopropan-1-alkene-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With the S-E-6-[3-in DCM (5ml) (Uncle-Butoxy carbonyl is amino) third-1-alkene-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 99) (50mg, 0.09mmol) is cooled to 5 ℃. To wherein adding TFA (1ml), this mixture 5 ℃ of lower stirrings 1 hour, was then stirred 4 hours at ambient temperature. Remove volatile materials by evaporation, residue is dissolved in the methyl alcohol, and it is poured on SCX2 (10g) ion exchange column. Fall impurity with methanol-eluted fractions, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. Grind by the evaporation desolventizing and with ether, obtain title compound (25mg, 63%).

NMR(DMSO)：2.07-2.12(m，3H)，2.20(s，3H)，2.32-2.44(m，1H)， 3.35(d，2H)，3.70-3.85(m，2H)，5.48(d，1H)，6.05(s，1H)，6.20-6.28(m，2H)， 6.68(s，1H)，6.75-6.82(m，1H)，7.45(dd，1H)，7.89-7.95(m，2H)，8.65(d，1H)， 8.85(s，1H)，11.50(s，1H)；m/z 444[MH]+。

Embodiment 105

S-6-[3-methyl aminopropan-1-alkynes-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With S-6-iodo-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 98) (500mg, 0.97mmol), 3-methyl aminopropan-1-alkynes (134mg, 1.9mmol) two (triphenyl phosphine) chlorination palladium (II) (27mg, 0.04mmol), cuprous iodide (I) (4mg, 0.02mmol), the mixture of triethylamine (0.7ml, 5mmol) in acetonitrile (12ml) under 75 ℃ the sealing container under the microwave radiation heating 15 minutes. This reactant mixture is extracted with EtOAc, will extract thing merging and water it is washed, dry (MgSO₄) and by the evaporation desolventizing. Residue is carried out purifying with silica gel column chromatography, with DCM/ methyl alcohol/ammoniacal liquor (100: 0: 0 to polarity increase to 85: 15: 1) wash-out, obtain title compound (219mg, 50%).

NMR(DMSO)：2.00-2.12(m，3H)，2.20(s，3H)，2.32(m，2H)，2.35(s， 3H)，3.5(s，2H)，3.65-3.8(m，2H)，5.46(d，1H)，6.02(s，1H)，6.45(s，1H)， 6.65(s，1H)，7.45(dd，1H)，7.87-7.98(m，2H)，8.67(d，1H)，9.05(s，1H)，11.6(s， 1H)；m/z 456[MH]+。

Embodiment 106 to 111

Embodiment 106 to 111 uses the method similar to embodiment 105 described methods to be prepared.

Embodiment 106

S-6-[3-methoxy propyl-1-alkynes-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-iodo-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 98) and 3-methoxy propyl-1-alkynes. With the reversed-phase HPLC that uses the C18 post product is carried out purifying, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. Receipts rate: 70mg, 53%.

NMR(DMSO)：2.0-2.18(m，3H)，2.19(s，3H)，2.30-2.42(m，2H)，3.33(s， 3H)，3.63-3.70(m，1H)，3.73-3.80(m，1H)，4.30(s，3H)，5.45(d，1H)，6.03(s， 1H)，6.45(s，1H)，6.67(s，1H)，7.45(dd，1H)，7.88-7.96(m，2H)，8.66(d，1H)； m/z 457[MH]+。

Embodiment 107

S-6-[3-hydroxyl third-1-alkynes-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-iodo-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 98) and third-2-alkynes-1-alcohol. With the reversed-phase HPLC that uses the C18 post product is carried out purifying, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. Receipts rate: 50mg, 30%.

NMR(DMSO)：2.01-2.15(m，4H)，2.18(s，3H)，2.30-2.40(m，1H)，3.62- 3.70(m，1H)，3.72-3.8(m，1H)，4.25(s，3H)，5.04(t，1H)，6.04(s，3H)，6.45(s， 1H)，6.65(s，1H)，7.45(m，1H)，7.88-7.97(m，2H)，8.65(d，1H)，9.08(s，1H)， 11.55(s，1H)；m/z 443[MH]+。

Embodiment 108

S-6-[2-(trimethyl silyl) acetylene base]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-iodo-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 98) and trimethyl silyl acetylene (trimethylsilyacetylene). Receipts rate: 225mg, 50%.

NMR(DMSO)：0.25(s，9H)，2.02-2.19(m，3H)，2.20(s，3H)，2.30- 2.42(m，1H)，3.62-3.80(m，2H)，5.45(d，1H)，6.04(s，1H)，6.45(s，1H)，6.69(s， 1H)，7.48(dd，1H)，7.85-7.98(m，2H)，8.65(s，1H)，9.05(s，1H)，11.60(s，1H)； m/z 485[MH]+。

Embodiment 109

S-6-[3-(N-methyl acetyl is amino) third-1-alkynes-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[the different  azoles of 2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-iodo-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 98) and 3-(N-methyl acetyl is amino) third-1-alkynes (method 59). Receipts rate: 50mg, 26%.

NMR(DMSO)：2.02-2.15(m，5H)，2.20(s，3H)，2.31-2.40(m，1H)， 2.93(s，3H)，2.97-3.01(m，1H)，3.64-3.71(m，1H)，3.73-3.80(m，1H)，4.38(s， 2H)，5.45(d，1H)，6.04(s，1H)，6.45(s，1H)，6.65(s，1H)，7.45(dd，1H)，7.88- 7.96(m，2H)，8.66(d，1H)，9.08(s，1H)；m/z 498[MH]+。

Embodiment 110

S-6-[3-(dimethylamino) third-1-alkynes-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-iodo-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 98) and 3-(dimethylamino) third-1-alkynes. With the reversed-phase HPLC that uses C1 8 posts product is carried out purifying, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. Receipts rate: 32mg, 18%.

NMR(DMSO)：2.01-2.15(m，3H)，2.19(s，3H)，2.28(s，6H)，2.32- 2.42(m，1H)，3.42(s，2H)，3.64-3.71(m，1H)，3.72-3.80(m，1H)，5.45(d，1H)， 6.05(s，1H)，6.45(s，1H)，6.68(s，1H)，7.45(d，1H)，7.86-7.95(m，2H)，8.66(d， 1H)，9.05(s，1H)，11.55(s，1H)。

Embodiment 111

S-6-[3-acetyl aminopropan-1-alkynes-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-iodo-4-(5-methyl isophthalic acid H-pyrazoles-3-the base amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 98) and 3-acetyl aminopropan-1-alkynes (using the method similar to method 59 to make). Receipts rate: 44mg, 24%.

NMR(DMSO)：1.88(s，3H)，2.02-2.17(m，3H)，2.20(s，3H)，2.30- 2.42(m，1H)，3.62-3.70(m，1H)，3.72-3.80(m，1H)，4.1(d，2H)，5.45(d，1H)， 6.05(s，1H)，6.45(s，1H)，6.65(s，1H)，7.45(dd，1H)，7.88-7.96(m，2H)，8.05(s， 1H)，8.75(d，1H)，9.08(s，1H)，11.55(s，1H)；m/z 484[MH]+。

Embodiment 112

S-6-[2-(ethoxy carbonyl) ethyl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With S-6-iodo-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 98) (70mg, 0.14mmol), bromination 3-(ethoxy carbonyl) ethyl zinc (0.82ml 1M diethyl ether solution), two (triphenyl phosphine) chlorination palladiums (II) (7mg, 0.01mmol) THF (2ml) and dimethylacetylamide (DMA) (1ml) in heating 30 minutes under the microwave radiation in the sealing container under 70 ℃. This mixture is diluted with EtOAc, wash with water, dry (MgSO₄) and remove volatile materials by evaporation. Residue is carried out purifying with silica gel chromatograph, carry out wash-out with methyl alcohol/DCM (3: 97), and then further carry out purifying with the reversed-phase HPLC that uses the C18 post, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out, obtain title compound (20mg, 30%).

NMR(DMSO)：1.12(t，3H)，2.0-2.2(m，3H)，2.19(s，3H)，2.30-2.40(m， 1H)，2.55-2.60(m，1H)，2.66-2.70(m，3H)，3.64-3.80(m，2H)，4.05(q，2H)， 5.44(d，1H)，6.0(s，1H)，6.16(s，1H)，6.65(s，1H)，7.45(dd，1H)，7.87-7.95(m， 2H)，8.65(s，1H)；m/z 489[MH]+。

Embodiment 113

S-E-6-[2-(methoxycarbonyl) ethene-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With S-6-iodo-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 98) (200mg, 0.39mmol), methyl acrylate (0.336ml), 1,1 '-two (diphenylphosphino) ferrocene chlorination palladium (II) (64mg, 0.08mmol), the mixture of tetrabutylammonium iodide (288mg, 0.78mmol) in DMF (2.5ml), water (0.5ml) and triethylamine (0.5ml) under 130 ℃ the sealing container under the microwave radiation heating 15 minutes. With this mixture ethyl acetate extraction, will extract thing merging and water it will be washed, dry (Na₂SO ₄) and remove volatile materials by evaporation. With the reversed-phase HPLC that uses the C18 post residue is carried out purifying, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out, obtains title compound (50mg, 28%).

NMR(DMSO)：2.05-2.18(m，3H)，2.20(s，3H)，2.38-2.45(m，1H)， 3.73(s，3H)，3.75-3.89(m，2H)，5.48(d，1H)，6.10(s，1H)，6.48(s，1H)，6.70(s， 1H)，6.80(d，1H)，7.23(d，1H)，7.48(dd，1H)，7.88-7.98(m，2H)，8.65(d，1H)， 9.37(s，1H)，11.6(s，1H)；m/z 473[MH]+。

Embodiment 114

S-6-acetylene base-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With potash (17mg, 0.12mmol) join S-6-[2-(trimethyl silyl) acetylene base]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] also this mixture was at room temperature stirred 18 hours in the solution of pyrimidine (embodiment 108) (50mg, 0.1mmol) in methyl alcohol (1ml). Water dilutes this mixture and with EtOAc it is extracted. To extract thing and merge, use the salt water washing, dry (Na₂SO ₄) and by the evaporation desolventizing. This residue is ground and by filtering it is collected with ether, obtain title compound (21mg, 50%).

NMR(DMSO)：2.01-2.15(m，3H)，2.20(s，3H)，2.30-2.45(m，1H)，3.65- 3.80(m，2H)，3.94(s，1H)，5.45(d，1H)，6.05(s，1H)，6.50(s，1H)，6.69(s，1H)， 7.48(dd，1H)，7.85-7.98(m，2H)，8.68(d，1H)，9.10(s，1H)，11.55(s，1H)； m/z 413[MH]+。

Embodiment 115

6-methoxy-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With the different  azoles of 4-hydroxyl-6-methoxy-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (method 34) and 3-amino-5-cyclopropyl-1H-pyrazoles (method 7 of WO 03/048133) process as described in the embodiment 26, obtain title compound (245mg, 48%).

NMR(DMSO)：0.68(m，2H)，0.84-0.88(m，2H)，1.85(m，1H)，2.02- 2.10(m，2H)，2.12-2.19(m，1H)，2.31-2.42(m，1H)，3.36(s，3H)，3.66-3.79(m， 2H)，4.17(q，2H)，5.46(d，1H)，6.0(s，1H)，6.38(s，1H)，6.65(s，1H)，7.44(dd， 1H)，7.89-7.95(m，2H)，8.65(d，1H)，8.94(s，1H)；m/z 459[MH]+。

Embodiment 116

S-6-methoxy-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Title compound be by with the chirality HPLC of chiralpak AD post to (embodiment 115) that this racemic compound separates to be prepared, carry out wash-out with methanol/ethanol (85: 15).

Embodiment 117

S-6-methoxy-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Title compound be by with the chirality HPLC of chiralpak AD post to (embodiment 30) that this racemic compound separates to be prepared, carry out wash-out with methanol/ethanol (85: 15).

Embodiment 118

S-6-[3-aminopropan-1-alkynes-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With hydration hydrazine (24 μ l, 0.49mmol) join S-6-[3-(N-phthalimido) third-1-alkynes of being arranged in THF (1ml) and ethanol (0.1ml)-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[the different  azoles of 2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (method 60) (50mg, 0.09mmol) in and this mixture was at room temperature stirred 1 hour, then with it 60 ℃ of lower heating 30 minutes. This mixture is extracted with EtOAc, will extract thing and merge, wash with water, dry (MgSO₄) and by the evaporation desolventizing. With the reversed-phase HPLC that uses the C18 post residue is carried out purifying, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. The fraction that will comprise product extracts dry (MgSO with the sodium bicarbonate aqueous solution neutralization and with DCM₄) and by the evaporation desolventizing, obtain title compound (15mg, 39%).

NMR(DMSO)：1.25-1.30(m，2H)，1.52-1.65(m，1H)，2.04-2.15(m，3H)， 2.20(s，3H)，3.55(s，2H)，3.65-3.80(m，2H)，5.45(d，1H)，6.05(s，1H)，6.42(s， 1H)，6.65(s，1H)，7.44(dd，1H)，7.85-7.95(m，2H)，8.65(s，1H)，9.0(s，1H)， 11.50(s，1H)；m/z 442[MH]+。

Embodiment 119

S-6-[2-(N-methyl carbamoyl) ethyl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With S-6-[2-(ethoxy carbonyl) ethyl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 112) (80mg, 0.16mmol), first amine (3ml 2M methanol solution) and 1, the mixture of 8-diazonium base two ring [5.4.0] 11 carbon-7-alkene (DBU) (0.1ml, 0.67mmol) was heating 1.5 hours under the microwave radiation in the sealing container under 105 ℃. This mixture is extracted with EtOAc, will extract thing and merge, wash with water, dry (MgSO₄) and by the evaporation desolventizing. With the reversed-phase HPLC that uses the C18 post residue is carried out purifying, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. The fraction that will comprise product extracts dry (MgSO with the sodium bicarbonate aqueous solution neutralization and with DCM₄) and by the evaporation desolventizing, obtain title compound (25mg, 30%).

NMR(DMSO)：2.02-2.19(m，2H)，2.19(s，3H)，2.32-2.44(m，3H)， 2.58(s，3H)，2.59-2.69(m，2H)，3.68-3.80(m，2H)，5.45(d，1H)，6.04(s，1H)， 6.20(s，1H)，6.68(s，1H)，7.30(s，1H)，7.45(dd，1H)，7.88-7.98(m，2H)，8.68(d， 1H)，8.78(s，1H)，11.5(s，1H)；m/z 474[MH]+。

Embodiment 120

S-4-(5-ethyl-1H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine

With 4-(5-ethyl-1H-pyrazoles-3-base is amino)-2-chlorine pyrimidine (method 65) (200mg, 0.9mmol), S-2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines (method 64) (300mg, 1.2mmol) and diisopropyl ethyl amine (0.22ml, 1.4mmol) at the mixture of oneself alcohol in (10ml) 150 ℃ of lower heating 24 hours. Make residue cooling and wash with EtOAc dilution and water. Should the dry (MgSO of organic solution₄) and by the evaporation desolventizing. Residue is carried out purifying with silica gel chromatograph, carry out wash-out with EtOAc/ hexane/methanol (50: 50: 0 to polarity increase to 98: 0: 2), obtain title compound (212mg, 55%).

NMR(DMSO)：1.19(t，3H)，2.06-2.19(m，3H)，2.30-2.40(m，1H)， 2.56(q，2H)，3.66-3.80(m，2H)，3.94(s，3H)，5.45(d，1H)，6.12(s，1H)，6.30(s， 1H)，6.59(s，1H)，7.08(dd，1H)，7.89(d，1H)，8.10(d，1H)，8.26(d，1H)，8.92(s， 1H)，11.55(s，1H)；m/z 433[MH]+。

Embodiment 121 and 122

Embodiment 121 and 122 uses the method similar to the method for embodiment 120 to be prepared.

Embodiment 121

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine

Initial material: 2-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (method 26) and S-2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines (method 64). Receipts rate: 147mg, 49 %.

NMR(DMSO)：2.05-2.18(m，3H)，2.20(s，3H)，2.32-2.40(m，1H)，3.66- 3.78(m，2H)，3.94(s，3H)，5.45(d，1H)，6.08(s，1H)，6.30(s，1H)，6.59(s，1H)， 7.09(dd，1H)，7.88(d，1H)，8.09(d，1H)，8.28(d，1H)，8.85(s，1H)；m/z 419 [MH]+。

Embodiment 122

S-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine

Initial material: 2-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine (method 28) and S-2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines (method 64). Receipts rate: 143mg, 51 %.

NMR(DMSO)：0.64-0.69(m，2H)，0.84-0.90(m，2H)，1.80-1.90(m，1H)， 2.02-2.19(m，3H)，2.30-2.41(m，1H)，3.67-3.80(m，2H)，3.96(s，3H)，5.48(d， 1H)，6.02(s，1H)，6.30(s，1H)，6.59(s，1H)，7.09(dd，1H)，7.89(d，1H)，8.10(d， 1H)，8.29(d，1H)，8.90(s，1H)，11.60(s，1H)；m/z 445[MH]+。

Embodiment 123

The different  azoles of 6-(uncle N--butoxy carbonyl) amino-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine-6-base formic acid (method 43) (300mg; 0.69mmol) in uncle-butanols (30ml), stir and to wherein adding diphenyl phosphoryl azide (286mg; 0.97mmol); then to wherein adding triethylamine (140 μ l, 0.99mmol) and this mixture is heated under 90 ℃ and stirring 16 hours. Carry out purifying with this mixture evaporation and concentration and with residue with the reversed-phase HPLC that uses the C18 post, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. Make the fraction that the comprises product 20g SCX-2 post of flowing through, carry out wash-out with methyl alcohol, then with 2N methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain the title compound (40mg, 12%) of white powder form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.45 (s, 9H), 2.00-2.15 (m, 3H), (2.15 s, 3H), 2.35 (m, 1H), (3.60-3.80 m, 2H), 5.42 (d, 1H), (6.00 s, 1H), 6.68 (s, 1H), (7.40 t, 1H), 7.85 (t, 1H), (7.95 d, 1H), 8.65 (d, 1H); M/z 504 [MH]+.

Embodiment 124

6-(4-(uncle N--butoxy carbonyl is amino) piperidines-1-the yl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With the different  azoles of 6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine (embodiment 17) (150mg, 0.35mmol) and 4-(N-Uncle-Butoxy carbonyl amino) mixture of piperidines (700mg, 3.5mmol) joins in the two  alkane (4ml) and with it and heated 60 minutes under 150 ℃ under the microwave radiation in the sealing container. This reactant mixture crude product is carried out purifying with the reversed-phase HPLC that uses the C18 post, and water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. Make this fraction that comprises product SCX-2 post of flowing through, carry out wash-out with methyl alcohol, then use 2N methyl alcohol ammoniacal liquor releasing product. By the evaporation desolventizing, obtain the title compound (134mg, 64%) of white solid form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.20-1.30 (m, 1H), 1.35 (s, 9H), 1.7 (m, 2H), 2.10 (m, 3H), 2.15 (s, 3H), 2.35 (m, 1H), 2.90 (t, 2H), 3.45 (m, 1H), 3.67 (m, 1H), 3.75 (m, 1H), 4.00 (m, 2H), (5.34 d, 1H), 6.65 (s, 1H), 7.40 (m, 1H), (7.85 t, 1H), 7.90 (d, 1H), 8.60 (d, 1H); M/z 587[MH]+.

Embodiment 124a

The different  azoles of 6-(4-amino piperidine-1-yl) 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With 6-(4-(N-Uncle-Butoxy carbonyl is amino) piperidines-1-yl)-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 124) (120mg, 0.20mmol) in DCM (10ml), stir, to wherein adding three fluorine acetic acid (2ml) and this mixture at room temperature being stirred 3 hours. Be dissolved in methyl alcohol (10ml) with this mixture evaporation and concentration and with residue and make its 20g SCX-2 ion exchange column of flowing through, use methanol-eluted fractions impurity, then with 2M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain the title compound (79mg, 81%) of cream-colored powder type.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.35 (m, 1H), 1.45 (m, 1H), 1.90 (m, 2H), 2.00-2.10 (m, 3H), 2.15 (s, 3H), 2.35 (m, 1H), 2.82 (m, 2H), 3.20 (m, 1H), 3.65-3.80 (m, 2H), 4.10 (t, 2H), 5.35 (d, 1H), (6.3 s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.95 (d, 1H), 8.60 (d, 1H); M/z 487[MH]+.

Embodiment 125 to 132

Embodiment 125 to 132 uses the method similar to the method for embodiment 124 to be prepared.

Embodiment 125

The different  azoles of 6-piperazine-1-base-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine

Initial material: the different  azoles of 6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 17) and piperazine. Receipts rate: 204mg, 73%, the white powder form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.00-2.15 (m, 3H), 2.20 (s, 3H), (2.35 m, 1H), 3.00-3.15 (m, 5H), 3.60-3.80 (m, 6H), 5.40 (d, 1H), 5.50 (s, 1H), (6.00 s, 1H), 6.70 (s, 1H), (7.40 t, 1H), 7.85 (t, 1H), (7.95 d, 1H), 8.65 (d, 1H); M/z 473[MH]+.

Embodiment 126

S-6-{4-[2-(2-hydroxyl base oxethyl) ethyl] piperazine-1-yl }-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Initial material: the different  azoles of S-6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 96) and 2-[2-(hydroxyl base oxethyl) ethyl] piperazine. Receipts rate: 142mg, 79%, the faint yellow solid form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.00-2.15 (m, 3H), 2.15 (s, 3H), 2.35 (m, 1H), 2.70-2.90 (m, 6H), 3.45 (m, 2H), 3.35 (m, 6H), 3.65 (t, 2H), 3.68 (m, 1H), 3.75 (m, 1H), 5.35 (d, 1H), 5.95 (s, 1H), (6.65 s, 1H), 7.38 (m, 1H), 7.85 (t, 1H), 7.95 (d, 1H), 8.65 (d, 1H); M/z 561[MH]+.

Embodiment 127

S-6-(1-formyl base-piperazine-4-the yl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Initial material: the different  azoles of S-6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 96) and 1-formyl piperazine. Receipts rate: 55mg, 31%, the faint yellow solid form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.00-2.15 (m, 3H), 2.15 (s, 3H), 2.35 (m, 1H), 3.30-3.50 (m, 8H), 3.70 (m, 1H), (3.77 m, 1H), 5.37 (d, 1H), 5.55 (s, 1H), 6.67 (s, 1H), 7.38 (t, 1H), (7.33 t, 1H), 7.83 (t, 1H), 7.90 (d, 1H), 8.00 (s, 1H), 8.60 (d, 1H); M/z 501[MH]+.

Also the HPLC purifies and separates by embodiment 127 goes out embodiment 128:-

Embodiment 128

The different  azoles of S-6-piperazine-1-base-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine

Receipts rate: 64mg, 38%, the faint yellow solid form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.00-2.15 (m, 3H), 2.15 (s, 3H), (2.35 m, 1H), 3.05 (m, 4H), (3.60 m, 4H), 3.65-3.80 (m, 2H), (5.35 d, 1H), 5.95 (s, 1H), (7.40 m, 1H), 7.85 (t, 1H), (7.93 d, 1H), 8.60 (d, 1H); M/z 473 [MH]+.

Embodiment 129

S-6-(4-isopropyl piperazine-1 the base)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Initial material: the different  azoles of S-6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 96) and 1-isopropyl piperazine. Receipts rate: 94mg, 52%, cream-colored powder type.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.05 (t, 6H), 2.00-2.15 (m, 3H), 2.20 (s, 3H), 2.35 (m, 1H), 2.65 (m, 4H), (3.00 m, 1H), 3.50 (m, 4H), 3.60-3.80 (m, 2H), 5.45 (d, 1H), 5.95 (s, 1H), (6.65 s, 1H), 7.40 (t, 1H), 7.85 (t, 1H), 8.90 (d, 1H), 8.60 (d, 1H); M/z 515[MH]+.

Embodiment 130

S-6-[(4-(2-hydroxyl ethyl) piperazine-1-yl)]-and the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Initial material: the different  azoles of S-6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 96) and 1-(2-hydroxyl ethyl) piperazine. Receipts rate: 110mg, 61%, cream-colored powder type.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.00-2.15 (m, 3H), 2.20 (s, 3H), 2.35 (m, 1H), 2.80-2.95 (m, 6H), 3.55 (t, 2H), (3.65 t, 2H), 3.65-3.80 (m, 2H), 5.45 (d, 1H), 5.55 (s, 1H), 5.95 (s, 1H), (6.65 s, 1H), 7.50 (t, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.60 (d, 1H); M/z 517[MH]+.

Embodiment 131

S-6-[(3R)-3-hydroxyl pyrrolidines-1-yl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Initial material: the different  azoles of S-6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base amino) pyrimidine (embodiment 96) and (3R)-3-hydroxyl pyrrolidines. Receipts rate: 92mg, 55%, the purple powder type.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃) 1.75 (m, 1H), 1.95 (m, 1H), 2.00-2.15 (m, 3H), 2.20 (s, 3H), 2.35 (m, 1H), 3.25-3.45 (m, 4H), 3.65 (m, 1H), 3.75 (m, 1H), 4.30 (m, 1H), 5.40 (d, 1H), 5.55 (s, 1H), (6.70 s, 1H), 7.35 (t, 1H), 7.80 (t, 1H), 7.90 (d, 1H), 8.60 (d, 1H); M/z 474[MH]+.

Embodiment 132

S-6-[(3R)-3-dimethylamino-pyrrolidines-1-yl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Initial material: the different  azoles of S-6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base amino) pyrimidine (embodiment 96) and (3R)-3-(dimethylamino)-pyrrolidines. Receipts rate: 128mg, 73%, the brown powder form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.75 (m, 1H), 2.00-2.15 (m, 4H), 2.18 (s, 3H), 2.22 (s, 6H), 2.35 (m, 1H), 2.77 (m, 1H), 3.15 (t, 1H), 3.27 (q, 1H), 3.40-3.50 (m, 2H), 3.75 (m, 2H), 5.40 (d, 1H), (5.50 s, 1H), 5.95 (s, 1H), 6.20 (s, 1H), (7.45 t, 1H), 7.90-8.00 (m, 1H), 8.65 (d, 1H); M/z 501[MH]+.

Embodiment 133

S-6-(the 4-THP trtrahydropyranyl the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With the different  azoles of S-6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl-4-(5-methyl-1H-pyrazoles-3-base amino) pyrimidine (embodiment 96) (150mg, 0.35mmol) join in the 4-amino tetrahydro pyran (4ml) and with it in heating 1 hour under the microwave radiation in the sealing container under 150 ℃. This reactant mixture crude product is carried out purifying with the reversed-phase HPLC that uses the C18 post, and water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. Make this fraction that comprises product 20g SCX-2 post of flowing through, use methanol-eluted fractions, then with 2N methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain the title compound (52mg, 30 %) of filbert powder type.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.15 (m, 1H), 1.45 (m, 1H), 1.55 (m, 1H), 1.80 (m, 1H), 2.00-2.10 (m, 3H) 2.15 (s, 3H), (2.35 m, 1H), 3.25 (t, 1H), (3.35 m, 1H), 3.65 (m, 2H), (3.70-3.85 m, 3H), 5.35 (d, 1H), (5.85 s, 1H), 6.68 (s, 1H), 5.40 (t, 1H), (7.85 t, 1H), 7.90 (d, 1H), 8.60 (d, 1H); M/z 488 [MH]+.

Embodiment 134 to 139

Embodiment 134 to 139 uses the method similar to embodiment 133 described methods to be prepared.

Embodiment 134

The different  azoles of S-6-morpholine generation-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Initial material: the different  azoles of S-6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 96) and morpholine. Receipts rate: 119mg, 71%, rose pink powder type.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.00-2.15 (m, 3H), 2.20 (s, 3H), (2.35 m, 1H), 3.35 (m, 4H), 3.55 (m, 4H), 3.60-3.80 (m, 2H), 5.37 (d, 1H), (5.55 s, 1H), 6.65 (s, 1H), (7.40 m, 1H), 8.85 (t, 1H), (8.90 d, 1H), 8.60 (d, 1H); M/z 474[MH]+.

Embodiment 135

The different  azoles of S-6-(2-methoxy ethyl) amino-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Initial material: the different  azoles of S-6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 96) and 2-methoxy ethyl amine. Receipts rate: 85mg, 53%, the pale yellow powder form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.00-2.15 (m, 3H), 2.20 (s, 3H), (2.35 m, 1H), 3.20 (s, 3H), (3.20-3.40 m, 4H), 3.60-3.80 (m, 2H), (5.40 d, 1H), 6.68 (s, 1H), (7.40 dd, 1H), 7.85 (t, 1H), (7.90 d, 1H), 8.60 (d, 1H); M/z 462[MH]+.

Embodiment 136

The S-6-[(N-2-methoxy ethyl)-the N-methyl is amino]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Initial material: the different  azoles of S-6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 96) and N-(2-methoxy ethyl)-first amine. receipts rate: 110mg, 66%, cream-colored powder type.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.00-2.15 (m, 3H), 2.20 (s, 3H), 2.35 (m, 1H), 2.60-2.75 (m, 5H), 3.45 (t, 3H), (3.55 t, 2H), 3.60-3.80 (m, 2H), 5.45 (d, 1H), 5.60 (s, 1H), 5.95 (s, 1H), (6.65 s, 1H), 7.40 (t, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.60 (d, 1H); M/z 476[MH]+.

Embodiment 137

S-6-((2R)-2-hydroxyl third-1-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Initial material: the different  azoles of S-6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base amino) pyrimidine (embodiment 96) and (2R)-basic amine of 2-hydroxyl third-1-. receipts rate: 52mg, 32%, the brown powder form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.10 (d, 3H), 2.00-2.15 (m, 3H), (2.20 s, 3H), 2.35 (m, 1H), 3.25-3.40 (m, 2H), 3.65 (m, 1H), 3.65-3.85 (m, 2H), (5.40 d, 1H), 5.55 (s, 1H), 6.70 (s, 1H), 7.40 (t, 1H), 8.45 (t, 1H), (7.90 d, 1H), 8.60 (d, 1H); M/z 462[MH]+.

Embodiment 138

S-6-[N-(2-hydroxyl ethyl)-N-ethylamino]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Initial material: the different  azoles of S-6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 96) and N-(2-hydroxyl ethyl) ethyl amine. Receipts rate: 113mg, 70%, the yellow powder form

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.05 (t, 2H), 2.00-2.15 (m, 3H), 2.20 (s, 3H), 2.35 (m, 1H), 3.30 (m, 4H), (3.55 m, 2H), 3.67 (m, 1H), 3.77 (m, 1H), 5.40 (d, 1H), 5.55 (s, 1H), 6.70 (s, 1H0,7.40 (t, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.60 (d, 1H); M/z 476[MH]+.

Embodiment 139

The different  azoles of S-6-dimethylamino-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Initial material: the different  azoles of S-6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 96) and dimethylamine. receipts rate: 86mg, 57 %, brown powder form

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.00-2.15 (m, 3H), 2.15 (s, 3H), (2.35 m, 1H), 2.90 (s, 6H), 3.70 (m, 1H), 3.75 (m, 1H), 540 (d, 1H), (5.55 s, 1H), 5.90 (s, 1H), 6.65 (s, 1H), 7.40 (t, 1H), 7.85 (t, 1H), (7.90 d, 1H), 8.60 (d, 1H); M/z 432[MH]+.

Embodiment 140

The different  azoles of S-6-methyl amino-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine

With the different  azoles of S-6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-1H-pyrazoles-3-base amino) pyrimidine (embodiment 96) (150mg, 0.35mmol) joins 2M and is arranged in the first amine (4ml) of methyl alcohol and it was being heated 90 minutes under the microwave radiation at the sealing container under 120 ℃. Carry out purifying with this mixture evaporation and concentration and with residue with the reversed-phase HPLC that uses the C18 post, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. Make the fraction that the comprises product 20g SCX-2 post of flowing through, use methanol-eluted fractions, then with 2N methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain the title compound (47mg, 32%) of white powder form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.00-2.15 (m, 3H), 2.15 (s, 3H), (2.35 m, 1H), 2.70 (s, 3H), (3.65-3.75 m, 2H), 5.45 (d, 1H), (5.85 s, 1H), 6.65 (s, 1H), (7.40 m, 1H), 8.85 (t, 1H), (8.90 d, 1H), 8.65 (s, 1H); M/z 418 [MH]+.

Embodiment 141

The different  azoles of S-6-chloro-2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With the different  azoles of S-2-[3-(2-pyrazine base)-5-yl] pyrrolidines (method 55) (166mg, 0.77mmol), 2,6-two chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (method 29) (170mg, 0.70) and N, the mixture of N-diisopropyl ethyl amine (134 μ l, 0.77mmol) in dimethylbenzene stirs and heated 2 days at 70 ℃. To wherein adding the second equivalent N, N-diisopropyl ethyl amine (134 μ l, 0.77mmol) also heated this mixture 2 days again. With this mixture evaporation and concentration, residue is carried out purifying with silica gel column chromatography, carry out wash-out with hexane/EtOAc (100: 0 to polarity increase to 0: 100), obtain the title compound (109mg, 37%) of cream-colored powder type.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.00-2.15 (m, 3H), 2.15 (s, 3H), (2.40 m, 1H), 3.65 (m, 1H), (3.75 m, 1H), 5.43 (d, 1H), (5.60 s, 1H), 6.00 (s, 1H), (6.35 s, 1H), 6.75 (s, 1H), (8.65 m, 2H), 9.10 (s, 1H); M/z 424[MH]+.

Embodiment 142

The different  azoles of 6-morpholine generation (Mopholino)-2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With the different  azoles of S-6-chloro-2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl-4-(5-methyl-1H-pyrazoles-3-base amino) pyrimidine (embodiment 141) (94mg, 0.22mmol) join in the morpholine (4ml) and with it in heating 30 minutes under the microwave radiation in the sealing container under 150 ℃. With this reactant mixture evaporation and concentration and with silica gel column chromatography it is carried out purifying, carry out wash-out with DCM/2M methyl alcohol ammoniacal liquor (100: 0 to polarity increase to 95: 5), obtain the title compound (75mg, 72%) of pale yellow powder form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.00-2.15 (m, 3H), 2.15 (s, 3H), (2.35 m, 1H), 3.35 (m, 4H), (3.55 m, 4H), 3.65-3.80 (m, 2H), (5.37 d, 1H), 5.55 (s, 1H), (5.80 s, 1H), 6.70 (s, 1H), (8.65 m, 2H), 9.10 (s, 1H); M/z 475 [MH]+.

Embodiment 143

The different  azoles of 6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

With S-2-(the different  azoles of 3-(2-pyridine radicals)-5-yl) pyrrolidines (method 42) (262mg, 1.22mmol) just-stir in the butanols (40ml) and to wherein adding 2,6-two chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine (method 57) (300mg, 1.11mmol), then add N, N-diisopropylamine (233 μ l, 1.33) also stirs this mixture 2 days under 60 ℃. With this mixture evaporation and concentration, to wherein adding saturated sodium bicarbonate aqueous solution (50ml), (3 * 25ml) extract with DCM with this mixture. Organic extract is merged water (50ml) and salt solution (50ml) washing, dry (MgSO₄) and by the evaporation desolventizing. Residue is carried out purifying with silica gel column chromatography, carry out wash-out with hexane/EtOAc (50: 50 to polarity increase to 0: 100), obtain the title compound (280mg, 56%) of white solid form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 0.65 (m, 2H), 0.85 (m, 2H), 1.85 (m, 1H), 2.05 (m, 2H), 2.15 (m, 1H), 2.35 (m, 1H), 3.65 (m, 1H), 3.75 (m, 1H), 5.40 (d, 1H), 5.55 (s, 1H), 5.90 (s, 1H0,6.35 (s, 1H), 6.65 (s, 1H), 7.40 (m, 1H), 7.85 (t, 1H), 7.90 (d, 1H), 8.60 (d, 1H); M/z 449[MH]+.

Embodiment 144

6-(2-hydroxyl the base oxethyl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

Hydrogenation sodium (60% is arranged in the dispersion of oil, 71mg, 1.78mmol) is joined in the ethylene glycol (4ml) also with this mixture stirring 5 minutes. To wherein adding the different  azoles of S-6-chloro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl-4-(5-cyclopropyl-1H-pyrazoles-3-base amino) pyrimidine (embodiment 143) (160mg, 0.35mmol) and with this mixture in heating 45 minutes under the microwave radiation in the sealing container under 150 ℃. This crude mixture is carried out purifying with the reversed-phase HPLC that uses the C18 post, and water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. The fraction that will comprise product is poured on the 20g SCX-2 post, uses methanol-eluted fractions, then with 2N methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain the title compound (23mg, 14%) of pale yellow powder form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 0.65 (m, 2H), 0.85 (m, 2H), 1.85 (m, 1H), 2.00-2.15 (m, 3H), 2.35 (m, 1H), 3.55-3.80 (m, 4H), 4.15 (m, 2H), 5.40 (d, 1H), 5.55 (s, 1H), 5.75 (s, 1H), 5.90 (s, 1H), (6.67 s, 1H), 7.45 (m, 1H), 7.85 (t, 1H), 7.95 (d, 1H), 8.65 (d, 1H). M/z 475[MH]+.

Embodiment 145

6-[4-(uncle-butoxy carbonyl) piperazine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With 6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 17) (250mg, 0.6mmol) and N-(Uncle-Butoxy carbonyl) mixture of piperazine (222mg, 6.0mmol) in Isosorbide-5-Nitrae-two  alkane (4ml) heating 90 minutes under the microwave radiation in the sealing container under 160 ℃. This reactant mixture crude product is carried out purifying with the reversed-phase HPLC that uses the C18 post, and water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through an isolute SCX-2 ion exchange column. With methyl alcohol this post is carried out wash-out to elute any neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, thereby obtain the required product (85mg, 25%) of white solid form.

NMR(DMSO-d ₆, under 100 ℃): 1.43 (s, 9H), 2.09 (m, 3H), 2.19 (s, 3H), 2.37 (m, 1H), 3.34 (m, 4H), 3.40 (m, 4H), 3.73 (m, 2H), 5.39 (d, 1H), 5.77 (br s, 1H), 5.97 (br s, 1H), 6.68 (s, 1H), (7.48 dd, 1H), 7.92 (m, 2H), 8.32 (br s, 1H), 8.65 (d, 1H), 11.41 (br s, 1H); M/z 573[MH]+.

Embodiment 146

6-(4-acetyl group piperazine-1-yl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Title compound is to use the method similar to embodiment 145 described methods, with 6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-the base amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 17) and 4-acetyl group piperazine be prepared. Receipts rate: 182mg, 60%.

NMR(DMSO-d ₆, under 100 ℃): 1.94 (s, 3H), 2.09 (m, 3H), 2.19 (s, 3H), 2.37 (m, 1H), 3.44 (m, 8H), (3.73 m, 2H), 5.39 (d, 1H), 5.77 (br s, 1H), 5.97 (br s, 1H), 6.68 (s, 1H), (7.46 dd, 1H), 7.92 (m, 2H), 8.30 (br s, 1H), 8.65 (d, 1H), 11.38 (br s, 1H); M/z 514[MH]+.

Embodiment 147

6-[2-(uncle-butoxy carbonyl)-2,7-diazaspiracyclic [3.5] ninth of the ten Heavenly Stems-7-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With 6-chloro-N-(3-methyl isophthalic acid H-pyrazoles-5-yl)-2-[2-(the 3-pyridine-different  azoles of 2-base-5-yl) pyrrolidines-1-yl] pyrimidine-4-amine (embodiment 17) (300mg, 0.7mmol) and 2-(Uncle-Butoxy carbonyl)-2, the mixture of 7-diazaspiracyclic [3.5] nonanes (949mg, 4.2mmol) in Isosorbide-5-Nitrae-two  alkane (8ml) heating 120 minutes under the microwave radiation in the sealing container under 160 ℃. Make this mixture cooling and remove volatile materials by evaporation. Residue is carried out purifying with silica gel column chromatography, carry out wash-out with DCM/ methyl alcohol/ammoniacal liquor (100: 0: 0 to polarity increase to 90: 10: 1), obtain the product (235mg, 55%) of lavender solid form.

NMR(DMSO-d ₆, under 100 ℃): 1.42 (s, 9H), 1.59 (t, 4H), 2.07 (m, 3H), 2.16 (s, 3H), 2.37 (m, 1H), 3.37 (m, 4H), 3.52 (m, 4H), 3.71 (m, 2H), 5.39 (d, 1H), 5.81 (br s, 1H), 5.94 (br s, 1H), (6.63 s, 1H), 7.45 (dd, 1H), 7.92 (m, 2H), 8.24 (br s, 1H), 8.65 (d, 1H); M/z 614[MH]+.

Embodiment 148

6-(2,7-diazaspiracyclic [3.5] ninth of the ten Heavenly Stems-7-yl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With 6-[2-(Uncle-Butoxy carbonyl)-2,7-diazaspiracyclic [3.5] ninth of the ten Heavenly Stems-7-yl]-4-(5-methyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] mixture of pyrimidine (embodiment 147) (11 0mg, 0.19mmol) and TFA (2ml) at room temperature stirred 60 minutes. Remove volatile materials by evaporation, residue is dissolved among the DCM, it is poured on the isolute SCX-2 ion exchange column. With methyl alcohol this post is carried out wash-out to elute any neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain the required product of yellow solid form. (66mg, 68%).

NMR(DMSO-d ₆, under 100 ℃): 1.51 (t, 4H), 2.07 (m, 3H), 2.16 (s, 3H), 2.37 (m, 1H), 3.22 (m, 4H), (3.36 m, 4H), 3.71 (m, 2H), 5.39 (d, 1H), 5.77 (br s, 1H), 5.94 (br s, 1H), (6.63 s, 1H), 7.45 (dd, 1H), 7.92 (m, 2H), 8.24 (br s, 1H), 8.65 (d, 1H); M/z 513[MH]+.

Embodiment 149

S-6-[4-(2-amino-ethyl) piperazine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) (100mg, 0.24mmol), 1-(2-amino-ethyl) piperazine (186mg, 1.4mmol) mixture in Isosorbide-5-Nitrae-two  alkane (4ml) is in heating 120 minutes under the microwave radiation in the sealing container under 150 ℃. This reactant mixture crude product is carried out purifying with the reversed-phase HPLC that uses the C18 post, and water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through an isolute SCX-2 ion exchange column. With methyl alcohol this post is carried out wash-out to elute any neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, residue ground with ether and collect product by filtering, obtain the title compound (68mg, 55 %) of white solid form.

NMR(DMSO-d ₆, under 100 ℃): 2.05 (m, 3H), 2.19 (s, 3H), 2.31 (m, 1H), 2.38 (m, 6H), 2.53 (m, 2H), 3.40 (t, 4H), 3.71 (m, 2H), 5.39 (d, 1H), 5.77 (br s, 1H), 5.95 (br s, 1H), 6.66 (s, 1H), (7.44 dd, 1H), 7.92 (m, 2H), 8.30 (br s, 1H), 8.65 (d, 1H), 11.38 (br s, 1H); M/z 516[MH]+.

Embodiment 150 to 159

Embodiment 150 to 159 uses the method similar to embodiment 149 described methods to be prepared.

Embodiment 150

S-6-[4-(3-hydroxyl propyl group) piperazine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and 1-(3-hydroxyl propyl group)-piperazine. Receipts rate: 84mg, 66%.

NMR(DMSO-d ₆, under 100 ℃): 1.50 (m, 2H), 2.09 (m, 3H), 2.19 (s, 3H), 2.36 (m, 7H), 3.42 (t, 4H), 3.49 (t, 2H), 3.73 (m, 2H), 5.39 (d, 1H), 5.77 (br s, 1H), 5.95 (br s, 1H), 6.68 (s, 1H), (7.44 dd, 1H), 7.94 (m, 2H), 8.30 (br s, 1H), 8.68 (d, 1H), 11.45 (br s, 1H); M/z 531[MH]+.

Embodiment 151

S-6-[4-(2-cyano ethyl) piperazine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and 1-(2-cyano ethyl) piperazine. Receipts rate: 69mg, 36%.

NMR(DMSO-d ₆, under 100 ℃): 2.08 (m, 3H), 2.19 (s, 3H), 2.39 (m, 1H), 2.42 (t, 4H), 2.59 (s, 4H), 3.42 (t, 4H), 3.71 (m, 2H), 5.39 (d, 1H), 5.77 (br s, 1H), 5.95 (br s, 1H), 6.68 (s, 1H), (7.44 dd, 1H), 7.94 (m, 2H), 8.28 (br s, 1H), 8.68 (d, 1H), 11.40 (br s, 1H); M/z 527[MH]+.

Embodiment 152

S-6-[4-(2-methoxy ethyl) piperazine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and 1-(2-methoxy ethyl) piperazine. Receipts rate: 84mg, 44%.

NMR(DMSO-d ₆, under 100 ℃): 2.08 (m, 3H), 2.19 (s, 3H), 2.36 (m, 7H), 3.25 (s, 3H), 3.43 (t, 4H), 3.46 (t, 2H), 3.71 (m, 2H), 5.39 (d, 1H), 5.77 (br s, 1H), 5.95 (br s, 1H), 6.68 (s, 1H), (7.48 dd, 1H), 7.94 (m, 2H), 8.28 (br s, 1H), 8.68 (d, 1H), 11.40 (br s, 1H); M/z 532[MH]+.

Embodiment 153

S-6-(4-acetyl group piperazine-1-yl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and 1-acetyl group piperazine. Receipts rate: 66mg, 36%.

NMR(DMSO-d ₆, under 100 ℃): 2.01 (s, 3H), 2.08 (m, 3H), 2.19 (s, 3H), 2.36 (m, 1H), 3.48 (m, 8H), (3.71 m, 2H), 5.39 (d, 1H), 5.77 (br s, 1H), 5.95 (br s, 1H), 6.68 (s, 1H), (7.48 dd, 1H), 7.94 (m, 2H), 8.28 (br s, 1H), 8.68 (d, 1H), 11.40 (br s, 1H); M/z 515[MH]+.

Embodiment 154

S-6-[4-(ethylsulfonyl) piperazine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and 1-(ethylsulfonyl) piperazine. Receipts rate: 122mg, 60%.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 0.96 (t, 3H), 1.90 (m, 3H), (1.99 s, 3H), 2.22 (m, 1H), 2.73 (m, 2H), 2.96 (m, 4H), 3.33 (m, 4H), (3.55 m, 2H), 5.17 (d, 1H), (6.48 s, 1H), 7.21 (dd, 1H), (7.72 m, 2H), 8.44 (d, 1H); M/z 566[MH]+.

Embodiment 155

S-6-[2-(2-hydroxyl base oxethyl) ethylamino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and 2-(2-hydroxyl base oxethyl) ethyl-amine. Receipts rate: 84mg, 48%.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.06 (m, 3H), 2.16 (s, 3H), 2.33 (m, 1H), 3.40 (m, 8H), 3.71 (m, 2H), 5.40 (d, 1H), 6.67 (s, 1H), (7.38 dd, 1H), 7.89 (m, 2H), 8.62 (d, 1H); M/z 496[MH]+.

Embodiment 156

S-6-[2-(acetyl is amino) ethylamino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and 2-(acetyl is amino) ethyl amine. Receipts rate: 39mg, 22%.

NMR(DMSO-d ₆, under 100 ℃): 1.80 (s, 3H), 2.07 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.19 (m, 4H), 3.71 (m, 2H), 5.42 (d, 1H), 5.52 (br s, 1H), 5.87 (br s, 1H), 6.06 (br s, 1H), 6.68 (s, 1H), (7.49 br s, 1H), 7.43 (dd, 1H), 7.94 (m, 2H), (8.12 br s, 1H), 8.66 (d, 1H), 11.40 (br s, 1H); M/z 489[MH]+.

Embodiment 157 also is by the HPLC purifying from identical Reaction Separation out :-

Embodiment 157

The S-6-[2-aminoethylamino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Receipts rate: 15mg, 9%.

NMR(DMSO-d ₆, under 100 ℃): 2.10 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 2.67 (t, 2H), 3.17 (m, 2H), (3.71 m, 2H), 5.42 (d, 1H), 5.57 (br s, 1H), 5.90 (br s, 1H), 6.06 (br s, 1H), (6.68 s, 1H), 7.48 (dd, 1H), 7.94 (m, 2H), 8.12 (br s, 1H), 8.68 (d, 1H); M/z 447[MH]+.

Embodiment 158

S-6-[4-methyl cyclohexane base is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and 4-methyl cyclohexane base amine. Receipts rate: 112mg, 48%.

NMR(DMSO-d ₆, under 100 ℃): 0.84 (dd, 3H), 1.40 (m, 9H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.45 (m, 1H), 3.71 (m, 2H), 5.39 (m, 1H), 5.54 (br s, 1H), 5.82 (br s, 1H), 5.89 (br s, 1H), (6.63 s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), (8.03 br s, 1H), 8.64 (s, 1H), 11.41 (br s, 1H); M/z 500 [MH]+.

Embodiment 159

S-6-[4-hydroxyl cyclohexyl is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and 4-hydroxyl cyclo-hexylamine. Title compound is to use the method preparation similar to the method for embodiment 1 49, just should react 180 ℃ of lower heating 6 hours. Receipts rate: 83mg, 35%.

NMR(DMSO-d ₆, under 100 ℃): 1.16 (m, 4H), 1.81 (m, 4H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.38 (m, 1H), 3.50 (br s, 1H), 3.71 (m, 2H), 4.01 (d, 1H), 5.39 (d, 1H), 5.49 (br s, 1H), 5.82 (br s, 1H), 5.89 (br s, 1H), 6.63 (s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), 8.02 (br s, 1H), 8.64 (d, 1H), 11.35 (br s, 1H); M/z 502[MH]+.

Embodiment 160

S-6-[is suitable-3,4-dihydroxy pyrrolidine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) (100mg, 0.24mmol), suitable-3,3-dimethyl-2,4-dioxa-7-aza-bicyclo [3.3.0] octane (203mg, 1.4mmol) mixture in Isosorbide-5-Nitrae-two  alkane (3ml) is in heating 120 minutes under the microwave radiation in the sealing container under 150 ℃. Make the cooling of this reactant mixture, remove volatile materials and residue is carried out purifying with silica gel column chromatography by evaporation, carry out wash-out with DCM/ methyl alcohol/ammoniacal liquor (100: 0: 0 to polarity increase to 90: 10: 1). This product that has carried out purifying is dissolved in methyl alcohol (4ml) and the 2M hydrochloric acid (4ml) and with it stirred at ambient temperature 120 minutes. This reactant mixture crude product is carried out purifying with the reversed-phase HPLC that uses C1 8 posts, and water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through an isolute SCX-2 ion exchange column. With methyl alcohol this post is carried out wash-out to elute any neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, this residue is ground with ether and by filtering it is collected, obtain the title compound (22mg, 19%) of white solid form.

NMR(DMSO-d ₆, under 100 ℃): 2.08 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.15 (m, 1H), 3.24 (m, 1H), 3.42 (m, 1H), 3.51 (m, 1H), 3.71 (m, 2H), 4.08 (s, 2H), 5.42 (d, 1H), 5.47 (br s, 1H), (5.90 br s, 1H), 6.68 (s, 1H), 7.48 (dd, 1H), (7.94 m, 2H), 8.38 (br s, 1H), 8.68 (d, 1H); M/z 491[MH]+.

Embodiment 161

S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine

With 2,6-two chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (method 29) (134mg, 0.55mmol), the different  azoles of S-2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines (method 66) (130mg, 0.6mmol), N, the mixture of N-diisopropyl ethyl amine (78mg, 0.6mmol) and dimethylbenzene (5ml) was 70 ℃ of lower heating 3 days. Make this crude product by an isolute SCX-2 ion exchange column. With methyl alcohol this post is carried out wash-out to elute any neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing and with silica gel column chromatography residue is carried out purifying, carry out wash-out with EtOAc/ hexane (0: 100 to polarity increase to 100: 0). This product that has carried out purifying is ground with ether and by filtering it collected, obtain the title compound (110mg, 47%) of white solid form.

NMR(DMSO-d ₆, under 100 ℃): 2.10 (m, 3H), 2.19 (s, 3H), (2.40 m, 1H), 3.71 (m, 2H), (5.42 d, 1H), 6.00 (s, 1H), (6.41 s, 1H), 6.73 (s, 1H), (7.52 dd, 1H), 8.90 (d, 2H), (9.21 s, 1H), 11.62 (br s, 1H); M/z 424[MH]+.

Embodiment 162

S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{3-(3-first oxygen base pyrazine-2-yl) different  azoles-5-yl } pyrrolidines-1-yl] pyrimidine

With 2,6-two chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (method 29) (162mg, 0.66mmol), S-2-[3-(2-first oxygen base pyrazine-3-yl) different  azoles-5-yl] pyrrolidines (method 68) (180mg, 0.73mmol), N, N-diisopropyl ethyl amine (95mg, 0.73mmol) and the mixture of n-butyl alcohol (5ml) 65 ℃ of lower heating 16 hours, then with it 80 ℃ of lower heating 2 hours. This reactant mixture crude product is carried out purifying with the reversed-phase HPLC that uses the C18 post, and water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through an isolute SCX-2 ion exchange column. With methyl alcohol this post is carried out wash-out to elute any neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, residue is ground with ether and by filtering it is collected, obtain the title compound (117mg, 39%) of cream-colored solid form; M/z 454 [MH]+.

Embodiment 163

S-6-morpholine generation-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine

With S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-the base amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] mixture of pyrimidine (embodiment 161) (100mg, 0.24mmol) in morpholine (3ml) heated 40 minutes under the microwave radiation sealing in the container under 150 ℃. This reactant mixture crude product is carried out purifying with the reversed-phase HPLC that uses the C18 post, and water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through an isolute SCX-2 ion exchange column. With methyl alcohol this post is carried out wash-out to elute any neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. Grind with ether by the evaporation desolventizing and with residue, obtain the title compound (53mg, 46%) of white solid form.

NMR(DMSO-d ₆, under 100 ℃): 2.10 (m, 3H), 2.17 (s, 3H), (2.36 m, 1H), 3.44 (m, 4H), 3.60 (m, 4H), 3.71 (m, 2H), 5.42 (d, 1H), (5.57 s, 1H), 5.90 (s, 1H), 6.68 (s, 1H), 7.52 (dd, 1H), 8.35 (br s, 1H), (8.90 d, 2H), 11.40 (br s, 1H); M/z 476[MH]+.

Embodiment 164

S-6-morpholine generation-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{3-(3-first oxygen base pyrazine-2-yl) different  azoles-5-yl } pyrrolidines-1-yl] pyrimidine

Title compound is to use the method similar to embodiment 163 described methods, by S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base amino)-2-[2-{3-(3-first oxygen base pyrazine-2-yl) different  azoles-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 162) and morpholine begin to be prepared. Receipts rate: 15mg, 12 %.

NMR(DMSO-d ₆, under 100 ℃): 2.07 (m, 3H), 2.17 (s, 3H), (2.36 m, 1H), 3.47 (m, 4H), 3.60 (m, 4H), 3.71 (m, 2H), 4.01 (s, 3H), (5.42 d, 1H), 5.75 (br s, 1H), (5.96 br s, 1H), 6.66 (s, 1H), (8.31 s, 2H), 11.40 (br s, 1H); M/z 506 [MH]+.

Also from this identical reaction, isolated embodiment 165:-with the HPLC purifying

Embodiment 165

S-6-morpholine generation-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(3-hydroxyl pyrazine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Receipts rate: 32mg, 26%.

NMR(DMSO-d ₆, under 100 ℃): 2.07 (m, 3H), 2.17 (s, 3H), (2.36 m, 1H), 3.47 (m, 4H), 3.60 (m, 4H), 3.71 (m, 2H), 5.47 (d, 1H), (5.75 s, 1H), 5.96 (s, 1H), (6.71 s, 1H), 7.52 (m, 2H), (8.33 s, 1H), 11.75 (br s, 1H); M/z 492[MH]+.

Embodiment 166

S-6-[4-methyl piperazine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-the base amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] mixture of pyrimidine (embodiment 96) (150mg, 0.36mmol) in 1-methyl piperazine (3ml) heated 40 minutes under the microwave radiation sealing in the container under 150 ℃. Make the cooling of this mixture and it is directly carried out purifying with reversed-phase HPLC of use C18 post, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through an isolute SCX-2 ion exchange column. With methyl alcohol this post is carried out wash-out to elute any neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, residue is ground with hexane and by filtering it is collected, obtain the title compound (152mg, 87%) of white solid form.

NMR(DMSO-d ₆, under 100 ℃): 2.08 (m, 3H), 2.16 (s, 3H), (2.38 m, 1H), 3.34 (m, 4H), 3.60 (m, 4H), 3.71 (m, 2H), 5.39 (d, 1H), (5.74 s, 1H), 5.95 (s, 1H), (6.68 s, 1H), 7.50 (dd, 1H), (8.38 br s, 1H), 8.92 (d, 2H); M/z 488[MH]+.

Embodiment 167 to 171

Embodiment 167 to 171 uses the method similar to embodiment 166 described methods to be prepared.

Embodiment 167

The S-6-[cyclobutyl is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and cyclobutyl amine. Receipts rate: 79mg, 37 %.

NMR(DMSO-d ₆, under 100 ℃): 1.87 (m, 6H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.71 (m, 2H), 4.14 (m, 1H), 5.39 (d, 1H), 5.49 (br s, 1H), 5.89 (br s, 1H), 6.22 (br s, 1H), 6.63 (s, 1H), (7.42 dd, 1H), 7.90 (m, 2H), 8.12 (br s, 1H), 8.64 (d, 1H), 11.38 (br s, 1H); M/z 458[MH]+.

Embodiment 168

The different propoxyl group third-1-base of S-6-[3-is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and the different propoxyl group third-1-base of 3-amine. Receipts rate: 89mg, 38%.

NMR(DMSO-d ₆, under 100 ℃): 1.04 (d, 6H), 1.65 (m, 2H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.18 (m, 2H), 3.35 (t, 2H), 3.49 (m, 1H), 3.70 (m, 2H), 5.39 (d, 1H), 5.54 (br s, 1H), 5.89 (br s, 1H), 5.99 (br s, 1H), 6.64 (s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), 8.02 (br s, 1H), 8.64 (d, 1H), 11.38 (br s, 1H); M/z 505[MH]+.

Embodiment 169

S-6-[2-(morpholine-4-yl) ethylamino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and 2-(morpholine-4-yl) ethyl amine. This product is ground with ether. Receipts rate: 100mg, 41%.

NMR(DMSO-d ₆, under 100 ℃): 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 5H), 2.41 (t, 2H), 3.26 (m, 2H), 3.54 (m, 4H), 3.70 (m, 2H), 5.40 (dd, 1H), 5.53 (br s, 1H), 5.91 (br s, 1H), 5.92 (br s, 1H), (6.64 s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), 8.08 (br s, 1H), 8.64 (d, 1H); M/z 518[MH]+.

Embodiment 170

S-6-[2-(dimethylamino) ethylamino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and 2-(dimethylamino) ethyl amine. Receipts rate: 90mg, 40%.

NMR(DMSO-d ₆, under 100 ℃): 2.06 (m, 3H), 2.12 (s, 6H), (2.17 s, 3H), 2.36 (m, 3H), 3.26 (m, 2H), 3.70 (m, 2H), 5.43 (dd, 1H), (5.53 br s, 1H), 5.91 (br s, 2H), 6.64 (s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), (8.08 br s, 1H), 8.64 (d, 1H); M/z 476[MH]+.

Embodiment 171

S-6-[(2S)-2-hydroxyl third-1-base is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-the base amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and (the 2S)-basic amine of 2-hydroxyl third-1-. Receipts rate: 28mg, 13%.

NMR(DMS0-d ₆, under 100 ℃): 1.06 (d, 3H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.08 (m, 1H), 3.18 (m, 1H), 3.70 (m, 3H), 4.27 (s, 1H), 5.39 (dd, 1H), 5.53 (br s, 1H), 5.90 (br s, 1H), 5.95 (br s, 1H), 6.64 (s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), (8.05 br s, 1H), 8.64 (d, 1H), 11.39 (br s, 1H); M/z 463 [MH]+.

Embodiment 172

S-6-[2-methyl-prop-1-base is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-the base amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] mixture of pyrimidine (embodiment 96) (200mg, 0.47mmol) and different butylamine (2ml) heated 30 minutes under the microwave radiation sealing in the container under 150 ℃. Make this reaction cooling and it is poured in the sodium bicarbonate aqueous solution. By filter collecting the precipitation of gained, wash with water and its vacuum is dry, obtain the title compound (170mg, 79%) of orange solids form.

NMR(DMSO-d ₆, under 100 ℃): 0.85 (dd, 6H), 1.78 (m, 1H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), (2.95 m, 2H), 3.70 (m, 2H), 5.40 (d, 1H), 5.58 (br s, 1H), 5.89 (br s, 1H), (6.08 br s, 1H), 6.64 (s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), 8.66 (d, 1H); M/z 460[MH]+.

Embodiment 173 to 179

Embodiment 173 to 179 uses the method similar to embodiment 172 described methods to be prepared.

Embodiment 173

The S-6-[3-methoxy-propyl is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and 3-METHOXY PROPYL AMINE. Receipts rate: 160mg, 72%.

NMR(DMSO-d ₆, under 100 ℃): 1.68 (m, 2H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.18 (m, 2H), 3.20 (s, 3H), 3.33 (t, 2H), 3.70 (m, 2H), 5.39 (dd, 1H), 5.54 (s, 1H), 5.86 (s, 1H), (6.01 br s, 1H), 6.64 (s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), 8.64 (dd, 1H); M/z 477[MH]+.

Embodiment 174

S-6-[4-ethyl piperazidine-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and 1-ethyl piperazidine. Receipts rate: 200mg, 85%.

NMR(DMSO-d ₆, under 100 ℃): 0.97 (t, 3H), 2.06 (m, 3H), (2.17 s, 3H), 2.36 (m, 7H), 3.41 (m, 4H), 3.70 (m, 2H), 5.39 (dd, 1H), (5.75 s, 1H), 5.94 (s, 1H), 6.64 (s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), (8.31 br s, 1H), 8.64 (d, 1H); M/z 502[MH]+.

Embodiment 175

The S-6-[3-ethoxycarbonyl propyl is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and 3-ethoxycarbonyl propyl amine. Receipts rate: 105mg, 46%.

NMR(DMSO-d ₆, under 100 ℃): 1.06 (t, 3H), 1.68 (m, 2H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.18 (m, 2H), 3.38 (m, 4H), 3.70 (m, 2H), 5.39 (dd, 1H), 5.53 (s, 1H), 5.88 (s, 1H), (6.01 t, 1H), 6.64 (s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), 8.64 (d, 1H); M/z 491[MH]+.

Embodiment 176

S-6-[(2R)-oxolane-2-base methyl is amino]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and (2R)-oxolane-2-base first amine. receipts rate: 196mg, 86%.

NMR(DMSO-d ₆, under 100 ℃): 1.55 (m, 1H), 1.77 (m, 3H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.20 (m, 2H), 3.56 (m, 1H), 3.70 (m, 3H), 3.91 (m, 1H), 5.39 (dd, 1H), 5.56 (s, 1H), 5.88 (s, 1H), 6.00 (t, 1H), 6.64 (s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), 8.64 (d, 1H); M/z 488.5[MH]+.

Embodiment 177

S-6-(the different propoxyl group ethylamino of 2-)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) and 2-isopropyl oxyethylamines serving. Receipts rate: 180mg, 78%.

NMR(DMSO-d ₆, under 100 ℃): 1.03 (dd, 6H), 2.06 (m, 3H), 2.17 (s, 3H), 2.36 (m, 1H), 3.30 (m, 4H), (3.48 m, 1H), 3.70 (m, 2H), 5.40 (dd, 1H), 5.53 (s, 1H), 5.89 (s, 1H), (5.95 t, 1H), 6.64 (s, 1H), 7.42 (dd, 1H), 7.90 (m, 2H), 8.66 (d, 1H); M/z 490[MH]+.

Embodiment 178

S-6-morpholine generation-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine

Initial material: S-6-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 180) and morpholine. Receipts rate: 145mg, 66 %.

NMR(DMSO-d ₆, under 100 ℃): 0.65 (m, 2H), 0.86 (m, 2H), (1.84 m, 1H), 2.09 (m, 3H), 2.39 (m, 1H), 3.39 (m, 4H), 3.57 (m, 4H), (3.72 m, 2H), 5.42 (dd, 1H), 5.72 (s, 1H), 5.89 (s, 1H), 6.69 (s, 1H), (7.55 dd, 1H), 8.89 (d, 2H); M/z 502[MH]+.

Embodiment 179

S-6-methyl amino-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine

With initial material: S-6-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] ethanolic solution of pyrimidine (embodiment 180) and excessive 2M first amine descends to heat 90 minutes at 120 ℃. Receipts rate: 125mg, 64%.

NMR(DMSO-d ₆, under 100 ℃): 0.67 (m, 2H), 0.85 (m, 2H), 1.82 (m, 1H), 2.09 (m, 3H), 2.36 (m, 1H), 2.70 (d, 3H), 3.72 (m, 2H), 5.42 (dd, 1H), 5.50 (br s, 1H), 5.83 (br s, 1H), 5.97 (br s, 1H), (6.69 s, 1H), 7.55 (dd, 1H), 8.12 (br s, 1H), 8.94 (d, 2H), 11.51 (br s, 1H); M/z 445[MH]+.

Embodiment 180

S-6-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine

With 2,6-two chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine (method 57) (910mgs, 3.4mmol), the different  azoles of S-2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines (method 66) (800mg, 0.37mmol), N, the mixture of N-diisopropyl ethyl amine (480mg, 0.37mmol) and n-butyl alcohol (20ml) was 75 ℃ of lower heating 16 hours. Remove volatile materials and residue is carried out purifying with the reversed-phase HPLC that uses the C18 post by evaporation, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through an isolute SCX-2 ion exchange column. With methyl alcohol this post is carried out wash-out to elute any neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain title compound (850mg, 55%).

NMR(DMSO-d ₆, under 100 ℃): 0.71 (m, 2H), 0.91 (m, 2H), 1.88 (m, 1H), 2.09 (m, 2H), 2.18 (m, 1H), (2.43 m, 1H), 3.72 (m, 2H), 5.47 (dd, 1H), 5.98 (s, 1H), 6.40 (s, 1H), (6.74 s, 1H), 7.55 (dd, 1H), 8.94 (d, 2H), 9.27 (s, 1H), 11.72 (br s, 1H); M/z 450[MH]+.

Embodiment 181

S-6-methyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{3-(3-first oxygen base pyrazine-2-yl) different  azoles-5-yl } pyrrolidines-1-yl] pyrimidine

With 2-chloro-6-methyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (method 56) (63mg, 0.26mmol), S-2-[3-(2-first oxygen base pyrazine-3-yl) different  azoles-5-yl] pyrrolidines (method 68) (70mg, 0.28mmol), the mixture of oneself alcohol (3ml) of diisopropyl ethyl amine (0.09ml, 0.52mmol) and 1-is 120 ℃ of lower heating 6 hours. This reactant mixture crude product is carried out purifying with the reversed-phase HPLC that uses the C18 post, and water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through an isolute SCX-2 ion exchange column. With methyl alcohol this post is carried out wash-out to elute any neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, residue is ground with ether and by filtering it is collected, obtain the title compound (49mg, 44 %) of white solid form.

NMR(DMSO-d ₆, under 100 ℃): 12.06 (m, 3H), 2.12 (s, 3H), (2.17 s, 3H), 2.36 (m, 1H), 3.70 (m, 2H), 4.00 (s, 3H), 5.45 (d, 1H), (6.01 br s, 1H), 6.22 (br s, 1H), (6.64 s, 1H), 8.30 (s, 2H), (8.74 br s, 1H), 11.51 (br s, 1H); M/z 435 [MH]+.

Embodiment 182

S-6-first oxygen base-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine

Hydrogenation sodium (88mg, 1.1mmol) is joined in the methyl alcohol (2ml) also with this mixture stirring 5 minutes. To wherein adding S-6-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-the base amino)-different  azoles of 2-[2-{3-(pyrimidine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 180) (200mg, 0.44mmol) also heats this mixture 30 minutes under the microwave radiation sealing in the container under 120 ℃. Make the cooling of this reactant mixture and it is poured in the cold aqueous ammonium chloride solution. Be dissolved in the methyl alcohol by the precipitation of filtration collection gained and with it. This solution is poured in the water and by filtering collecting precipitation, water washs it and it is carried out drying in the vacuum baking oven, obtains the title compound (81mg, 41%) of white solid form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 0.63 (m, 2H), 0.85 (m, 2H), 1.82 (m, 1H), 2.09 (m, 3H), 2.36 (m, 1H), 3.70 (s, 3H), 3.72 (m, 2H), 5.42 (dd, 1H), 6.69 (s, 1H), 7.49 (dd, 1H), 8.88 (d, 2H); M/z 446[MH]+.

Embodiment 183

S-6-(2-methoxy ethoxy)-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Title compound is to use the method similar to embodiment 182 described methods, by S-6-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-the base amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 180) and 2-methyl cellosolve begin to be prepared. Receipts rate: 80mg, 37 %.

NMR(DMSO-d ₆, under 100 ℃): 0.67 (m, 2H), 0.85 (m, 2H), 1.82 (m, 1H), 2.09 (m, 3H), 2.36 (m, 1H), 3.24 (s, 3H), 3.52 (m, 2H), 3.72 (m, 2H), 4.25 (m, 2H), 5.42 (dd, 1H), 5.74 (s, 1H), 5.92 (s, 1H), 6.69 (s, 1H), 7.55 (dd, 1H), 8.68 (br s, 1H), 8.91 (d, 2H), 11.5 (br s, 1H); M/z 490[MH]+.

Embodiment 184

S-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

With 4-(5-ethyl-1H-pyrazoles-3-base is amino)-2-chlorine pyrimidine (method 65) (224mg, 1.0mmol), S-2-(the different  azoles of 3-(2-pyridine radicals)-5-yl) pyrrolidines (method 42) (268mg, 1.25mmol) and N, N-diisopropylamine (322mg, 0.43ml 2.5mmol) mixture in oneself alcohol (10ml) of 1-was 150 ℃ of lower heating 18 hours. By the evaporation desolventizing, and residue is suspended in sodium bicarbonate aqueous solution (25ml) neutralization, and (4 * 25ml) extract with EtOAc. Organic extract is merged, with salt solution (2 * 25ml) washings, dry (MgSO₄) and by the evaporation desolventizing. Residue is ground with ether, by filtering it is collected and is dried, obtain the title compound (202mg, 50%) of yellowish-brown solid form.

NMR(DMSO)：1.18(m，3H)，2.02(m，3H)，2.35(m，1H)，2.50(m，2H)， 3.56(m，1H)，3.78(m，1H)，5.42(d，1H)，6.00(br m，1H)，6.25(br m，1H)， 6.67(s，1H)，7.47(m，1H)，7.90(m，3H)，8.63(d，1H)，9.40(br s，1H)，11.80(br s，1H)；m/z 403[MH]+。

Embodiment 185

S-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

With 4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-2-chlorine pyrimidine (method 28) (224mg, 1.0mmol) and S-2-(the different  azoles of 3-(2-pyridine radicals)-5-yl) pyrrolidines (method 42) process with embodiment 184 described methods, obtain the title compound (210mg, 50%) of yellowish-brown crystalline solid forms.

NMR(DMSO)：0.65(m，2H)，0.87(m，2H)，1.82(br m，1H)，2.02(m， 3H)，2.35(m，1H)，3.55(m，1H)，3.80(m，1H)，5.40(d，1H)，5.90(br m，1H)， 6.20(br m，1H)，6.65(s，1H)，7.47(m，1H)，7.85(br s，1H)，7.95(m，3H)， 8.65(m，1H)，9.40(br s，1H)，11.85(br s，1H)；m/z 415[MH]+。

Embodiment 186

S-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 5-fluoro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

2-chloro-4-(5-ethyl-1H-pyrazoles-3-base is amino)-5-FU (method 69) and S-2-(the different  azoles of 3-(2-pyridine radicals)-5-yl) pyrrolidines (method 42) are processed with embodiment 184 described methods. With silica gel column chromatography product is carried out purifying, carry out wash-out with EtOAc/ hexanes mixtures (50: 50 to polarity increase to 100: 0), obtain the title compound (221mg, 53 %) of faint yellow solid form.

NMR(DMSO)：1.17(t，3H)，2.08(m，3H)，2.38(m，1H)，2.57(q，2H)， 3.65(m，1H)，3.75(m，1H)，5.37(d，1H)，6.18(br s，1H)，6.62(s，1H)，7.42(m， 1H)，7.90(m，3H)，8.62(d，1H)，8.80(br s，1H)，11.60(br s，1H)；m/z 421 [MH]+。

Embodiment 187

S-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 5-fluoro-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

2-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-5-FU (method 27) and S-2-(the different  azoles of 3-(2-pyridine radicals)-5-yl) pyrrolidines (method 42) are processed with embodiment 184 described methods. With silica gel column chromatography product is carried out purifying, carry out wash-out with EtOAc/ hexanes mixtures (50: 50 to polarity increase to 100: 0), obtain the title compound (192mg, 44 %) of faint yellow solid form.

NMR(DMSO)：0.67(m，2H)，0.87(m，2H)，1.85(br m，1H)，2.02(m，3H)， 2.38(m，1H)，3.55(m，1H)，3.80(m，1H)，5.37(d，1H)，5.95(br s，1H)，6.70(s， 1H)，7.50(m，1H)，7.95(m，3H)，8.66(d，1H)，9.45(br s，1H)，12.00(br s，1H)； m/z 433[MH]+.

Embodiment 188

4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 6-methyl-2-{2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines-1-yl } pyrimidine

With 2-chloro-6-methyl-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine (method 70) (210mg, 0.84mmol), the different  azoles of S-2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines (method 66) (200mg, 0.92mmol), N, the mixture of oneself alcohol (4.0ml) of N-diisopropyl ethyl amine (0.16ml, 1.18mmol) and anhydrous 1-was heating 45 minutes under the microwave radiation in the sealing container under 150 ℃. Make the cooling of this reactant mixture, then it is directly carried out purifying with reversed-phase HPLC of use C18 post, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. The fraction that will comprise product is poured on the 10g isolute SCX-2 ion exchange column. With methyl alcohol this post is carried out wash-out with any neutral thing of wash-out, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, residue is ground with ether and by filtering it is collected, obtain title compound (212mg, 59%).

NMR(DMSO-d ₆, under 100 ℃): 0.65 (m, 2H), 0.85 (m, 2H), 1.85 (m, 1H), 2.05 (m, 2H), 2.10 (s, 3H), 2.15 (m, 1H), 2.35 (m, 1H), 3.70 (m, 1H), 3.75 (m, 1H), 5.47 (dd, 1H), 5.90 (br s, 1H), (6.15 br s, 1H), 6.65 (s, 1H), 7.50 (t, 1H), (8.75 br s, 1H), 8.90 (d, 2H), 11.55 (br s, 1H); M/z 430[MH]+.

Embodiment 189

4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 6-methyl-2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

With 2-chloro-6-methyl-4-(5-cyclopropyl-1H-pyrazoles-3-base amino) pyrimidine (method 70) and the different  azoles of S-2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines (method 55) processes as described in the embodiment 1 88, obtain title compound (218mg, 71%).

NMR(DMSO-d ₆, under 100 ℃): 0.65 (m, 2H), 0.85 (m, 2H), 1.83 (heptet, 1H), 2.05 (m, 2H), 2.11 (s, 3H), 2.15 (m, 1H), 2.35 (m, 1H), 3.67 (m, 1H), 3.75 (m, 1H), 5.48 (dd, 1H), 5.95 (br s, 1H), (6.15 br s, 1H), 8.65 (m, 2H), 8.75 (br s, 1H), 9.12 (br s, 1H), 11.55 (br s, 1H); M/z 430[MH]+.

Embodiment 190

4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 6-methyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

2-chloro-6-methyl-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine (method 70) and S-2-(the different  azoles of 3-(2-pyridine radicals)-5-yl) pyrrolidines (method 42) are processed as described in the embodiment 188, obtain title compound (242mg, 66%).

NMR(DMSO-d ₆, under 100 ℃): 0.65 (m, 2H), 0.85 (m, 2H), 1.83 (heptet, 1H), 2.05 (m, 2H), 2.12 (s, 3H), 2.15 (m, 1H), 2.37 (m, 1H), 3.68 (m, 1H), 3.75 (m, 1H), 5.45 (dd, 1H), 5.95 (br s, 1H), 6.15 (br s, 1H), 7.60 (s, s, 1H), (7.43 dd, 1H), 7.85 (dd, 1H), (7.92 d, 1H), 8.61 (d, 1H), (8.75 br s, 1H), 11.55 (br s, 1H); M/z 429[MH]+.

Embodiment 191

6-(3-hydroxyl propyl group)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

With 3-amino-1H-5-methyl pyrazoles (87mg, 0.894mmol) join and carrying out the 4-chloro-6-(3-hydroxyl propyl group) that the stirs-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl in the solution of pyrimidine (method 71) (230mg, 0.596mmol) in anhydrous NMP (3ml). To wherein adding the hydrogen chloride (298 μ l, 1.19mmol) of the 6M that is arranged in two  alkane and should reacting and under 120 ℃, stir under the nitrogen and heating 20 hours. Make this reaction cooling and this reactant mixture is applied on the 10g isolute SCX2 ion exchange column. With methyl alcohol this post is carried out wash-out to remove neutral substance, then with 2M methyl alcohol ammoniacal liquor product is carried out wash-out. By evaporation desolventizing and residue carried out purifying with the hurried chromatogram of silica gel from the fraction that comprises product, carry out wash-out with methyl alcohol/DCM (5: 95). Then, this product that has carried out purifying is dissolved in the ethyl acetate and water washs it, dry (Na₂SO ₄) and by the evaporation desolventizing. Residue is ground with the DCM/ hexane and by filtering it is collected, obtain the title compound (99mg, 37%) of white solid form.

NMR(DMSO)：1.75(m，2H)，2.1(m，3H)，2.4(s，3H)，3.42(m，2H)， 3.72(m，2H)，4.02(s，1H)，5.43(d，1H)，6.02(s，1H)，6.2(s.1H)，6.66(s，1H)， 7.43(t，1H)，7.9(m，2H)，8.65(d，1H)，8.73(s，1H)，11.47(s，1H)；m/z 447 [MH]+。

Embodiment 192

S-6-(3-hydroxyl propyl group)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

Isolate the S enantiomter of embodiment 191 with the chirality HPLC that uses Chiralpak AD post, with methyl alcohol as the wash-out agent.

Embodiment 193

The different  azoles of S-6-propyl group-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With two (triphenyl phosphine) chlorination palladiums (II) (34mg) join carrying out S-6-iodo-2-{2-[the different  azoles of 3-(pyridine-2-the yl)-5-yl] pyrrolidines-1-yl that stirs-4-(the basic amino of the 5-methyl isophthalic acid H-pyrazoles-3-) solution of pyrimidine (embodiment 98) (250mg, 0.486mmol) in anhydrous dimethyl yl acetamide (7.5ml) and anhydrous THF (2.5ml) in. Then, to wherein add the 0.5M bromination just-solution of propyl group zinc in THF (3.9ml, 1.94mmol) and should react and stir at ambient temperature 24 hours. Again to wherein add one part of 0.5M bromination just-solution of propyl group zinc in THF (3.9ml, 1.94mmol) and should react and stir again 24 hours. Then, add entry and ethyl acetate and this mixture filtered to remove insoluble material in this reactant mixture. Isolate filtrate layers and water and saturated brine organic layer is washed, dry (Na₂SO ₄), by the evaporation desolventizing. With the reversed-phase HPLC that uses the C18 post residue is carried out purifying, water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out, obtains the title product (115mg, 55%) of white solid form.

NMR(DMSO-d ₆, under 373deg K): 0.9 (t, 3H), 1.63 (m, 2H), 2.12 (m, 3H), 2.18 (s, 3H), 2.4 (m, 3H), (3.72 m, 1H), 3.83 (m, 1H), 5.5 (d, 1H), 6.0 (s, 1H), 6.27 (s, 1H), (6.75 s, 1H), 7.45 (t, 1H), 7.9 (m, 2H), 8.65 (d, 1H), 9.43 (s, 1H); M/z 431[MH]+

Embodiment 194

S-6-chloro-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With 2,6-two chloro-4-(5-ethyl-1H-pyrazoles-3-base is amino) pyrimidine (method 72) and S-2-(the different  azoles of 3-(2-pyridine radicals)-5-yl) pyrrolidines (method 42) are processed as described in the embodiment 143, obtain title compound (80mg, 48%);

NMR(DMSO-d ₆, under 100 ℃): 1.1 (t, 3H), 2.05 (m, 2H), 2.15 (m, 1H), 2.35 (m, 2H), 2,55 (q, 2H), (3.65 m, 1H), 3.75 (m, 1H), 5.4 (d, 1H), (6.05 br s, 1H), 6.4 (br s, 1H), 6.65 (s, 1H), (7.45 m, 1H), 7.90 (m, 2H), 8.65 (d, 1H), 9.25 (br s, 1H), 11.65 (br s, 1H); M/z 438[MH]+.

Embodiment 195

S-6-(2-hydroxyl base oxethyl)-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With S-6-chloro-4-(5-ethyl-1H-pyrazoles-3-the base amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 194) and ethylene glycol processes as described in the embodiment 208, obtain title compound (80mg, 49%).

NMR(DMSO-d ₆ 100℃)：1.17(t，3H)，2.10(m，3H)，2.45(m，1H)， 2.55(q，2H)，3.60(q，2H)，3.75(m，2H)，4.18(m，2H)，4.35(t，1H)，5.42(d，1H)， 5，75(br s，1H)，6.00(br s，1H)，6.66(s，1H)，7.45(m，1H)，7.92(m，2H)， 8.65(br s，1H)，8.65(d，1H)；m/z 464[MH]+。

Embodiment 196

S-6-(2-methoxy ethoxy)-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With S-6-chloro-4-(5-ethyl-1H-pyrazoles-3-the base amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 194) and 2-methyl cellosolve process as described in the embodiment 208, obtain title compound (122mg, 56%).

NMR(DMSO-d ₆, under 100 ℃): 1.18 (t, 3H), 2.10 (m, 3H), 2.30 (m, 1H), 2.52 (q, 2H), 3.20 (s, 3H), 3.50 (q, 2H), 3.70 (m, 1H), 3.75 (m, 1H), 4.25 (t, 2H), 5.40 (d, 2H), 5.75 (br s, 1H), 6.00 (br s, 1H), 6.69 (s, 1H), 7.40 (m, 1H), 7.90 (m, 2H), (8.60 d, 1H), 8.60 (br s, 1H), 11.50 (br s, 1H); M/z 478[MH]+.

Embodiment 197

S-6-morpholine generation-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With S-6-chloro-4-(5-ethyl-1H-pyrazoles-3-the base amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 194) and morpholine process as described in the embodiment 166, obtain title compound (67mg, 30%).

NMR(DMSO-d ₆, under 100 ℃): 1.20 (t, 3H), 2.10 (m, 3H), 2.35 (m, 1H), 2.55 (q, 2H), 3.40 (m, 4H), 3.60 (m, 4H), 3.75 (m, 2H), 5.40 (d, 1H), 5.80 (br s, 1H), 6.00 (br s, 1H), 6.65 (s, 1H), (7.45 m, 1H), 7.95 (m, 1H), 8.35 (br s, 1H), 8.65 (d, 1H), 11.45 (br s, 1H); M/z 489[MH]+.

Embodiment 198

S-6-(4-methyl piperazine-1-yl)-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

S-6-chloro-4-(5-ethyl-1H-pyrazoles-3-the base amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 194) and 1-methyl piperazine process as embodiment 166 is described, obtain title compound (110mg, 49%).

NMR(DMSO-d ₆, under 100 ℃): 1.15 (t, 3H), 2.00 (m, 3H), 2.25 (s, 3H), 2.35 (m, 5H), 2,55 (q, 2H), (3.30 m, 4H), 3.60 (m, 2H), 5.30 (q, 1H), (5.70 br s, 1H), 5.90 (br s, 1H), 6.60 (s, 1H), (7.40 m, 1H), 7.90 (m, 1H), 8.25 (br s, 1H), 8.65 (d, 1H), 11.30 (br s, 1H); M/z 502[MH]+.

Embodiment 199

S-6-chloro-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(2-pyrazine base)-5-yl } pyrrolidines-1-yl] pyrimidine

With 2,6-two chloro-4-(5-ethyl-1H-pyrazoles-3-base amino) pyrimidine (method 72) and the different  azoles of S-2-[3-(2-pyrazine base)-5-yl] pyrrolidines (method 55) processes as embodiment 141 is described, obtain title compound (800mg, 48%).

NMR(DMSO-d ₆, under 100 ℃): 1.18 (t, 3H), 2.05 (m, 3H), (2.15 m, 1H), 2.55 (q, 2H), 3.65 (m, 1H), 3.75 (m, 1H), 5.45 (d, 1H), (6.04 br s, 1H), 6.40 (br s, 1H), (6.78 s, 1H), 8.70 (m, 2H), (9.14 s, 1H), 9.25 (br s, 1H); M/z 439[MH]+.

Embodiment 200 to 207

Following single enantiomter is by separating to be prepared to this racemic compound with chirality HPLC.

Embodiment 200

S-6-first oxygen base-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Title compound be by with the chirality HPLC of chiralpak AD post to (embodiment 48) that this racemic compound separates to be prepared, carry out wash-out with methyl alcohol.

Embodiment 201

S-6-(2-methoxy ethoxy)-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Title compound be by with the chirality HPLC of chiralpak AD post to (embodiment 214) that this racemic compound separates to be prepared, carry out wash-out with methyl alcohol.

Embodiment 202

S-6-pyrrolidines-1-base-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Title compound be by with the chirality HPLC of Chiralpak AS post to (embodiment 95) that this racemic compound separates to be prepared, carry out wash-out with methyl alcohol.

Embodiment 203

S-6-methoxy-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-2-[2-(the different  azoles of 3-cyclopropyl-5-yl) pyrrolidines-1-yl] pyrimidine

Title compound be by with the chirality HPLC of Chiralpak AS post to (embodiment 13) that this racemic compound separates to be prepared, carry out wash-out with methanol/ethanol (85: 15).

Embodiment 204

S-6-morpholino carbonyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Title compound be by with the chirality HPLC of chiralpak AD post to (embodiment 58) that this racemic compound separates to be prepared, carry out wash-out with methanol/ethanol (85: 15).

Embodiment 205

S-6-carbamoyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Title compound be by with the chirality HPLC of chiralpak AD post to (embodiment 61) that this racemic compound separates to be prepared, carry out wash-out with methanol/ethanol (85: 15).

Embodiment 206

S-5-fluoro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Title compound is by with the chirality HPLC with Chiralpak AS post (embodiment 20) that this racemic compound separates to be prepared being carried out wash-out with methyl alcohol.

Embodiment 207

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Title compound be by with the chirality HPLC of Chiralpak AS post to (embodiment 23) that this racemic compound separates to be prepared, carry out wash-out with methyl alcohol.

Embodiment 208

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(2-hydroxyl the base oxethyl)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Hydrogenation sodium (94mg, 2.35mmol) is joined in the ethylene glycol (4ml) in batches. With this mixture stirring 10 minutes and to wherein adding S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 96) (200mg, 0.47mmol). Should react and in the sealing container, under the microwave radiation, heat 1 hour under 150 ℃. Should react extinguishing with 2M hydrochloric acid, then water dilutes and with DCM it is extracted. To extract thing and merge, use the salt water washing, dry (Na₂SO ₄) and by the evaporation desolventizing. With the reversed-phase HPLC that uses the C18 post residue is carried out purifying, water/acetonitrile/TFA (70: 30: 0.2 to polarity be reduced to 30: 70: 0.2) carries out wash-out. The fraction that comprises product is poured on the SCX-2 post, with the neutral impurity of wash-out, then with 3N methyl alcohol ammoniacal liquor product is carried out wash-out with methanol wash. Grind with ether (ether) by the evaporation desolventizing and with residue, obtain title compound (131mg, 62%).

NMR(DMSO)：2.08(m，3H)，2.17(s，3H)，2.36(m，1H)，3.61(m，2H)， 3.71(m，2H)，4.18(m，2H)，5.4(d，1H)，5.75(s，1H)，5.95(s，1H)，6.68(s，1H)， 7.4(m，1H)，7.88(m，1H)，7.94(d，1H)，8.62(d，1H)；m/z 449[MH]+。

Embodiment 209 to 233

Embodiment 209 to 233 uses the method similar to embodiment 208 described methods to be prepared. Reaction time is 30 minutes to 2 hours. In some cases, with 10 equivalents alcohol (alcohol) and 1 to 2ml 2-acetone as solvent. Can replace hydrochloric acid should react extinguishing with glacial acetic acid; And can in the situation of not carrying out the water-based post processing, directly carry out the HPLC purifying to this reactant mixture.

The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺
The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺	209	Embodiment 96 and N, N-two (2-hydroxyl ethyl) first amine	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(2-N-[2-hydroxyl ethyl]-N-methyl-amino } second oxygen base)-the different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	(2.10 m, 3H), 2.19 (s, 3H), (2.27 s, 3H), 2.4 (m, 1H), (2.69 t, 2H), 3.95 (m, 2H), (3.45 t, 2H), 3.72 (m, 2H), (4.23 t, 2H), 5.4 (d, 1H), (5.75 s, 1H), 5.96 (s, 1H), (6.69 s, 1H), 7.43 (m, 1H), 7.9 (m, 2H), (8.6 s, 1H), 8.63 (d, 1H), 11.45 (br s, 1H) are not by deuterate	506
210	Embodiment 96 and 2-morpholine are for ethanol	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(the 2-morpholine is for second oxygen base)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	(2.08 m, 3H), 2.19 (s, 3H), 2.36 (m, 5H), (2.58 t, 2H), 3.51 (t, 4H), 3.92 (m, 2H), (4.23 m, 2H), 5.4 (d, 1H), 5.77 (s, 1H), 5.97 (s, 1H), 6 68 (s, 1H), (7.43 m, 1H), 7.91 (m, 2H), 8.6 (s, 1H), 8.63 (d, 1H), 11.48 (br s, 1H) are not by deuterate	518	209	Embodiment 96 and N, N-two (2-hydroxyl ethyl) first amine			506
210	Embodiment 96 and 2-morpholine are for ethanol			518	211	Embodiment 96 and first mercaptan	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(first sulphur the base)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	2 08(m，3H)，2.17(s，3H)， 2.35(m，4H)，3.7(m，1H)， 3.79(m，1H)，5.42(d，1H)， 5.99(s，1H)，6 27(s，1H)，6 65(s， 1H)，7.4(m，1H)，7.86(m，1H)， 7.93(d，1H)，8 62(d，1H)	435

The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺
The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺	212	Embodiment 17 and oxolane-3-base methyl alcohol	4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(oxolane-3-base first oxygen base)-2-[the different  azoles of 2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	1.57(m，1H)，1.92(m，1H)， 2.09(m，3H)，2.2(s，3H)，2.36(m， 1H)，3.44(m，1H)，2.52(m，1H)， 3.58(m，1H)，3.6-3.8(m，4H)， 4.09(m，2H)，5.38(d，1H)， 5.74(s，1H)，5.99(s，1H)，6.68(s， 1H)，7.41(m，1H)，7.87(m，1H)， 7.95(d，1H)，8.64(d，1H)	489
213	Embodiment 96 and 2-(2-hydroxyl base oxethyl) ethanol	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(2-(2-hydroxyl base oxethyl) second oxygen the base)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	2.07(m，3H)，2.16(s，3H)， 2.35(m，1H)，3.41(m，2H)， 2.46(m，2H)，3.61(m，2H)， 3.72(m，2H)，4.25(t，2H)，5.49(d， 1H)，5.74(s，1H)，5.95(s，1H)， 6.66(s，1H)，7.4(m，1H)，7.85(m， 1H)，7.93(d，1H)，8.62(d，1H)	493	212	Embodiment 17 and oxolane-3-base methyl alcohol			489
213	Embodiment 96 and 2-(2-hydroxyl base oxethyl) ethanol			493	214	Embodiment 17 and 2-methyl cellosolve	4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 6-(2-methoxy ethoxy)-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	2.08(m，3H)，2.16(s，3H)， 2.36(m，1H)，3.19(s，3H)， 3.47(m，2H)，3.66(m，1H)， 3.77(m，1H)，4.24(m，2H)， 5.38(d，1H)，5.68(s，1H)，5.96(s， 1H)，6.66(s，1H)，7.38(m，1H)， 7.83(m，1H)，7.92(d，1H)， 8.61(d，1H)	463

The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺
The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺	215	Embodiment 96 and 1,3-PD	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(3-hydroxyl propoxyl group)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	1.68(m，2H)，2.0(m，3H)，2.09(s， 3H)，2.29(m，1H)，3.39(t，2H)， 3.63(m，2H)，4.14(m，2H)， 5.32(d，1H)，5.65(s，1H)，5.85(s， 1H)，6.58(s，1H)，7.34(t，1H)， 7.78(t，1H)，7.84(d，1H)，8.55(d， 1H)	463
216	Embodiment 96 and 2-(2-methoxy ethoxy) ethanol	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-[2-(2-methoxy ethoxy) second oxygen base]-the different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	2.07(m，3H)，2.16(s，3H)， 2.47(m，1H)，3.2(s，3H)，3.38(m， 2H)，3.48(m，2H)，3.59(m，2H)， 3.72(m，2H)，4.24(t，2H)，5.39(d， 1H)，5.72(s，1H)，5.95(s，1H)， 6.66(s，1H)，7.4 (m，1H)，7.86(m，1H)，7.92(d， 1H)，8.63(d，1H)	507	215	Embodiment 96 and 1,3-PD			463
216	Embodiment 96 and 2-(2-methoxy ethoxy) ethanol			507	217	Embodiment 96 and cellosolvo	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(2-ethoxy ethoxy)-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	1.05(t，3H)，2.08(m，3H)，2.17(s， 3H)，2.39(m，1H)，3.4(q，2H)， 3.56(m，2H)，3.73(m，2H)， 4.25(m，2H)，5.4(d，1H)，5.77(s， 1H)，5.97(s，1H)，6.69(s，1H)， 7.45(m，1H)，7.92(m，2H)， 8.63(m，2H)，11.5(br s，1H)	477

The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH)+
The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH)+	218	Embodiment 96 and 3-morpholine generation third-1-alcohol	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(3-morpholine generation third-1-base oxygen base)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	1.84(m，2H)，2.09(m，3H)， 2.17(s，3H)，2.38(m，1H)， 2.65(m，4H)，2.94(br s，2H)， 3.62(m，4H)，3.73(m，2H)， 4.22(m，2H)，5.4(d，1H)，5.77(s， 1H)，5.98(s，1H)，6.69(s，1H)， 7.45(m，1H)，7.92(m，2H)， 8.65(m，2H)	532
219	Embodiment 96 and 3-methoxy propyl-1-alcohol	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(3-methoxy propyl-1-base oxygen the base)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	1.83(m，2H)，2.08(m，3H)， 2.17(s，3H)，2.32(m，1H)，3.2(s， 3H)，3.37(t，2H)，3.72(m，2H)， 4.19(t，2H)，5.4(d，1H)，5.76(s， 1H)，5.96(s，1H)，6.67(s，1H)， 7.45(m，1H)，7.92(m，2H)， 8.61(s，1H)，8.65(d，1H)	477	218	Embodiment 96 and 3-morpholine generation third-1-alcohol			532
219	Embodiment 96 and 3-methoxy propyl-1-alcohol			477	220	Embodiment 96 and N-(2-hydroxyl ethyl)-pyrrolidines-2-ketone	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-[2-(2-oxo-pyrrolidine-1-yl) second oxygen base]-the different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	1.87(m，2H)，2.1(m，3H)， 2.17(m，5H)，2.38(m，1H)， 3.33(t，2H)，3.45(m，2H)， 3.75(m，2H)，4.27(m，2H)， 5.41(d，1H)，5.76(s，1H)，5.96(s， 1H)，6.69(s，1H)，7.44(m，1H)， 7.93(m，2H)，8.65(d，2H)， 11.5(br s，1H)	516

The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺
The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺	221	Embodiment 96 and (2S)-2-methoxy propyl-1-alcohol	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-[(2S)-2-methoxy propyl-1-base oxygen base]-the different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	1.04(d，3H)，2.1(m，3H)，2.19(s， 3H)，2.39(m，1H)，3.21(s，3H)， 3.53(m，1H)，3.74(m，2H)， 4.11(d，2H)，5.39(d，1H)，5.79(s， 1H)，5.97(s，1H)，6.68(s，1H)， 7.45(m，1H)，7.91(m，2H)， 8.65(d，2H)，11.5(br s，1H)	477
222	Embodiment 96 and 3-first sulphur base third-1-alcohol	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-[3-(first sulphur base) third-1-base oxygen base]-the different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	1.88(m，2H)，2.01(s，3H)， 2.09(m，3H)，2.18(s，3H)， 2.37(m，1H)，2.5(under DMSO peak，2H)，3.72(m，2H)，4.22(t， 2H)，5.4(d，1H)，5.76(s，1H)， 5.96(s，1H)，6.68(s，1H)，7.44(m， 1H)，7.92(m，2H)，8.59(s，1H)， 8.63(d，1H)，11.47(br s，1H)	493	221	Embodiment 96 and (2S)-2-methoxy propyl-1-alcohol			477
222	Embodiment 96 and 3-first sulphur base third-1-alcohol			493	223	Embodiment 96 and (5S)-5-hydroxyl methyl-pyrrolidines-2-ketone	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-[(2S)-and 5-oxo-pyrrolidine-2-yl) first oxygen base]-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	1.74(m，1H)，2.1(m，6H)，2.18(s， 3H)，2.39(m，1H)，3.73(m，3H)， 4.1(m，2H)，5.4(d，1H)，5.78(s， 1H)，5.94(s，1H)，6.7(s，1H)， 7.25(s，1H)，7.44(m，1H)， 7.92(m，2H)，8.63(d，2H)	502

The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺
The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺	224	Embodiment 96 and (5R)-5-hydroxyl methyl-pyrrolidines-2-ketone	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-[(2R)-and 5-oxo-pyrrolidine-2-yl) first oxygen base]-2-[2-{ the different  azoles of 3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	1.75(m，1H)，2.1(m，6H)，2.18(s， 3H)，2.38(m，1H)，3.74(m，3H)， 4.1(m，2H)，5.4(d，1H)，5.8(s， 1H)，5.97(s，1H)，6.71(s，1H)， 7.3(s，1H)，7.45(m，1H)，7.91(m， 2H)，8.65(d，2H)，11.5(br s，1H)	502
225	Embodiment 96 and 2-1-(2-hydroxyl ethyl) imidazoles alkane-2-ketone	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-[2-(imidazoles alkane-2-ketone-1-yl) second oxygen base]-the different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	2.08(m，3H)，2.17(s，3H)， 2.37(m，1H)，3.18(t，2H)， 3.32(m，4H)，3.72(m，2H)， 4.25(m，2H)，5.41(d，1H)， 5.78(s，1H)，5.86(s，1H)，5.97(s， 1H)，6.7(s，1H)，7.44(m，1H)， 7.92(m，2H)，8.65(d，2H)， 11.5(br s，1H)	517	224				502
225				517	226	The sub-method a of embodiment 96 and ethanol	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 6-second oxygen base-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	1.2(t，3H)，2.09(m，3H)，2.17(s， 3H)，2.38(m，1H)，3.72(m，2H)， 4.19(q，2H)，5.39(d，1H)，5.75(s， 1H)，5.97(s，1H)，6.68(s，1H)， 7.45(m，1H)，7.91(m，2H)， 8.57(s，1H)，8.65(d，1H)， 11.46(br s，1H)	433
227	Embodiment 96 and (2R)-1, the sub-method a of 2-propane diols	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 6-hydroxyl-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	2.1(m，3H)，2.18(s，3H)，2.36(m， 1H)，3.62(m，1H)，3.8(m，1H)， 5.45(s，1H)，5.53(s，1H)，5.84(s， 1H)，6.77(s，1H)，7.47(m，1H)， 7.94(m，2H)，8.34(s，1H)， 8.68(d，1H)	405	226	The sub-method a of embodiment 96 and ethanol			433

The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺
The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺	228	Embodiment 242 and 2-methyl cellosolve	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(2-methoxy ethoxy)-2-[2-{ the different  azoles of 3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	2.07(m，3H)，2.13(s，3H)， 2.37(m，1H)，3.18(s，3H)， 3.48(m，2H)，3.68(m，1H)， 3.75(m，1H)，4.24(m，2H)， 5.37(d，1H)，5.75(s，1H)，5.93(s， 1H)，6.65(s，1H)，7.81(s，1H)， 7.98(s，1H)，8.6(s，1H)，11.43(s， 1H)	469
229	Embodiment 242 and ethylene glycol	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(2-hydroxyl base oxethyl)-2-[2-{ the different  azoles of 3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	2.09(m，3H)，2.17(s，3H)， 2.38(m，1H)，3.61(m，2H)， 3.72(m，2H)，4.17(m，2H)， 4.33(s，1H)，5.4(d，1H)，5.78(s， 1H)，5.94(s，1H)，6.68(s，1H)， 7.85(d，1H)，7.99(d，1H)，8.62(s， 1H)，11.48(s，1H)	455	228	Embodiment 242 and 2-methyl cellosolve			469
229	Embodiment 242 and ethylene glycol			455	230	Embodiment 96 and (2R)-1, the sub-method b of 2-propane diols	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-[(2R)-2-hydroxyl third-1-base oxygen base]-the different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	1.07(d，3H)，2.09(m，3H)， 2.18(s，3H)，2.38(m，1H)， 3.42(m，1H)，3.71(m，2H)，3.85- 4.07(m，2H)，4.3(d，1H)，5.4(d， 1H)，5.76(br d，1H)，5.94(s，1H)， 6.67(s，1H)，7.43(m，1H)，7.9(m， 2H)，8.6(s，1H)，8.64(d，1H)， 11.45(br s，1H)	463

The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺
The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺	231	The sub-method c of embodiment 199 and 2-methyl cellosolve	S-4-(5-ethyl-1H-pyrazoles-3-base is amino)-6-(2-methoxy ethoxy)-2-[2-{ the different  azoles of 3-(pyrazine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	1.18(t，3H)，2.1(m，3H)，2.4(m， 1H)，2.55(q，2H)，3.21(s，3H)， 3.53(m，2H)，3.73(m，2H)， 4.25(t，2H)，5.41(d，1H)，5.77(s， 1H)，6.0(s，1H)，6.77(s，1H)， 8.65(s，1H)，8.7(m，2H)，9.16(s， 1H)，11.51(s，1H)	478
232	The sub-method c of embodiment 199 and methyl alcohol	S-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 6-first oxygen base-2-[2-{3-(pyrazine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	1.2(t，3H)，2.12(m，3H)，2.42(m， 1H)，2.56(q，2H)，3.75(s，3H)， 3.78(m，2H)，5.47(d，1H)，5.8(s， 1H)，6.02(s，1H)，6.7(s，1H)， 8.66(s，1H)，8.72(m，2H)，9.16(s， 1H)	434	231	The sub-method c of embodiment 199 and 2-methyl cellosolve			478
232	The sub-method c of embodiment 199 and methyl alcohol			434	233	The sub-method c of embodiment 243 and ethylene glycol	S-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-6-(2-hydroxyl base oxethyl)-2-[the different  azoles of 2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	0.64(d，2H)，0.87(d，2H)， 1.82(m，1H)，2.07(m，3H)， 2.38(m，1H)，3.62(m，2H)， 3.71(m，2H)，4.15(m，2H)， 4.33(t，1H)，5.4(d，1H)，5.75(s， 1H)，5.9(s，1H)，6.67(s，1H)， 7.83(d，1H)，7.98(d，1H)，8.64(s， 1H)，11.55(s，1H)	481

Sub-method

A. directly with hplc to carrying out purifying with the reaction of glacial acetic acid mixture extinguishing.

B. will react extinguishing with glacial acetic acid, the water dilution, then with the DCM extraction, dry (Na₂SO ₄), then evaporation uses the hplc purifying.

C. will react extinguishing with saturated ammonium chloride solution, then with the DCM extraction, dry (Na₂SO ₄), then evaporation uses the hplc purifying.

Embodiment 234

S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-6-(tetrahydropyran-4-base oxygen the base)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With cesium fluoride (681mg, 3.5mmol) and S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-the base amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl pyrrolidines-1-yl] pyrimidine (embodiment 96) (300mg, 0.71mmol) heated 2 hours under the microwave radiation sealing in the container under 200 ℃ in (3ml) at tetrahydrochysene-4-pyrans pure (pyranol). Extract with this reactant mixture water dilution and with DCM. To extract thing and merge, use the salt water washing, dry (Na₂SO ₄) and by the evaporation desolventizing. With the reversed-phase HPLC that uses the C18 post residue is carried out purifying, water/acetonitrile/TFA (70: 30: 0.2 to polarity be reduced to 30: 70: 0.2) carries out wash-out. The fraction that will comprise product is poured on the SCX-2 post, uses methanol wash, then with 7N methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain title compound (107mg, 31%).

NMR(DMSO)：1.41(m，1H)，1.61(m，2H)，1.94(m，1H)，2.05(m，3H)， 2.17(s，3H)，2.35(m，1H)，3.29(t，1H)，3.44(m，1H)，3.65(m，2H)，3.8(m，2H)， 4.96(m，1H)，5.33(d，1H)，5.7(s，1H)，5.96(s，1H)，6.65(s，1H)，7.4(m，1H)， 7.84(m，1H)，7.91(d，1H)，8.61(d，1H)；m/z 489[MH]+。

Embodiment 235

S-5-fluoro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With 2-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-5-FU (method 27 (b)) (175mg, 0.77mmol), S-2-(the different  azoles of 3-(thiazole-2-yl)-5-yl) pyrrolidines (method 77) (187mg, 0.85mmol) and diisopropyl ethyl amine (0.28ml, 1.6mmol) at the mixture of oneself alcohol of 1-in (3ml) 130 ℃ of lower heating 48 hours. By the evaporation desolventizing and residue carried out purifying with column chromatography, carry out wash-out with EtOAc/ hexane (1: 1 to polarity increase to 2: 1). This product that has carried out purifying is ground with ether and by filtering it is collected, obtain title compound (79mg, 25%)

NMR(DMSO)：2.06(m，3H)，2.18(s，3H)，2.38(m，1H)，3.64(m，1H)， 3.76(m，1H)，5.36(d，1H)，6.11(s，1H)，6.62(s，1H)，7.85(d，1H)，7.9(d，1H)， 7.98(d，1H)，8.82(br s，1H)，11.64(br s，1H)；m/z 413[MH]+。

Embodiment 236 to 241

Embodiment 236 to 241 uses the method similar to embodiment 235 described methods to be prepared.

The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺
The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺	236	Method 73 and 2,5-, two chloro-4-(5-methyl-1H-pyrazoles-3-base is amino) pyrimidine	S-5-chloro-4-(5-methyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-4-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	2.09(m，3H)，2.18(s，3H)， 2.35(m，1H)，3.65(m，1H)， 3.75(m，1H)，5.35(d，1H)， 6.17(s，1H)，6.51(s，1H)， 7.95(s，1H)，8.06(s，1H)， 9.04(s，1H)	429
237	Method 77 and method 69	S-5-fluoro-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	1.19(t，3H)，2.09(m，3H)， 2.38(m，1H)，2.58(q，2H)， 3.64(m，1H)，3.75(m，1H)， 5.38(d，1H)，6.17(s，1H)， 6.62(s，1H)，7.85(d，1H)， 7.91(d，1H)，7.98(d，1H)， 8.85(br s，1H)，11.69(br s， 1H)	427	236				429
237	Method 77 and method 69			427	238	Method 77 and method 26	S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	2.09(m，3H)，2.17(s，3H)， 2.36(m，1H)，3.66(m，1H)， 3.78(m，1H)，5.43(d，1H)， 6.0(s，1H)，6.29(d，1H)， 6.64(s，1H)，7.77(d，1H)， 7.85(d，1H)，7.95(d，1H)	395
239	Method 77 and method 65 sub-method d	S-4-(5-ethyl-1H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	1.18(t，3H)，2.09(m，3H)， 2.3(m，1H)，2.55(q，2H)， 3.68(m，1H)，3.77(m，1H)， 5.43(d，1H)，6.07(s，1H)， 6.3(s，1H)，6.64(s，1H)， 7.86(m，2H)，7.98(d，1H)， 8.92(s，1H)，11.57(s，1H)	409	238	Method 77 and method 26			395

The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺
The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺	240	Method 77 and method 28 sub-method d	S-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-2-[the different  azoles of 2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	0.65(d，2H)，0.87(d，2H)， 1.85(m，1H)，2.06(m，3H)， 2.37(m，1H)，3.67(m，2H)， 5.43(d，1H)，5.96(s，1H)， 6.27(s，1H)，6.59(s，1H)， 7.82(m，2H)，7.97(d，1H)， 8.89(s，1H)，11.55(s，1H)	421
241	Method 77 and method 27 sub-method d	S-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 5-fluoro-2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	0.67(m，2H)，0.88(m，2H)， 1.83(m，1H)，2.08(m，3H)， 2.35(m，1H)，3.64(m，1H)， 3.75(m，1H)，5.38(d，1H)， 6.09(s，1H)，6.61(s，1H)， 7.86(d，1H)，7.91(d，1H)， 7.99(d，1H)，8.83(s，1H)	439	240	Method 77 and method 28 sub-method d			421

Sub-method

D. crude product is used the hplc purifying, the fraction that will comprise product is poured on the SCX-2 ion exchange column, carries out wash-out to remove neutral impurity with methyl alcohol, then with methyl alcohol ammoniacal liquor product is carried out wash-out.

Embodiment 242

S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

2,6-, two chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (method 29) and S-2-(the different  azoles of 3-(thiazole-2-yl)-5-yl) pyrrolidines (method 77) are processed as described in the embodiment 96. With silica gel column chromatography the product crude product is carried out purifying, carry out wash-out with EtOAc/ hexane (7: 3). This product that has carried out purifying is ground with ether and by filtering it is collected, obtain the title compound (0.89g, 57%) of white solid form.

NMR(DMSO)：2.09(m，3H)，2.18(s，3H)，2.39(m，1H)，3.66(m，1H)， 3.75(m，1H)，5.42(d，1H)，5.97(s，1H)，6.39(s，1H)，6.71(s，1H)，7.85(d，1H)， 7.98(d，1H)，9.22(s，1H)，11.62(s，1H)；m/z 429[MH]+。

Embodiment 243

S-6-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With 2,6-two chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine (method 57) and S-2-(the different  azoles of 3-(thiazole-2-yl)-5-yl) pyrrolidines (method 77) are processed as described in the embodiment 242, obtain the title compound (183mg, 29%) of white solid form.

NMR(DMSO 373K+d4AcOH)：0.65(m，2H)，0.88(m，2H)，1.8(m， 1H)，2.04(m，2H)，2.13(m，1H)，2.37(m，1H)，3.65(m，1H)，3.72(m，1H)， 5.42(d，1H)，5.94(s，1H)，6.38(s，1H)，6.67(s，1H)，7.81(d，1H)，7.97(s，1H)； m/z 455[MH]+。

Embodiment 244

S-6-morpholine generation-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-the base amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine (embodiment 242) (150mg, 0.35mmol) and morpholines (3ml) heated 30 minutes under the microwave radiation sealing in the container under 120 ℃. This reactant mixture is carried out purifying with the reversed-phase HPLC that uses the C18 post, and water/acetonitrile/TFA (97.5: 2.5: 0.2 to polarity be reduced to 60: 40: 0.2) carries out wash-out. The fraction that will comprise product is poured on the SCX-2 post, falls neutral impurity with methanol wash, then with 3.5N methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, residue is ground with ether and by filtering it is collected, obtain the title compound (72mg, 43%) of cream-colored solid form.

NMR(DMSO)：2.07(m，3H)，2.16(s，3H)，2.37(m，1H)，3.35(m，4H)， 3.57(m，4H)，3.71(m，2H)，5.37(d，1H)，5.75(s，1H)，5.94(s，1H)，6.64(s，1H)， 7.85(d，1H)，7.99(d，1H)，8.34(s，1H)，11.42(s，1H)；m/z 480[MH]+。

Embodiment 245 to 248

Embodiment 245 to 248 uses the method similar to embodiment 244 described methods to be prepared.

The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺
The embodiment sequence number	Initial material	The compound title	NMR(DMSO 373K+d4AcOH)	m/z(MH) ⁺	245	Embodiment 199 and morpholine	S-6-morpholine generation-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrazine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	1.18(t，3H)，2.07(m，3H)， 2.37(m，1H)，2.53(q，2H)， 3.37(m，4H)，3.58(m，4H)， 3.72(m，2H)，5.41(d，1H)， 5.76(s，1H)，5.98(s，1H)，6.73(s， 1H)，8.35(s，1H)，8.7(m，2H)， 9.14(s，1H)，11.45(s，1H)	489
246	Embodiment 242 and 2-methoxy ethyl amine method e	S-6-(the 2-methoxy ethyl is amino)-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[the different  azoles of 2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	2.05(m，3H)，2.15(s，3H)， 2.33(m，1H)，2.68(s，3H)， 3.71(m，2H)，5.4(d，1H)，5.49(s， 1H)，5.83(s，1H)，5.99(s，1H)， 6.65(s，1H)，7.83(d，1H)，7.97(d， 1H)，8.19(br s，1H)	424	245	Embodiment 199 and morpholine			489
246	Embodiment 242 and 2-methoxy ethyl amine method e			424	247	Embodiment 242 and first amine method f	S-6-methyl amino-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	2.05(m，3H)，2.14(s，3H)， 2.35(m，1H)，3.19(s，3H)，3.3(m， 4H)，3.69(m，2H)，5.37(d，1H)， 5.54(s，1H)，5.86(s，1H)，6.62(s， 1H)，7.8(d，1H)，7.95(d，1H)	468
248	Embodiment 242 and the sub-method g of 1-methyl piperazine	S-6-(4-methyl piperazine-1 base)-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-{ the different  azoles of 3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine	2.05(m，3H)，2.15(s，3H)， 2.26(m，4H)，2.36(m，1H)， 3.37(m，4H)，3.71(m，2H)， 5.35(d，1H)，5.77(s，1H)，5.94(s， 1H)，6.64(s，1H)，7.85(d，1H)， 7.98(d，1H)，8.26(br s，1H)	493	247	Embodiment 242 and first amine method f			468

Sub-method

E. 150 ℃ of lower heating 90 minutes.

F. the solution of first amine in ethanol. 90 minutes 5g. post-reaction treatment of heating under 130 ℃: the dilution of-water, with the EtOAc extraction, dry (Na₂SO ₄) and evaporate volatile materials. With silica gel column chromatography residue is carried out purifying, carry out wash-out with methyl alcohol/DCM/ ammoniacal liquor (5: 95: 0, then 5: 94: 1).

Embodiment 249

S-6-methyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With 2-chloro-6-methyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-pyrimidine (method 56) (200mg, 0.89mmol), S-2-(the different  azoles of 3-(thiazole-2-yl)-5-yl) pyrrolidines (method 77) (218mg, 0.98mmol) and N, N-diisopropyl ethyl amine (0.37ml, 2.1mmol) is suspended in oneself alcohol (4ml) of 1-and with it and was heating 3 hours under the microwave radiation in the sealing container under 150 ℃. Reactant mixture is carried out purifying with the reversed-phase HPLC that uses the C18 post, and water/acetonitrile/TFA (97.5: 2.5: 0.2 to polarity be reduced to 60: 40: 0.2) carries out wash-out. The fraction that will comprise product be poured on the SCX-2 ion exchange column and with methanol wash to remove neutral substance, then with 3.5N methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, residue is ground with ether and by filtering it is collected, obtain the title compound (164mg, 45%) of white solid form.

NMR(DMSO)：2.07(m，3H)，2.12(s，3H)，2.18(s，3H)，2.36(m，1H)， 3.71(m，2H)，5.43(d，1H)，5.99(s，1H)，6.19(s，1H)，6.64(s，1H)，7.85(d，1H)， 7.98(d，1H)，8.73(s，1H)，11.5(s，1H)；m/z 409[MH]+。

Embodiment 250

S-6-[3-(methyl sulphonyl) propyl group-1-oxygen base]-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With peroxidating sulfate mono potassium, sulfuric acid hydrogen potassium, potassium sulfate complex compound (oxone^TM) (227mg, 0.37mmol) solution in water (1.3ml) is added drop-wise to and carrying out the S-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) that stirs-6-[3-(first sulphur base) third-1-base oxygen base]-the different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] in the solution of pyrimidine (embodiment 222) (130mg, 0.26mmol) in THF (1.3ml). This mixture was at room temperature stirred 2 hours, and then water dilutes and with the 1M potassium hydroxide aqueous solution its pH is transferred to 8. This mixture is merged with ethyl acetate (x3) extraction and with organic extract, with salt water washing and drying (Na₂SO ₄). Carry out purifying by the evaporation desolventizing and with residue with the reversed-phase HPLC of use C18 post, water/acetonitrile/TFA (70: 30: 0.2 to polarity be reduced to 30: 70: 0.2) washs. The fraction that will comprise product is poured on the SCX-2 ion exchange column, with methyl alcohol this post is washed, and then with 3.5N methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, residue is ground with ether and by filtering it is collected, obtain the title compound (45mg, 33%) of cream-colored solid form.

NMR(DMSO)：2.09(m，5H)，2.17(s，3H)，2.37(m，1H)，2.94(s，3H)， 3.13(t，2H)，3.72(m，2H)，4.28(m，2H)，5.4(d，1H)，5.78(s，1H)，5.95(s，1H)， 6.7(s，1H)，7.44(m，1H)，7.92(m，2H)，8.66(d，2H)，11.5(br s，1H)；m/z 525 [MH]+。

Embodiment 251

The different  azoles of S-6-(2-methoxy ethoxy)-2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

With the method similar to the method for embodiment 208 to the different  azoles of S-6-chloro-2-{2-[3-(pyrazine-2-yl)-5-yl] pyrrolidines-1-yl-4-(5-cyclopropyl-1H-pyrazoles-3-base amino) pyrimidine (embodiment 91) and 2-methyl cellosolve process, just with silica gel column chromatography the product crude product is carried out purifying, carry out wash-out with hexane/EtOAc (80: 20 to polarity increase to 0: 100), obtain the title compound (70mg, 21%) of pale yellow powder form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 0.65 (m, 2H), 0.85 (m, 2H), 1.85 (m, 1H), 2.00-2.15 (m, 3H), 2.40 (m, 1H), 3.20 (s, 3H), 3.50 (m, 2H), 3.70 (m, 1H), 3.75 (m, 1H), 4.25 (t, 2H), 5.40 (d, 1H), (5.55 s, 1H), 5.70 (s, 1H), 5.90 (s, 1H), (6.70 s, 1H), 8.65 (m, 2H), 9.10 (s, 1H); M/z 490[MH]+.

Embodiment 252

The different  azoles of S-6-chloro-2-{2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines-1-yl }-4-(5-ethyl-1H-pyrazoles-3-base is amino) pyrimidine

With the method similar to embodiment 161 described methods to 2,6-two chloro-4-(5-ethyl-1H-pyrazoles-3-base amino) pyrimidine (method 72) and the different  azoles of S-2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines (method 66) processes, obtain the title compound (364mg, 49%) of white powder form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.15 (m, 3H), 2.00-2.20 (m. 3H), (2.40 m, 1H), 2.55 (m, 2H), (3.65 m, 1H), 3.75 (m, 1H), (5.45 d, 1H), 6.05 (br s, 1H), (6.47 s, 1H), 6.70 (s, 1H), (7.48 t, 1H), 8.85 (d, 2H); M/z 438 [MH]+.

Embodiment 253

The different  azoles of S-6-first oxygen base-2-{2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines-1-yl }-4-(5-ethyl-1H-pyrazoles-3-base is amino) pyrimidine

With the method similar to embodiment 94 described methods to the different  azoles of S-6-chloro-2-{2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines-1-yl-4-(5-ethyl-1H-pyrazoles-3-base amino) pyrimidine (embodiment 252) processes, obtain the title compound (118mg, 80%) of pink powder form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.15 (t, 3H), 2.00-2.15 (m, 3H), 2.35 (m, 1H), 2.55 (q, 2H), 3.70 (m, 4H), 3.75 (m, 1H), 5.40 (d, 1H), 5.55 (s, 1H), 6.67 (s, 1H), 7.45 (t, 1H), 8.85 (d, 2H); M/z 434[MH]+.

Embodiment 254

The different  azoles of S-6-ethyl-2-{2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines-1-yl }-4-(5-ethyl-1H-pyrazoles-3-base is amino) pyrimidine

With the different  azoles of S-2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines (method 66) (198mg, 0.91mmol), the mixture of 6-ethyl-2-chloro-4-(5-ethyl-1H-pyrazoles-3-base amino) pyrimidine (method 79) (210mg, 0.83mmol) and two-isopropyl ethyl amine in oneself alcohol (4ml) in heating 60 minutes under the microwave radiation under 150 ℃. Make this reactant mixture crude product 10g SCX post of flowing through, use methanol-eluted fractions, then with 2M methyl alcohol ammoniacal liquor product is carried out wash-out and by the evaporation desolventizing. With residue column chromatography purifying, with DCM/2M methyl alcohol ammoniacal liquor (100: 0 to polarity increase to 90: 10) wash-out, obtain the title compound (78mg, 22 %) of filbert powder type.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.00-1.20 (m, 6H), 2.00-2.15 (m, 3H), (2.35-2.45 m, 3H), 2.55 (q, 2H), (3.65-3.80 m, 2H), 5.45 (d, 1H), (5.60 s, 1H), 6.10 (s, 1H), (6.20 s, 1H), 6.70 (s, 1H), (7.50 t, 1H), 8.90 (d, 2H); M/z 432[MH]+.

Embodiment 255

The different  azoles of S-6-amino methyl-2-{2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines-1-yl }-4-(5-ethyl-1H-pyrazoles-3-base is amino) pyrimidine

With the method similar to embodiment 140 described methods to the different  azoles of S-6-chloro-2-{2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines-1-yl-4-(5-ethyl-1H-pyrazoles-3-base amino) pyrimidine (embodiment 252) processes, obtain the title compound (20mg, 13%) of brown solid.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.15 (t, 3H), 2.00-2.15 (m, 3H), .35 (m, 1H), 2.55 (q, 2H), (2.65 s, 3H), 3.60-3.80 (m, 2H), (5.45 d, 1H), 5.60 (s, 1H), (5.90 s, 1H), 6.70 (s, 1H), 7.45 (, 1H), 8.85 (d, 2H); M/z 433 [MH]+.

Embodiment 256

The different  azoles of S-6-ethyl-2-{2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

With the method similar to embodiment 254 described methods to 6-ethyl-2-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base amino) pyrimidine (method 80) and the different  azoles of S-2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines (method 66) processes, obtain the title compound (230mg, 68%) of brown powder form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 0.65 (m, 2H), 0.85 (m, 2H), 1.10 (t, 3H), 1.80 (m, 1H), 2.05 (m, 2H), (2.15 m, 1H), 2.30-2.45 (m, 3H), 3.67 (m, 1H), 3.75 (m, 1H), 5.45 (dd, 1H), (5.55 s, 1H), 5.95 (s, 1H), 6.15 (s, 1H), 7.48 (t, 1H), 8.85 (d, 2H); M/z 444[MH]+.

Embodiment 257

The different  azoles of S-6-cyclopropyl-2-{2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

With the method similar to embodiment 254 described methods to 6-cyclopropyl-2-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base amino) pyrimidine (method 81) and the different  azoles of S-2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines (method 66) processes, obtain the title compound (89mg, 27%) of brown powder form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 0.65-0.90 (m, 7H), 0.95 (m, 1H), 1.70 (m, 1H), 1.85 (m, 1H), 2.00-2.15 (m, 3H), (2.35 m, 1H), 3.65 (m, 1H), 3.75 (m, 1H), 5.35 (dd, 1H), 5.65 (s, 1H), (6.00 s, 1H), 6.20 (s, 1H), 6.65 (s, 1H), 7.50 (t, 1H), 8.90 (d, 1H); M/z 456[MH]+.

Embodiment 258

The different  azoles of S-6-cyclopropyl-2-{2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines-1-yl }-4-(5-ethyl-1H-pyrazoles-3-base is amino) pyrimidine

With the method similar to embodiment 254 described methods to 6-cyclopropyl-2-chloro-4-(5-ethyl-1H-pyrazoles-3-base amino) pyrimidine (method 82) and the different  azoles of S-2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines (method 66) processes, obtain the title compound (80mg, 49%) of brown powder form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 0.70-0.80 (m, 3H), 0.95 (m, 1H), 1.15 (t, 3H), 1.70 (m, 1H), 2.00-2.15 (m, 3H), 2.35 (m, 1H), 2.55 (q, 2H), 3.65 (m, 1H), 3.75 (m, 1H), 5.35 (dd, 1H), 5.60 (s, 1H), (6.05 s, 1H), 6.20 (s, 1H), 6.65 (s, 1H), 7.45 (t, 1H), 8.90 (d, 2H); M/z 444[MH]+.

Embodiment 259

The different  azoles of S-6-(2-methoxy ethoxy)-2-{2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines-1-yl }-4-(5-ethyl-1H-pyrazoles-3-base is amino) pyrimidine

With the method similar to embodiment 208 described methods to the different  azoles of S-6-chloro-2-{2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines-1-yl-4-(5-ethyl-1H-pyrazoles-3-base amino) pyrimidine (embodiment 252) and 2-methyl cellosolve process, just with silica gel column chromatography the product crude product is carried out purifying, carry out wash-out with DCM/2M methyl alcohol ammoniacal liquor (100: 0 to polarity increase to 95: 5), obtain the title compound (118mg, 47%) of white solid form.

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.15 (t, 3H), 2.00-2.20m, 3H), 2.40 (m, 1H), 2.55 (q, 2H), 3.20 (s, 3H), 3.50 (m, 2H), 3.65 (m, 1H), 3.75 (m, 1H), 4.25 (t, 2H), 5.40 (dd, 1H), 5.55 (s, 1H), (5.70 s, 1H), 6.00 (s, 1H), 6.70 (s, 1H), 7.45 (t, 1H), 8.85 (d, 2H); M/z 478[MH]+.

Embodiment 260

S-6-methyl-2-{2-[3-(3-first oxygen base pyrazine-2-yl) different  azoles-5-yl] pyrrolidines-1-yl }-4-(5-ethyl-1H-pyrazoles-3-base is amino) pyrimidine

With 2-chloro-6-methyl-4-(5-ethyl-1H-pyrazoles-3-base is amino) pyrimidine (method 83) (105mg, 0.44mmol), S-2-[3-(2-first oxygen base pyrazine-3-yl) different  azoles-5-yl] pyrrolidines (method 68) (120mg, 0.49mmol), the mixture of diisopropyl ethyl amine (0.12ml, 0.69mmol) and oneself alcohol (3ml) is in heating 1 hour under the microwave radiation in the sealing container under 150 ℃. This reactant mixture crude product is poured on the isolute SCX-2 ion exchange column. With methyl alcohol this post is carried out wash-out to elute any neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing and residue carried out purifying with silica gel column chromatography, carry out wash-out with DCM/2M methyl alcohol ammoniacal liquor (100: 0 to polarity increase to 90: 10), obtain the title compound (86mg, 44%) of khaki solid form.

NMR(DMSO-d ₆, under 100 ℃): 1.21 (t, 3H), 2.07 (m, 3H), (2.16 s, 3H), 2.37 (m, 1H), 2.58 (q, 2H), 3.71 (m, 2H), 4.01 (s, 3H), (5.50 dd, 1H), 6.08 (s, 1H), 6.22 (s, 1H), 6.63 (s, 1H), 8.33 (s, 2H), (8.78 br s, 1H), 11.51 (br s, 1H); M/z 449[MH]+.

Embodiment 261

S-6-chloro-2-{2-[3-(3-first oxygen base pyrazine-2-yl) different  azoles-5-yl] pyrrolidines-1-yl }-4-(5-ethyl-1H-pyrazoles-3-base is amino) pyrimidine

With 2,6-two chloro-4-(5-ethyl-1H-pyrazoles-3-base is amino) pyrimidine (method 72) (570mg, 2.2mmol), S-2-[3-(2-first oxygen base pyrazine-3-yl) different  azoles-5-yl] pyrrolidines (method 68) (600mgs, 2.4mmol), the mixture of diisopropyl ethyl amine (310mg, 2.4mmol) in n-butyl alcohol (10ml) be 75 ℃ of lower heating 16 hours. By the evaporation desolventizing and residue carried out purifying with silica gel column chromatography, carry out wash-out with hexane/EtOAc (80: 20 to polarity increase to 0: 100), obtain the title compound (450mg, 44%) of white foam form.

NMR(DMSO-d ₆, under 100 ℃): 1.21 (t, 3H), 2.07 (m, 3H), (2.37 m, 1H), 2.58 (q, 2H), 3.71 (m, 2H), 4.01 (s, 3H), 5.50 (dd, 1H), (6.08 s, 1H), 6.42 (s, 1H), (6.66 s, 1H), 8.33 (s, 2H), (9.27 s, 1H), 11.61 (s, 1H); M/z 469[MH]+.

Embodiment 262

S-6-methyl-2-{2-[3-(3-first oxygen base pyrazine-2-yl) different  azoles-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

With the method similar to embodiment 260 described methods to 2-chloro-6-methyl-4-(5-cyclopropyl-1H-pyrazoles-3-base amino) pyrimidine (method 70) and S-2-[3-(2-first oxygen base pyrazine-3-yl) different  azoles-5-yl] pyrrolidines (method 68) processes, obtain title compound (88mg, 40%).

NMR(DMSO-d ₆, under 100 ℃): 0.68 (m, 2H), 0.89 (m, 2H), 1.89 (m, 1H), 2.07 (m, 3H), 2.18 (s, 3H), (2.37 m, 1H), 3.71 (m, 2H), 4.01 (s, 3H), 5.50 (dd, 1H), 5.97 (s, 1H), (6.17 s, 1H), 6.66 (s, 1H), 8.33 (s, 2H), 8.72 (br s, 1H), 11.58 (br s, 1H); M/z 461[MH]+.

Embodiment 263

S-6-morpholine generation-2-{2-[3-(3-first oxygen base pyrazine-2-yl) different  azoles-5-yl] pyrrolidines-1-yl }-4-(5-ethyl-1H-pyrazoles-3-base is amino) pyrimidine

With S-6-chloro-2-{2-[3-(3-first oxygen base pyrazine-2-yl) different  azoles-5-yl] pyrrolidines-1-yl }-4-(5-ethyl-1H-pyrazoles-3-base amino) mixture of pyrimidine (embodiment 261) (250mg, 0.5mmol) in morpholine (3ml) be in heating 2 hours under the microwave radiation in the sealing container under 70 ℃. This reactant mixture crude product is carried out purifying with the reversed-phase HPLC that uses the C18 post, and water/acetonitrile/TFA (95: 5: 0.2 to polarity be reduced to 0: 100: 0.2) carries out wash-out. To comprise the fraction merging of product and make it pass through an isolute SCX-2 ion exchange column. With methyl alcohol this post is carried out wash-out to elute any neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. Grind with hexane by the evaporation desolventizing and with residue, by filtering it is collected, obtain the title compound (81mg, 31%) of white solid form.

NMR(DMSO-d ₆, under 100 ℃): 1.20 (t, 3H), 2.07 (m, 3H), (2.37 m, 1H), 2.58 (q, 2H), 3.39 (m, 4H), 3.59 (m, 4H), 3.71 (m, 2H), (4.01 s, 3H), 5.44 (dd, 1H), 5.77 (br s, 1H), 6.01 (br s, 1H), 6.62 (s, 1H), (8.27 s, 3H), 11.42 (br s, 1H); M/z 520[MH]+.

Embodiment 264

The different  azoles of S-6-morpholine generation-2-[2-{3-(3-hydroxyl pyrazine-2-yl)-5-yl } pyrrolidines-1-yl]-4-(5-ethyl-1H-pyrazoles-3-base is amino)-pyrimidine

Title compound is with the form of accessory substance be separated from the preparation of embodiment 263 (30mg, 11%).

NMR(DMSO-d ₆, under 100 ℃): 1.20 (t, 3H), 2.07 (m, 3H), (2.37 m, 1H), 2.58 (q, 2H), 3.39 (m, 4H), 3.59 (m, 4H), 3.71 (m, 2H), (5.40 dd, 1H), 5.81 (s, 1H), 6.03 (s, 1H), 6.71 (s, 1H), 7.58 (s, 2H), (8.31 s, 1H), 11.42 (br s, 1H); M/z 505[MH]+.

Embodiment 265

S-6-methyl-2-{2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With 6-methyl-2-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (method 56) (200mg, 0.9mmol), S-2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines (method 64) (262mg, 1.1mmol) and diisopropyl ethyl amine (0.22ml, 1.25mmol) at the mixture of oneself alcohol in (5ml) in heating 105 minutes under the microwave radiation in the sealing container under 150 ℃. Remove volatile materials by evaporation, residue is dissolved in EtOAc, wash with water, dry (MgSO₄), and by the evaporation desolventizing. Residue is carried out purifying with silica gel column chromatography, carry out wash-out with EtOAc/ hexane (1: 1), obtain title compound (160mg, 42%).

NMR(DMSO)：2.0-2.2(m，9H)，2.30-2.40(m，1H)，3.65-3.70(m，2H)， 3.90(s，3H)，5.40(dd，1H)，6.0(s，1H)，6.19(s，1H)，6.60(s，1H)，7.10(dd，1H)， 8.10(dd，1H)，8.25(d，1H)，8.70(s，1H)，11.45(s，1H)；m/z 433[MH]+。

Embodiment 266

S-5-fluoro-2-{2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl }-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

With 2-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-5-FU (method 27) (150mg, 0.6mmol), S-2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines (method 64) (194mg, 0.8mmol), diisopropyl ethyl amine (0.29ml, 1.6mmol) at the mixture of oneself alcohol in (10ml) 150 ℃ of lower heating 24 hours. Make this mixture cooling, remove volatile materials by evaporation, residue is dissolved among the EtOAc, wash with water, dry (MgSO₄) and by the evaporation desolventizing. Residue is carried out purifying with silica gel column chromatography, with EtOAc/ hexane (50: 50 to polarity increase to 70: 30) wash-out, obtain title compound (95mg, 35%).

NMR(DMSO)：0.65(m，2H)，0.89(m，2H)，1.85(s，1H)，1.98-2.10(m， 3H)，2.30-2.40(m，1H)，3.50-3.60(m，1H)，3.70-3.80(m，1H)，3.90(s，3H)， 5.35(d，1H)，6.00(s，1H)，6.60(s，1H)，7.10(dd，1H)，7.90(s，1H)，8.20(dd， 1H)，8.30(d，1H)，9.45(s，1H)，12.0(s，1H)；m/z 463[MH]+。

Embodiment 267

S-5-fluoro-4-(5-ethyl-1H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine

With the method similar to embodiment 266 described methods to 2-chloro-4-(5-ethyl-1H-pyrazoles-3-base amino)-5-FU (method 69) and S-2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines (method 64) processes, obtain title compound (67mg, 24%).

NMR(DMSO)：1.40(t，3H)，2.02-2.20(m，3H)，2.32-2.40(m，1H)，2.50- 2.60(m，2H)，3.63-3.70(m，1H)，3.73-3.80(m，1H)，3.95(s，3H)，5.38(dd，1H)， 6.20(s，1H)，6.65(s，1H)，7.06(dd，1H)，7.90(s，1H)，8.10(d，1H)，8.28(d，1H)， 8.80(s，1H)，11.70(s，1H)；m/z 451[MH]+。

Embodiment 268

S-5-fluoro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine

With the method similar to embodiment 266 described methods to 2-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base amino)-5-FU (method 27 (b)) and S-2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines (method 64) processes, obtain title compound (140mg, 37%).

NMR(DMSO)：2.01-2.15(m，3H)，2.20(s，3H)，2.30-2.40(m，1H)，3.61- 3.69(m，1H)，3.70-3.78(m，1H)，3.95(s，3H)，5.38(d，1H)，6.18(s，1H)，6.58(s， 1H)，7.08(dd，1H)，7.90(s，1H)，8.10(dd，1H)，8.28(d，1H)，8.82(s，1H)， 11.65(s，1H)；m/z 437[MH]+。

Embodiment 269

S-6-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine

With 2,6-two chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine (method 57) (300mg, 1.1mmol), S-2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines (method 64) (299mg, 1.22mmole), diisopropyl ethyl amine (0.46ml) mixture in dimethylbenzene (10ml) is 80 ℃ of lower heating 18 hours. By the evaporation desolventizing, residue is dissolved among the EtOAc, wash dry (MgSO with water₄) and by the evaporation desolventizing. Residue is carried out purifying with silica gel column chromatography, carry out wash-out with EtOAc/ hexane (45: 55), obtain title compound (300mg, 57%).

NMR(DMSO)：0.62-0.70(m，2H)，0.86-0.90(m，2H)，1.80-1.89(m，1H)， 2.05-2.20(m，2H)，2.31-2.42(m，1H)，3.62-3.78(m，2H)，3.95(s，1H)，5.44(dd， 1H)，6.00(s，1H)，6.39(s，1H)，6.65(s，1H)，7.08(dd，1H)，8.10(d，1H)， 8.28(dd，1H)，9.25(s，1H)；m/z 479[MH]+。

Embodiment 270

S-6-chloro-4-(5-ethyl-1H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine

With the method similar to embodiment 269 described methods to 2,6-two chloro-4-(5-ethyl-1H-pyrazoles-3-base amino) pyrimidine (method 72) and S-2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines (method 64) processes, obtain title compound (240mg, 44%).

NMR(DMSO)：1.2(t，3H)，2.02-2.20(m，3H)，2.32-2.45(m，1H)，2.55(q， 2H)，3.62-3.80(m，2H)，3.95(s，3H)，5.45(dd，1H)，6.08(s，1H)，6.40(s，1H)， 6.65(s，1H)，7.09(dd，1H)，9.10(d，1H)，8.28(d，1H)，9.35(s，1H)，11.65(s， 1H)；m/z 467[MH]+。

Embodiment 271

S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine

With the method similar to embodiment 269 described methods to 2,6-two chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base amino) pyrimidine (method 29) and S-2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines (method 64) processes, obtain title compound (240mg, 44%).

m/z 463[MH]+。

Embodiment 272

S-6-(2-hydroxyl base oxethyl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine

Hydrogenation sodium (106mg, 2.65mmol) is joined in the ethylene glycol (4ml) also with this mixture stirring 10 minutes. To wherein adding S-6-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine (embodiment 271) (180mg, 0.4mmol) also heats this mixture 30 minutes under the microwave radiation sealing in the container under 150 ℃. Make this mixture cooling, extract with the aqueous ammonium chloride solution dilution and with EtOAc. To extract thing and merge, dry (MgSO₄), and by the evaporation desolventizing. Residue is carried out purifying with silica gel column chromatography, carry out wash-out with EtOAc/ hexane (50: 50 to polarity increase to 90: 10), obtain title compound (60mg, 32%).

NMR(DMSO)：2.01-2.18(m，3H)，2.14(s，3H)，2.35-2.42(m，1H)， 3.64(s，2H)，3.68-3.77(m，2H)，3.96(s，3H)，4.10-4.18(m，1H)，4.19-4.28(m， 1H)，4.34(s，1H)，5.41(dd，1H)，5.79(s，1H)，6.00(s，1H)，6.65(s，1H)，7.10(dd， 1H)，8.10(dd，1H)，8.28(d，1H)，8.62(s，1H)；m/z 479[MH]+。

Embodiment 273

S-6-(2-hydroxyl base oxethyl)-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine

With the method similar to embodiment 272 described methods to S-6-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine (embodiment 269) and ethylene glycol processes, obtain title compound (50mg, 20%).

NMR(DMSO)：0.62-0.70(m，2H)，0.82-0.90(m，2H)，1.30-1.35(m，1H)， 1.81-1.90(m，1H)，2.05-2.20(m，2H)，2.37-2.45(m，1H)，3.45(s，2H)，3.59- 3.65(m，1H)，3.65-3.75(m，1H)，3.95(s，3H)，4.14-4.25(m，2H)，4.35(t，1H)， 5.40(d，1H)，5.75(s，1H)，5.91(s，1H)，6.62(s，1H)，7.10(s，1H)，7.70(dd，1H)， 8.10(dd，1H)，8.25(d，1H)，8.60(s，1H)，11.55(s，1H)；m/z 505[MH]+。

Embodiment 274

S-6-(2-hydroxyl base oxethyl)-4-(5-ethyl-1H-pyrazoles-3-base is amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine

With the method similar to embodiment 272 described methods to S-6-chloro-4-(5-ethyl-1H-pyrazoles-3-base amino)-2-[2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines-1-yl] pyrimidine (embodiment 270) and ethylene glycol processes, obtain title compound (37mg, 16%).

NMR(DMSO)：1.15(t，3H)，2.02-2.18(m，3H)，2.32-2.42(m，1H)，3.60- 3.65(m，2H)，3.68-3.77(m，2H)，3.96(s，3H)，4.10-4.18(m，1H)，4.18-4.25(m， 1H)，4.33(s，1H)，5.40(d，1H)，5.80(s，1H)，6.00(s，1H)，6.61(s，1H)，7.08(dd， 1H)，8.10(d，1H)，8.28(d，1H)，8.65(s，1H)，11.5(s，1H)；m/z 493[MH]+。

Embodiment 275

S-6-methyl-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyrimidine-2-base)-5-yl } pyrrolidines-1-yl] pyrimidine

With the method similar to embodiment 260 described methods to 2-chloro-6-methyl-4-(5-ethyl-1H-pyrazoles-3-base amino) pyrimidine (method 83) and the different  azoles of S-2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines (method 66) processes, obtain title compound (77mg, 56%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.15 (t, 3H), 2.00-2.15 (m, 6H), (2.35 m, 1H), 2.55 (q, 2H), 3.65 (m, 1H), 3.75 (m, 1H), 5.40 (dd, 1H), (5.60 s, 1H), 6.05 (s, 1H), (6.20 s, 1H), 6.65 (s, 1H), (7.40 t, 1H), 8.90 (t, 2H); M/z 418[MH]+.

Embodiment 276

S-6-methyl-4-(5-ethyl-1H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With the method similar to embodiment 260 described methods 2-chloro-6-methyl-4-(5-ethyl-1H-pyrazoles-3-base is amino) pyrimidine (method 83) and S-2-(the different  azoles of 3-(2-pyridine radicals)-5-yl) pyrrolidines (method 42) are processed, obtain title compound (134mg, 51%).

NMR(DMSO-d ₆, under 100 ℃): 1.15 (t, 3H), 2.00-2.15 (m, 6H), (2.35 m, 1H), 2.55 (q, 2H), 2.65-3.80 (m, 2H), 5.45 (dd, 1H), 6.05 (br s, 1H), (6.20 br s, 1H), 6.65 (s, 1H), 7.40 (m, 1H), 7.90 (m, 2H), 8.65 (d, 1H), (8.70 br s, 1H), 11.50 (br s, 1H); M/z 417[MH]+.

Embodiment 277

The different  azoles of S-6-(3-methoxy-propyl)-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With the method similar to embodiment 249 described methods 2-chloro-6-(3-methoxy-propyl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (method 87) and S-2-(the different  azoles of 3-(2-pyridine radicals)-5-yl) pyrrolidines (method 42) are processed, obtain title compound (60mg, 19%).

NMR(DMSO)：1.75-1.81(m，2H)，2.03-2.20(m，3H)，2.21(s，3H)，2.30- 2.42(m，3H)，3.20(s，3H)，3.30(t，2H)，3.65-3.80(m，2H)，5.44(dd，1H)， 6.01(s，1H)，6.18(s，1H)，6.65(s，1H)，7.43，(dd，1H)，7.88-7.97(m，2H)， 8.65(d，1H)，8.74(s，1H)，11.45(s，1H)；m/z 461[MH]+。

Method

Initial material preparation :-

The initial material that is used for top embodiment can obtain or can be prepared with standard method by known material by commercial sources. For example, with following reaction some used in the top reaction initial materials are carried out non-limitative illustration.

Method 1 and 2

Below compound be that the similar method of the described method of m-methoxybenzaldehyde oxime is prepared in the method 35 of using to WO 03/048133.

Method	Initial material	The compound title	NMR(CDCl ₃)	m/z(MH) ⁺
Method	Initial material	The compound title	NMR(CDCl ₃)	m/z(MH) ⁺	1 ^a	#	Cyclopropyl aldoxime (cyclopropylcarboxaldehyde oxime)	0.60(m，2H)，0.90(m， 2H)，1.60(m，0.25H)， 2.30(m，0.75H)，6.05(d， 0.75H)，6.95(d，0.25H)， 8.60(br s，0.25H)， 9.00(br s，0.75H)	n/a
2 ^b	#	Thiazole-2-base aldoxime	7.75(d，0.4H)，7.91(d， 0.4H)，7.97(d，0.6H)， 8.00(m，1.2H)，8.33(s， 0.4H)，11.95(br s， 0.4H)，12.18(br s，0.6H)	n/a	1 ^a	#	Cyclopropyl aldoxime (cyclopropylcarboxaldehyde oxime)		n/a

^aAbout 3: 1 mixture # of E/Z isomers can obtain by commercial sources

^bAbout 3: 2 mixture of E/Z isomers

Method 3

5-(uncle-butoxy carbonyl the amino methyl)-different  azoles of 3-cyclopropyl

Title compound is to be begun to use that the method similar to the method 69 described methods of WO 03/048133 is prepared and used in the situation of not carrying out purifying by cyclopropyl aldoxime (method 1).

Method 4

5-(uncle-butoxy carbonyl the amino methyl)-different  azoles of 3-(thiazole-2-yl)

Title compound is to be begun to use to the method 22 of WO 03/048133 method similar with 43 described methods by thiazole-2-base aldoxime (thiazol-2-ylcarboxaldehyde oxime) (method 2) to be prepared in two steps.

NMR：1.40(s，9H)，4.35(d，2H)，6.77(s，1H)，7.60(br t，1H)，7.98(d， 1H)，8.07(d，1H)；m/z 226[MH-C ₄H ₈]+。

Method 5

The different  azoles of 5-amino methyl-3-cyclopropyl

With 5-(Uncle-The butoxy carbonyl amino methyl)-the different  azoles of 3-cyclopropyl crude product (method 3) (37.4g, 0.157mol) and 3M hydrochloric acid (80ml) in methyl alcohol (100ml) 50 ℃ of lower heating 2 hours. Remove methyl alcohol and the water-based residue is washed with DCM by evaporation. By careful adding 40% sodium hydrate aqueous solution the pH of water layer is transferred to 12, then use DCM (x4) that it is extracted. To extract thing and merge, use the salt water washing, then dry (Na₂SO ₄) and remove volatile materials by evaporation, obtain the title compound (11.5g, 53%) of grease form.

NMR(CDCl ₃)：0.80(m，2H)，1.00(m，2H)，2.00(m，1H)，3.90(s，2H)， 5.78(s，1H)；m/z 277[2M+H]+。

Method 6

The different  azoles of 5-amino methyl-3-(thiazole-2-yl)

Title compound be by 5-(Uncle-The butoxy carbonyl amino methyl)-3-(thiazole-2-yl) different  azoles (method 4) begins to use the method similar to the method 56 described methods of WO 03/048133 to be prepared.

NMR：4.41(s，2H)，7.14(s，1H)，8.03(d，1H)，8.11(d，1H)，8.62(s，3H)； m/z 182[MH]+。

Method 7

[the different  azoles of 3-(pyridine-2-yl)-5-yl] methyl [(1E)-and phenylmethylene] amine

With the benzaldehyde (373mg that newly distills, 3.5mmol) join in the solution of the different  azoles of 5-amino methyl-3-(pyridine-2-yl) (method 70 of WO 03/048133) (0.614mg, 3.5mmol) in anhydrous DCM (18ml). Then, to wherein adding 4  molecular sieves (1.75g) and with this mixture gentle agitation 20 hours under nitrogen. By removing by filter this molecular sieve and filtrate being evaporated. Residue is dissolved in the toluene also with this solution evaporation and concentration. Make the product crystallization and by filtering it is collected, obtain title compound (900mg, 97%).

NMR(CDCl ₃)：4.97(s，2H)，6.87(s，1H)，7.32(m，1H)，7.43(m，3H)， 7.77(m，3H)，8.06(d，1H)，8.44(s，1H)，8.67(d，1H)；m/z 264[MH]+。

Method 8 to 11

Embodiment 8 to 11 uses the method identical with the method for embodiment 7 to be prepared :-

Method	Initial material	The compound title	NMR	m/z(MH) ⁺
Method	Initial material	The compound title	NMR	m/z(MH) ⁺	8	#	(the different  azoles of 3-methyl-5-yl) methyl [(1E)-and phenylmethylene] amine	2.20(s，3H)，4.84(s，2H)， 6.28(s，1H)，7.42-7.48(m， 3H)，7.78(dd，2H)， 8.50(s，1H)	n/a
9	Method 5	(the different  azoles of 3-cyclopropyl-5-yl) methyl [(1E)-and phenylmethylene] amine	CDCl ₃ 0.80(m，2H)，1.00(m， 2H)，2.00(m，1H)，4.80(s， 2H)，5.85(s，1H)，7.42(m， 2H)，7.78(dd，2H)， 8.38(s，1H)	227	8	#			n/a
9	Method 5			227	10	Method 6	[the different  azoles of 3-(thiazole-2-yl)-5-yl] methyl [(1E)-and phenylmethylene] amine 2-	5.0(s，2H)，6.95(s，1H)， 7.47(m，3H)，7.77(m， 2H)，7.96(d，1H)，8.05(d， 1H)，8.56(s，1H)	n/a
11	The different  azoles ## of 5-amino methyl-3-(pyridine-3-yl)	[the different  azoles of 3-(pyridine-3-yl)-5-yl] methyl [(1E)-and phenylmethylene] amine	4.97(s，2H)，6.6(s，1H)， 7.43(m，4H)，7.82(d，2H)， 8.15(d，1H)，8.47(s，1H)， 8.67(d，1H)，9.02(S，1H)	n/a	10	Method 6			n/a

Described in the method 68 of ##WO03/048133

# can obtain by commercial sources

Method 12

The different  azoles of 2-[3-(pyridine-2-yl)-5-yl] pyrrolidines

Will be just-butyl lithium (7.5ml 1.82M hexane solution, 13.74mmol) join under nitrogen and carrying out 2 of stirring at-78 ℃, 2,6,6-tetramethyl piperidine (2.5ml, 14.9mmol) in the solution in THF (99ml), so that temperature remains on the temperature that is lower than-65 ℃. Then, this solution was stirred 15 minutes at-78 ℃. Then, in 5 minutes to wherein adding [the different  azoles of 3-(pyridine-2-yl)-5-yl] methyl [(1E)-phenylmethylene] amine (method 7) (3.0g, 11.45mmol) solution in anhydrous THF (51ml), temperature is remained on-70 ℃ or be lower than the temperature of this temperature, this mixture was stirred 15 minutes at-78 ℃. Then, in 1 minute, to wherein dripping 1-chloro-3-iodopropane (1.53ml, 14.31mmol), then this mixture was stirred 15 minutes at-78 ℃, make it be warming up to the environment temperature and it was at room temperature stirred 18 hours. In this reactant mixture, add ether, then add entry and with this mixture strong agitation 5 minutes. Carry out layer and separate, with the organic layer water, then wash with salt solution, dry (Na₂SO ₄), evaporation obtains by the imines crude product of alkylation. Directly be dissolved in this kind imines in the ethanol (24ml) and to wherein adding 2M hydrochloric acid (48ml). This mixture was stirred 18 hours at ambient temperature. Remove ethanol by evaporation, again to wherein adding entry and water layer being washed with ether (x2). Near terminal point the time, by adding solid sodium carbonate and 40% sodium hydrate aqueous solution the pH of this aqueous solution is transferred to 11.5. This kind aqueous solution was stirred 2 hours at ambient temperature, maintain 11.5 to wherein adding 40% NaOH with the pH with this solution more during this period.

Carry out purifying with a kind of solution to the gained crude product in following two kinds of methods :-

Purification process A

Then, add DCM (70ml) and two carbonic acid di-tert-butyls (2.74g, 12.57mmol) and with this mixture strong agitation 2.5 hours at ambient temperature in the aqueous solution of this crude product. Carry out layer and separate and water, then with salt solution organic layer is washed, dry (Na₂SO ₄), remove volatile materials by evaporation. On Biotage 40M silica gel cylinder, with column chromatography this residue is carried out purifying, carry out wash-out with DCM/EtOAc (93: 7), obtain the 1-(uncle-butoxy carbonyl) of the waxy solid form-different  azoles of 2-[3-(pyridine-2-yl)-5-yl] pyrrolidines (181g, 50%).

NMR (mixture-peak of rotational isomeric body is designated as the peak of main rotational isomeric body): 1.24 (s, 9H), 1.95 (m, 3H), (2.28 m, 1H), 3.35 (m, 1H), (3.5 m, 1H), 5.0 (m, 1H), 6.76 (s, 1H), (7.5 m, 1H), 7.97 (m, 2H), 8.68 (d, 1H); M/z 316[MH]+.

With 1-(Uncle-Butoxy carbonyl)-and the different  azoles of 2-[3-(pyridine-2-yl)-5-yl] pyrrolidines (0.56g, 1.78mmol) in the mixture of ethanol (5ml) and 2M hydrochloric acid (1.5ml), stirred 18 hours at ambient temperature, then it was heated under 60 ℃ 2 hours again. This reactive evaporation is concentrated and to wherein adding entry. Near terminal point the time, by adding solid sodium carbonate and 40% sodium hydrate aqueous solution the pH of this solution is transferred to 12.5. This aqueous solution with DCM (x4) extraction, is merged organic extract dry (Na₂SO ₄), evaporate, obtain the title compound (183mg, 48 %) of brown oil form.

NMR：1.8(m，3H)，2.13(m，1H)，2.9(t，2H)，4.35(t，1H)，6.8(s，1H)， 7.48(t，1H)；7.96(m，2H)，8.67(d，1H)；m/z 216[MH]+。

Purification process B

The aqueous solution of this crude product is extracted with DCM (x4), organic extract is merged, dry (Na₂SO ₄) and by the evaporation desolventizing. Residue is carried out purifying with silica gel column chromatography, use ether, then use DCM/ methyl alcohol (100: 0 to polarity increase to 95: 5) to carry out wash-out, obtain title compound.

Method 13 is to 16a

Embodiment 13 to 16a uses the method identical with the method for embodiment 12 to be prepared :-

Method	Initial material	The compound title	NMR	m/z(MH) ⁺
Method	Initial material	The compound title	NMR	m/z(MH) ⁺	13 ^b，c	Method 8	2-(the different  azoles of 3-methyl-5-yl) pyrrolidines	1.97-1.73(m，3H)，2.02- 2.12(m，1H)，2.18(s， 3H)，2.82-2.90(m，2H)， 4.18-4.22(m，1H)， 6.14(s，1H)	153
14 ^b	Method 9	2-(the different  azoles of 3-cyclopropyl-5-yl) pyrrolidines	CDCl ₃ 0.78(m，2H)，0.98(m， 2H)，1.95(m，4H)， 2.15(m，1H)，3.15(m， 2H)，4.25(m，1H)， 5.75(s，1H)	179	13 ^b，c	Method 8	2-(the different  azoles of 3-methyl-5-yl) pyrrolidines		153
14 ^b	Method 9			179	15 ^b	Method 10	The different  azoles of 2-[3-(thiazole-2-yl)-5-yl] pyrrolidines	1.75(m，3H)，2.10(m， 1H)，2.89(t，2H)， 4.33(m，1H)，6.78(s， 1H)，7.95(d，1H)， 8.03(d，1H)	222

Method	Initial material	The compound title	NMR	m/z(MH) ⁺
Method	Initial material	The compound title	NMR	m/z(MH) ⁺	16 ^a，d 16(a) ^bef	Method 11 methods 7	The different  azoles of 2-[3-(pyridine-3-yl)-5-yl] the different  azoles of pyrrolidines 2-[3-(pyridine-2-yl)-5-yl] piperidines	1.77(m，3H)，2.1(m， 1H)，2.88(t，2H)， 4.35(m，1H)，6.93(s， 1H)，7.5(t，1H)，8.22(d， 1H)，8.65(d，1H)，9.02(s， 1H) 1.43(m，4H)，1.75(m， 1H)，1.93(m，1H)， 2.63(m，2H)，2.95(d， 1H)，3.87(d，1H)，6.8(s， 1H)，7.47(t，1H)， 7.93(m，2H)，8.67(d， 1H)	216 230

^aWith purification process A purifying

^bWith purification process B purifying

^cUse chromatogram purification, use ether, then use DCM/ methyl alcohol (100: 0 to polarity increase to 90: 10) to carry out wash-out

^dBy the different  azoles of 1-(uncle-butoxy carbonyl)-2-[3-(pyridine-3-yl)-5-yl] pyrrolidines makes-NMR (mixture-peak of rotational isomeric body is designated as the peak of main rotational isomeric body): 1.27 (s, 9H), 1.93 (m, 3H), (2.27 m, 1H), 3.35 (m, 2H), (5.0 m, 1H), 7.0 (s, 1H), 7.53 (t, 1H), (8.23 d, 1H), 8.07 (d, 1H), 9.05 (s, 1H); M/z 316[MH]+.

^fBe prepared with 4-chloro-1-iodobutane

^eBy the different  azoles of 1-(uncle-butoxy carbonyl)-2-[3-(pyridine-3-yl)-5-yl] piperidines makes-NMR 1.36 (m, 11H) 1.62 (m, 2H), (1.8 m, 1H), 2.17 (d, 1H), (2.72 t, 1H), 3.92 (d, 1H), (6.88 s, 1H), 7.47 (dd, 1H), (7.9 t, 1H), 8.0 (d, 1H), 8.07 (d, 1H); M/z 330[MH]+.

Method 17

2-(the different  azoles of 3-cyclopropyl-5-yl) pyrrolidines-1-carboximidamide

2-(the different  azoles of 3-cyclopropyl-5-yl) pyrrolidines (method 14) (2.05g, 11.5mmol) and the mixture of formamidinesulfinic acid (1.425g, 11.5mmol) in anhydrous methyl alcohol (30ml) were heated 18 hours under 60 ℃. Be dissolved in the water by the evaporation desolventizing and with residue. The aqueous solution is washed with water, then remove by evaporation and anhydrate. Residue is ground with ether/DCM, collect solid product and with it in dry 18 hours of 50 ℃ of lower vacuum, obtain the monosulfate (1.839mg, 41%) of title compound; M/z 221[MH]+.

Method 18

2-[2-(the different  azoles of 3-cyclopropyl-5-yl] pyrrolidines-1-yl]-4-hydroxyl-6-methoxy methyl yl pyrimidines

With two-(trimethyl silyl) sodium amides (3.65ml 2M THF solution, 7.3mmol) join 2-(the different  azoles of 3-cyclopropyl-5-yl) pyrrolidines-1-carboximidamide monosulfate (method 17) (1.83g, 6.09mmol) and the solution of 4-first oxygen base acetyl acetic acid methyl esters (0.867ml, 6.7mmol) in methyl alcohol (30ml) in and with the heating 4 hours under refluxing of this mixture. By the evaporation desolventizing and residue carried out purifying with silica gel chromatograph, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 95: 5). This product that has carried out purifying is ground with ether, then with this solid recrystallizing methanol, obtain the title compound (565mg, 29%) of white solid form.

NMR(DMSO-d ₆+d ₄-acetic acid): 0.67 (m, 2H), 0.90 (m, 2H), 1.93 (m, 4H), 3.25 (s, 3H), 3.40 (m, 1H), 3.64 (m, 1H), 3.98 (dd, 2H), (5.24 d, 1H), 5.61 (s, 1H), 5.95 (s, 1H); M/z 317[MH]+.

Method 19

4-chloro-2-[2-(the different  azoles of 3-cyclopropyl-5-yl] pyrrolidines-1-yl]-6-methoxy methyl yl pyrimidines

With 2-[2-(the different  azoles of 3-cyclopropyl-5-yl] pyrrolidines-1-yl]-heating 45 minutes under refluxing of the mixture of 4-hydroxyl-6-methoxy methyl yl pyrimidines (method 18) (563mg, 1.78mmol) and phosphoryl chloride phosphorus oxychloride (1ml, 10.7mmol). Remove volatile materials by evaporation, residue is dissolved among the DCM, with the saturated sodium bicarbonate aqueous solution washing, dry (Na₂SO ₄), evaporation. Residue is carried out purifying with silica gel chromatograph, carry out wash-out with DCM/ ether (100: 0, then 80: 20), obtain the title compound (511mg, 81%) of yellow oil form.

NMR：0.67(m，2H)，0.95(m，2H)，1.95(m，4H)，2.25(m，1H)，3.30(m， 3H)，3.52(m，1H)，3.65(m，1H)，4.30(m，2H)，5.25(d，1H)，6.00(s，1H)，6.70(s， 1H)；m/z 335[MH]+。

Method 21

The different  azoles of 5-amino methyl-3-(oxolane-3-yl)

This kind compound is to use to method 3 method similar with method described in 5 to be prepared with suitable initial material.

NMR(DMSO)：1.88(m，3H)，2.25(m，1H)，3.44(m，1H)，3.62(m，1H)， 3.7-3.82(m，4H)，3.96(m，1H)，6.25(s，1H)；m/z 169[MH]+。

Method 22

[the different  azoles of 3-(oxolane-3-yl)-5-yl] methyl [(1E)-and phenylmethylene] amine

This kind compound is to use the method similar to method 7 described methods to be begun to be prepared by the compound of method 21.

NMR(DMSO)：1.99(m，1H)，2.25(m，1H)，3.45(m，1H)，3.65(m，1H)， 3.8(m，2H)，3.96(m，1H)，4.85(s，2H)，6.37(s，1H)，7.47(m，3H)，7.75(m，2H)， 8.51(s，1H)。

Method 23

[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] methyl [(1E)-and phenylmethylene] amine

This kind compound is to use the method similar to method 7 described methods, is begun to be prepared by 5-amino methyl-3-(2-first oxygen yl pyridines-3-yl) different  azoles (being prepared as described in the WO 03/048133).

NMR(DMSO)：4.02(s，3H)，4.95(s，2H)，6.8(s，1H)，7.0(t，1H)， 7.45(m，2H)，7.8(m，2H)，8.24(m，2H)，8.45(s，1H)；m/z 294[MH]+。

Method 24

The different  azoles of 2-[3-(oxolane-3-yl)-5-yl] pyrrolidines

This kind compound is to use the method similar to method 12 described methods, is begun to be prepared by the compound of method 22.

NMR(DMSO)：1.7(m，3H)，1.9-2.15(m，2H)，2.15(m，1H)，2.84(m， 2H)，3.18(br s，1H)，3.45(m，1H)，3.62(m，1H)，3.78(m，2H)，3.97(m，2H)， 4.2(t，1H)，6.04(s，1H)。

Method 25

2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines

This kind compound is to use the method similar to method 12 described methods, is begun to be prepared by the compound of method 23.

NMR(DMSO)：1.75(m，3H)，2.13(m，1H)，2.9(m，2H)，3.96(s，3H)， 4.3(t，1H)，6.69(s，1H)，7.1(t，1H)，8.13(d，1H)，8.28(d，1H)；m/z 246 [MH]+。

Method 26

2-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With 2,4-dichloro pyrimidine (2.97g, 20mmol), 3-amino-5-methyl isophthalic acid H-pyrazoles (2.14g, 22mmol) and N, the mixture of N-diisopropyl ethyl amine (2.82g, 22mmol) in anhydrous THF (75ml) is 50 ℃ of lower stirrings 18 hours. By the evaporation desolventizing, residue is distributed between DCM (75ml) and water (50ml). By filtering the precipitation of collecting gained, then water washs it with ether, and it is dry in 50 ℃ of lower vacuum, obtains the title compound (1.08g, 26%) of colourless crystallization solid form.

NMR(DMSO)：2.20(s，3H)，6.05(s，1H)，7.10(d，1H)，8.10(d，1H)， 9.80(br s，1H)，11.85(br s，1H)；m/z 210[MH]+。

Method 27,27 (b) and 28

Method 27,27 (b) is to use the method similar to method described in the method 26 with 28 compound, is prepared with suitable initial material.

Method 27

2-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino)-5-FU

Receipts rate: 546mg, 23%.

NMR(DMSO)：0.7(m，2H)，0.93(m，2H)，1.9(m，2H)，6.22(s，1H)， 8.2(d，1H)，10.3(s，1H)，12.2(s，1H)；m/z 254[MH]+。

Method 27 (b)

2-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-5-FU

Receipts rate: 3.02g, 66%.

NMR(DMSO)：2.2(s，3H)，6.3(s 1H)，8.2(d，1H)，10.3(br s，1H)， 12.2(br s，1H)；m/z 228[MH]+。

Method 28

2-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

Receipts rate: 323mg, 14%.

NMR(DMSO)：0.66(m，2H)，0.92(m，2H)，1.86(m，1H)，5.90(br m 1H)， 8.14(d，1H)，10.22(br s，1H)，12.14(br s，1H)；m/z 236[MH]+。

Method 29

2,6-, two chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

2,4,6-trichloropyrimidine (1.0g, 5.4mmol), 3-amino-5-methyl isophthalic acid H-pyrazoles (0.53g, 5.4mmol) and the mixture of sodium carbonate (0.57g, 5.4mmol) in ethanol (25ml) were at room temperature stirred 18 hours. To wherein adding entry and by filter collecting the precipitation of gained, water and a small amount of methyl alcohol wash, drying obtains the title compound (1.15g, 88 %) of colourless crystallization solid form.

NMR(DMSO)2.23(s，3H)，6.01(s，1H)，7.24(s，1H)，10.25(br s，1H)， 11.9(br s，1H)；m/z 244[MH]+。

Method 30

The different  azoles of 4-hydroxyl-6-methyl-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With 4-hydroxyl-6-methyl-2-sulphur methyl pyrimidine (362mg, 2.3mmol) and the different  azoles of 2-[3-(2-pyridine radicals)-5-yl] mixture of pyrrolidines (500mg, 2.3mmol) be placed under the nitrogen atmosphere and with it 150 ℃ of lower heating 18 hours. This mixture is carried out purifying with silica gel chromatograph, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 96: 4), obtain title compound (420mg, 56 %).

NMR(DMSO)：1.94-2.1(m，6H)，2.10-2.14(m，1H)，3.45(q，1H)， 3.75(q，1H)，5.42-5.55(m，2H)，2.74(s，1H)，7.50(t，1H)，7.88-7.99(m，2H)， 8.64(d，2H)；m/z 324[MH]+

Method 31

4-hydroxyl-6-methyl-2-[2-(the different  azoles of 3-methyl-5-yl) pyrrolidines-1-yl] pyrimidine

This kind compound is to use the method similar to method 30 described methods, uses suitable initial material to be prepared, and obtains title compound (270mg, 81%).

NMR(DMSO)：1.84-2.0(m，6H)，2.16(s，3H)，2.20-2.28(m，1H)，3.38- 3.45(m，1H)，3.62-3.72(m，1H)，5.39(d，1H)，5.54(s，1H)，6.10(s，1H)；m/z 261[MH]+。

Method 32

The different  azoles of 6-ethyl-4-hydroxyl-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

With propiono ethyl acetate (350mg; 2.4mmol), the different  azoles of 2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-carboximidamide three fluoroacetate (method 38) (901mg; 2.43mmol), the mixture of methyl alcohol sodium (144mg, 7.7mmol) in butanols (10ml) be 120 ℃ of lower heating 18 hours. Make the cooling of this mixture and it directly is poured on the isolute SCX2 ion exchange column. With this post with DCM/ methyl alcohol (4: 1) wash-out to remove neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. Solvent evaporated is also carried out purifying with residue with silica gel chromatograph, carries out wash-out with DCM/ methyl alcohol (98: 2 to polarity increase to 95: 5), obtains title compound (360mg, 46 %).

NMR(DMSO)：0.99(t，3H)，2.0-2.1(m，3H)，2.2-2.3(m，3H)，3.48(m， 1H)，3.74-3.80(m，1H)，5.43(d，1H)，5.49(s，1H)，6.76(s，1H)，7.48(dd，1H)， 7.88-7.99(m，2H)，8.64(d，1H)，11.0(s，1H)；m/z 338[MH]+。

Method 33 to 35

The compound of method 33 to 35 is to use the method similar to method 32 described methods, is prepared with suitable initial material.

Method 33

The different  azoles of 4-hydroxyl-6-(3-methoxy-propyl)-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Receipts rate: 575mg, 35%.

NMR(DMSO)：1.60-1.68(m，1H)，2.0-2.1(m，2H)，2.20-2.35(m，2H)， 3.08(s，3H)，3.10-3.15(m，1H)，3.50(q，1H)，3.78(t，1H)，5.40(d，1H)，5.49(s， 1H)，6.76(s，1H)，7.50(dd，1H)，7.89-7.99(m，2H)，8.64(d，1H)，11.10(s，1H)； m/z 382[MH]+。

Method 34

The different  azoles of 4-hydroxyl-6-(methoxy)-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Receipts rate: 1g, 48%.

NMR(DMSO)：2.0-2.14(m，3H)，2.13-2.38(m，1H)，3.28(s，3H)，3.46(q， 1H)，3.78(t，1H)，4.01(q，2H)，5.42(d，1H)，5.62(s，1H)，6.78(s，1H)，7.50(dd， 1H)，7.9-8.0(m，2H)，8.64(d，1H)；m/z 354[MH]+。

Method 35

4-hydroxyl-6-(penta-3-alkene-1-the yl)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Receipts rate: 1g, 33%.

NMR(DMSO)：1.42(s，3H)，2.0-2.15(m，5H)，2.2-2.38(m，3H)，3.52(q， 1H)，3.73-3.80(m，1H)，5.22(s，2H)，5.42(d，1H)，5.48(s，1H)，6.75(s，1H)， 7.48(dd，1H)，7.89-7.99(m，2H)，8.63(d，1H)，11.05(s，1H)；m/z 378 [MH]+。

Method 35 (a) is to 37

Method 35 (a) to 37 compound is to use the method similar to method 30 described methods, is prepared with suitable initial material.

Method 35 (a)

The different  azoles of 4-hydroxyl-6-(methoxy)-2-[2-{3-(pyridine-3-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Be prepared as initial material with 4-hydroxyl-6-methoxy-2-methylthiopyrimidine.

Receipts rate: 804mg, 61%.

NMR(DMSO)：2.02(m，3H)，2.27(m，1H)，3.30(s，3H)，3.50(m，1H)， 3.73(m，1H)，4.00(q，2H)，5.42(d，1H)，5.43(d，1H)，5.65(s，1H)，6.79(s，1H)， 7.50(dd，1H)，8.22(d，1H)，8.65(d，1H)，9.02(s，1H)；m/z 354[MH]+。

Method 36

The different  azoles of 4-hydroxyl-6-methoxy-2-[2-{3-(thiazole-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Receipts rate: 451mg, 31%.

NMR(DMSO)：2.04(m，3H)，2.28(m，1H)，3.25(s，3H)，3.47(m，2H)， 3.75(m，1H)，4.0(m，1H)，5.41(d，1H)，5.62(s，1H)，6.8(s，1H)，7.95(d，1H)， 8.02(d，1H)；m/z 360[MH]+。

Method 37

The different  azoles of 4-hydroxyl-2-[2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl]-the 6-trifluoromethyl pyrimidine

Be prepared as initial material with 2-ethylmercapto group-4-hydroxyl-6-trifluoromethyl pyrimidine.

Receipts rate: 710mg, 30%.

NMR(CDCl ₃)：2.30(m，4H)，3.65(m，1H)，3.94(m，1H)，5.60(m，1H)， 6.10(s，1H)，6.80(s，1H)，6.80(s，1H)，7.34(t，1H)，7.78(t，1H)，8.02(d，1H)， 8.64(d，1H)；m/z 378[MH]+。

Method 38

The different  azoles of 2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-carboximidamide (three fluoroacetate)

Under 0 ℃, TFA (30ml) is joined the N of cooling, N '-two (Uncle-Butoxy carbonyl)-2-[the different  azoles of 3-(pyridine-2-the yl)-5-yl] solution of pyrrolidines-1-carboximidamide (method 39) in DCM (150ml) in. This mixture 0 ℃ of lower stirring 1 hour, is made it to heat and stirred 18 hours to the environment temperature and with it again. Remove volatile materials and residue is ground with the DCM/ ether/hexane by evaporation. Collect product by filtering, obtain title compound (2.2g,＞100%).

NMR(DMSO)：1.9-2.2(m，3H)，2.3-2.4(m，1H)，3.42(q，1H)，3.72(t， 1H)，5.35(d，1H)，6.95(s，1H)，7.41(s，2H)，7.50(t，1H)，7.92-8.02(m，2H)， 8.7(d，1H)；m/z 258[MH]+。

Method 39

N, the different  azoles of N '-two (uncle's butoxy carbonyl)-2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-carboximidamide

With the different  azoles of 2-[3-(pyridine-2-yl)-5-yl] pyrrolidines (method 12) (1.5g, 7mmol) joins N, N '-two (Uncle's fourthOxygen base carbonyl)-N "-(trifluoromethyl sulfonyl) guanidine (2.59g, 6.6mmol) and the solution of triethylamine (0.975ml) in DCM in and this mixture was stirred 8 hours at ambient temperature. Then, this mixture is washed with water dry (MgSO₄) and remove volatile materials by evaporation. Residue is carried out purifying with silica gel chromatograph, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 98: 2), obtain title compound (2.3g, 70%).

NMR(DMSO)：1.32(s，18H)，1.9-2.1(m，3H)，2.25-2.35(m，1H)，3.41- 3.50(m，1H)，3.72-3.80(m，1H)，5.41(s，1H)，6.79(s，1H)，7.50(dd，1H)，7.9- 8.0(m，2H)，8.68(d，1H)，9.48(s，1H)。

Method 40

S-2-(the different  azoles of 3-methyl-5-yl) pyrrolidines

Under nitrogen, will be just-butyl lithium (6.29ml 1.6M hexane solution, 10.1mmol) join be cooled to-5 ℃ acetoxime (368mg, 5.0mmol) at anhydrous THF (20ml) thus in solution in so that the temperature of this reaction be maintained on the temperature that is lower than 0 ℃. Add fully fashionable, with this mixture 0 ℃ of lower stirring 1 hour. Then, with the speed that reaction temperature maintained the temperature that is lower than 0 ℃ to wherein add N-(Uncle-Butoxy carbonyl)-L-PROLINE the N '-solution of first oxygen base-N '-methyl acid amides (1.0g, 3.87mmol) in anhydrous THF (30ml). Add fully fashionable, with this mixture 0 ℃ of lower stirring 3.5 hours. With the saturated aqueous ammonium chloride extinguishing of this reactant mixture, remove organic solvent by evaporation and also this water-based residue is extracted with carrene. To extract the thing merging and pass through the evaporation desolventizing. Residue is ground with different-hexane, obtain solid intermediate oxime (617mg). With this kind oxime (617mg, 2.28mmmol) and triethylamine (0.41ml, 2.96mmol) be dissolved among the anhydrous THF (20ml) also at ambient temperature to wherein adding first sulphonyl chlorine (0.19ml, 2.54mmol) and this mixture being stirred 30 minutes at ambient temperature. Remove volatile materials by evaporation, residue is dissolved in the water and extracts with carrene. To extract the thing merging and by the evaporation desolventizing, obtain the intermediate first sulphonic acid ester of grease form. This kind first sulphonic acid ester is joined the 4M hydrogen chloride that is positioned at Isosorbide-5-Nitrae-two  alkane (15ml, 90mmol) also to be heated this mixture 30 minutes under refluxing. Make this mixture cooling, then it is poured on the isolute SCX-2 ion exchange column of a 50g. With methyl alcohol this post is carried out wash-out to elute any neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing and residue carried out purifying with silica gel chromatograph, carry out wash-out with DCM/ methyl alcohol (100: 0 to polarity increase to 90: 10), obtain the title compound (273mg, 46%) of grease form.

NMR(CDCl ₃)：1.90(m，3H)，2.17(m，1H)，3.05(m，1H)，3.10(m，1H)， 4.30(m，1H)，5.95(s，1H)；m/z 153[MH]+。

Method 41

Uncle S-N--butoxy carbonyl-2-(the different  azoles of 3-(2-pyridine radicals)-5-yl) pyrrolidines

Under-3 ℃, in 2 hours, the solution of the clorox with 13% in water (4.6ml) joins the S-N-that is strongly carrying out stirringUncle-Butoxy carbonyl-2-acetylene base pyrrolidines is (such as Bull. Soc.Chim.Fr.1997,134,141-144 and J.Med.Chem.1994,37,4455-4463 is described to be made like that) (1.0g, 5.2mmol) in and the pyridine-solution of 2-base aldoxime (577mg, 4.72mmol) in carrene (15ml). After adding fully, should react 0 ℃ of lower stirring 2.5 hours. Then, this mixture water and carrene are diluted, carry out layer and distribute and separate. Water and salt solution wash dry (Na successively again with organic layer₂SO ₄) and remove volatile materials by evaporation. Residue is carried out purifying with silica gel chromatograph, carry out wash-out with 10% different hexane/ethyl acetate (90: 10 to polarity increase to 75: 25), obtain the title compound (0.69g, 47%) of wax-like thing solid form.

NMR (DMSO) (main rotational isomeric body): 1.4 (s, 9H), 1.95 (m, 3H), (2.28 m, 1H), 3.35 (m, 1H), (3.5 m, 1H), 5.0 (s, 1H), 6.76 (s, 1H), (7.5 m, 1H), 7.97 (m, 2H), 8.68 (d, 1H); M/z 316[MH]+. Rotation α_D=-104.8 (c=1.0, methyl alcohol).

Method 42

S-2-(the different  azoles of 3-(2-pyridine radicals)-5-yl) pyrrolidines

Under 0 ℃, in 10 minutes, three fluorine acetic acid (2.3ml) are joined and carrying out the S-N-that stirsUncle-In butoxy carbonyl-2-(the different  azoles of 3-(2-the pyridine radicals)-5-yl) solution of pyrrolidines (method 41) (0.744g, 2.36mmol) in carrene (12ml). Should react 0 ℃ of lower stirring 1 hour, then it be stirred 18 hours at ambient temperature. Remove volatile materials and residue is dissolved in the distilled water (23ml) by evaporation. Near terminal point, by the careful solid sodium carbonate that adds, then add 40% sodium hydrate aqueous solution the pH of this solution is transferred to 10.5. This aqueous solution is extracted with carrene (x4), organic extract is merged, dry (Na₂SO ₄) and by the evaporation desolventizing, obtain the title compound (0.446g, 88%) of gummy form.

NMR(DMSO)：1.8(m，3H)，2.13(m，1H)，2.9(t，2H)，4.35(t，1H)，6.8(s， 1H)，7.48(t，1H)；7.96(m，2H)，8.67(d，1H)；m/z 216[MH]+。Rotationα _D=-15.2 (c=1.0, methyl alcohol).

Method 43

The different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine-6-base formic acid

With 2-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine-6-base formic acid sodium salt (method 44) (58mg, 0.21mmol) and the different  azoles of 2-[3-(pyridine-2-yl)-5-yl] solution of pyrrolidines (method 12) (54mg, 0.25mmol) in water (4ml) is 110 ℃ of lower heating 18 hours. By filtering solid product is separated from this thermal reaction mixture, with cold water washing and dry. Then, this product is ground with ether, obtain title compound (48.1mg, 53%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.05 (m, 3H), 2.17 (s, 3H), (2.35 m, 1H), 3.75 (m, 1H), 3.85 (m, 1H), 5.50 (dd, 1H), 6.07 (s, 1H), (6.70 S, 1H), 6.88 (s, 1H), (7.40 m, 1H), 7.85 (t, 1H), (7.95 d, 1H), 8.65 (d, 1H); M/z 433[MH]+.

Method 44

2-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine-6-base formic acid sodium salt

With 2,4-dichloro pyrimidine-6-base formic acid (method 45) (528mg, 2.73mmol), 3-amino-5-methyl pyrazoles (279mg, 2.87mmol) and the mixture of mixture in water (10ml) of sodium carbonate (578mg, 5.46mmol) 50 ℃ of lower heating 18 hours. Make this mixture cooling and collect product by filtering, water washs it and it is carried out drying, obtains title compound (430mg, 77%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.20 (s, 3H), 6.03 (s, 1H), 7.28 (s, 1H); M/z 254[MH]+.

Method 45

2,4-dichloro pyrimidine-6-formic acid

The mixture of 2,4-dihydroxy-pyrimidine-6-formic acid (50g, 0.32mol), phosphoryl chloride phosphorus oxychloride (298ml, 3.2mol) and DMA (44.7ml, 0.35mol) was heated 5 hours under refluxing. Make the cooling of this mixture, remove volatile materials and residue is poured in the mixture of ice and water by evaporation. With this aqueous mixture extracted with diethyl ether, use carbon decoloring, filter and from filtrate, remove volatile materials by evaporation. Residue is processed with hot different-hexane, by removing by filter insoluble substance and by filtrate is evaporated desolventizing, obtaining title compound (29.05g, 47.6%).

NMR(DMSO-d ₆)：8.15(s，1H)；m/z 191[MH]-。

Method 46

Uncle 1--butoxy-2-(2-methyl-2H-tetrazolium-5-yl) pyrrolidines

With 1-Uncle-Butoxy-2-(2H-tetrazolium-5-yl) pyrrolidines (method 47) (500mg, 2.2mmol), carbonic acid caesium (1.43g, 4.4mmol), the mixture of iodomethane (0.41ml, 6.6mmol) in acetonitrile (15ml) at room temperature stirred 12 hours. This solution is gushed from the solid material updip, then this solution is distributed between water and ethyl acetate. Organic matter is separated dry (MgSO₄) and remove volatile materials by evaporation. Residue is carried out purifying with silica gel chromatograph, carry out wash-out with different hexane/ethyl acetate (100: 0 to polarity increase to 0: 100), obtain clarifying the title compound (175mg, 33%) of grease form.

NMR(CDCl ₃)：1.35(d，9H)，2.03(m，3H)，2.31(m，1H)，3.50(m，1H)， 3.66(m，1H)，4.31(s，3H)，5.17(m，1H)。

Method 47

Uncle 1--butoxy-2-(2H-tetrazolium-5-yl) pyrrolidines

WillUncle-Butoxy-2-Cyanopyrolidine (3g, 15.3mmol), sodium azide (1.49g, 23.0mmol) and ammonium chloride (1.22g, the 23mmol) mixture in DMF (15ml) was 95 ℃ of lower heating 48 hours. Then, should react between ethyl acetate and water and distributed. Isolate organic matter, dry (MgSO₄) and remove volatile materials by evaporation. Residue is ground with ether and by filtering it is collected, obtain the title compound (0.79g, 22%) of white solid form.

NMR(CDCl ₃)：1.50(s，9H)，2.06(m，2H)，2.34(m，1H)，2.94(m，1H)， 3.43(m，2H)，5.07(dd，1H)。

Method 48

2,6-, two bromo-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

2,4,6-, three bromo pyrimi piperidines (3.5g, 11mmol), 5-methyl isophthalic acid H-pyrazoles (1.077g, 11mmol), the mixture of sodium carbonate (1g) in ethanol (50ml) were stirred 18 hours under nitrogen at ambient temperature. Remove volatile materials and residue is dissolved in DCM and the minimum methyl alcohol by evaporation. With the solution with water washing of gained, dry (Na₂SO ₄) and by evaporation reduction solvent volume. Product is precipitated out, and by filtering it is collected, and obtains title compound (1.7g, 47 %).

NMR(DMSO)：2.20(s，3H)，5.80(s，1H)，7.92(s，1H)；m/z 334 [MH]+。

Method 49

6-bromo-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-(2-(the different  azoles of 3-(pyridine-2-yl)-5-yl) pyrrolidines) pyrimidine

With 2,6-two bromo-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (method 48) (235mg, 0.7mmol), 2-(the different  azoles of 3-(2-pyridine radicals)-5-yl) pyrrolidines (method 12) (167mg, 0.77mmol) and the mixture of DIPEA (0.272ml, 1.55mmol) in dimethylbenzene (2.5ml) 80 ℃ of lower heating 18 hours. Remove volatile materials and residue is dissolved in ethyl acetate and the minimum methyl alcohol by evaporation. With the solution with water washing of gained, dry (MgSO₄) and by the evaporation desolventizing. Residue is dissolved among the minimum DCM and with it to descend to store 18 hours at-10 ℃. By filtering the precipitation of collecting gained, obtain title compound (140mg, 50%).

NMR(DMSO)：1.98-2.40(m，7H)，3.50-3.60(m，1H)，3.64-3.80(m，1H)， 5.38(d，1H)，5.85(s，1H)，6.75(s，1H)，7.50(t，1H)，7.88-8.0(m，2H)，8.64(s， 1H)，9.68(s，1H)；m/z 468[MH]+。

Method 50

The different  azoles of S-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine-6-base formic acid

With 2-chloro-4-(5-methyl isophthalic acid H-pyrazoles-3-base amino) pyrimidine-6-base formic acid sodium salt (method 44) and the different  azoles of S-2-[3-(pyridine-2-yl)-5-yl] pyrrolidines (method 42) processes as described in the method 43, obtains title compound.

Method 51

6-[N-(acetyl-amino) carbamoyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(2-acetyl group-5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

Under 0 ℃, with acetyl chlorine (0.28ml, 3.94mmol) join the different  azoles of 6-hydrazides-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 77) (800mg, 1.79mmol) and the mixture of triethylamine (0.6ml, 4.13mmol) in anhydrous THF (20ml) in. This reaction is heated stirred 1 hour to the environment temperature and with it again. Remove volatile materials by evaporation, the residue water is ground and by filtering it is collected, obtain title compound (911mg, 96%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 1.90 (s, 3H), 2.10 (m, 3H), 2.18 (s, 3H), 2.42 (m, 1H), 2.52 (s, 3H), (3.76 m, 1H), 3.85 (m, 1H), 5.55 (dd, 1H), 6.50 (s, 1H), 6.70 (s, 1H), (7.05 s, 1H), 7.38 (m, 1H), 7.85 (t, 1H), 7.92 (d, 1H), 8.61 (d, 1H); M/z 531[MH]+.

Method 52

6-[(4-aminomethyl phenyl sulfonyloxy) methyl]-the different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-2-N-[4-aminomethyl phenyl sulphonyl base]-1H-pyrazoles-3-base is amino) pyrimidine

With p-toluenesulfonyl chloride (3.0g, 15.7mmol) join the different  azoles of 6-hydroxyl methyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 80) (3.13g, 7.49mmol), in the mixture of triethylamine (2.5ml, 18mmol) in anhydrous THF (50ml). The mixture of gained was at room temperature stirred 1 hour, then it was heated 4 hours under refluxing. Remove volatile materials and residue is dissolved in the water by evaporation, extract with DCM. With the organic extract merging and by the evaporation desolventizing. Residue is carried out purifying with silica gel chromatograph, with DCM (100%), then use ether (100%) to carry out wash-out, obtain title compound (containing 31% 6-chloromethyl derivative) (1.69g, 31%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.10 (m, 3H), 2.20 (s, 3H), 2.29 (s, 3H), 2.35 (s, 3H), 2.38 (m, 1H), 3.70 (m, 1H), 3.75 (m, 1H), 4.40 (s, 2H), 5.45 (dd, 1H), 6.45 (s, 1H), 6.68 (s, 1H), 6.75 (s, 1H), 7.10 (d, 2H), 7.38 (d, 2H), 7.42 (m, 1H), 7.55 (d, 2H), 7.75 (d, 2H), 7.90 (m, 2H), 8.62 (d, 1H); M/z 727 [MH]+.

Method 53

The different  azoles of S-6-chloromethyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl }-4-(5-methyl-2-N-[4-aminomethyl phenyl sulphonyl base]-1H-pyrazoles-3-base is amino) pyrimidine

With p-toluenesulfonyl chloride (624mg, 3.26mmol) join the different  azoles of S-6-hydroxyl methyl-2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine (embodiment 86) (570.4mg, 1.36mmol) and N, in the mixture of N-diisopropyl ethyl amine (0.467ml, 3.40mmol) in anhydrous THF (20ml). This mixture was at room temperature stirred 1 hour, then under refluxing, heated 4 hours. Remove volatile materials by evaporation, residue is dissolved in the water and extracts with DCM. To extract thing and merge, by the evaporation desolventizing and with silica gel chromatograph residue be carried out purifying, and with carrene (100%), then use ether (100%) to carry out wash-out, obtain title compound (403mg, 50%).

NMR(DMSO-d ₆+d ₄-acetic acid is under 100 ℃): 2.05 (m, 3H), 2.20 (s, 3H), 2.35 (s, 3H), 2.38 (m, 1H), 3.65 (m, 1H), 3.76 (m, 1H), 4.35 (s, 2H), 5.40 (dd, 1H), 6.43 (s, 1H), 6.50 (s, 1H), 6.65 (s, 1H), 7.35 (d, 2H), 7.42 (m, 1H), 7.72 (d, 2H), 7.85 (t, 1H), 7.90 (m, 1H), 8.62 (d, 1H); M/z 591[MH]+.

Method 54

Pyrazine-2-aldoxime

Under-78 ℃, with 1N aluminum hydride lithium at THF (73.8ml, 73.8mmol) in solution join in the suspension of pyrazine-2-formic acid methyl esters (20g, 145mmol) in anhydrous THF (300.0ml), simultaneously reaction temperature is remained on the temperature that is lower than-72 ℃. Adding fashionablely fully, this reactant mixture was being stirred under-78 ℃ 20 minutes again, then using glacial acetic acid (20.0ml) extinguishing. The mixture of gained heated remove volatile materials to room temperature and by evaporation. Residue is dissolved in the 3N hydrochloric acid (116ml) and with DCM extracts. To extract thing and merge, with saturated sodium bicarbonate aqueous solution washing and solvent evaporated. Residue is carried out purifying with silica gel chromatograph, and usefulness DCM/ ether (100: 0, then 80: 20, then 0: 100) carry out wash-out, obtain pyrazine-2-aldehyde (15.67g, 100 %). Be dissolved in immediately it in chloroform (200ml) that is cooled to 0 ℃ and to wherein adding single hydroxylamine hydrochloride (11.02g, 159.5mmol) and triethylamine (24.2ml, 117.4mmol). Then, this reactant mixture was at room temperature stirred 0.5 hour, and by the evaporation desolventizing. Residue is suspended in the ether (500ml) and by removing by filter insoluble substance. With the filtrate evaporation and with chromatography residue is carried out purifying, and usefulness DCM/ ether (100: 0, then 80: 20, then 0: 100) carry out wash-out, obtain the title compound (5.5g, 31%) of solid form.

NMR(DMSO-d ₆)：8.15(s，1H)，8.62(dd，2H)，8.99(s，1H)。

Method 55

The different  azoles of S-2-[3-(2-pyrazine base)-5-yl] pyrrolidines

The solution (5.95ml, 12.51mmol) of clorox with 13% in water joins S-N-Uncle-In the mixture of butoxy carbonyl-2-ethynl pyrrolidines (1.344g, 6.88mmol), pyrazine-2-aldoxime (770mg, 6.26mmol) and DCM (50ml), keep simultaneously reaction temperature to be lower than-3 ℃. Then, this reactant mixture was stirred 5 hours at ambient temperature. To wherein adding entry, isolate organic layer and solvent evaporated. Residue is dissolved in the hydrogen chloride of the 4M that is arranged in Isosorbide-5-Nitrae-two  alkane (20ml) and methyl alcohol (30ml), with the heating 1 hour under refluxing of this mixture. Make the cooling of this mixture, remove volatile materials by evaporation, residue is dissolved in the water and with the 10M sodium hydrate aqueous solution pH of this solution is transferred to 12. This aqueous mixture is extracted with DCM, to extract thing and merge, evaporation is carried out purifying with silica gel chromatograph to residue, use DCM, then use ether/DCM (20: 80) and extract with methyl alcohol/DCM (2: 98 to polarity increase to 10: 90) at last. Then, this product that has carried out purifying is ground with ether and by filtering it collected, obtain title compound (344mg, 25%).

NMR(DMSO-d ₆)：1.78(m，3H)，2.17(m，1H)，4.38(dd，1H)，6.87(s，1H)， 8.78(dd，2H)，9.21(s，1H)；m/z 217[MH]+。

Method 56

2-chloro-6-methyl-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

With solid sodium carbonate (1.2g, 11.3mmol) join 2,4-two chloro-6-methyl pyrimidine (1.7g, 10.3mmol) and 5-amino-3-methyl isophthalic acid H-pyrazoles (1.0g, 10.3mmol) in without the solution in the water-ethanol (50ml) and this mixture is stirred under 42 ℃ and heated 3 days. Make this mixture cooling, by removing by filter insoluble material and with ethanol (10ml) the filter pad being washed. From filtrate, remove volatile materials by evaporation, keep bathing temperature and be lower than 40 ℃. Residue is carried out purifying with silica gel chromatograph immediately, carry out wash-out with methyl alcohol/DCM (5: 95 to polarity increase to 20: 80), obtain the title compound (758mg, 33%) of white solid form.

NMR(CDCl ₃)：2.17(s，3H)，2.11(s，3H)，5.88(br s，1H)，7.85(br s，1H)， 8.80(br s，1H)；m/z 224[MH]+。

Method 57

2,6-, two chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

2,4,6-trichloropyrimidine and 3-amino-5-cyclopropyl-1H-pyrazoles (method 7 of WO 03/048133) are processed as described in method 29, obtained title compound (12g, 55%).

NMR(DMSO)：0.75(m，2H)，0.95(m，2H)，1.95(m，1H)，1.35(m，1H)， 5.65(br s，1H)，7.70(br s，1H)，10.60(s，1H)，12.20(s，1H)；m/z 270 [MH]+。

Method 58

3-(uncle-butoxy carbonyl is amino) third-1-alkene-1-ylboronic acid [2,3-dihydroxy-2,3-dimethylbutane] ester

Under 0 ℃, borine methyl sulfide complex (8.4ml 2M THF solution) is added drop-wise in the solution of australene (5.4ml, 34mmol) in THF (10ml) also with this mixture stirring 1 hour. This mixture is heated to the environment temperature, stirred 2 hours, then be cooled to 0 ℃. Then, slowly to wherein add 3-(Uncle-Butoxy carbonyl amino) solution of third-1-alkynes (2.0g, 13mmol) in THF (5ml) also stirred this mixture 18 hours at ambient temperature. This mixture is cooled to 0 ℃ and to wherein dripping acetaldehyde (14.3ml, 0.25mmol). This mixture was stirred 5 hours, then to wherein adding excessive acetaldehyde and passing through the evaporation desolventizing. Be arranged in 2 of heptane to wherein adding, 3-dihydroxy-2,3-dimethylbutane (2.4g, 20mmol) also stirred this mixture 18 hours at ambient temperature. This mixture is washed with water dry (Na₂SO ₄) and solvent evaporated. Residue is carried out purifying with silica gel column chromatography, carry out wash-out with EtOAc/ hexane (10: 90 to polarity increase to 18: 82), obtain title compound, with its direct use.

Method 59

3-(N-methyl acetyl is amino) third-1-alkynes

Acetic anhydride (1.2ml, 12.7mmol) is added drop-wise in N-methyl propargyl amine (400mg, 5.8mmol) and the solution of 4-dimethylaminopyridine (70mg, 0.67mmol) in pyridine (15ml). This mixture is at room temperature stirred 18 hours also by the evaporation desolventizing. Residue is dissolved among the EtOAc, and water washs it and it is carried out drying (MgSO₄) and by the evaporation desolventizing. Residue is carried out purifying with silica gel chromatograph, carry out wash-out with methyl alcohol/DCM (5: 95, then 10: 90), obtain title compound (136mg, 22%).

NMR(DMSO)：1.99(s，3H)，2.98(s，3H)，4.12(s，2H)，4.15(s，1H)。

Method 60

S-6-[3-(N-phthalimido) third-1-alkynes-1-yl]-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino)-2-[the different  azoles of 2-{3-(pyridine-2-yl)-5-yl } pyrrolidines-1-yl] pyrimidine

Make S-6-iodo-4-(5-methyl isophthalic acid H-pyrazoles-3-base the is amino)-different  azoles of 2-[2-{3-(pyridine-2-yl)-5-yl with embodiment 105 described methods } pyrrolidines-1-yl] pyrimidine (embodiment 98) and 3-(N-phthalimido) third-1-alkyne reaction, obtain title compound (150mg, 45%).

NMR(DMSO)：2.00-2.12(m，3H)，2.18(s，3H)，2.32-2.41(m，1H)， 3.61-3.69(m，1H)，3.70-3.78(m，1H)，4.61(s，2H)，5.45(s，1H)，5.68(s，1H)， 6.01(s，1H)，6.45(s，1H)，6.65(s，1H)，7.44(dd，1H)，7.84-7.96(m，7H)，8.65(d， 1H)，9.05(s，1H)，11.55(s，1H)；m/z 572[MH]+。

Method 61

2-chlorine pyridine-3-base aldoxime

The solution of hydroxylamine hydrochloride (533mg, 7.6mmol) in water (1.8ml) is added drop-wise to the NaOH (708mg, 17mmol) that is arranged in water (2ml). Then, the solution with gained is added drop-wise in the solution of 2-chlorine pyridine-3-base aldehyde (1g, 7mmol) in ethanol (7ml), water (7ml) and ice (15g). This mixture was at room temperature stirred 18 hours. With 6M hydrochloric acid this mixture is neutralized to pH7. By the solid collected by filtration product, water washs it and it is carried out drying, obtains title compound (800mg, 73%).

NMR(DMSO)：7.45(dd，1H)，8.18(dd，1H)，8.32(s，1H)，8.42(dd，1H)； m/z 157[MH]+。

Method 62

The different  azoles of S-N-(uncle-butoxy carbonyl)-2-[3-(2-chlorine pyridine-3-yl)-5-yl] pyrrolidines

Under about 0 to 5 ℃, clorox (aqueous solution of 5.3ml 13%) is added drop-wise to strongly carrying out the 2-chlorine pyridine that stirs-3-base aldoxime (method 61) (800mg, 5.1mmol) and S-N-Uncle-Butoxy carbonyl-2-acetylene base pyrrolidines is (such as Bull.Soc.Chim.Fr.1997,134,141-144 and J. Med.Chem.1994,37,4455-4463 is described to be made like that) in (1.99g, 10.2mmol) suspension in DCM (20ml). This mixture is heated and it was at room temperature stirred 18 hours. Remove volatile materials and residue is carried out purifying with silica gel chromatograph by evaporation, carry out wash-out with EtOAc/ hexane (20: 80), obtain title compound (955mg, 54%).

NMR(DMSO)：1.22-1.42(m，9H)，1.95-2.0(m，3H)，2.22-2.38(m，1H)， 3.30-3.40(m，1H)，3.43-3.55(m，1H)，5.0(s，1H)，6.78(s，1H)，7.58(s，1H)， 8.12(d，1H)，8.55(dd，1H)；m/z 350[MH]+。

Method 63

S-N-(uncle-butoxy carbonyl)-2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines

With S-N-(Uncle-Butoxy carbonyl)-and the different  azoles of 2-[3-(2-chlorine pyridine-3-yl)-5-yl] pyrrolidines (method 62) (950mg, 2.7mmol) and the heating 18 hours under refluxing of the mixture of methyl alcohol sodium (740mg, 13.7mmol) in methyl alcohol (25ml). Make this reactant mixture cooling, dilute with EtOAc. With this solution with water washing, dry (Na₂SO ₄) and by the evaporation desolventizing. Residue is carried out purifying with silica gel chromatograph, carry out wash-out with EtOAc/ hexane (15: 85), obtain title compound (675mg, 72%).

NMR(DMSO)：1.22-1.42(m，2H)，1.88-2.0(m，3H)，2.22-2.34(m，1H)， 3.34-3.42(m，1H)，3.42-3.53(m，1H)，3.95(s，3H)，4.98(s，1H)，6.67(s，1H)， 7.12(dd，1H)，8.14(dd，1H)，8.30(dd，1H)；m/z 346[MH]+。

Method 64

S-2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] pyrrolidines

With 2M hydrochloric acid (25ml) join S-N-(Uncle-Butoxy carbonyl)-and 2-[3-(2-first oxygen yl pyridines-3-yl) different  azoles-5-yl] in the solution of pyrrolidines (method 63) (670mg, 2mmol) in methyl alcohol (25ml) and this mixture was at room temperature stirred 2.5 days. With this mixture evaporation and concentration, with 40% sodium hydrate aqueous solution its pH is transferred to 7 and extract with DCM. To extract thing and merge, dry (MgSO₄) and by the evaporation desolventizing, obtain the title compound (300mg, 65%) of grease form.

NMR(DMSO)：1.70-1.82(m，3H)，1.98-2.07(m，1H)，2.86-2.91(m，2H)， 3.96(s，3H)，4.29-4.38(m，1H)，6.70(s，1H)，7.10(dd，1H)，8.13(dd，1H)， 8.28(dd，1H)；m/z 246[MH]+。

Method 65

4-(5-ethyl-1H-pyrazoles-3-base is amino)-2-chlorine pyrimidine

With 2,4-dichloro pyrimidine (2.97g, 20mmol), 5-amino-3-ethyl-1H-pyrazoles (2.44g, 22mmol) and N, the mixture of N-diisopropyl ethyl amine (3.8ml, 22mmol) in anhydrous THF (75ml) was 60 ℃ of lower heating 18 hours. Remove volatile materials by evaporation, the mixture of residue with DCM and water ground. By the solid collected by filtration product, the washing of water and ether, drying obtains the title compound (1.55g, 35%) of colourless crystallization solid form.

NMR(DMSO)：1.20(t，3H)，2.60(q，2H)，6.06(s，1H)，7.15(s，1H)， 8.10(d，1H)，9.80(s，1H)，11.83(br s，1H)；m/z 224[MH]+。

Method 66

The different  azoles of S-2-[3-(pyrimidine-2-base)-5-yl] pyrrolidines

Aqueous sodium hypochlorite solution (4.25ml, 7.45mmol) with 13% slowly joins and is cooled to 0 ℃ S-N-Uncle-Butoxy carbonyl-2-acetylene base pyrrolidines is (such as Bull.Soc.Chim.Fr.1997,134,141-144 and J.Med.Chem.1994,37,4455-4463 is described to be made like that) (1.45g, 7.45mmol) and pyrimidine-2-aldoxime (0.47g, 3.82mmol, Khimiya Geterotsiklicheskikh Soedinenii (1972), 10,1422-4) in the mixture in DCM (15ml). This reactant mixture is heated to the environment temperature, then it was stirred 12 hours. This mixture is diluted with ethyl acetate, carry out layer and separate, by evaporation desolventizing from organic layer. Residue is carried out purifying with silica gel column chromatography, carry out wash-out with EtOAc/ hexane (0: 100 to polarity increase to 100: 0). With the evaporation of product fraction, obtain a kind of grease of gold, it is solidified into solid (250mgs, 20%) when leaving standstill. Then, this kind dissolution of solid was stirred 45 minutes in TFA (2ml) and with it at ambient temperature. This reactive evaporation is dissolved among the DCM to drying and with residue, it is poured on the isolute SCX-2 ion exchange column. With methyl alcohol this post is carried out wash-out to elute any neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. To comprise the fraction evaporation of product, obtain the title compound (125mg, 15%) of orange solids form.

NMR(DMSO-d ₆)：1.78(m，3H)，2.14(m，1H)，2.92(t，2H)，4.36(t，1H)， 6.82(s，1H)，7.60(t，1H)，8.96(d，2H)；m/z 217[MH]+。

Method 67

3-first oxygen base pyrazine-2-aldoxime

With 3-first oxygen base pyrazine-2-aldehyde (Tetrahedron (1999), 56 (2), 265-273) (2.1g, 15mmol), hydroxylamine hydrochloride (1.27g, 18mmol), the mixture of ethanol (20ml) and triethylamine (4.17ml, 30mmol) was 60 ℃ of lower heating 90 minutes. Remove volatile materials and with silica gel column chromatography residue is carried out purifying by evaporation, carry out wash-out with hexane/EtOAc (100: 0 to polarity increase to 0: 100), obtain the title compound (740mg, 32%) of white solid form.

NMR(DMSO-d ₆)：3.96(s，3H)，8.22(s，2H)，8.23(m，1H)，11.89(s， 1H)。

Method 68

S-2-[3-(2-first oxygen base pyrazine-3-yl) different  azoles-5-yl] pyrrolidines

With clorox (aqueous solution of 5.23ml 13%, 9.16mmol) slowly join the carrying out that be cooled to 0 ℃ the S-N-that stirsUncle-Butoxy carbonyl-2-acetylene base pyrrolidines is (such as Bull.Soc. Chim.Fr 1997,134,141-144 and J.Med.Chem.1994,37,4455-4463 is described to be made like that) (1.07g, 5.50mmol), in the 3-first oxygen base pyrazine-solution of 2-aldoxime (method 67) (0.7g, 4.58mmol) in DCM (40ml). This reaction is heated to the environment temperature, then it was stirred 12 hours. Carry out layer and separate, desolventizing and residue is carried out purifying with silica gel column chromatography from organic layer is carried out wash-out with hexane/EtOAc (100: 0 to polarity increase to 0: 100). When leaving standstill, this product that has carried out purifying is solidified into solid, it is dissolved among the TFA (10ml) also this mixture was at room temperature stirred 30 minutes. Remove volatile materials and residue is dissolved among the DCM by evaporation, it is poured on the isolute SCX-2 ion exchange column. With methyl alcohol this post is carried out wash-out to elute any neutral substance, then with 7M methyl alcohol ammoniacal liquor product is carried out wash-out. By the evaporation desolventizing, obtain the title compound (260mgs, 23%) of brown oil form.

NMR(DMSO-d ₆)：1.78(m，3H)，2.14(m，1H)，2.92(t，2H)，4.01(s，3H)， 4.36(dd，1H)，6.78(s，1H)，8.36(s，2H)；m/z 247[M[H]+。

Method 69

2-chloro-4-(5-ethyl-1H-pyrazoles-3-base is amino)-5-FU

5-amino-1H-3-ethyl pyrazoles and 2,4-, two chloro-5-FUs are processed with method 65 described methods, obtained the title compound (1.89g, 78%) of rice white crystalline solid forms.

NMR(DMSO)：1.20(t，3H)，2.62(q，2H)，6.35(s，1H)，8.22(d，1H)， 10.35(s，1H)，12.25(br s，1H)；m/z 242[MH]+。

Method 70

2-chloro-6-methyl-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

With sodium carbonate (2.15g, 20.25mmol) join and carrying out 2 of stirring, 4-two chloro-6-methyl pyrimidine (3g, 18.4mmol) and 3-amino-1H-5-cyclopropyl pyrazoles (2.25g, 18.4mmol) in without the solution in the water-ethanol (40ml) and with this mixture 40 ℃ of lower stirrings 4 days. By removing by filter insoluble material, will filter pad and wash with ethanol. From filtrate, remove volatile materials by evaporation, keep simultaneously bathing temperature and be lower than 40 ℃. Residue is used silica gel chromatography immediately, carry out wash-out with methyl alcohol/DCM (0: 100 to polarity increase to 20: 80), obtain the title product (1.9g, 46%) of white solid form.

NMR(DMSO)：0.65(m，2H)，0.90(m，2H)，2.25(s，3H)，5.90(br s，1H)， 7.05(br s，1H)，10.15(br s，1H)，12.10(br s，1H)；m/z 250[MH]+。

Method 71

4-chloro-6-(3-hydroxyl the propyl group)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } pyrimidine

2.5%w/v four oxidation osmiums are existedUncle-Solution in the butanols (0.47ml) joins and is carrying out intensively stirred 4-chloro-6-(penta-3-alkene-1-the yl)-different  azoles of 2-{2-[3-(pyridine-2-yl)-5-yl] pyrrolidines-1-yl } in the solution of pyrimidine (as described in the embodiment 34, making) in THF (10.5ml) and water (2.8ml). Then, to wherein adding solid periodic acid sodium (951mg, 4.44mmol). Should react and at room temperature stir 2 hours. Extract with this reactant mixture water dilution and with ethyl acetate. With ethyl acetate layer water and saturated brine washing, dry (Na₂SO ₄), and by the evaporation desolventizing. Residue is dissolved in THF (13.5ml) and the distilled water (5.0ml) and to wherein adding sodium borohydride (59mg, 1.59mmol). Should react and at room temperature stir 18 hours. This reactant mixture with ethyl acetate and water dilution, is carried out layer distribution and separates with layer. With ethyl acetate layer water and saturated brine washing, dry (Na₂SO ₄) and by the evaporation desolventizing. Residue with the hurried chromatogram purification of silica gel, is carried out wash-out with methyl alcohol/DCM (1.5: 98.5), obtain title compound (205mg, 36%).

NMR(DMSO-d ₆/300MHz)：1.67(m，2H)，2.06(m，3H)，2.42(m，3H)， 3.35(m，2H)，3.58(m，1H)，3.78(m，1H)，4.4(d，1H)，5.4(d，1)，6.67(s，1H)， 6.73(s，1H)，7.47(t，1H)，7.95(m，1H)，8.66(d，1H)；m/z 386[MH]+。

Method 72

2,6-, two chloro-4-(5-ethyl-1H-pyrazoles-3-base is amino) pyrimidine

2,4,6-trichloropyrimidine and 3-amino-5-ethyl-1H-pyrazoles (method 6 of WO 03/048133) are processed as described in the method 29, obtained title compound (2.48g, 51%).

NMR(DMSO-d ₆, under 100 ℃): 1.2 (t, 3H), 2.6 (q, 2H), 6.0 (s, 1H), 7.3 (br s, 1H), 10.2 (br s, 1H), 12.0 (br s, 1H); M/z 259[MH]+.

Method 73

S-2-(the different  azoles of 3-(thiazole-4-yl)-5-yl) pyrrolidines

With S-N-Uncle-Butoxy carbonyl-2-(the different  azoles of 3-(thiazole-4-yl)-5-yl) pyrrolidines (method 74) (334mg, 1.04mmol as described in the method 42, process, obtain the title compound (217mg, 94%) of yellow solid form.

NMR(DMSO)：1.75(m，3H)，2.1(m，1H)，2.9(t，2H)，4.32(t，1H)，6.72(s， 1H)，8.29(s，1H)，9.24(s，1H)；m/z 222[MH]+

Method 74

Uncle S-N--butoxy carbonyl-2-(the different  azoles of 3-(thiazole-4-yl)-5-yl) pyrrolidines

The solution of triethylamine (0.7ml, 5.4mmol) in THF (2ml) is added drop-wise to 0 ℃ the thiazole-4-chloral oxime (method 75) (730mg, 4.5mmol) and S-N-of being cooled to that is carrying out stirringUncle-Butoxy carbonyl-2-acetylene base pyrrolidines is (such as Bull.Soc.Chim.Fr.1997,134,141-144 and J.Med.Chem.1994,37, make like that described in the 4455-4463) in (0.96g, 4.95mmol) solution in THF (20ml). This mixture is heated to be stirred 18 hours to the environment temperature and with it. By the evaporation desolventizing, residue distributed between DCM and water and by removing by filter insoluble material. Carrying out layer separates, desolventizing from organic layer, with silica gel column chromatography residue is carried out purifying, carry out wash-out with hexane/EtOAc (3: 1 to polarity increase to 3: 2), the title compound of the acetylene that obtains reclaiming (634mg) and white solid form (334mg, 23 %).

NMR(DMSO)：1.25(s，5H)，1.38(s，4H)，1.93(m，3H)，2.26(m，1H)， 3.37(m，1H)，3.48(m，1H)，5.0(s，1H)，6.71(br d，1H)，8.32(s，1H)，9.23(s， 1H)；m/z 344[M+Na]+

Method 75

Thiazole-4-chloral oxime

N-chloro-succinimide (600mg, 4.5mmol) is joined in the thiazole that the is cooled to 0 ℃-solution of 4-aldoxime (method 76) (579mg, 4.5mmol) in DMF (4ml). Should react 0 ℃ of lower stirring 1 hour, and make it to heat and stirred again 2 hours to the environment temperature and with it. This mixture is diluted with ether and water. The ether layer is separated and water and salt solution wash it, by the solid collected by filtration product and with the dry (Na of filtrate₂SO ₄), by the evaporation desolventizing, obtain solid product. Two batches of solids are merged, obtain title compound crude product (730mg, 100%).

NMR(DMSO)：8.12(s，1H)，9.15(s，1H)，12.42(s，1H)；m/z 163 [MH]+

Method 76

Thiazole-4-aldoxime

Thiazole-4-aldehyde (Synthesis 1987,998) is processed with method 67 described methods, obtained title compound.

NMR(DMSO)：7.93(s，1H)，8.22(s，1H)，9.13(s，1H)，11.28(s，1H)。

Method 77

S-2-(the different  azoles of 3-(thiazole-2-yl)-5-yl) pyrrolidines

3M hydrochloric acid (26ml) is joined S-N-Uncle-Butoxy carbonyl-2-(the different  azoles of 3-(thiazole-2-yl)-5-yl) pyrrolidines (method 78) (8.32g, 26mmol) also this mixture was at room temperature stirred 18 hours in the solution in methyl alcohol (26ml), then 60 ℃ of lower stirrings 1 hour. Remove volatile materials by evaporation, water layer is washed with DCM, with 40% sodium hydrate aqueous solution its pH is transferred to 11-12 and also extract with DCM (x6). To extract thing and merge, dry (Na₂SO ₄) and by the evaporation desolventizing. Residue is carried out purifying with silica gel column chromatography, carry out wash-out with methyl alcohol/DCM (5: 95), obtain the title compound (4.01g, 70%) of yellow oil form.

NMR(DMSO)：1.75(m，3H)，2.10(m，1H)，2.89(t，2H)，4.33(m，1H)， 6.78(s，1H)，7.95(d，1H)，8.03(d，1H)；m/z 222[MH]+。

Method 78

Uncle S-N--butoxy carbonyl-2-(the different  azoles of 3-(thiazole-2-yl)-5-yl) pyrrolidines

N-chloro-succinimide (10.6g, 80mmol) is joined in the thiazole that is cooled to-5 ℃-solution of 2-aldoxime (method 2) (10.35g, 80mmol) in DMF (30ml) in batches. Should react-5 ℃ of lower stirrings 1 hour, it is slowly heated to the environment temperature. This mixture is diluted with ether, EtOAc and water. By the solid collected by filtration product. Organic layer is separated water and salt water washing, dry (Na₂SO ₄) and by the evaporation desolventizing, will bathe temperature and maintain the environment temperature, obtain solid product. The two batches of solids are merged, directly be dissolved in it among THF (200ml) and this solution is added drop-wise to and be cooled to 0 ℃ S-N-Uncle-Butoxy carbonyl-2-acetylene base pyrrolidines is (such as Bull.Soc.Chim.Fr.1997,134,141-144 and J.Med.Chem. 1994,37, prepare like that described in the 4455-4463) (31g, 160mmol) and in the solution of triethylamine (13.4ml, 96mmol) in THF (200ml), this mixture is slowly heated stirred 18 hours to the environment temperature and with it. By the evaporation desolventizing, add entry in the residue and this mixture is extracted with DCM. To extract thing and merge, use the salt water washing, dry (Na₂SO ₄) and by the evaporation desolventizing. Residue is carried out purifying with silica gel column chromatography, at first elute the initial acetylene that reclaims with EtOAc/ hexane (1: 4 to polarity increase to 1: 1), then elute the title compound (8.32g, 32%) of orange form.

NMR(DMSO)：1.22 and 1.38(2x br s，9H)，1.85(m，3H)，2.15(br m， 1H)，3.37(m，1H)，3.50(m，1H)，5.00(br m，1H)，6.78 and 6.83(2x br s，1H)， 7.97(d，1H)，8.05(d，1H)；m/z 266[MH-C ₄H ₉]+。

Method 79

6-ethyl-2-chloro-4-(5-ethyl-1H-pyrazoles-3-base is amino) pyrimidine

With 2,4-two chloro-6-ethyl-pyrimidine (J.Am.Chem.Soc.1936,58,78) (1.33g 7.53mmol) stirs in ethanol (50ml) and to wherein adding 5-ethyl-1H-3-amino-pyrazoles (method 6 of WO 03/048133) (0.836g, 7.53mmol), then add sodium carbonate (1.25g) and also this mixture was stirred 4 days under 40 ℃, then 55 ℃ of lower stirrings a whole night. By removing by filter insoluble inorganic matter and passing through evaporation desolventizing from filtrate. Also (3 * 50ml) extract with EtOAc with this mixture to wherein adding entry (100ml). To extract thing and merge, water (50ml), salt solution (50ml) washing, dry (MgSO₄) and by the evaporation desolventizing. Residue is carried out purifying with silica gel column chromatography, carry out wash-out with hexane/EtOAc (100: 0 to polarity increase to 0: 100), obtain the title compound (210mg, 11%) of white solid form.

NMR(DMSO-d ₆, under 100 ℃): 1.20 (m, 6H), 2.50-2.70 (m, 4H), 6.05 (s, 1H), 7.05 (br s, 1H), 9.70 (br s, 1H), 11.85 (br s, 1H); M/z 252[MH]+.

Method 80

6-ethyl-2-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

With the method similar to method described in the method 79 to 2,4-two chloro-6-ethyl-pyrimidine (J.Am. Chem.Soc.1936,58,78) and 5-cyclopropyl-1H-3-amino-pyrazoles (method 7 of WO 03/048133) process, obtain the title compound (464mg, 32%) of yellow powder form.

NMR(DMSO-d ₆, under 100 ℃): 0.65 (m, 2H), 0.90 (m, 2H), 1.15 (t, 3H), 1.90 (m, 1H), 2.55 (q, 2H), 5.95 (br s, 1H), 7.05 (br s, 1H), 9.70 (br s, 1H); M/z 264[MH]+.

Method 81

6-cyclopropyl-2-chloro-4-(5-cyclopropyl-1H-pyrazoles-3-base is amino) pyrimidine

With the method similar to method 79 described methods to 2,4-two chloro-6-cyclopropyl pyrimidine (Chem. Abs.1969,71,61412y) process with 5-cyclopropyl-1H-3-amino-pyrazoles (method 7 of WO 03/048133), obtain the title compound (200mg, 23%) of pink solid form.

NMR(DMSO-d ₆, under 100 ℃): 0.85 (m, 2H), 0.95 (m, 6H), 1.90 (m, 2H), 5.90 (s, 1H), 7.05 (br s, 1H), 9.60 (br s, 1H), 11.90 (br s, 1H); M/z 276 [MH]+.

Method 82

6-cyclopropyl-2-chloro-4-(5-ethyl-1H-pyrazoles-3-base is amino) pyrimidine

With the method similar to embodiment 79 described methods to 2,4-two chloro-6-cyclopropyl pyrimidine (Chem.Abs.1969,71,61412y) process with 5-ethyl-1H-3-amino-pyrazoles (method 6 of W0 03/048133), obtain the title compound (200mg, 23%) of pink solid form.

NMR(DMSO-d ₆, under 100 ℃): 0.95 (m, 4H), 1.20 (t, 3H), 1.90 (m, 1H), (2.60 q, 2H), 5.65 (s, 1H), 6.05 (br s, 1H), (7.05 br s, 1H), 9.60 (br s, 1H), 11.85 (br s, 1H); M/z 264[MH]+.

Method 83

2-chloro-6-methyl-4-(5-ethyl-1H-pyrazoles-3-base is amino) pyrimidine

With the method similar to method 56 described methods 2,4-, two chloro-6-methyl pyrimidines and 5-amino-3-ethyl-1H-pyrazoles (method 6 of WO 03/,048 133) are processed, obtained title compound (450mg, 42%).

NMR(DMSO-d ₆, under 100 ℃): 1.20 (t, 3H), 2.25 (s, 1H), 3.60 (q, 2H), 6.05 (s, 1H), 7.00 (br s, 1H), 9.70 (br s, 1H), 11.85 (br s, 1H); M/z 238 [MH]+.

Method 84

4-hydroxyl-4-sulfydryl-6-(3-methoxy-propyl) pyrimidine

With 6-first oxygen base-3-oxo caproic acid methyl esters (5.33g, 30.6mmol) solution in ethanol (20ml) join in 80 ℃ of lower heated thiocarbamides (3.29g, 43.3mmol) and the mixture of ethanol sodium in ethanol (solution of 22.4ml 21%wt/wt) and with this mixture 75 ℃ of lower stirrings 18 hours. Remove volatile materials by evaporation, residue is dissolved in the water and with 2M hydrochloric acid the pH of this solution is transferred to 3. In cooled on ice and by filtering collecting precipitation solid out, drying obtains title compound (2.52g, 43%) with this mixture.

NMR(DMSO)：1.78(q，2H)，2.39(t，2H)，3.22(s，3H)，3.28(q，2H)， 5.64(s，1H)；m/z 201[MH]+。

Method 85

2,4-dihydroxy-6-(3-methoxy-propyl) pyrimidine

Suspension in water (20ml) was 120 ℃ of lower heating 24 hours with 4-hydroxyl-4-sulfydryl-6-(3-methoxy-propyl) pyrimidine (method 84) (3.9g, 19.5mmol) and chlorine acetic acid (1.89g, 19.9mmol). Make the cooling of this mixture, with NaOH solution its pH is transferred to 7 and with EtOAc it is extracted. To extract thing and merge, dry (Na₂SO ₄) and by the evaporation desolventizing, obtain the title compound (1.9g, 55%) of solid form.

NMR(DMSO)：1.78(q，2H)，2.31(t，2H)，3.21(s，3H)，3.30(q，2H)， 5.29(s，1H)；m/z 185[MH]+。

Method 86

2,4-, two chloro-6-(3-methoxy-propyl) pyrimidine

Solution in phosphoryl chloride phosphorus oxychloride (20ml) was 90 ℃ of lower heating 30 minutes with 2,4-dihydroxy-6-(3-methoxy-propyl) pyrimidine (method 85) (1.9g 10.2mmol) and DMA (2ml). Make this mixture cooling, to wherein adding frozen water and with EtOAc this mixture being extracted. To extract thing and merge, with 2M salt acid elution, dry (Na₂SO ₄) and by the evaporation desolventizing. Residue is carried out purifying with silica gel column chromatography, carry out wash-out with hexane/EtOAc (50: 50), obtain title compound (1.5g, 68%).

NMR(DMSO)：1.88(q，2H)，2.78(t，2H)，3.21(s，3H)，3.32(t，2H)， 7.72(s，1H)；m/z 221[MH]+。

Method 87

2-chloro-6-(3-methoxy-propyl)-4-(5-methyl isophthalic acid H-pyrazoles-3-base is amino) pyrimidine

2,4-, two chloro-6-(3-methoxy-propyl) pyrimidines (method 86) and 3-amino-1H-5-methyl pyrazoles are processed as described in the method 70, obtained title compound (200mg, 32%).

NMR(DMSO)：1.88(q，2H)，2.20(s，3H)，2.59(t，2H)，3.21(s，3H)， 3.32(t，2H)，3.38(t，2H)，6.05(s，1H)，7.04，(s，1H)，9.65(s，1H)，11.80(s，1H)； m/z 282[MH]+。

Pharmacology is analyzed

Be used for to survey to the inhibitory action of Igf-1r kinase activity and downstream signal conduction with to the optionally method of insulin receptor kinase and the conduction of Egfr signal

Used abbreviation:

PBS (PBS/T) is the salt solution of phosphate buffered, pH7.4 (have 0.05% tween 20)

HEPES is N-[2-hydroxyl ethyl] piperazine-N '-[2 ethane sulfonic aicd]

DTT is dithiothreitol (DTT)

TMB is tetramethyl biphenyl amine

DMSO is dimethyl sulfoxide (DMSO)

BSA is that bovine serum albumin is white

ATP is atriphos

DMEM is Da Erbaike (family name) improvement Yi Geer (family name) culture medium (Dulbecco ' s modified Eagle ' s Medium)

FBS/FCS is tire ox/little cow's serum

HBSS is the salt solution of Hanks balance

HRP is the horseradish peroxidase enzyme

SDS is lauryl sodium sulfate

IGF-I (IGF-1R) is insulin-like growth factor-I (IGF-1 receptor)

EGF is epidermal growth factor

IGF-1R kinase assay

a) Protein cloning, expression and purification

Construct encoding contains glutathione-S-transferase (GST), thrombin cleavage site, and IGF-1R Intracellular domain (amino acids 930-1367) and subsequently referred to as fusion protein GST-IGFR DNA molecules and using standard molecular biology techniques (Molecular Cloning-A Laboratory Manual, Second Edition, 1989; Sambrook, Fritsch and Maniatis; Cold Spring Harbour Laboratory Press) and cloned into pFastBac1 (Life Technologies Ltd, UK) in.

According to the manufacturer's protocol to produce recombinant viruses.

Briefly, the GST-IGFR containing the pFastBac-1 vector containing baculovirus transformed into Poison genome (bacmid DNA) of E.coli DH10Bac cells and through cell transposition things Parts, and the gentamicin resistance gene and including containing baculovirus polyhedrin promoter GST-IGFR expression cassette (expression cassette) of pFastBac carrier directly transposable to the area Bacmid DNA. By gentamicin, kanamycin, tetracycline and X-gal to choose, The resulting white colonies should contain recombinant encoding GST-IGFR bacmid DNA. From some of the BH10Bac white colonies cultured small-scale plasmid DNA was extracted and used CellFECTIN rod test Agent (Life Technologies Ltd, UK) following the manufacturer's instructions and transfected containing 10% to Serum TC100 medium (Life Technologies Ltd, UK) for the growth of the Spodoptera frugiperda Sf21 cells. By 72 hours after transfection cells were collected culture Group to harvest the virus particles. 100ml infection with 0.5ml culture medium containing a concentration of 1 × 10 ...⁷Briefly, the GST-IGFR containing the pFastBac-1 vector containing baculovirus transformed into Poison genome (bacmid DNA) of E.coli DH10Bac cells and through cell transposition things Parts, and the gentamicin resistance gene and including containing baculovirus polyhedrin promoter GST-IGFR expression cassette (expression cassette) of pFastBac carrier directly transposable to the area Bacmid DNA. By gentamicin, kanamycin, tetracycline and X-gal to choose, The resulting white colonies should contain recombinant encoding GST-IGFR bacmid DNA. From some of the BH10Bac white colonies cultured small-scale plasmid DNA was extracted and used CellFECTIN rod test Agent (Life Technologies Ltd, UK) following the manufacturer's instructions and transfected containing 10% to Serum TC100 medium (Life Technologies Ltd, UK) for the growth of the Spodoptera frugiperda Sf21 cells. By 72 hours after transfection cells were collected culture Group to harvest the virus particles. 100ml infection with 0.5ml culture medium containing a concentration of 1 × 10 ...

By using glutathione - agarose affinity chromatography, and eluted with glutathione The GST-IGFR protein was purified. Briefly, the cells were 50mM HEPES pH 7.5 (Sigma, H3375), 200mM NaCl (Sigma, S7653), Complete protease inhibitor mix Compound (Complete Protease Inhibitor cocktail) (Roche, 1 873 580) and 1mM DTT (Sigma, D9779) - hereinafter referred to as lysis buffer - dissolved. Will be clarified Load lysate supernatant was filled to a glutathione Sepharose column (Amersham Pharmacia Biotech UK Ltd.). With lysis buffer contaminants from the substrate Wash down until the UV absorbance at 280nm under a return to baseline. Containing 20mM reduction with Glutathione (Sigma, D2804) in solubilization buffer and eluted pooled GST fusion protein containing White fractions containing them dialyzed into 50mM HEPES, pH 7.5,200 mM NaCl, 10 % Glycerol (v / v), 3mM reduction of glutathione and 1mM DTT buffer containing glycerin Medium. ...

The enzyme was purified through the activity of synthetic poly GluAlaTyr (EAY) 6:3:1 peptide (Sigma-Aldrich Company Ltd, UK, P3899) phosphorylation by ELISA detection system 96 - well format plate measurements.

b.i) Reagents used

Stock solution

200mM HEPES, pH 7.4 stored at 4 ℃ (Sigma, H3375)

1M DTT was stored at -20 ℃ (Sigma, D9779)

100mM Na ₃VO ₄Be stored at 4 ℃ (Sigma, S6508)

1M MnCl ₂Be stored at 4 ℃ (Sigma, M3634)

1mM ATP stored at -20 ℃ (Sigma, A3377)

Neat Triton X-100 was stored at room temperature (Sigma, T9284)

10mg/ml BSA was stored at 4 ℃ (Sigma, A7888)

Enzyme solution

GST-IGF-1R fusion protein, 75ng/ml, in 100mM HEPES, pH 7.4,5 mM DTT, 0.25mM Na₃VO ₄, 0.25% Triton X-100, 0.25mg/ml BSA, the new preparation The.

Cofactor solution

100mM HEPES，pH 7.4，60mM MnCl ₂，5mM ATP。

Substrate poly EAY

Sigma substrate poly (Glu, Ala, Tyr) 6:3:1 (P3899). Were prepared in PBS to a maximum 1mg/ml and stored at -20 ℃.

Test plate

Nunc Maxisorp 96 well immunoplate (immunoplates) (Life Technologies Ltd, UK).

Antibody

Anti - phosphotyrosine antibody, monoclonal, obtained from Upstate Biotechnology Inc., NY, USA (UBI 05-321). Each test plate using 11ml PBS / T +0.5% BSA diluted 3μl. Sheep - anti - mouse IgG HRP-conjugated secondary antibodies obtained from Amersham Pharmacia Biotech UK Ltd. (NXA931). 20μl of each test plate the stock solution was diluted to 11ml PBS / T +0.5% BSA.

TMB solution

In the dark at room temperature 1mg TMB tablets (Sigma T5525) were dissolved in 1ml DMSO (Sigma, D8779) for 1 hour. This solution was added to 9ml of freshly prepared 50mM Phosphate - citrate buffer pH 5.0 +0.03% sodium perborate [1 per 100ml of distilled water Buffer capsules (Sigma P4922)] in.

Stop solution for the 1M H₂SO ₄(Fisher Scientific UK.Cat.No. S/9200/PB08)。

Test compound

Was dissolved in DMSO to 10mM, then diluted with distilled water, the test hole, in the 1-2% of DMSO to give a final concentration of 200 to 0.0026μM range.

b.ii) pilot program

With PBS poly EAY substrate was diluted to 1μg/ml, and then number of 100μl per well The amount allocated to a 96 - well plate. The plate was sealed and incubated at 4 ℃ overnight. Been abandoned The amount of the plate poly EAY solution was washed (2x PBS / T; each hole 250μl PBS), in the wash Between polyester dry (blotting dry). Then, the plate was washed again (1 × 50mM HEPES, pH 7.4; each hole 250μl) and dry (this is important in order to remove background phosphate water Level). The test compound solution and 40μl 10μl kinase was added to each well together. Then, 50μl was added to each well and the plate was cofactor solution incubated at room temperature for 60 minutes.

The plate was emptied (i.e. discard its contents) with PBS / T was washed twice (each well 250μl), the The dry between washes. 100μl were added to each well diluted anti - phosphotyrosine antibody and The plate was incubated at room temperature for 60 minutes.

The plate was evacuated again with PBS / T washed twice (each hole 250ul), washed at all times Between dry. 100μl were added to each well diluted sheep - anti - mouse IgG antibody and the plate At room temperature for 60 minutes. Discarded and the plate was used inclusions PBS / T (per well 250μl) was washed two Times, each time in between dry. 100μl TMB added to each well and the plate was incubated at room temperature for 5-10 Min (these solutions in the presence of horseradish peroxidase in the case blue).

Each hole 50μl H₂SO ₄To terminate the reaction (the blue solution turns yellow), and in 450nm under Versamax plate reader (Molecular Devices Corporation, CA, USA) or under conditions similar to reading the plate.

The compounds of Examples found in the above test of less than 100μM of IC50.

c) the IGF-stimulated cell proliferation inhibition

Lammers, who has already overexpressing human IGF-1 receptor in murine fibroblasts Cells (NIH3T3) the construction described (EMBO J ,8,1369-1375, 1989). These cells IGF-I showed the proliferation response, can be mixed into the newly synthesized DNA to its BrdU Measurement. Used in the following tests for the IGF-stimulated proliferation inhibitory compounds to determine Material effect:

c.i) Reagents used:

Cell proliferation ELISA, BrdU (colorimetric) [Boehringer Mannheim (Diagnostics and Biochemicals) Ltd, UK.Cat no.1 647 229]. DMEM, FCS, Glutamine, HBSS (were obtained from Life Technologies Ltd., UK). Remove the charcoal / dextran FBS (HyClone SH30068.02, Perbio Science UK Ltd). BSA (Sigma, A7888).

Human recombinant IGF-1 Animal / media level (GroPep Limited ABN 78 008 176 298, Australia.Cat No.IU 100).

IGF preparation and storage

The 100μg lyophilized IGF is reconstructed in 100ul 10mM HCl.

Add 400μl of 1mg/ml BSA in PBS

25μl aliquots @ 200μg/ml IGF-1

Be stored at -20 ℃.

For testing purposes:

10μl reserves IGF +12.5 ml growth medium, get 8 × 160ng/ml reserve materials.

Complete growth medium

DMEM, 10% FCS, 2mM glutamine.

Starvation medium

DMEM, 1% removed charcoal / dextran FCS, 2mM glutamine.

Test compound

First, the compound was dissolved in DMSO to 10mM, and then DMEM +1% FCS + Glutamine was diluted to obtain each test concentration 0.0.45μM hole 100 to which the DMSO 1-0.00045% final concentration.

c.ii) pilot program

Day 1

Cells grown NIH3T3/IGFR harvest index and in complete growth medium per well 1.2 × 10⁴The number of cells in 100μl volume of inoculated into flat-bottomed 96-well tissue culture grade plates (Costar 3525) in.

Day 2

Using a multichannel pipette Carefully removed from each well, the growth medium. With 200μl HBSS These holes will be carefully cleaned three times. 100μl were added to each well and the plates were cultured starved medium 24 hours.

Day 3

The 50μl 4X concentrate of test compound was added to the appropriate wells. Before joining the IGF These cells were incubated for 30 minutes using the compound alone. For cells treated with IGF, the Addition of an appropriate volume (i.e. 25μl) of starvation medium so that the final volume per well up to 200μl, then 160ng/ml Add 25μl IGF-1 (to give a final concentration of 20ng/ml). No control cells stimulated with IGF also joined suitable volume (ie 50μl) starvation medium so The final volume of each well up to 200μl. The plates were incubated for 20 hours.

Day 4

With BrdU Cell Proliferation Elisa according to manufacturer's programs on mixed into cells The BrdU (at 4 hours after mixing period) for evaluation.

The compounds of Examples found in the above test of less than 50μM in the IC50.

d) Mechanism Analysis

By measuring IGF-IR, Akt and MAPK (ERK1 and 2) in response to the MCF-7 cells (ATCC No.HTB-22) IGF-I stimulated the phosphorylation resulting from a change to determine the IGF-IR-mediated signal transduction inhibition. In the same cell line used for the response to the EFG The MAPK phosphorylation to measure the selectivity.

d.i) Reagents used:

RPMI 1640 culture medium, RPMI 1640 without phenol red medium, FCS, glutamine (Were obtained from Life Technologies Ltd., UK).

Remove the charcoal / dextran FBS (HyClone SH30068.02, Perbio Science UK Ltd).

SDS(Sigma，L4390)。

2 - mercaptoethanol (Sigma, M6250).

Bromophenol blue (Sigma, B5525).

Ponceau S (Sigma, P3504).

Tris base (TRIZMA^TM base，Sigma，T1503)。

Glycine (Sigma, G7403).

Methanol (Fisher Scientific UK.Cat.No.M/3950/21).

Milk powder (Dried milk powder) (Marvel^TM，Premier Brands UK Ltd.)。

Human recombinant EGF (Promega Corporation, WI, USA.Cat.No.G5021).

Complete growth medium

RPMI 1640,10% FCS, 2mM glutamine

Starvation medium

RPMI1640 medium without phenol red, 1% of the removed carbon / dextran FCS, 2mM Glutamine.

Test compound

First, the compound was dissolved in DMSO to 10mM, and then with RPMI without phenol red 1640 +1% FCS +2 mM glutamine diluted to each test hole 100 to 0.0.45μM The range in which the final concentration of DMSO was 1-0.00045%.

Western transfer buffer

50mM Tris base, 40mM glycine, 0.04% SDS, 20% methanol.

Laemmli buffer x2:

100mM Tris-HCl pH6.8, 20% glycerol, 4% SDS.

Sample buffer x4:

200mM 2 - mercapto-ethanol, distilled water, 2% bromophenol blue.

An anti-

Rabbit anti-human IGF-1Rβ. (Santa Cruz Biotechnology Inc., USA, Cat.No sc-713)

Rabbit anti - insulin / IGF-1R [pYpY^1162/1163]Dual Phosphospecific(BioSource International Inc，CA，USA.Cat No.44-8041)。

Mouse anti -PKBα/Akt (Transduction Laboratories, KY, USA.Cat.No. P67220)

Rabbit anti-Phospho-Akt (Ser473) (Cell Signalling Technology Inc, MA, USA.Cat.No. # 9271).

Rabbit anti -p44/p42 MAP kinase (Cell Signalling Technology Inc, MA, USA. Cat.No. # 9102).

Rabbit anti-Phospho p44/p42 MAP kinase (Cell Signalling Technology Inc, MA, USA.Cat.No. # 9101).

Mouse anti - actin clone AC-40 (Sigma-Aldrich Company Ltd, UK, A4700).

Antibody dilution

Antibody	Diluted in PBST	Located in the two anti-PBST
Antibody	Diluted in PBST	Located in the two anti-PBST	IGFR	1:200 with 5% milk	Anti - rabbit, with 5% milk
Phospho-IGFR	1:1000 with 5% milk	Anti - rabbit, with 5% milk	IGFR	1:200 with 5% milk	Anti - rabbit, with 5% milk
Phospho-IGFR	1:1000 with 5% milk	Anti - rabbit, with 5% milk	Akt	1:1000 with 5% milk	Anti - mouse with 5% milk
PhosphoAkt	1:1000 with 5% milk	Anti - rabbit, with 5% milk	Akt	1:1000 with 5% milk	Anti - mouse with 5% milk
PhosphoAkt	1:1000 with 5% milk	Anti - rabbit, with 5% milk	MAPK	1:1000 with 5% milk	Anti - rabbit, with 5% milk
Phospho-MAPK	1:1000 with 5% milk	Anti - rabbit, with 5% milk	MAPK	1:1000 with 5% milk	Anti - rabbit, with 5% milk
Phospho-MAPK	1:1000 with 5% milk	Anti - rabbit, with 5% milk	Actin	1:1000 with 5% milk	Anti - mouse with 5% milk

Two anti-

Goat anti - rabbit, HRP connection (Cell Signalling Technology Inc, MA, USA. Cat.No. # 7074).

Sheep - anti - mouse IgG HRP-conjugated (Amersham Pharmacia Biotech UK Ltd.Cat.No.NXA931).

Lieutenant in PBST +5% milk anti - rabbit diluted to 1:2000.

Lieutenant in PBST +5% milk anti - mouse diluted to 1:5000.

d.ii) pilot program

Cell Processing

The MCF-7 cells with 1 × 10⁵Cells / well in 1ml complete growth medium number of Coated 24-well plate. The plate was incubated for 24 hours to precipitate the cells. The medium was removed and the The board with PBS (2ml / well) and gently washed three times. 1ml was added to each well and starved medium The plate was incubated for 24 hours to serum starvation these cells.

Then, 25μl of each compound dilution was added and the cells and the compound was in 37 ℃ incubated for 30 min. After 30 minutes incubation of the compound according to the appropriate conditions to each well Adding 25μl IGF (for 20ng/ml final concentration) or EGF (for 0.1ng/ml final Terms of the concentration) and the cells with IGF or EGF at 37 ℃ for 5 minutes. Removing the training Support group (removed with a pipette), then adding 100μl 2x Laemmli buffer. In the cell into the OK harvest until the plates stored at 4 ℃. (These cells were added to the Laemmli buffer Red liquid within 2 hours after should be harvested. )

To harvest the cells, a pipette and eliminate duplicate boxes Laemmli buffer / Cell mixture and transfer it to 1.5ml Eppendorf tubes. The cell lysates of the harvested production Preservation at -20 ℃ until needed. You can use the DC protein assay kit (Bio-Rad Laboratories, USA, according to manufacturer's instructions) to determine the protein concentration of the lysate.

Western blot technique

With 4x sample buffer to prepare cell samples, with 21 injections and boil 5 Minutes. And molecular weight of an equal volume of the sample load gradient to 4-12% Bis-Tris gel (Invitro gen BV, The Netherlands) and the gel on the Xcell SureLock^TMMini-Cell system (Invitrogen) on with the provided solution and according to the manufacturer's instructions Operation. By using Western transfer buffer in the gel blot to Xcell SureLock^TMMini-Cell apparatus Hybond C Extra^TMMembrane (Amersham Pharmacia Biotech UK Ltd.) On 1 hour at 30 volts. The films were imprinted with 0.1% Ponceau S Staining the proteins were transferred so visible, then according to molecular weight standards for horizontal cut Cultured for a variety of antibodies strip. These individual pieces were used to detect IGF-1R, Akt, MAPK and actin controls.

Membrane (Amersham Pharmacia Biotech UK Ltd.) On 1 hour at 30 volts. The films were imprinted with 0.1% Ponceau S Staining the proteins were transferred so visible, then according to molecular weight standards for horizontal cut Cultured for a variety of antibodies strip. These individual pieces were used to detect IGF-1R, Akt, MAPK and actin controls....

Membrane (Amersham Pharmacia Biotech UK Ltd.) On 1 hour at 30 volts. The films were imprinted with 0.1% Ponceau S Staining the proteins were transferred so visible, then according to molecular weight standards for horizontal cut Cultured for a variety of antibodies strip. These individual pieces were used to detect IGF-1R, Akt, MAPK and actin controls....₅₀。

For example, the following table shows the typical activity of the compounds of the invention. The second column shows the table Obtained from for the overexpression of IGF-stimulated human IGF-1 receptor murine fibroblasts (NIH3T3) inhibition of the test (c) of the IC₅₀Data:

Example No.	IC ₅₀(μM) - Test (c)
Example No.	IC ₅₀(μM) - Test (c)	5	0.13
23	0.11	5	0.13
23	0.11	35	0.56
38	0.054	35	0.56

Claims

1 of the formula (I) compound

Or a pharmaceutically acceptable salt thereof,

Of which:

R ¹Represents a trifluoromethyl group, or a (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each group optionally substituted by one or more groups independently selected from halogen and (C1-C6) Alkoxy substituents;

R ²Represents hydrogen, halogen or trifluoromethyl;

R ³Represents hydrogen, hydroxy or halogen or (C 1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) Alkynyl group, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C3-C8) cycloalkyl-carbonyl group, (C3-C8) cycloalkyl (C1-C6) alkyl-carbonyl group, (C1-C6) alkoxycarbonyl, amino, (C1-C6) Alkylamino, di - [(C1-C6) alkyl] amino, (C3-C8) cycloalkyl group, (C3-C8) cycloalkyl (C1-C6) alkyl group, (C1-C6) alkoxy group, a carbamoyl group, (C1-C6) alkyl group Formyl, di - [(C1-C6) alkyl] carbamoyl,-C (O) R^3b、-OR ^3b、-SR ^3b、-NHR ^3b, -N [(C1-C6) alkyl] R^3b、-S(O) _mR ^3aOr-N (R^3c)C(O)R ^3a, Where R^3aRepresents (C1-C6) Alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) alkoxy, m Is 0, 1 or 2, R^3bMeans containing at least one heteroatom selected from nitrogen, oxygen and sulfur atoms, a saturated hetero ring 4 -, 5 - or 6 - membered monocyclic heterocycle, and R^3cRepresents hydrogen or (C1-C6) alkyl,

Or R³Means containing at least one heteroatom selected from nitrogen, oxygen and sulfur hetero ring atom a 5 - to 6 - member saturated And a monocyclic heterocyclic ring,

Or R³Means containing at least one heteroatom selected from nitrogen, oxygen and sulfur hetero ring atom a 5 - to 6 - membered heteroaryl Aromatic ring,

Or R³Represents 2,7 - diaza-spiro [3.5] nonyl,

R ³Of each group or ring may optionally be substituted with one or more substituents independently selected from (C1-C6) alkyl Group, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkyl, (C1-C6) alkoxy (C1-C6) Alkoxy, halogen, hydroxy, trifluoromethyl, tri - [(C1-C4) alkyl] silyl, cyano, amino Group, (C1-C6) alkylamino, di - [(C1-C6) alkyl] amino, (C3-C8) cycloalkyl group, (C3-C6) cycloalkyl (C1-C3) alkyl, amino (C1-C6) alkyl, (C1-C6) alkyl group (C1-C6) alkyl, di - [(C1-C6) alkyl] amino (C1-C6) alkyl, (C3-C8) cycloalkyl group (C1-C6) alkyl, (C3-C6) cycloalkyl (C1-C3) alkylamino (C1-C6) alkyl, (C1-C6) alkyl Alkoxycarbonyl, carbamoyl, (C1-C6) alkylcarbamoyl, di - [(C1-C6) alkyl] amino Carbamoyl group, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-C6) alkyl group, wherein R ...^3aOf each group or ring may optionally be substituted with one or more substituents independently selected from (C1-C6) alkyl Group, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkyl, (C1-C6) alkoxy (C1-C6) Alkoxy, halogen, hydroxy, trifluoromethyl, tri - [(C1-C4) alkyl] silyl, cyano, amino Group, (C1-C6) alkylamino, di - [(C1-C6) alkyl] amino, (C3-C8) cycloalkyl group, (C3-C6) cycloalkyl (C1-C3) alkyl, amino (C1-C6) alkyl, (C1-C6) alkyl group (C1-C6) alkyl, di - [(C1-C6) alkyl] amino (C1-C6) alkyl, (C3-C8) cycloalkyl group (C1-C6) alkyl, (C3-C6) cycloalkyl (C1-C3) alkylamino (C1-C6) alkyl, (C1-C6) alkyl Alkoxycarbonyl, carbamoyl, (C1-C6) alkylcarbamoyl, di - [(C1-C6) alkyl] amino Carbamoyl group, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-C6) alkyl group, wherein R ...^3cAlkanoyl group is as defined above amino - N (R^3c)C(O)R ^3a, Or may optionally contain at least one heteroatom selected from nitrogen, oxygen and sulfur hetero-atoms 3 -, 4 -, 5 -, 6 - or 7 - membered saturated monocyclic substituents, these substituents in any of the Of which may be optionally substituted by one or more (C1-C4) alkyl, hydroxy or cyano;

-NQ ¹That contains a nitrogen atom and optionally containing one or more heteroatoms selected from nitrogen, oxygen And sulfur ring heteroatom additional N-linked 5 - to 6 - membered saturated monocyclic ring;

Q ²Means containing at least one heteroatom selected from nitrogen, oxygen and sulfur hetero ring atom a 5 - to 6 - membered heteroaryl Aromatic ring, the ring is Q³And optionally substituted at any available ring atom by one or more Is independently selected from (C1-C6) alkyl or (C1-C6) alkoxy (each of which may be optionally substituted with one or more Groups independently selected from halogen, amino, hydroxy and trifluoromethyl substituent), halogen, nitro Group, a cyano group,-NR⁴R ⁵, Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C3-C8) Cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxycarbonyl, (C1-C4) alkyl-carbonyl group, (C1-C4) Alkylcarbonylamino, phenylcarbonyl,-S (O)_p(C1-C4) alkyl,-C (O) NR⁶R ⁷And-SO₂NR ⁸R ⁹Additional substituents, wherein R⁴、R ⁵、R ⁶、R ⁷、R ⁸And R⁹Each independently Represents hydrogen or (C1-C6) alkyl, or when connected thereto, and it is connected to the nitrogen atom together, R⁴And R⁵, Or R⁶And R⁷, Or R⁸And R⁹May each independently form a saturated heterocyclic ring and p is 0, Or 2;

Q ³Represents (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl Or may comprise at least one heteroatom selected from nitrogen, oxygen and sulfur hetero ring atoms, saturated or unsaturated 5 - to 6 - Membered monocyclic ring, and wherein Q³Optionally substituted by one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy (each of which may be optionally substituted with one or more groups independently selected from halogen, amino, Hydroxy and trifluoromethyl substituent), halogen, nitro, cyano,-NR¹⁰R ¹¹, A carboxyl group, Hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) Alkylcarbonyl, (C1-C6) alkylcarbonyl group, a phenylcarbonyl group,-S (O)_n(C1-C6) alkyl Group,-C (O) NR¹²R ¹³And-SO₂NR ¹⁴R ¹⁵The substituent, wherein R¹⁰、R ¹¹、R ¹²、 R ¹³、R ¹⁴And R¹⁵Each independently represents hydrogen or (C1-C6) alkyl, or when connected thereto, and its When connected to a nitrogen atom together, R¹⁰And R¹¹, Or R¹²And R¹³, Or R¹⁴And R¹⁵May each independently Site to form a saturated heterocyclic ring and n is 0, 1 or 2;

And wherein any saturated monocyclic ring optionally bear 1 or 2 oxo or thioxo substituents.

(2) as claimed in claim 1, wherein:

R ²Represents hydrogen, halogen or trifluoromethyl;

R ³Represents hydrogen or halo, or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl group, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) Cycloalkyl (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C3-C8) cycloalkyl-carbonyl group, (C3-C8) Cycloalkyl (C1-C6) alkyl-carbonyl group, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkyl group, Two - [(C1-C6) alkyl] amino, (C3-C8) cycloalkyl group, (C3-C8) cycloalkyl (C1-C6) alkyl Amino, (C1-C6) alkoxy group, a carbamoyl group, (C2-C6) alkanoyl group,-C (O) R^3b、 -OR ^3b、-SR ^3b、-NHR ^3b,-N [(C1-C6) alkyl] R^3bOr-S (O)_mR ^3aGroup, wherein R^3aRepresents (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl or (C1-C6) An alkoxy group, m is 0, 1 or 2, and R^3bThat contains one or more heteroatoms selected from nitrogen, oxygen and sulfur, Hetero atoms, a 5 - to 6 - membered saturated monocyclic,

R ³Of each group or ring may optionally be substituted with one or more substituents independently selected from (C1-C6) alkyl Group, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl Methyl, cyano, amino, (C1-C6) alkylamino, di - [(C1-C6) alkyl] amino, (C3-C8) Cycloalkyl group, (C3-C6) cycloalkyl (C1-C3) alkyl group, (C1-C6) alkoxycarbonyl, amino Carbamoyl group, (C1-C6) alkylcarbamoyl, di - [(C1-C6) alkyl] carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-6) alkyl Acyl group or may optionally contain one or more heteroatoms selected from nitrogen, oxygen and sulfur heteroatoms 4 -, 5 -, 6 - or 7 - membered saturated monocyclic substituents; ...

-NQ ¹Of each group or ring may optionally be substituted with one or more substituents independently selected from (C1-C6) alkyl Group, (C1-C6) alkoxy, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl Methyl, cyano, amino, (C1-C6) alkylamino, di - [(C1-C6) alkyl] amino, (C3-C8) Cycloalkyl group, (C3-C6) cycloalkyl (C1-C3) alkyl group, (C1-C6) alkoxycarbonyl, amino Carbamoyl group, (C1-C6) alkylcarbamoyl, di - [(C1-C6) alkyl] carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-6) alkyl Acyl group or may optionally contain one or more heteroatoms selected from nitrogen, oxygen and sulfur heteroatoms 4 -, 5 -, 6 - or 7 - membered saturated monocyclic substituents; ...

Q ²Means containing at least one heteroatom selected from nitrogen, oxygen and sulfur hetero ring atom a 5 - to 6 - membered heteroaryl group Ring which is Q³And optionally substituted at any available ring atom by one or more separate Site is selected from (C1-C6) alkyl or (C1-C6) alkoxy (each of which may be optionally substituted with one or more Is independently selected from halogen, amino, hydroxy and trifluoromethyl substituent), halogen, nitro, Cyano,-NR⁴R ⁵, Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C3-C8) Cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxycarbonyl, (C1-C4) alkyl-carbonyl group, (C1-C4) Alkylcarbonylamino, phenylcarbonyl,-S (O)_p(C1-C4) alkyl,-C (O) NR⁶R ⁷And-SO₂NR ⁸R ⁹The substituent, wherein R⁴、R ⁵、R ⁶、R ⁷、R ⁸And R⁹Each independently represent hydrogen or (C1-C6) alkyl, or when connected thereto, and it is connected to the nitrogen atom together, R⁴And R⁵Or R⁶And R⁷, Or R⁸And R⁹May each independently form a saturated heterocyclic ring and p is 0, 1 or 2;

Q ³Represents (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl Or may comprise at least one heteroatom selected from nitrogen, oxygen and sulfur hetero ring atoms, saturated or unsaturated 5 - to 6 - Membered monocyclic ring, and wherein Q³Optionally substituted by one or more substituents independently selected from (C1-C6) alkyl or (C1-C6) alkoxy (each of which may be optionally substituted with one or more groups independently selected from halogen, amino, Hydroxy and trifluoromethyl substituent), halogen, nitro, cyano,-NR¹⁰R ¹¹, A carboxyl group, Hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) Alkylcarbonyl, (C1-C6) alkylcarbonyl group, a phenylcarbonyl group,-S (O)_n(C1-C6) alkyl Group,-C (O) NR¹²R ¹³And-SO₂NR ¹⁴R ¹⁵The substituent, wherein R¹⁰、R ¹¹、R ¹²、 R ¹³、R ¹⁴And R¹⁵Each independently represents hydrogen or (C1-C6) alkyl, or when connected thereto, and its When connected to a nitrogen atom together, R¹⁰And R¹¹, Or R¹²And R¹³, Or R¹⁴And R¹⁵May each independently Site and form a saturated heterocyclic ring and n is 0, 1 or 2.

3 as claimed in claim 1, wherein Compound 1, wherein:

R ¹Represents a trifluoromethyl group, or a (C1-C6) alkyl, (C3-C8) cycloalkyl or (C3-C8) cycloalkyl (C1-C6) alkyl, each group optionally substituted by halogen or (C1-C6) alkoxy;

R ²Represents hydrogen, halogen or trifluoromethyl;

R ³Represents hydrogen or (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) Alkyl, (C1-C6) alkoxy, (C1-C6) alkylcarbonyl, (C3-C8) cycloalkyl-carbonyl group,

(C3-C8) cycloalkyl (C1-C6) alkyl-carbonyl group, (C1-C6) alkoxycarbonyl, (C1-C6) alkyl Amino, (C3-C8) cycloalkyl group, (C3-C8) cycloalkyl (C1-C6) alkyl group, (C1-C6) Alkoxy group or a-S (O)_mR ^3aGroup, each group optionally substituted by at least one substituent selected from (C1-C6) alkyl Alkoxy, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, hydroxy, trifluoromethyl, or any Optionally containing one or more heteroatoms selected from nitrogen, oxygen and sulfur hetero-atoms 4 - to 7 - membered saturated monocyclic take The substituent groups, wherein R^3aRepresents (C1-C6) alkyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl Yl (C1-C6) alkyl or (C1-C6) alkoxy group, m is 0, 1 or 2;

Q ²Means containing at least one heteroatom selected from nitrogen, oxygen and sulfur hetero ring atom a 5 - to 6 - membered heteroaryl group Ring which is Q³And optionally substituted at any available ring atom by one or more The same or different substituents selected from (C1-C6) alkyl or (C1-C6) alkoxy (each of which may optionally be At least one group selected from halogen, amino, hydroxy and trifluoromethyl substituent), halogen, nitro Group, a cyano group,-NR⁴R ⁵, Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C3-C8) Cycloalkyl (C1-C6) alkyl, (C1-C4) alkoxycarbonyl, (C1-C4) alkyl-carbonyl group, (C1-C4) Alkylcarbonylamino, phenylcarbonyl,-S (O)_p(C1-C4) alkyl,-C (O) NR⁶R ⁷And-SO₂NR ⁸R ⁹Additional substituents, wherein R⁴、R ⁵、R ⁶、R ⁷、R ⁸And R⁹Each independently Represents hydrogen or (C1-C6) alkyl, or when connected thereto, and it is connected to the nitrogen atom together, R⁴And R⁵, Or R⁶And R⁷, Or R⁸And R⁹May each independently form a saturated heterocyclic ring and p is 0, Or 2;

Q ³Represents (C1-C6) alkyl, (C3-C6) cycloalkyl or (C3-C6) cycloalkyl (C1-C6) alkyl Or may comprise at least one heteroatom selected from nitrogen, oxygen and sulfur hetero ring atoms, saturated or unsaturated 5 - to 6 - Membered monocyclic ring, and wherein Q³Optionally substituted by at least one substituent selected from (C1-C6) alkyl or (C1-C6) alkoxy Group (each of which may optionally be substituted at least one group selected from halogen, amino, hydroxy and trifluoromethyl Yl substituted), halo, nitro, cyano,-NR¹⁰R ¹¹, Carboxy, hydroxy, (C2-C6) alkenyl, (C3-C8) cycloalkyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkyl-carbonyl group, (C1-C6) alkyl-carbonyl Group, a phenyl carbonyl group,-S (O)_n(C1-C6) alkyl,-C (O) NR¹²R ¹³And-SO₂NR ¹⁴R ¹⁵The substituent, wherein R¹⁰、R ¹¹、R ¹²、R ¹³、R ¹⁴And R¹⁵Each independently represents Hydrogen or (C1-C6) alkyl, or when connected thereto, and it is connected to the nitrogen atom together, R¹⁰And R¹¹, Or R¹²And R¹³, Or R¹⁴And R¹⁵May each independently form a saturated heterocyclic ring and n is 0, 1 or 2.

4 to any one of the preceding claims, wherein R¹Represents (C1-C4) alkyl Group or a (C3-C6) cycloalkyl.

5 to any one of the preceding claims, wherein R²Represents hydrogen or halogen.

As claimed in claim 5, wherein R²Represents halogen.

7 to any one of the preceding claims, wherein R³Represents hydrogen, hydroxy or Halogen or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl (C1-C6) alkyl Alkoxy, (C1-C6) alkyl-carbonyl group, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkyl group, Two - [(C1-C6) alkyl] amino, (C3-C8) cycloalkyl group, (C3-C8) cycloalkyl (C1-C6) alkyl Amino, (C1-C6) alkoxy group, a carbamoyl group, (C1-C6) alkylcarbamoyl, di - [(C1-C6) alkyl] carbamoyl,-C (O) R^3b、-OR ^3b、-NHR ^3b,-N [(C1-C6) alkyl Yl] R^3b、-S(O) _mR ^3aOr-N (R^3c)C(O)R ^3aGroup, wherein R^3aRepresents (C1-C6) alkyl or (C1-C6) alkoxy group, m is 0, 1 or 2, R^3bMeans containing at least one heteroatom selected from nitrogen, oxygen and sulfur Ring heteroatom saturated 4 -, 5 - or 6 - membered monocyclic heterocycle, and R^3cRepresents hydrogen or (C1-C6) alkyl Group, or R³Means containing at least one heteroatom selected from nitrogen, oxygen and sulfur hetero ring atom a 5 - to 6 - member saturated And a monocyclic heterocyclic ring, or R³Means containing at least one heteroatom selected from nitrogen, oxygen and sulfur ring heteroatom, 5 - To 6 - membered heteroaryl aromatic ring, or R³Represents 2,7 - diaza-spiro [3.5] nonane group, R³In each group Or a cycloalkyl group may optionally be substituted with one or more substituents independently selected from (C1-C6) alkyl, (C1-C6) alkoxy Group, (C1-C6) alkoxy (C1-C6) alkyl, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, Hydroxy, trifluoromethyl, tri - [(C1-C4) alkyl] silyl, cyano, amino, (C1-C6) alkyl Amino, di - [(C1-C6) alkyl] amino, amino (C1-C6) alkyl, (C1-C6) alkyl group (C1-C6) alkyl, di - [(C1-C6) alkyl] amino (C1-C6) alkyl, (C1-C6) alkoxycarbonyl, Carbamoyl, (C1-C6) alkylcarbamoyl, di - [(C1-C6) alkyl] carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-C6) Alkanoyl, wherein R ...^3aIn each group Or a cycloalkyl group may optionally be substituted with one or more substituents independently selected from (C1-C6) alkyl, (C1-C6) alkoxy Group, (C1-C6) alkoxy (C1-C6) alkyl, (C1-C6) alkoxy (C1-C6) alkoxy, halogen, Hydroxy, trifluoromethyl, tri - [(C1-C4) alkyl] silyl, cyano, amino, (C1-C6) alkyl Amino, di - [(C1-C6) alkyl] amino, amino (C1-C6) alkyl, (C1-C6) alkyl group (C1-C6) alkyl, di - [(C1-C6) alkyl] amino (C1-C6) alkyl, (C1-C6) alkoxycarbonyl, Carbamoyl, (C1-C6) alkylcarbamoyl, di - [(C1-C6) alkyl] carbamoyl, (C1-C6) alkylthio, (C1-C6) alkylsulfonyl, (C1-C6) alkylsulfinyl, (C1-C6) Alkanoyl, wherein R ...^3cAs defined in claim 1, wherein the alkanoyl group - N (R^3c)C(O)R ^3a, Or may optionally contain one or more heteroatoms selected from nitrogen, oxygen and sulfur hetero-atoms 3 -, 4 -, 5 -, 6 - or 7 - membered saturated monocyclic substituents, these substituents in any of the Of which may be optionally substituted by one or more (C1-C4) alkyl, hydroxy or cyano, and its Any saturated monocyclic ring optionally bear 1 or 2 oxo or thioxo substituents.

8 any one of the preceding claims, wherein R³Represents hydrogen or halogen, Or (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) Alkylcarbonyl, (C1-C6) alkoxycarbonyl, amino, (C1-C6) alkylamino, di - [(C1-C6) Alkyl] amino, carbamoyl,-C (O) R^3b、-OR ^3b、-SR ^3b、-NHR ^3b,-N [(C1-C6) Alkyl] R^3bOr-S (O)_mR ^3aGroup, wherein R^3aAnd R^3bAs defined in claim 1,

Or R³Means containing at least one heteroatom selected from nitrogen, oxygen and sulfur hetero ring atom a 5 - or 6 - member saturated And a monocyclic heterocyclic ring,

Or a group of the ring may optionally be substituted with one or more as defined in claim 1 substituent Replaced.

9 to any one of the preceding claims, wherein R³Represents hydrogen or (C1-C4) Alkyl, (C1-C3) alkoxy or (C3-C5) cycloalkyl group,

Or R³Means containing at least one ring selected from nitrogen and oxygen hetero atom a 5 - to 6 - membered saturated single Heterocyclic ring,

Each group or ring may optionally be substituted with one or more substituents independently selected from hydroxy and (C1-C3) alkoxy Substituent group.

10 to any one of the preceding claims, wherein R³Represents hydrogen.

11 to any one of the preceding claims, wherein NQ¹Representation contains a Two nitrogen atoms and optionally contains at least one may be the same or different selected from nitrogen, oxygen and sulfur Additional ring heteroatom a 5 - to 6 - membered saturated monocyclic.

12 as claimed in claim 11, wherein NQ¹A pyrrolidinyl or piperidinyl.

13 to any one of the preceding claims, wherein Q²Representation contains a Or the two may be the same or different selected from nitrogen and oxygen hetero ring atom a 5 - to 6 - membered heteroaryl group Ring, which ring may be Q³And optionally substituted with at least one independently selected from (C1-C6) alkyl Group, (C1-C6) alkoxy, halogen and (C3-C8) cycloalkyl substituents.

As claimed in claim 13, wherein said heteroaromatic ring is selected from iso-yl  Group, and tetrazolyl.

15 as claimed in claim 14, wherein said heteroaromatic ring is iso  oxazolyl.

16 to any one of the preceding claims, wherein Q³Represents (C1-C6) Alkyl, (C3-C8) cycloalkyl or optionally substituted, optionally containing at least one heteroatom selected from nitrogen, oxygen And sulfur ring heteroatom saturated or unsaturated 5 - to 6 - membered monocyclic.

As claimed in claim 16, wherein Q³Represents (C1-C4) alkyl or (C3-C6) cycloalkyl or optionally substituted may contain one or two identical or different substituents selected From nitrogen, oxygen and sulfur hetero ring atom a 5 - to 6 - membered unsaturated monocyclic member.

18 as claimed in claim 16 or claim 17, wherein Q³Represents an optionally taken Substituted one or two may be the same or different selected from nitrogen, oxygen and sulfur ring heteroatom, 5 - 6 - member unsaturated monocyclic.

19 as claimed in claim 18, wherein Q³Represents thiazolyl, pyrazinyl, ethyl Pyridyl or pyridyl group.

20 as claimed in claim 1, wherein R¹Represents (C1-C4) alkyl or (C3- C6) cycloalkyl group; R²Represents halogen; R³Represents hydrogen;-NQ¹Representation contains a nitrogen atom and either Optionally containing at least one heteroatom selected from nitrogen, oxygen and sulfur ring heteroatom additional 5 - or 6-membered monocyclic saturated Ring; Q²Represents substituted may contain one or two identical or different ring heteroatoms selected from nitrogen and oxygen Hetero atoms, a 5 - to 6 - membered heteroaryl aromatic ring; and Q³Represents (C1-C4) alkyl or (C3-C6) cycloalkyl or Optionally substituted one or two may be the same or different selected from nitrogen, oxygen and sulfur ring Hetero atoms, a 5 - to 6 - membered unsaturated monocyclic member.

21 as claimed in claim 20, wherein-NQ¹Represents pyrrolidinyl or piperidinyl Group; Q²Means iso  tetrazolyl or a tetrazolyl group; and Q³Represents methyl, cyclopropyl, thiazolyl, four Tetrahydrofuran, pyrazinyl, thiazolyl, pyrimidinyl or pyridyl group.

22 as claimed in claim 20 or claim 21, wherein-NQ¹Represents pyrrolidinyl; Q²Expression of different  oxazolyl; and Q³Represents thiazolyl, pyrazinyl, pyrimidinyl or pyridyl group.

23 as claimed in claim 20 or claim 21, wherein-NQ¹Represents pyrrolidinyl or Piperidinyl group; Q²Expression of different  oxazolyl; and Q³Represents methyl, cyclopropyl, thiazolyl or pyridyl.

24 as claimed in claim 1 of the formula (I) compound, which is selected from one or more of the following:

5 - chloro -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol Zol-3 - ylamino) pyrimidine;

5 - chloro -2 - [2 - (3 - methyl isobutyl -5 - yl] pyrrolidin-1 - yl] -4 - (5 - tert - butyl-1H-pyrazol-3 - Ylamino) pyrimidine;

5 - chloro -2 - [2 - (3 - methyl isobutyl -5 - yl] pyrrolidin-1 - yl] -4 - (5 - cyclopropyl-1H-pyrazol-3 - Ylamino) pyrimidine;

5 - chloro -2 - [2 - (3 - cyclopropylisoxazol-5  - yl] pyrrolidin-1 - yl] -4 - (5 - cyclopropyl-1H-pyrazole - ³ - amino) pyrimidine;

5 - chloro -2 - [2 - (3 - cyclopropylisoxazol-5  - yl] pyrrolidin-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - Ylamino) pyrimidine;

5 - chloro -2 - [2 - (3 - methyl isobutyl -5 - yl] pyrrolidin-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl Amino) pyrimidine;

5 - chloro -2 - {2 - [3 - (thiazol-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol Zol-3 - ylamino) pyrimidine;

5 - chloro -2 - {2 - [3 - (thiazol-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - cyclopropyl-1H- Pyrazol-3 - ylamino) pyrimidine;

5 - chloro -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - cyclopropyl-1H- Pyrazol-3 - ylamino) pyrimidine;

5 - chloro -2 - {2 - [3 - (pyridin-3 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol Zol-3 - ylamino) pyrimidine;

5 - chloro -2 - {2 - [3 - (pyridin-3 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - cyclopropyl-1H- Pyrazol-3 - ylamino) pyrimidine;

2 - [2 - (3 - cyclopropylisoxazol-5  - yl) pyrrolidin-1 - yl] -6 - methoxy-4 - (5 - methyl - 1H-pyrazol-3 - ylamino) pyrimidine;

2 - [2 - (3 - cyclopropylisoxazol-5  - yl) pyrrolidin-1 - yl] -6 - methoxy-4 - (5 - cyclopropyl - 1H-pyrazol-3 - ylamino) pyrimidine;

5 - chloro -2 - (2 - (3 - (pyridin-2 - yl) isoxazol-5  - yl) piperidin-1 - yl) -4 - (5 - methyl-1H-pyrazole - ³ - amino) pyrimidine;

5 - chloro -2 - [2 - (3 - {tetrahydrofuran-3 - yl}-5 iso  - yl] pyrrolidin-1 - yl] -4 - (5 - methyl - 1H-pyrazol-3 - ylamino) pyrimidine;

5 - chloro-4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - [2 - (3 - {tetrahydrofuran-3 - yl} iso  -5 - yl] pyrrolidin-1 - yl] - pyrimidine;

6 - chloro-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] Pyrrolidin-1 - yl} pyrimidine;

5 - chloro-4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - Yl] piperidin-1 - yl} pyrimidine;

5 - chloro -2 - {2 - [3 - (2 - methoxy-pyridin-3 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl Yl-1H-pyrazol-3 - ylamino) pyrimidine;

5 - fluoro-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] Pyrrolidin-1 - yl} - pyrimidine;

4 - (5 - cyclopropyl-1H-pyrazol-3 - yl)-5 - fluoro-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - Yl] pyrrolidin-1 - yl} pyrimidine;

S-5-Chloro-2 - {2 - [3 - methyl isobutyl -5 - yl] pyrrolidin-1 - yl} -4 - (5 - cyclopropyl-1H-pyrazole - ³ - amino) pyrimidine;

4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrole Adamantan-1 - yl} pyrimidine;

4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyridine Slightly pentacosa-1 - yl} pyrimidine;

4 - (5 - cyclopropyl-1H-pyrazol-3 - yl)-6 - methyl - 2 - [2 - {3 - (pyridin-2 - yl) isoxazol  yl - 5 - yl} pyrrolidin-1 - yl] pyrimidine;

4 - (5 - methyl-1H-pyrazol-3 - yl)-6 - methyl - 2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - Yl} pyrrolidin-1 - yl] pyrimidine;

4 - (5 - cyclopropyl-1H-pyrazol-3 - yl)-6 - methyl - 2 - [2 - (3 - methyl isobutyl -5 - yl) pyridine Slightly adamantan-1 - yl] pyrimidine;

6 - ethyl-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - Yl} pyrrolidin-1 - yl] pyrimidine;

6 - (3 - methoxy-propyl) -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl)  isobutyl-5 - yl] pyrrolidin-1 - yl] pyrimidine;

6 - methoxy-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) iso  -5 - yl} pyrrolidin-1 - yl] pyrimidine;

4 - (5 - cyclopropyl-1H-pyrazol-3 - yl)-6 - methoxy-2 - [2 - {3 - (pyridin-2 - yl)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

6 - methoxy-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (thiazol-2 - yl) iso  -5 - yl] pyrrolidin-1 - yl} pyrimidine;

6 - methoxy-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-3 - yl) iso  -5 - yl} pyrrolidin-1 - yl] pyrimidine;

4 - (5 - methyl-1H-pyrazol-3 - ylamino) -6 - (pent-3 - en-1 - yl) -2 - [2 - {3 - (pyridin-2 - yl)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrole Adamantan-1 - yl} -6 - (trifluoromethyl) pyrimidine;

4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyridine Slightly adamantan-1 - yl} -6 - (trifluoromethyl) pyrimidine;

S-6-ethyl-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - Yl} pyrrolidin-1 - yl] pyrimidine;

S-5-Chloro-2 - {2 - [3 - (thiazol-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl-1H- Pyrazol-3 - ylamino) pyrimidine;

S-5-Chloro-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - cyclopropyl - 1H-pyrazol-3 - ylamino) pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - yl)-6 - methyl - 2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - Yl} pyrrolidin-1 - yl] pyrimidine;

S-5-Chloro-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl-1H- Pyrazol-3 - ylamino) pyrimidine;

S-5-Chloro-2 - {2 - [3 - (2 - methoxy-pyridin-3 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - Methyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - (3-N, N-dimethylaminopropyl) -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin -2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

6 - (3 - pyrrolidin-1 - yl-propyl) -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin - 2 - group)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

6 - methoxycarbonyl-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyridin-2 - yl) iso  -5 - yl] pyrrolidin-1 - yl} pyrimidine;

6 - (2 - hydroxyethyl-carbamoyl) -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (Pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} pyrimidine;

4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrole Adamantan-1 - yl} -6 - (pyrrolidin-1 - ylcarbonyl) pyrimidine;

6 - methoxy-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyridin-2 - yl)) iso  yl - 5 - yl] pyrrolidin-1 - yl} pyrimidine;

5 - chloro-4 - (3 - cyclopropyl-1H-pyrazol-5 - yl) -2 - [2 - (2 - methyl-2H-tetrazol-5 - yl) pyridine Slightly adamantan-1 - yl] pyrimidine;

6-N-ethyl-piperazin-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyridin-2 - yl)  isobutyl-5 - yl] pyrrolidin-1 - yl} pyrimidine;

6-N-methyl-piperazinyl (piperazyl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidine - 1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - morpholino-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol  yl - 5 - yl] pyrrolidin-1 - yl} pyrimidine;

6 - (3 - (N, N-dimethylamino) propyn-1 - yl) -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - (2 - (3 - (pyridin-2 - yl) isoxazol-5  - yl) pyrrolidin-1 - yl) pyrimidine;

6 - methyl-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - (3 - pyridin-2 - yl isobutyl  - 5 - yl) pyrrolidin-1 - yl] pyrimidine;

6 - (2 - methoxyethyl) amino-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyridin - 2 - group)  isobutyl-5 - yl] pyrrolidin-1 - yl} pyrimidine;

6 - methoxycarbonyl-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl Yl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - (N-methylcarbamoyl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - Yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - morpholino-carbonyl-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl Yl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - (N-(2 - methoxy-ethyl) carbamoyl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyridine Slightly adamantan-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - (N-hydroxy-carbamoyl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - Yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - carbamoyl-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl Yl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-methoxycarbonyl-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - Methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-(N-(2 - methoxy-ethyl) carbamoyl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] Pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-[N-(2 - methoxyethyl)-N-methyl-carbamoyl] -2 - {2 - [3 - (pyridin-2 - yl) iso  -5 - yl] pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-[N-(2 - (acetylamino) ethyl) carbamoyl] -2 - {2 - [3 - (pyridin-2 - yl) oxazole iso  -5 - Yl] pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-{N-[2 - (2 - hydroxyethoxy) ethyl] carbamoyl} -2 - {2 - [3 - (pyridin-2 - yl) iso -5 - yl] pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-[N-((R) -2 - hydroxy-propyl)-carbamoyl] -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - Yl] pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-[N-(4 - hydroxybutyl) carbamoyl] -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyridine Slightly adamantan-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-[N-((2R) -2,3 - dihydroxy-propyl)-carbamoyl] -2 - {2 - [3 - (pyridin-2 - yl) iso  -5 - yl] pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-[N-(carbamoylmethyl) carbamoyl] -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - Yl] pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-((3R) -3 - hydroxy-pyrrolidin-1 - yl-carbonyl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] Pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-{N-[2 - (methylthio) ethyl] carbamoyl} -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - Yl] pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-(N-cyclopropyl-carbamoyl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidine - 1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-(N-cyclopentyl-carbamoyl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidine - 1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-(azetidin-1 - yl-carbonyl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidine - 1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-(N-methylcarbamoyl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - Yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - (N-carbamoyl-amino) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - Yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - [N-(acetylamino) carbamoyl] -2 - {243 - (pyridin-2 - yl) isoxazol-5  - yl] pyridine Slightly adamantan-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - (5 - methyl - [1,3,4] -  oxadiazol-2 - yl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrole Adamantan-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - hydroxy-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl - 1H-pyrazol-3 - ylamino) pyrimidine;

6 - (morpholino-methyl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - Methyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - (4 - methyl-piperazin-1 - ylmethyl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - Yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - (dimethylaminomethyl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - (pyrrolidin-1 - ylmethyl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} - 4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - Amino-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl - 1H-pyrazol-3 - ylamino) pyrimidine;

S-6-hydroxymethyl-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl Yl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-ethoxy-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - Methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-[(2 - methoxyethoxy) methyl] -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidine -1 - Yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-5-Chloro-2 - {2 - [3 - (pyrazin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - cyclopropyl - 1H-pyrazol-3 - ylamino) pyrimidine;

S-6-methyl-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyrazin-2 - yl) isoxazol-5  - Yl] pyrrolidin-1 - yl} pyrimidine;

S-6-chloro-4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyrazin-2 - yl) isoxazol-5  - Yl] pyrrolidin-1 - yl} pyrimidine;

S-4-(5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyrazin-2 - yl) isoxazol-5  - yl] Pyrrolidin-1 - yl} -6 - (2 - methoxy-ethylamino)-pyrimidine;

S-6-methyl-amino - {2 - [3 - (pyrazin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - Cyclopropyl Yl-1H-pyrazol-3 - ylamino) pyrimidine;

S-4-(5 - cyclopropyl-1H-pyrazol-3 - yl)-6 - methoxy - {2 - [3 - (pyrazin-2 - yl) oxazole iso  -5 - Yl] pyrrolidin-1 - yl} pyrimidine;

6 - pyrrolidin-1 - yl -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl Yl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-chloro-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} Pyrrolidin-1 - yl] pyrimidine;

S-6-(2,2,6,6 - tetramethyl-piperidin-4 - yl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] Pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-iodo-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} Pyrrolidin-1 - yl] pyrimidine;

SE-6-[3 - (tert - butoxycarbonyl-amino) prop-1 - en-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl Amino) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-vinyl-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) oxazole iso  -Yl} - pyrrolidin-1 - yl] pyrimidine;

SE-6-(3 - hydroxy-prop-1 - en-1 - yl) -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (Pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[3 - (tert - butoxycarbonyl-amino) prop-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - ylamino) - 2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[3 - amino-propan-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - Yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

SE-6-[3 - amino-prop-1 - en-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (Pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[3 - methylamino-prop-1 - yn-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (Pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[3 - methoxy-prop-1 - yn-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (Pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[3 - hydroxy-prop-1 - yn-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin -2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[2 - (trimethylsilyl) ethynyl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[3 - (N-methyl-acetylamino) prop-1 - yn-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl amino Yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[3 - (dimethylamino) prop-1 - yn-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[3 - acetylamino-propan-1 - yn-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (Pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[2 - (ethoxycarbonyl) ethyl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin -2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

SE-6-[2 - (methoxycarbonyl) ethylene-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-ethynyl-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) oxazole iso  -Yl} - pyrrolidin-1 - yl] pyrimidine;

6 - methoxy-4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-methoxy-4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-methoxy-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) iso -5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[3 - amino-prop-1 - yn-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin -2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[2 - (N-methylcarbamoyl) ethyl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - [3 - (2 - methoxy-pyridin-3 - yl) isoxazol  yl - 5 - yl] pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - [3 - (2 - methoxy-pyridin-3 - yl) isoxazol  yl - 5 - yl] pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - [2 - [3 - (2 - methoxy-pyridin-3 - yl) iso  -5 - yl] pyrrolidin-1 - yl] pyrimidine;

6 - (N-tert - butoxycarbonyl) amino-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - Yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - (4 - amino-piperidin-1 - yl) 2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - (4 - (N-tert - butoxycarbonyl-amino) piperidin-1 - yl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol  yl - 5 - yl] pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - piperazin-1 - yl -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl- -1H-pyrazol-3 - ylamino) pyrimidine;

S-6-{4 - [2 - (2 - hydroxyethoxy) ethyl] piperazin-1 - yl} -2 - {2 - [3 - (pyridin-2 - yl) iso  -5 - yl] pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-(1 - formyl - piperazin-4 - yl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - Yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-piperazin-1 - yl -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl Yl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-(4 - isopropyl-piperazin-1-yl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - Yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-[(4 - (2 - hydroxyethyl) piperazin-1 - yl)] -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyridine Slightly adamantan-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-[(3R) -3 - hydroxy-pyrrolidin-1 - yl] -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrole Adamantan-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-[(3R) -3 - dimethylamino - pyrrolidin-1 - yl] -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - Yl] pyrrolidin-1 - yl}-4-(5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-(4 - tetrahydropyranyl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - Yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-morpholino -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl - 1H-pyrazol-3 - ylamino) pyrimidine;

S-6-(2 - methoxyethyl) amino-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - Yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-[(N-2-methoxy-ethyl)-N-methyl-amino] -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] Pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-((2R) -2 - hydroxy-prop-1 - yl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrole Adamantan-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-[N-(2 - hydroxyethyl)-N-ethyl amino] -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] Pyrrolidin-1 - yl} -4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-dimethylamino-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - Methyl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-methylamino-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl Yl-1H-pyrazol-3 - ylamino) pyrimidine;

S-6-chloro -2 - {2 - [3 - (pyrazin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl-1H- Pyrazol-3 - ylamino) pyrimidine;

6 - morpholino (Mopholino) -2 - {2 - [3 - (pyrazin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} - 4 - (5 - methyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - chloro -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - cyclopropyl-1H- Pyrazol-3 - ylamino) pyrimidine;

6 - (2 - hydroxy-ethoxy) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - cyclopropyl-1H-pyrazol-3 - ylamino) pyrimidine;

6 - [4 - (tert - butoxycarbonyl) piperazin-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

6 - (4 - acetyl-piperazin-1 - yl) -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin - 2 - group)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

6 - [2 - (tert - butoxycarbonyl) -2,7 - diaza-spiro [3.5] non-7 - yl] -4 - (5 - methyl-1H-pyrazol Zol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

6 - (2,7 - diaza-spiro [3.5] non-7 - yl) -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[4 - (2 - aminoethyl) piperazin-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[4 - (3 - hydroxypropyl) piperazin-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[4 - (2 - cyano-ethyl)-piperazin-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[4 - (2 - methoxyethyl) piperazin-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-(4 - acetyl-piperazin-1 - yl) -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin -2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[4 - (ethylsulfonyl) piperazin-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[2 - (2 - hydroxyethoxy) ethyl] amino] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[2 - (acetylamino) ethyl] amino] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (Pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[2 - amino-ethyl-amino] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin - 2 - group)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[4 - methyl-cyclohexyl-amino] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin- -2 - Yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[4 - hydroxy-cyclohexyl-amino] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin- -2 - Yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[cis -3,4 - dihydroxy-pyrrolidin-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-chloro-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyrimidin-2 - yl) isoxazol-5  - yl} Pyrrolidin-1 - yl] pyrimidine;

S-6-chloro-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (3 - methoxy-pyrazin-2 - yl) iso -5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-morpholino-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyrimidin-2 - yl) oxazole iso  -Yl} - pyrrolidin-1 - yl] pyrimidine;

S-6-morpholino-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (3 - methoxy-pyrazin-2 - Yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-morpholino-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (3 - hydroxy-pyrazin-2 - yl)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[4 - methyl-piperazin-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin - 2 - group)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[cyclobutyl amino] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[3 - isopropoxy-propan-1 - yl-amino] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (Pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[2 - (morpholin-4 - yl) ethylamino] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (Pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[2 - (dimethylamino) ethyl] amino] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[(2S) -2 - hydroxy-prop-1 - yl-amino] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (Pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[2 - methyl-prop-1 - yl-amino] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin -2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[3 - methoxy-propyl-amino] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin- -2 - Yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[4 - ethyl-piperazin-1 - yl] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin - 2 - group)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[3 - ethoxy-propyl-amino] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin- -2 - Yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[(2R) - tetrahydrofuran-2 - yl methyl-amino] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-(2 - isopropoxy-ethyl-amino) -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin -2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-morpholino-4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyrimidin-2 - yl) iso  -5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-methyl-4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyrimidin-2 - yl) iso -5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-chloro-4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyrimidin-2 - yl) isoxazol-5  - Yl} pyrrolidin-1 - yl] pyrimidine;

S-6-methyl-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (3 - methoxy-pyrazin-2 - yl)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-methoxy-4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyrimidin-2 - yl) iso  -5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-(2 - methoxy-ethoxy) -4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyrimidin- -2 - Yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - ethyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyridine Slightly pentacosa-1 - yl} pyrimidine;

S-4-(5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] Pyrrolidin-1 - yl} pyrimidine;

S-4-(5 - ethyl-1H-pyrazol-3 - yl)-5 - fluoro-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] Pyrrolidin-1 - yl} pyrimidine;

S-4-(5 - cyclopropyl-1H-pyrazol-3 - yl)-5 - fluoro-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - Yl] pyrrolidin-1 - yl} pyrimidine;

4 - (5 - cyclopropyl-1H-pyrazol-3 - yl)-6 - methyl - 2 - {2 - [3 - (pyrimidin-2 - yl) isoxazol  yl - 5 - yl] pyrrolidin-1 - yl} pyrimidine;

4 - (5 - cyclopropyl-1H-pyrazol-3 - yl)-6 - methyl - 2 - {2 - [3 - (pyrazin-2 - yl) isoxazol  yl - 5 - yl] pyrrolidin-1 - yl} pyrimidine;

4 - (5 - cyclopropyl-1H-pyrazol-3 - yl)-6 - methyl - 2 - {2 - [3 - (pyridin-2 - yl) isoxazol  yl - 5 - yl] pyrrolidin-1 - yl} pyrimidine;

6 - (3 - hydroxy-propyl) -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyridin-2 - yl) iso -5 - yl] pyrrolidin-1 - yl} pyrimidine;

S-6-(3 - hydroxy-propyl) -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - {2 - [3 - (pyridin-2 - yl)  isobutyl-5 - yl] pyrrolidin-1 - yl} pyrimidine;

S-6-propyl-2 - {2 - [3 - (pyridin-2 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl} -4 - (5 - methyl - 1H-pyrazol-3 - ylamino) pyrimidine;

S-6-chloro-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} Pyrrolidin-1 - yl] pyrimidine;

S-6-(2 - hydroxy-ethoxy) -4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - Yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-(2 - methoxy-ethoxy) -4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin - 2 - group)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-morpholino-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) oxazole iso  -Yl} - pyrrolidin-1 - yl] pyrimidine;

S-6-(4 - methyl-piperazin-1 - yl) -4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin - 2 - group)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-chloro-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (2 - pyrazinyl) isoxazol-5  - yl} Pyrrolidin-1 - yl] pyrimidine;

S-6-methoxy-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) oxazole iso  -Yl} - pyrrolidin-1 - yl] pyrimidine;

S-6-(2 - methoxy-ethoxy) -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin - 2 - group)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-pyrrolidin-1 - yl -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-morpholino-carbonyl-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) iso -5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-carbamoyl-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) iso -5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-5-fluoro-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} Pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrazol Slightly adamantan-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - (2 - hydroxy-ethoxy) -2 - [2 - {3 - (pyridin-2 - Yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - (2 - {N-[2 - hydroxy-ethyl]-N-methyl - amino} Ethoxy) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - (2 - morpholino-ethoxy) -2 - [2 - {3 - (pyridin - 2 - group)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - (methylthio) -2 - [2 - {3 - (pyridin-2 - yl) iso  -5 - yl} pyrrolidin-1 - yl] pyrimidine;

4 - (5 - methyl-1H-pyrazol-3 - ylamino) -6 - (tetrahydrofuran-3 - ylmethoxy) -2 - [2 - {3 - (pyridin -2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - (2 - (2 - hydroxyethoxy) ethoxy) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

4 - (5 - methyl-1H-pyrazol-3 - ylamino) -6 - (2 - methoxyethoxy) -2 - [2 - {3 - (pyridin-2 - Yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - (3 - hydroxy-propoxy) -2 - [2 - {3 - (pyridin-2 - Yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - [2 - (2 - methoxyethoxy) ethoxy] -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - (2 - ethoxy-ethoxy) -2 - [2 - {3 - (pyridin - 2 - group)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - (3 - morpholino-propan-1 - yl) -2 - [2 - {3 - (Pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - (3 - methoxy-prop-1 - yl) -2 - [2 - {3 - (Pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - [2 - (2 - oxo-pyrrolidin-1 - yl) ethoxy] -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - [(2S) -2 - methoxy-prop-1 - yl] -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - [3 - (methylthio) prop-1 - yl] -2 - [2 - {3 - (Pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - [(2S) -5 - oxo-pyrrolidin-2 - yl) methoxy] - 2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - [(2R) -5 - oxo-pyrrolidin-2 - yl) methoxy] - 2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - [2 - (imidazolidin-2 - one-1 - yl) ethoxy] -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - yl)-6 - ethoxy-2 - [2 - {3 - (pyridin-2 - yl) oxazole iso  -Yl} - pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - yl)-6 - hydroxy-2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - Yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - (2 - methoxyethoxy) -2 - [2 - {3 - (thiazol - 2 - group)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - (2 - hydroxy-ethoxy) -2 - [2 - {3 - (thiazol-2 - Yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - [(2R) -2 - hydroxy-prop-1 - yl] -2 - [2 - {3 - (Pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - ethyl-1H-pyrazol-3 - ylamino) -6 - (2 - methoxyethoxy) -2 - [2 - {3 - (pyrazin - 2 - group)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - ethyl-1H-pyrazol-3 - yl)-6 - methoxy -2 - [2 - {3 - (pyrazin-2 - yl) oxazole iso  -Yl} - pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - cyclopropyl-1H-pyrazol-3 - ylamino) -6 - (2 - hydroxy-ethoxy) -2 - [2 - {3 - (thiazol - 2 - group)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - ylamino) -6 - (tetrahydropyran-4 - yl) -2 - [2 - {3 - (pyridin -2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-5-fluoro-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (thiazol-2 - yl) isoxazol-5  - yl} Pyrrolidin-1 - yl] pyrimidine;

S-5-chloro-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (thiazol-4 - yl) isoxazol-5  - yl} Pyrrolidin-1 - yl] pyrimidine;

S-5-fluoro-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (thiazol-2 - yl) isoxazol-5  - yl} Pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (thiazol-2 - yl) isoxazol-5  - yl} pyrazol Slightly adamantan-1 - yl] pyrimidine;

S-4-(5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (thiazol-2 - yl) isoxazol-5  - yl} pyrazol Slightly adamantan-1 - yl] pyrimidine;

S-4-(5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (thiazol-2 - yl) isoxazol-5  - yl} Pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - cyclopropyl-1H-pyrazol-3 - yl)-5 - fluoro-2 - [2 - {3 - (thiazol-2 - yl) isoxazol-5  - Yl} pyrrolidin-1 - yl] pyrimidine;

S-6-chloro-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (thiazol-2 - yl) isoxazol-5  - yl} Pyrrolidin-1 - yl] pyrimidine;

S-6-chloro-4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (thiazol-2 - yl) isoxazol-5  - Yl} pyrrolidin-1 - yl] pyrimidine;

S-6-morpholino-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (thiazol-2 - yl) oxazole iso  -Yl} - pyrrolidin-1 - yl] pyrimidine;

S-6-morpholino-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyrazin-2 - yl) oxazole iso  -Yl} - pyrrolidin-1 - yl] pyrimidine;

S-6-(2 - methoxy-ethylamino) -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (thiazol- -2 - Yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-methyl-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (thiazol-2 - yl) iso  -5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-(4 - methyl-piperazin-1-yl) -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (thiazol - 2 - group)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-methyl-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (thiazol-2 - yl) isoxazol-5  - Yl} pyrrolidin-1 - yl] pyrimidine;

S-6-[3 - (methylsulfonyl) propyl-1 - oxy] -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-4-(5 - cyclopropyl-1H-pyrazol-3 - ylamino) -6 - (2 - methoxyethoxy) -2 - [2 - {3 - (pyrazin- -2 - Yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-methyl-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (3 - methoxy-pyrazin-2 - yl)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-chloro-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (3 - methoxy-pyrazin-2 - yl) iso -5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-chloro-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyrimidin-2 - yl) isoxazol-5  - yl} Pyrrolidin-1 - yl] pyrimidine;

S-6-methoxy-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyrimidin-2 - yl) oxazole iso  -Yl} - pyrrolidin-1 - yl] pyrimidine;

S-6-ethyl-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyrimidin-2 - yl) isoxazol-5  - Yl} pyrrolidin-1 - yl] pyrimidine;

S-6-methyl-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyrimidin-2 - yl) iso  -5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-ethyl-4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyrimidin-2 - yl) oxazole iso  -Yl} - pyrrolidin-1 - yl] pyrimidine;

S-6-cyclopropyl-4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyrimidin-2 - yl) iso  -5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-cyclopropyl-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyrimidin-2 - yl) oxazole iso  -Yl} - pyrrolidin-1 - yl] pyrimidine;

S-6-(2 - methoxy-ethoxy) -4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyrimidin - 2 - group)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-methyl-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - [3 - (2 - methoxy-pyridin-3 - yl)  isobutyl-5 - yl] pyrrolidin-1 - yl] pyrimidine;

S-5-fluoro-4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - [2 - [3 - (2 - methoxy-pyridin-3 - yl)  isobutyl-5 - yl] pyrrolidin-1 - yl] pyrimidine;

S-5-fluoro-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - [3 - (2 - methoxy-pyridin-3 - yl) iso -5 - yl] pyrrolidin-1 - yl] pyrimidine;

S-6-(2 - hydroxy-ethoxy) -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - [3 - (2 - methoxy- Pyridin-3 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl] pyrimidine;

S-6-chloro-4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - [2 - [3 - (2 - methoxy-pyridin-3 - yl)  isobutyl-5 - yl] pyrrolidin-1 - yl] pyrimidine;

S-6-chloro-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - [3 - (2 - methoxy-pyridin-3 - yl) iso -5 - yl] pyrrolidin-1 - yl] pyrimidine;

S-6-(2 - hydroxy-ethoxy) -4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - [2 - [3 - (2 - methoxy- Yl-3 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl] pyrimidine;

S-5-fluoro-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - [3 - (2 - methoxy-pyridin-3 - yl) iso -5 - yl] pyrrolidin-1 - yl] pyrimidine;

S-6-(2 - hydroxy-ethoxy) -4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - [3 - (2 - methoxy- Pyridin-3 - yl) isoxazol-5  - yl] pyrrolidin-1 - yl] pyrimidine;

S-6-methyl-4 - (5 - cyclopropyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (3 - methoxy-pyrazin-2 - Yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-morpholino-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (3 - methoxy-pyrazin-2 - Yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-chloro-4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - [3 - (2 - methoxy-pyridin-3 - yl) iso -5 - yl} pyrrolidin-1 - yl] pyrimidine;

S-6-methyl-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyrimidin-2 - yl) isoxazol-5  - Yl} pyrrolidin-1 - yl] pyrimidine;

S-6-methyl-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - yl) isoxazol-5  - Yl} pyrrolidin-1 - yl] pyrimidine;

S-6-morpholino-4 - (5 - ethyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (3 - hydroxy-pyrazin-2 - yl)  isobutyl-5 - yl} pyrrolidin-1 - yl] pyrimidine; and

S-6-(3 - methoxy-propyl) -4 - (5 - methyl-1H-pyrazol-3 - yl) -2 - [2 - {3 - (pyridin-2 - Yl) isoxazol-5  - yl} pyrrolidin-1 - yl] pyrimidine;

And its pharmaceutically acceptable salts thereof.

25 A method as claimed in claim containing from 1 to 24 in any one of the formula (I) compounds or A pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additives, diluents or carriers A pharmaceutical composition.

26 A process as claimed in claim 25, wherein the pharmaceutical composition, which comprises as Of claims 1 to 24 as defined in any one of formula (I) compound or a pharmaceutically acceptable salt thereof, and Pharmaceutically acceptable additives, diluents or carrier.

27 for use in therapy as claimed in claims 1 to 24, any one of the formula (I) compound Or a pharmaceutically acceptable salt thereof.

28. Regulation of the human or animal body for insulin-like growth factor 1 receptor activity, such as the right to Claims 1 to 24 in any one of the formula (I) compound or a pharmaceutically acceptable salt thereof.

29 as claimed in claim 1 to 24 in any one of the formula (I) compound or a pharmaceutically acceptable The salt in the preparation of a medicament for the treatment of cancer applications.

30 as claimed in claim 1 to 24 in any one of the formula (I) compound or a pharmaceutically Salt used in the preparation for the regulation of insulin-like growth factor 1 receptor activity of the drug application.

31 A method of treating cancer, which comprises administering a therapeutically effective amount to a patient as claimed in claim 1 to 24 in any one of the formula (I) compound or a pharmaceutically acceptable salt thereof.

32 A process as claimed in claim 1 of formula (I) compound or a pharmaceutically acceptable salt thereof A method which comprises

(i) the formula (II) with a compound of formula (III) reaction of a compound,

Wherein L¹Represents a leaving group (such as halogen or sulfonyloxy group such as methanesulfonyloxy group or a Benzene -4 - sulfonyloxy) and R¹，R ²And R³As defined for formula (I) above, only if required to Any functional group protected,

Wherein Q¹And Q²As defined for formula (I) above, but if desired, any functional group Protected;

Or

(ii) the formula (IV) with a compound of formula (V) reaction of a compound,

Wherein L²Represents a leaving group (such as halogen or sulfonyloxy group such as methanesulfonyloxy group or a Benzene -4 - sulfonyloxy) and R²、R ³、Q ¹And Q²As defined for formula (I) as described in, but if necessary It will be any functional group protected,

Where R¹As defined for formula (I) above, but if necessary, protecting any functional group Up;

Or

(iii) the formula (VI) with a compound of formula (VII) reaction of a compound,

Wherein Q¹And Q²As defined for formula (I) above, but if desired, any functional group Protected,

Wherein X represents an oxygen atom and q is 1 or X represents a nitrogen atom and q is 2, R²¹Independent Represents a (C1-C6) alkyl and R²And R³As defined for formula (I) above, only if required to Any functional group protected;

Or

(iv) the formula (VIII) is reacted with hydrazine compound,

Where R¹，R ²，R ³，NQ ¹And Q²As defined for formula (I) above, only if required to Any functional group protected;

Or

(v) for which R³Is (C1-C6) alkoxy, amino, (C1-C6) alkylamino, di - [(C1-C6) Alkyl] amino, amino,-OR^3b、-SR ^3b、-NHR ^3b,-N [(C1-C6) alkyl] R^3bOr where m is 0 and R^3aAnd R^3bIs as defined above (and the group R³Optionally substituted by at least one of the above Substituted groups defined) of the-S (O)_mR ^3aGroup of the formula (I), the compound of the formula (IX) a compound Material and the compound of formula H-Xa reaction, wherein Xa is selected from OR²²、NH ₂、NHR ²²、 N(R ²²) ₂、NH ₂、OR ^3b、SR ^3b、NHR ^3b, N [(C1-C6) alkyl] R^3bAnd SR^3aWherein R²²Is optionally substituted (C1-C6) alkyl and R^3aAnd R^3bEach as defined above, only If desired, any protected functional group,

Wherein L³Represents a leaving group (such as halogen or sulfonyloxy group such as methanesulfonyloxy group or a Benzene -4 - sulfonyloxy) and R¹、R ²、Q ¹And Q²As defined for formula (I) above, but if necessary If any functional group protected;

Or

(vi) for which R³Is optionally substituted ring containing at least one nitrogen and optionally containing One or more heteroatoms selected from nitrogen, oxygen and sulfur hetero-atoms additional 5 - or 6 - membered saturated monocyclic heterocycle Formula (I), the compound of the formula (IX) with a compound of formula (Xb) reaction of a compound,

Wherein Q⁴In addition to the nitrogen atom is optionally further contain in addition one or more heteroatoms selected from nitrogen, oxygen and Hetero atom a 5 - or 6 - membered saturated monocyclic heterocyclic ring, the ring being optionally substituted by at least one fixed Substituted groups defined, or with an optionally substituted 2,7 - diaza-spiro [3.5] nonane Group;

Or

(vii) for which R³Is (C2-C6) alkenyl or (C2-C6) alkynyl group, and R³Optionally substituted by at At least one of the groups defined above substituted formula (I), the compound of the formula (IX) a compound Materials of the formula (Xc) or the formula (Xc ') reaction of a compound,

H-C≡C-R ²³ (Xc)

Where R²³Is selected from hydrogen and optionally substituted (1-4C) alkyl or (C1-C4) alkoxy A carbonyl group;

Or

(viii) for which R³Is connected via a carbon atom to the pyrimidine ring of formula (I), compound Words, the formula (IX) with a compound wherein R³Appropriately selected from R as defined above³Group and M A metal-containing group such as ZnBr, B (OH)₂, CuCN or SnBu₃The formula M-R³The compound Was subjected to reaction;

(ix) for which R³Is (C1-C6) alkoxycarbonyl (and R³Optionally substituted by at least one The substituted groups defined) of the formula (I), the compound of the formula (X) wherein the compound of (C1-C6) alkyl optionally substituted by at least one of the groups defined above and, if necessary substituted If any protected functional group of the formula HO-(C1-C6) alkyl group anti- Should,

Where R¹、R ²、Q ¹And Q²As defined for formula (I) above, but if necessary, to any He protected functional group; or

(x) for which R³Is containing at least one heteroatom selected from nitrogen, oxygen and sulfur hetero-atoms, 5 - membered heteroaryl group Ring (and R³Optionally substituted by at least one of the groups defined above substituted) of the formula (I) compound , The starting material with a suitable dehydrating agent and a suitable internal condensation reaction. For example, the In which R³Is 1,3,4 -  oxadiazolyl of the formula (I), the compound of the formula (XI) with a compound Suitable dehydrating agents, such as hydroxide (methoxycarbonyl-sulfamoyl) triethylammonium reaction,

Wherein Z represents any suitable defined above for R³Substituent group and R¹、R ²、Q ¹And Q²As defined for formula (I) above, but if desired, any protected functional group; or

(xi) for which R³Is at least one of the groups defined above, substituted (C1-C6) alkyl Group, (C3-C6) alkenyl, (C3-C6) alkynyl group or a (C1-C6) alkoxy groups of the formula (I), compound Words, the formula (XII) with a compound of formula as defined above, H-Xa, (Xb), (Xc), (Xc ') or M-R³Reaction of a compound,

Wherein L³Represents a leaving group as defined above group, W represents an optionally substituted (C1- C6) alkyl, (C3-C6) alkenyl, (C3-C6) alkynyl group or a (C1-C6) alkoxy, and R¹、R ²、Q ¹And Q²As defined for formula (I) above, but if desired, any protected functional group;

And optionally in (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x) Or (xi) after one or more of the following steps:

· The resulting compound is converted into another compound of the invention

Forming a pharmaceutically acceptable salt of said compound.