JP2007519662A - Pyrazolo [1,5-a] pyrimidin-7-yl-amine derivatives for use in the treatment of protein kinase dependent diseases - Google Patents

Abstract

  The present invention relates to the use of pyrazolo [1,5a] pyrimidin-7-ylamine compounds and salts thereof for the manufacture of pharmaceutical formulations for the treatment of kinase-dependent diseases, novel pyrazolo [1,5a The present invention relates to a method for producing pyrimidine-7-ylamine compounds and novel pyrazolo [1,5a] pyrimidin-7-ylamine compounds.

Description

Detailed Description of the Invention

SUMMARY OF THE INVENTION The present invention relates to the use of pyrazolo [1,5a] pyrimidin-7-ylamine derivatives in the treatment of protein kinase dependent diseases or for the manufacture of pharmaceutical compositions for the treatment of the diseases, in the treatment of the diseases. Use of pyrazolo [1,5a] pyrimidin-7-ylamine derivatives, pharmaceutical preparations containing pyrazolo [1,5a] pyrimidin-7-ylamine derivatives for the treatment of the disease, novel pyrazolo [1,5a] pyrimidine-7- Illamine derivatives, novel pyrazolo [1,5a] pyrimidin-7-ylamine derivatives and methods for producing pharmaceutical formulations, use or use of pyrazolo [1,5a] pyrimidin-7-ylamine derivatives as described above, and / or animals Or relates to these pyrazolo [1,5a] pyrimidin-7-ylamine derivatives for use in the treatment of the human body.

Background of the invention:
Pyrazolo [1,5-a] pyrimidin-7-yl-amine derivatives are known in the literature for ligands of the benzodiazepine receptor (eg, S. Selleri et al., Bioorg. Med. Chem 7 (12), 2705-11 (1999). )), Antagonists of corticotropin releasing factor (EP1097709), angiotensin II receptor antagonists (eg S. Takeshi et al., Japn. Pharm. Bull. 47 (7), 928-38 (1999)), monoxide synthesis It has been reported as an enzyme inhibitor (JP10101671), analgesic (WO95535298), bactericidal agent (EP071792) or anti-inflammatory agent (WO9218504).

  We have found according to the invention that pyrazolo [1,5-a] pyrimidin-7-ylamine residues can also be used as templates for the design of potent kinase inhibitors.

  In view of numerous protein kinase inhibitors and numerous proliferative and other protein kinase-related diseases, there is a continuing need for new developments of compounds that are useful as protein kinase inhibitors and therefore in the treatment of related diseases. .

  What is desired from the perspective of potential treatments for proliferative diseases is that a number of compound classes can be used to tailor each specific protein kinase or protein kinase class and thus allow specific treatments to be performed. Is to have. Therefore, there is a strong need for the discovery of a new class of compounds that allows such specific inhibitory effects.

SUMMARY OF THE INVENTION The class of pyrazolo [1,5a] pyrimidin-7-ylamine compounds described herein, especially the new compounds falling into this class, surprisingly have pharmacologically advantageous properties and are specific for kinases. Type or class or group, especially c-Abl, Bcr-Abl, c-Kit, c-Raf, Flt-1, Flt-3, KDR, Her-1, PDGFR-kinase, c-Src, RET-receptor kinase , FGF-R1, FGF-R2, FGF-R3, FGF-R4, Ephrin receptor kinase (eg, EphB2 kinase, EphB4 kinase and related Eph kinase), casein kinase (CK-1, CK-2, G-CK) , Pak, ALK, ZAP70, Jak1, Jak2, Axl, Cdk1, cdk4, cdk5, M such as et, FAK, Pyk2, Syk, insulin receptor kinase, Tie-2 or Bcr-Abl, c-Kit, c-Raf, Flt-3, FGF-R3, PDGF-receptor, RET, and Met It was found to allow inhibition of a constitutively activated variant of kinase (activated kinase). The class of pyrazolo [1,5a] pyrimidin-7-ylamine compounds described herein further inhibits mutants of the kinase. In addition to this established activity, pyrazolo [1,5a] pyrimidin-7-ylamine derivatives achieve fine tuning for their backbone to act specifically with the binding site of a target kinase or kinase group. It opens up and offers a new perspective of kinase inhibitors of varying degrees of specificity, thus allowing a large number of substitution patterns that offer a wide range of possibilities. In view of these activities, the compounds can be used, inter alia, for the treatment of diseases associated with abnormal or excessive activity of such types of kinases, especially those described herein.

〔式中、
Ｒ_２はＨ；置換または非置換アリール；置換または非置換ヘテロアリール；置換または非置換脂肪族残基；官能基；またはピラゾロ[１,５ａ]ピリミジニル環に１個の連結基もしくは原子により連結している置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールまたは置換もしくは非置換脂肪族残基であり；
Ｒ_３はＨ、置換または非置換アリール、置換または非置換ヘテロアリール、置換または非置換脂肪族残基、官能基、またはピラゾロ[１,５ａ]ピリミジニル環に連結基もしくは原子により連結し得る置換もしくは非置換脂肪族残基であり得て、
Ｒ_２またはＲ_３の少なくとも一方は置換または非置換アリール；置換または非置換ヘテロアリール；またはピラゾロ[１,５ａ]ピリミジニル環に１個の連結基もしくは原子により連結している置換もしくは非置換ヘテロアリールまたは置換もしくは非置換アリール残基であり；
ＡはＨ、ハロゲン(例えばブロモ)、脂肪族部分、官能基、置換または非置換アリールまたは置換または非置換ヘテロアリールであり；そして
Ｒ_１はＨ、ハロゲンまたは低級アルキルである。〕
の化合物またはその薬学的に許容される塩の使用に関する。 Detailed Description of the Invention In one embodiment, the present invention provides a compound of formula (I) for the treatment of protein kinase dependent diseases:

[Where,
R ₂ is H; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted aliphatic residue; functional group; or a pyrazolo [1,5a] pyrimidinyl ring linked by one linking group or atom. Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted aliphatic residue;
R ₃ is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aliphatic residue, functional group, substituted or optionally linked to a pyrazolo [1,5a] pyrimidinyl ring by a linking group or atom Can be an unsubstituted aliphatic residue,
At least one of R ₂ or R ₃ is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or substituted or unsubstituted heteroaryl linked to the pyrazolo [1,5a] pyrimidinyl ring by one linking group or atom Or a substituted or unsubstituted aryl residue;
A is H, halogen (eg bromo), aliphatic moiety, functional group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and R ₁ is H, halogen or lower alkyl. ]
Or a pharmaceutically acceptable salt thereof.

A preferred embodiment is for the treatment of protein kinase dependent diseases:
R ₂ is H; lower alkyl; cycloalkyl; benzyl; benzothienyl, indyl substituted with lower alkyl, pyridyl or thiazolyl optionally substituted with lower alkyl; unsubstituted phenyl or; halo, hydroxy, alkoxy, benzyl With phenyl substituted with one or two substituents selected from the group consisting of oxy, cycloalkyl, amino, acetylamino, lower alkylsulfonamide and benzenesulfonamide substituted with one or two halo Yes;
R ₃ is H; lower alkyl optionally substituted with halo; phenyl, pyridyl, or oxazolyl;
A is
(a) H; halo; benzothienyl; pyridyl; methylpiperazinylphenoxyl; indolyl substituted with lower alkyl;
(b) one selected from unsubstituted or mono-, di- or tri-lower alkoxy, di-lower alkylaminyl, morpholinyl, which may optionally be disubstituted by alkyl Or phenyl substituted with more substituents,
Piperazinyl substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkyl piperazinyl, pyrrolidinyl, dialkylaminyl and lower alkanol; and R ₁ is H is there,
Use of the above compound or a pharmaceutically acceptable salt thereof.

  Protein kinase dependent diseases are preferably c-Abl, Bcr-Abl, c-Kit, c-Raf, Flt-1, Flt-3, Her-1, KDR, PDGFR-kinase, c-Src, RET-receptor Body kinases, FGF-R1, FGF-R2, FGF-R3, FGF-R4, Ephrin receptor kinases (eg, EphB2 kinase, EphB4 kinase and related Eph kinases), casein kinases (CK-1, CK-2, G- CK), Pak, ALK, ZAP70, Jak1, Jak2, Axl, Cdk1, cdk4, cdk5, Met, FAK, Pyk2, Syk, insulin receptor kinase, Tie-2 or Bcr-Abl, c-Kit, c-Raf, Of Flt-3, FGF-R3, PDGF-receptor, RET, and Met Constitutively activated variants of such kinases (activated kinases), and (especially abnormally highly expressed or activated) kinase-dependent diseases or diseases that depend on activation of the kinase pathway, or just before A disease dependent on two or more of any of the kinases described in.

  The protein kinase-dependent disease is more preferably c-abl, Flt-3, KDR, c-Src, RET, EphB4, c-kit, cdk1, FGFR-1, c-raf, Her-1, Ins-R or It depends on Tek.

  Most preferably, the disease to be treated is a proliferative disease, preferably a benign or especially malignant tumor, more preferably brain, kidney, liver, adrenal gland, bladder, breast, stomach (especially stomach tumor), ovary, colon, rectum, Prostate, pancreas, lung, vagina, thyroid carcinoma, sarcoma, glioblastoma, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, or head and neck tumor, epithelial hyperproliferation, especially psoriasis, prostate Hypertrophy, especially of epithelial character, abnormal growth, preferably breast cancer or leukemia.

  In a further embodiment, the disease to be treated is psoriasis; Kaposi's sarcoma; restenosis, eg, stent-induced restenosis; endometriosis; Crohn's disease; Hodgkin's disease; leukemia; arthritis such as rheumatoid arthritis; Fibromas; eye diseases such as diabetic retinopathy and neovascular glaucoma; kidney diseases such as glomerulonephritis; diabetic nephropathy; malignant nephrosclerosis; thrombotic microangiopathy syndrome; transplant rejection and glomeruli Diseases: Fibrotic diseases such as cirrhosis; mesangial cell proliferative diseases; arteriosclerosis; diseases induced by persistent angiogenesis such as nerve tissue injury.

  The compounds of the invention are also immunosuppressive agents for use in maintaining vascular prosthesis or vascular opening, eg, after insertion of a mechanical device such as a stent, for inhibition of vascular reocclusion following balloon catheter treatment. As an adjunct to wound healing without leaving scars and for the treatment of senile plaques and contact dermatitis.

〔式中、
Ｒ_２はＨ；置換または非置換アリール；置換または非置換ヘテロアリール；脂肪族残基；官能基；またはピラゾロ[１,５ａ]ピリミジニル環に１個の連結基もしくは原子により連結している置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールまたは脂肪族残基であり；
Ｒ_３はＨ、置換または非置換アリール、ヘテロアリール、脂肪族残基、官能基、またはピラゾロ[１,５ａ]ピリミジニル環に連結基もしくは原子により連結している脂肪族残基であり得て、
Ｒ_２またはＲ_３の少なくとも一方は置換または非置換アリール；置換または非置換ヘテロアリール；またはピラゾロ[１,５ａ]ピリミジニル環に１個の連結基もしくは原子により連結している置換もしくは非置換ヘテロアリールまたは置換もしくは非置換アリール残基である。ただし、Ｒ_２およびＡの両方が同時に非置換フェニルではなく；
ＡはＨ、ハロゲン(例えばブロモ)、脂肪族部分、官能基、置換または非置換アリールまたはヘテロアリールであり；そして
Ｒ_１はＨ、ハロゲンまたは低級アルキルである。〕
の化合物またはその薬学的に許容される塩に関する。 In a further aspect, the present invention provides a compound of formula (I):

[Where,
R ₂ is H; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; aliphatic residue; functional group; or substituted or attached to the pyrazolo [1,5a] pyrimidinyl ring by one linking group or atom Unsubstituted aryl, substituted or unsubstituted heteroaryl or an aliphatic residue;
R ₃ can be H, substituted or unsubstituted aryl, heteroaryl, aliphatic residue, functional group, or an aliphatic residue linked to a pyrazolo [1,5a] pyrimidinyl ring by a linking group or atom;
At least one of R ₂ or R ₃ is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or substituted or unsubstituted heteroaryl linked to the pyrazolo [1,5a] pyrimidinyl ring by one linking group or atom Or a substituted or unsubstituted aryl residue. Provided that both R ₂ and A are not simultaneously unsubstituted phenyl;
A is H, halogen (eg bromo), aliphatic moiety, functional group, substituted or unsubstituted aryl or heteroaryl; and R ₁ is H, halogen or lower alkyl. ]
Or a pharmaceutically acceptable salt thereof.

Preferred embodiments are:
R ₂ is H; lower alkyl; cycloalkyl; benzyl; benzothienyl, indyl substituted with lower alkyl, pyridyl or thiazolyl optionally substituted with lower alkyl; unsubstituted phenyl or; halo, hydroxy, alkoxy, benzyl With phenyl substituted with one or two substituents selected from the group consisting of oxy, cycloalkyl, amino, acetylamino, lower alkylsulfonamide and benzenesulfonamide substituted with one or two halo Yes;
R ₃ is H; lower alkyl optionally substituted with halo; phenyl, pyridyl, or oxazolyl;
A is
(a) H; halo; benzothienyl; pyridyl; methylpiperazinylphenoxyl; indolyl substituted with lower alkyl;
(b) one selected from unsubstituted or mono-, di- or tri-lower alkoxy, di-lower alkylaminyl, morpholinyl, which may optionally be disubstituted by alkyl Or phenyl substituted with more substituents,
Piperazinyl substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkyl piperazinyl, pyrrolidinyl, dialkylaminyl and lower alkanol; and R ₁ is H is there;
Provided that both R ₂ and A are not simultaneously unsubstituted phenyl,
It is said compound.

Most preferably, the compound is selected from the group consisting of:
3- {7-amino-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (3-Benzyloxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl} -phenol;
6- (3-methoxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3,5-dimethoxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Benzyloxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (4-Chloro-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- [4- (4-Methyl-piperazin-1-yl) -phenyl] -6-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
5-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -6-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -5-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
N- {4- [7-amino-3- (4-dimethylamino-phenyl) -pyrazolo [1,5-a] pyrimidin-6-yl] -phenyl} -2,3-dichloro-benzenesulfonamide;
4-chloro-benzenesulfonic acid 4- [7-amino-3- (4-dimethylamino-phenyl) -pyrazolo [1,5-a] pyrimidin-6-yl] -phenyl ester;
6- (4-Methoxy-phenyl) -5-methyl-3-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- (4-methoxy-phenyl) -5-methyl-6-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (4-Bromo-phenyl) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (4-Bromo-phenyl) -5-methyl-3-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (2,6-dichloro-phenyl) -3-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- (3-methoxy-phenyl) -6-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
3-bromo-5-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6-benzo [b] thiophen-3-yl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- (4-bromo-phenyl) -5-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;

3- [4- (4-Methyl-piperazin-1-yl) -phenyl] -6-thiophen-3-yl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
3-benzo [b] thiophen-3-yl-6- (3-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6-benzo-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-methoxy-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (1-methyl-1H-indol-3-yl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (4-methoxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (2-methoxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-methoxy-phenyl) -3-pyridin-3-yl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- {7-amino-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (3-Benzyloxy-phenyl) -3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- {7-amino-3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (2-Benzyloxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
2- {7-amino-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (4-Benzyloxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
4- {7-amino-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (2-Benzyloxy-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
2- {7-amino-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (4-Benzyloxy-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
4- {7-amino-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (2-Benzyloxy-phenyl) -3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;

2- {7-amino-3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (4-Benzyloxy-phenyl) -3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
4- {7-amino-3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (3-Benzyloxy-phenyl) -3- [1-methyl-1H-indol-3-yl) -pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- [7-amino-3- (1-methyl-1H-indol-3-yl) -pyrazolo [1,5-a] pyrimidin-6-yl] -phenol;
3- [7-amino-3-pyridin-3-yl-pyrazolo [1,5-a] pyrimidin-6-yl] -phenol;
6- (3-Benzyloxy-phenyl) -3- (2-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- [7-amino-3- (2-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-6-yl] -phenol;
3- [3- (4-Methyl-piperazin-1-yl) -phenyl] -6-thiophen-3-yl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- (2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -6-thiophen-3-yl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- [4- (4-Methyl-piperazin-1-yl) -phenyl] -6-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-amino-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-amino-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (2-amino-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- [4- (4-Methyl-piperazin-1-yl) -phenyl] -6- (4-methyl-thiazol-2-yl) -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6-benzo [b] thiophen-3-yl-3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;

6-benzo [b] thiophen-3-yl-3- [4-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- (3-methoxy-phenyl) -6-thiophen-3-yl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Benzyloxy-phenyl) -3- (3-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- [7-amino-3- (3-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-6-yl] -phenol;
(4- {7-Amino-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenyl) -carbamic acid ethyl ester 6- (3-Chloro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-phenyl) -5-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-phenyl) -3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidine-7- Ilamine;
6- (3-Chloro-phenyl) -3- [2-methoxy-4- (4-methyl-piperazin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidine-7- Ilamine;
3- {7-amino-3- [2-methoxy-4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (2-Chloro-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (2-Chloro-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (4-Fluoro-phenyl) -5-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;

6- (4-Fluoro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-phenyl) -5-methyl-3- {3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-yl] -phenyl} -pyrazolo [1,5- a] pyrimidin-7-ylamine;
6- (3-Chloro-4-fluoro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] pyrazolo [1,5-a] pyrimidin-7-ylamine ;
6- (3-Chloro-4-fluoro-phenyl) -5-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine-7- Ilamine;
6- (3-Bromo-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Bromo-benzyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Bromo-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-phenyl) -5-methyl-3- (3-morpholin-4-yl-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine; 6- (3-chloro-phenyl) ) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-phenyl) -3- [3-((2R, 6S) -2,6-dimethyl-morpholin-4-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] Pyrimidine-7-ylamine;
2- (4- {3- [7-Amino-6- (3-chloro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-3-yl] -phenyl} -piperazin-1-yl ) -Ethanol;
6-benzyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;

6- (3-Chloro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-fluoromethyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-4-fluoro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-4-fluoro-phenyl) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (4-Fluoro-phenyl) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
2- (4- {3- [7-Amino-6- (4-fluoro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-3-yl] -phenyl} -piperazin-1-yl ) -Ethanol;
6- (3,4-difluoro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3,4-difluoro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
2- (4- {3- [7-Amino-6- (3-chloro-4-fluoro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-3-yl] -phenyl} -piperazine -1-yl) -ethanol;
2- (4- {3- [7-amino-6- (3,4-difluoro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-3-yl] -phenyl} -piperazine-1 -Yl) -ethanol;

6- (3-Chloro-phenyl) -5-methyl-3- [3- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine-7- Ilamine;
6- (4-Fluoro-phenyl) -5-methyl-3- [3- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine-7- Ilamine;
6- (3-Chloro-phenyl) -3- [3- (4-diethylamino-piperidin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- [3- (4-diethylamino-piperidin-1-yl) -phenyl] -6- (4-fluoro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (4-Fluoro-phenyl) -5-methyl-3- [3- (4-methyl-4-oxy-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine-7- Ilamine;
6- (4-Fluoro-phenyl) -5-methyl-3- [3- (4-methyl-1,4-dioxy-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine- 7-ylamine;
6- (3-Chloro-phenyl) -3- [3- (4-dimethylamino-piperidin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3,4-Difluoro-phenyl) -3- [3- (4-dimethylamino-piperidin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine ;
6- (3-Chloro-phenyl) -5-methyl-3- (3,4,5-trimethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine; 6- (3,4-difluoro -Phenyl) -5-methyl-3- (3,4,5-trimethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-phenyl) -3- (3-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- [7-amino-3- (3,4-dimethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-6-yl] -pyridin-2-ol;
6-benzyl-3- (3,4-dimethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine; and 3- (3,4-dimethoxy-phenyl) -6- (3-fluoro- (Benzyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine.

  Yet another aspect is the use of the above compounds in the manufacture of a pharmaceutical composition.

  Yet another embodiment is a pharmaceutical composition comprising the above compound.

  The pharmaceutical composition preferably comprises the above compound and an acceptable pharmaceutical carrier.

  In another aspect, there is provided the use of the above compound in the manufacture of a pharmaceutical composition for use in the treatment of kinase dependent diseases.

の２Ｈ−ピラゾル−３−イルアミンを形成し、 A further aspect is a process for preparing the above compound comprising:
(a) reacting a nitrile, A—CH ₂ —C≡N with ethyl formate in the presence of an organic solvent to form a substituted 3-oxo-propionitrile;
(b) The substituted 3-oxo-propionitrile of step (a) and hydrazine monohydrate are condensed in an organic solvent to give a compound of formula (III):

Of 2H-pyrazol-3-ylamine,

の３−オキソ−プロピオニトリルを形成し、
(ｃ)式(II)の３−オキソ−プロピオニトリルおよび式(III)の２Ｈ−ピラゾル−３−イルアミンを、有機溶媒の存在下縮合して、式(Ｉ)の化合物を形成することを含む、方法である。 (d) The substituted nitrile is formylated in the presence of ethanolate and formic acid ethyl ester to give a compound of formula (II):

The 3-oxo-propionitrile of
(c) condensing 3-oxo-propionitrile of formula (II) and 2H-pyrazol-3-ylamine of formula (III) in the presence of an organic solvent to form a compound of formula (I). It is a method including.

〔式中、
Ｒ_２はＨ；置換または非置換アリール；置換または非置換ヘテロアリール；置換または非置換脂肪族残基；官能基；またはピラゾロ[１,５ａ]ピリミジニル環に１個の連結基もしくは原子により連結している置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールまたは置換もしくは非置換脂肪族残基であり；
Ｒ_３はＨ、置換または非置換アリール、置換または非置換ヘテロアリール、置換または非置換脂肪族残基、官能基、またはピラゾロ[１,５ａ]ピリミジニル環に連結基もしくは原子により連結している脂肪族残基であり、
Ｒ_２またはＲ_３の少なくとも一方は置換または非置換アリール；置換または非置換ヘテロアリール；またはピラゾロ[１,５ａ]ピリミジニル環に１個の連結基もしくは原子により連結している置換もしくは非置換ヘテロアリールまたは置換もしくは非置換アリール残基であり；
ＡはＨ、ハロゲン(例えばブロモ)、脂肪族部分、官能基、置換または非置換アリール、または置換または非置換ヘテロアリールであり；そして
Ｒ_１はＨ、ハロゲンまたは低級アルキルである。〕
のピラゾロ[１,５ａ]ピリミジン−７−イルアミン化合物またはその薬学的に許容される塩、該疾患の処置における式(Ｉ)の化合物の使用法、または該疾患の処置用の式(Ｉ)の化合物を含む医薬製剤に関する。 The present invention particularly relates to a compound of formula (I) for the treatment of a protein kinase (especially tyrosine protein kinase) dependent disease or for the manufacture of a pharmaceutical composition for use in the treatment of said disease.

[Where,
R ₂ is H; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted aliphatic residue; functional group; or a pyrazolo [1,5a] pyrimidinyl ring linked by one linking group or atom. Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted aliphatic residue;
R ₃ is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aliphatic residue, functional group, or a fat linked to a pyrazolo [1,5a] pyrimidinyl ring by a linking group or atom Family residues,
At least one of R ₂ or R ₃ is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or substituted or unsubstituted heteroaryl linked to the pyrazolo [1,5a] pyrimidinyl ring by one linking group or atom Or a substituted or unsubstituted aryl residue;
A is H, halogen (eg bromo), aliphatic moiety, functional group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R ₁ is H, halogen or lower alkyl. ]
Of the pyrazolo [1,5a] pyrimidin-7-ylamine compound or a pharmaceutically acceptable salt thereof, the use of a compound of formula (I) in the treatment of the disease, or of the formula (I) for the treatment of the disease The present invention relates to a pharmaceutical preparation containing a compound.

The present invention especially relates to the manufacture of pharmaceutical compositions for use in or for the treatment of protein kinase (especially tyrosine protein kinase) dependent diseases.
R ₂ is H; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted aliphatic residue; functional group; or a pyrazolo [1,5a] pyrimidinyl ring linked by one linking group or atom Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted aliphatic residue;
R ₃ is linked to H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aliphatic residue, functional group, or pyrazolo [1,5a] pyrimidinyl ring by a linking group or atom Family residues,
At least one of R ₂ or R ₃ is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or substituted or unsubstituted heteroaryl linked to the pyrazolo [1,5a] pyrimidinyl ring by one linking group or atom Or a substituted or unsubstituted aryl residue, where both R ₂ and A are not simultaneously unsubstituted phenyl;
A is H, halogen (eg bromo), aliphatic moiety, functional group, substituted or unsubstituted aryl or heteroaryl; and R ₁ is H, halogen or lower alkyl;
A compound of formula (I), or a pharmaceutically acceptable salt thereof, a use of a compound of formula (I) in the treatment of said disease, a pharmaceutical formulation comprising a compound of formula (I) for the treatment of said disease, It relates to compounds of formula (I) for use in the treatment of diseases.

  The present invention also relates to a method for treating a kinase-dependent disease comprising administering a pyrazolo [1,5a] pyrimidin-7-ylamine compound of formula (I) to a warm-blooded animal, particularly a human. The invention also provides a pharmaceutical formulation comprising a pyrazolo [1,5a] pyrimidin-7-ylamine compound of formula (I), especially for the treatment of kinase-dependent diseases, a novel pyrazolo [1,5a] pyrimidine of formula (I) It relates to a process for the preparation of -7-ylamine compounds, pyrazolo [1,5a] pyrimidin-7-ylamine compounds of the formula (I), and new starting materials and intermediates for their preparation. The invention also relates to the use of a compound of formula (I) for the manufacture of a pharmaceutical formulation for the treatment of kinase dependent diseases.

The general terms used above and below, unless specified otherwise, preferably have the following meanings within the context of this specification: “Aryl” means an aromatic radical having 6 to 14 carbon atoms In particular phenyl, naphthyl, indenyl, azulenyl or anthryl, which is unsubstituted or substituted by one or more, preferably one or two substituents, wherein Is selected from any of the functional groups defined below and is lower halo, alkyl, substituted alkyl, halo lower alkyl, such as trifluoromethyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower alkoxy, hydroxy, etc. Aryl, etherified or esterified hydroxy, amino, mono- or disubstituted amino, amino Lower alkyl, amino lower alkoxy; acetylamino; amidino, halogen, nitro, cyano, cyano lower alkyl, carboxy, esterified carboxy, especially lower alkoxycarbonyl such as methoxycarbonyl, n-propoxycarbonyl or iso-propoxycarbonyl, alkanoyl, Benzoyl, carbamoyl, N-mono- or N, N-disubstituted carbamoyl, carbamate, alkyl carbamate, amidino, guanidino, urea, ureido, mercapto, sulfo, lower alkylthio, sulfoamino, sulfonamide, benzosulfonamide, Sulfonate, phenyl, benzyl, phenoxy, benzyloxy, phenylthio, phenyl-lower alkylthio, alkylphenylthio, lower alkylsulfone Halogen-lower alkylsulfonyl such as finyl, phenylsulfinyl, phenyl-lower alkylsulfinyl, alkylphenylsulfinyl, lower alkanesulfonyl, phenylsulfonyl, phenyl-lower alkylsulfonyl, alkylphenylsulfonyl, halogen-lower alkyl mercapto, especially trifluoromethanesulfonyl , dihydroxybora (-B (OH) _2), heterocyclyl, and methylene di-lower alkylenedioxy bound to a neighboring C atom of the ring as oxy, phosphono (-P (= O) (OH ) 2), hydroxy - Lower alkoxyphosphoryl or di-lower alkoxyphosphoryl, carbamoyl, mono- or di-lower alkylcarbamoyl, mono- or di- (hydroxy-lower alkyl) -carbamoyl, or -N R ₄ R ₅ , wherein R ₄ and R ₅ may be the same or different and are each individually H; lower alkyl (eg, methyl, ethyl or propyl); or R ₄ and R ₅ together with an N atom, Including 3- to 8-membered heterocyclic rings containing 1-4 nitrogen, oxygen or sulfur atoms (eg, piperazinyl, lower alkyl-piperazinyl, azetidinyl, pyrrolidinyl, piperidino, morpholinyl, imidazolinyl).

Aryl is more preferably unsubstituted or halo (eg Cl, Br or F); hydroxy; lower alkyl (eg C ₁ -C ₃ lower alkyl or methyl); aryl (eg phenyl or benzyl); amino Amino lower alkyl (eg dimethylamino); acetylamino; amino lower alkoxy (eg ethoxyamine); substituted lower alkyl (eg fluoroethyl); alkoxy (eg methoxy or benzyloxy wherein the benzyl ring is 3, Substituted or unsubstituted, such as 4-dichlorobenzyloxy; sulfoamino; substituted or unsubstituted sulfonamides (eg, benzosulfonamide, chlorobenzenesulfonamide or 2,3-dichlorobenzenesulfonamide); substituted or unsubstituted Substituted sulfonates (e.g. Substituted urea (eg 3-trifluoro-methyl-phenylurea or 4-morpholin-4-yl-3-trifluoromethyl-phenyl-urea); alkyl carbamate or carbamate (eg ethyl —N-phenyl-carbamate) or —NR ₄ R ₅ {wherein R ₄ and R ₅ may be the same or different and are each independently H; lower alkyl (eg, methyl, ethyl or propyl); or R ₄ And R ₅ together with the N atom, a 3- to 8-membered heterocyclic ring containing 1-4 nitrogen, oxygen or sulfur atoms (eg piperazinyl, lower alkyl-piperazinyl, pyridyl, indolyl, thiophenyl, Thiazolyl, morpholinyl n-methylpiperazinyl, benzothiophenyl, azetidinyl , Pyrrolidinyl, piperidino or imidazolinyl), and when R ₄ and R ₅ together with N form a heterocyclic ring, the ring is one, two or more substituents described herein And is preferably selected from the group consisting of solubilizing groups selected from the group consisting of piperazinyl, pyrrolidinyl, alkyl such as methyl, or hydroxyalkyl such as ethanyl. A phenyl that is independently substituted with one or two substituents. Examples of heterocycles in which R ₄ and R ₅ together form N are morpholinyl which may be unsubstituted or substituted by methyl or dimethyl; unsubstituted or one, 2 Piperazinyl optionally substituted with 1 or 2 substituents, preferably methyl, oxy or ethanol; or unsubstituted or 1, 2 or 3 substituents, preferably pyrrolidinyl , Piperazinyl optionally substituted with amine, alkylamine, methylamine, dialkylamine, dimethylamine or diethylamine;

  Heteroaryl groups are preferably monocyclic but may be bi- or tricyclic and contain 3-24, preferably 4-16 ring atoms, where at least one or more In the above, preferably 1 to 4 ring carbons are substituted with a heteroatom selected from O, N or S. Preferably the heteroaryl group is pyridyl, indolyl, pyrimidyl, pyrazolyl, oxazolyl, thiophenyl, benzothiophenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, benzimidazolyl, pyrazolyl, indazolyl, purinyl, pyrazinyl, pyridazinyl, 4H-quinolidinyl, isoinolyl, quinolyl , Phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinolinyl, indolinidinyl, 3H-indolyl, isoindolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, flazanyl and benzo [d] pyrazole.

  More preferably the heteroaryl group is selected from the group consisting of pyridyl, indolyl, pyrimidyl, pyrazolyl, oxazolyl, thiophenyl or benzothiophenyl.

  Heteroaryl groups are unsubstituted or one or more substituents selected from the groups defined above for aryl, most preferably lower alkyls such as hydroxy, halogen, methyl, or methoxy or ethoxy And may be substituted with lower alkoxy.

  As used herein, an aliphatic group is a residue mainly composed of non-aromatic carbon. Examples of aliphatic residues include substituted or unsubstituted alkyl, cycloalkyl, alkenyl and alkynyl.

  Alkyl includes lower alkyl, preferably up to 7, preferably from 1 to 5 (including 5) carbon atoms, straight or branched; preferably, lower alkyl is n Pentyl such as pentyl, n-butyl, sec-butyl, isobutyl, butyl such as tert-butyl, propyl such as n-propyl or isopropyl, ethyl or methyl. Preferably lower alkyl is methyl, propyl or tert-butyl.

  The cycloalkyl group is preferably cyclopentyl, cyclohexyl or cycloheptyl and is unsubstituted or substituted with one or more, especially 1 or 2 substituents selected from the groups defined above for aryl. Most preferably lower alkyl such as methyl, lower alkoxy such as methoxy or ethoxy, or hydroxy.

  Alkenyl and alkynyl preferably have up to 7, preferably from 1 to 5 (inclusive) carbon atoms and may be straight or branched.

  Alkyl, cycloalkyl, alkenyl and alkynyl may be substituted or unsubstituted, when substituted, any of the substituents defined above for other alkyl, cycloalkyl, alkenyl, alkynyl, aryl, or Can be up to 3 substituents containing any of the functional groups defined above.

  Halo or halogen is preferably fluoro, chloro, bromo or iodo, most preferably fluoro, chloro or bromo.

The term “linking atom or group” as used herein refers to alkyl (eg, —CH ₂ —); oxy-O—; keto-CO—; thio-S—; sulfonyl-SO ₂ —; sulfoxide-SO—; amines -NH- or -NR-; carboxylic acid; alcohols; esters (-COO-); amide (-CONR -, - CONHR'-); sulfonamide _{(-SO 2 NH -, - SO} 2 NR'-); Sulfone (—SO ₂ —); Sulfoxide (—SO—); Amino group; Urea (—NH—CO—NH—, —NR—CO—NH—, —NH—CO—NR—, —NR—CO—NR -); Ether (-O-); carbamate (-NH-CO-O-, -NR-CO-O-); or inverse amide, sulfonamide and ester (-NH-CO-, -NR) —CO—, —NH—SO ₂ —, —NR—SO ₂ -, -OOC-).

The term “functional group” as used herein is: carboxylic acid; hydroxyl; halogen; cyano (—CN); ether (—OR); ketone (—CO—R); ester (—COOR); amide s (— CONH2, -CONHR, -CONRR '); a thioether (-SR); sulfonamide _{(-SO 2 NH 2, -SO 2} NHR, -SO 2 NRR'); sulfone _(-SO 2 -R); sulfoxides (-SO -R); amines (-NHR, NR'R); urea _{(-NH-CO-NH 2,} -NH-CO-NHR); ether (-O-R); halogen; carbamate (-NH-CO-OR ); Aldehyde-functional groups (—CHO); and also back-ads; sulfonamides and esters (—NH—CO—R, —NH—SO ₂ —R, —OOC—R);
R and R ′ are the same or different and can be H or any aliphatic, aryl or heteroaryl moiety as defined above.

  When the plural form is used for compounds, salts, pharmaceutical formulations, diseases and the like, it is also intended to mean a single compound, salt, and the like.

Salts are especially pharmaceutically acceptable salts of compounds of formula (I).
Such salts are formed, for example, as acid addition salts, preferably from organic or inorganic acids, with compounds of the formula (I) having a basic nitrogen atom, in particular pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic acids, phosphonic acids, sulfonic acids or sulfamic acids such as acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelin. Acids, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, glutamic acid or aspartic acid, amino acids such as maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4 -Aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid 1,5-naphthalene-disulfur Acid, 2-, 3- or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic acid, or ascorbine Other organic protic acids such as acids.

  In the presence of negatively charged radicals such as carboxy or sulfo, salts can also be formed with bases, such as metal or ammonium salts, such as alkali metal or alkaline earth metal salts, such as sodium, potassium, magnesium or calcium salts, Or with ammonia or a suitable organic amine, such as an ammonium salt with a tertiary monoamine such as triethylamine or tri (2-hydroxyethyl) amine, or a heterocyclic base such as N-ethyl-piperidine or N, N′-dimethylpiperazine is there.

  When a basic group and an acidic group are present in the same molecule, the compound of formula (I) can also form an inner salt.

  It is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates, for isolation or purification purposes. For therapeutic use, only pharmaceutically acceptable salts or free compounds are used (in the form of pharmaceutical preparations where applicable) and are therefore preferred.

  From the close relationship of the free form compounds and their salts, including tautomers or tautomeric mixtures and salts thereof, which can be used, for example, for the purification or identification of the compounds, as described above and below. And all references to compounds, especially compounds of formula (I), unless appropriate and expected, and unless otherwise stated, tautomers of these compounds, especially compounds of formula (I) It is to be understood that reference is also made to these compounds, in particular tautomeric mixtures of compounds of the formula (I), or salts of any of these.

  When a “compound ..., its tautomer; or a salt thereof” is described, it means “a compound ..., its tautomer, or a salt of a compound or tautomer” ”.

  All asymmetric carbon atoms can be present in the (R)-, (S)-or (R, S) -configuration, preferably in the (R)-or (S) -configuration. Substituents on the ring at atoms that are saturated may be present in cis-(= Z-) or trans (= E-) form, if possible. The compounds can therefore exist as a mixture of isomers or preferably as pure isomers, preferably as enantiomer-pure diasteromers or pure enantiomers.

  The invention also relates to prodrugs of compounds of formula (I) which are converted in vivo to compounds of formula (I) per se. It is to be understood that all references to compounds of formula (I) also refer to the corresponding prodrugs of compounds of formula (I), where appropriate and expected.

The compounds of formula (I) have valuable pharmacological properties and are useful in the treatment of kinase dependent diseases, eg as agents for treating proliferative diseases.
The term “treatment of tyrosine protein kinase dependent diseases” includes prophylactic or preferably therapeutic (palliative and / or curative) treatment of the diseases, in particular the following diseases.

  When the term “use” is subsequently described, this is to the appropriate and anticipated unless otherwise stated, each of any one or more of the embodiments of the invention described below, respectively. Including: use in the treatment of (especially tyrosine) protein kinase dependent diseases, use in the manufacture of a pharmaceutical composition for use in the treatment of the disease, pyrazolo [1,5a] pyrimidin-7-ylamine derivatives in the treatment of the disease , Pharmaceutical formulations containing pyrazolo [1,5a] pyrimidin-7-ylamine derivatives for treating the diseases, and pyrazolo [1,5a] pyrimidin-7-ylamine derivatives for use in treating the diseases . In particular, the diseases to be treated and therefore preferred for the use of the compounds of formula (I) are the following (especially tyrosine) protein kinase dependence ("dependence" is not only "mere dependence" but also "supported" Diseases, particularly corresponding proliferative diseases, more particularly c-Abl, Bcr-Abl, c-Kit, c-Raf, Flt-1, Flt-3, KDR, Her-1, PDGFR-kinase, c-Src, RET-receptor kinase, FGF-R1, FGF-R2, FGF-R3, FGF-R4, Ephrin receptor kinase (eg, EphB2 kinase, EphB4 kinase and related Eph kinase), casein kinase (CK-1 , CK-2, G-CK), Pak, ALK, ZAP70, Jak1, Jak2, Axl, Cdk1, cdk4, cdk5, M Kinases such as et, FAK, Pyk2, Syk, insulin receptor kinase, Tie-2 or Bcr-Abl, c-Kit, c-Raf, Flt-3, FGF-R3, PDGF-receptor, RET, and Met Is a disease dependent on a constitutively activated variant (activated kinase) (hereinafter “the kinase”) of a kinase-dependent disease, in particular a disease dependent on the kinase and (especially an abnormally high degree of Can be used to treat the kinase-dependent disease (expressed or structurally activated) or activation of the kinase pathway as well as diseases that depend on any combination of two or more of the described kinases.

  Most preferred are diseases dependent on c-abl, Flt-3, KDR, c-Src, RET, EphB4, c-kit, cdk1, FGFR-1, c-raf, Her-1, Ins-R and Tek Use of compounds of formula (I) for the treatment of c-abl, Flt-3, KDR, c-Src, RET, EphB4, c-kit, FGFR-1, c-raf, cdk1, Her-1 The use of compounds of formula (I) as Ins-R and Tek inhibitors.

  There are also experiments demonstrating the in vivo antitumor activity of compounds of formula (I).

  The compounds of formula (I) have valuable pharmacological properties and are useful as therapeutic agents for protein kinase dependent diseases such as proliferative diseases.

Inhibition of RET is measured as follows: baculovirus donor vector pFB-GSTX3 depends on human RET-Men2A corresponding to the wild-type kinase domain (wtRET) of RET, and activation mutations in wtRET and activation loop M918T Used to acidify recombinant baculovirus expressing the amino acid region 658-1072 (Swiss prot No. Q9BTB0) of the cytoplasmic kinase domain of RET-Men2B. The coding sequences of the cytoplasmic domains of wtRET and RET-Men2B are amplified by PCR from the plasmids pBABEpuro RET-Men2A and pBABEpuro RET-Men2B. The amplified DNA fragment and the pFB-GSTX3 vector are made compatible for ligation by digestion with SalI and KpnI. Ligation of these DNA fragments results in the baculovirus donor plasmids pFB-GX3-RET-Men2A and pFB-GX3-RET-Men2B, respectively.

Production of virus: A transfer vector containing the kinase domain is transfected into the DH10Bac cell line (GIBCO) and seeded on selective agar plates. Colonies without insertion of the fusion sequence into the viral genome (carried by bacteria) are blue. Single, white colonies are picked and viral DNA (bacmid) is isolated from the bacteria by standard plasmid purification methods. Sf9 cells or Sf21 (American Type Culture Collection) cells are then transfected into 25 cm ² flasks with viral DNA using the cellfectin reagent.

Determination of small scale protein expression in Sf9 cells: Virus-containing media is recovered from the transfected cell culture and used for infection to increase its titer. Virus-containing media obtained after two rounds of infection is used for large-scale protein expression. For large-scale protein expression, 100 cm ² round tissue culture plates are seeded at 5 × 10 ⁷ cells / plate and infected with 1 mL of virus-containing medium (approximately 5 MOI). After 3 days, the cells are scraped from the plate and centrifuged at 500 rpm for 5 minutes. Cell pellets from 10-20 100 cm ² plates were re-added to 50 mL ice cold lysis buffer (25 mM tris-HCl, pH 7.5, 2 mM EDTA, 1% NP-40, 1 mM DTT, 1 mM P MSF). Suspend. The cells are agitated on ice for 15 minutes and then centrifuged at 5,000 rpm for 20 minutes.

Purification of GST-labeled protein: The centrifuged cell lysate is loaded onto a 2 mL glutathione-Sepharose column (Pharmacia) and washed 3 times with 10 mL 25 mM tris-HCl, pH 7.5, 2 mM EDTA, 1 mM DTT, 200 mM NaCl. . The GST-labeled protein is then eluted by 10 applications (1 mL each) of 25 mM tris-HCl, pH 7.5, 10 mM reduced glutathione, 100 mM NaCl, 1 mM DTT, 10% glycerol and stored at −70 ° C.

Measurement of enzyme activity: Tyrosine protein kinase assay with either purified GST-wtRET or GST-RET-Men2B protein, 15 ng of GST-wtRET or GST-RET-Men2B protein, 20 mM tris-HCl, pH 7 _{.5,1mM MnCl 2, 10mM MgCl2,1mM DTT,} 3μg / mL poly (Glu, Tyr) 4: 1,1 % DMSO, final containing ^{2.0μM ATP (γ- [33 P]} -ATP 0.1μCi) Perform in a volume of 30 μL. Activity is assayed by measuring the incorporation of ³³ P from [γ ³³ P] ATP into poly (Glu, Tyr) 4: 1 in the presence or absence of inhibitors. The assay is performed in a 96-well plate at ambient temperature for 15 minutes under the following conditions and stopped by the addition of 20 μL of 125 mM EDTA. Subsequently, 40 μL of the reaction mixture is transferred to an Immobilon-PVDF membrane (Millipore) previously soaked in methanol for 5 minutes, rinsed with water and then soaked in 0.5% H ₃ PO ₄ for 5 minutes, unconnected Mount on vacuum manifold with source. After spotting all samples, vacuum is connected and each well rinsed with 200 μL 0.5% H ₃ PO ₄ . Remove the membrane and wash 4 times on a shaker with 1.0% H ₃ PO ₄ and once with ethanol. Membranes are dried at ambient temperature, mounted on a Packard TopCount 96 well frame and counted after the addition of 10 μL / well Microscint ™ (Packard). IC ₅₀ values are calculated by linear regression analysis of percent inhibition at 4 concentrations (usually 0.01, 0.1, 1 and 10 μM) in duplicate for each compound. One unit of protein kinase activity is defined as 1 nmole of ³³ P ATP transferred from [γ ³³ P] ATP to substrate protein / min / mg protein at 37 ° C.

IC ₅₀ calculation input 3 × 4 μL stopped assay on Immobilon membrane, unwashed background (3 wells) assay with H ₂ O instead of enzyme positive control (4 wells) 3% DMSO instead of compound
Solution control (1 well) No reaction mixture IC ₅₀ values are calculated by logarithmic regression analysis of the percent inhibition of each compound at 4 concentrations (usually starting at 10 μM, 3-fold or 10-fold dilution series). In each experiment, the actual inhibition by the reference compound is used to normalize the IC ₅₀ value based on the mean value of the reference inhibitor:
Standardized IC ₅₀ = Measured IC ₅₀ Average Reference IC ₅₀ Value / Measured Reference IC ₅₀
Example: 0.4 μM of reference inhibitor tested, mean 0.3 μM
Experimental reference compound 1.0 μM, normalization: 0.3 / 0.4 = 0.75 μM
For example, staurosporine or synthetic staurosporine derivatives are used as reference compounds.

Using this protocol, compounds of formula (I) are found to exhibit IC ₅₀ values in the range of 0.005-100 μM, preferably in the range of 0.01-2 μM, for RET inhibition.

The effectiveness of the compounds of the invention as inhibitors of c-Abl protein-tyrosine kinase activity can be demonstrated as follows: an in vitro enzyme assay was performed with the following modifications Geissler et al. In Cancer Res. 1992; 52: Performed in a 96-well plate filter binding assay as described in 4492-4498. The His-tagged kinase domain of c-Abl is cloned and expressed in the baculovirus / Sf9 system as described in Bhat et al. in J. Biol. Chem. 1997; 272: 16170-16175. The 37 kD protein (c-Abl kinase) is purified in a two-step process with a cobalt metal chelate column followed by an anion exchange column to give 1-2 mg / L of Sf9 cells (Bhat et al., Cited above). The purity of c-Abl kinase is> 90% as judged by SDS-PAGE after Coomassie blue staining. The assay includes (30 μL total volume): c-Abl kinase (50 ng), 20 mM Tris · HCl, pH 7.5, 10 mM MgCl ₂ , 10 μM Na ₃ VO ₄ , 1 mM DTT and 30 μg / 30% in the presence of 1% DMSO. 0.06 μCi / assay [γ ³³ P] -ATP (5 μM ATP) using mL poly-Ala, Glu, Lys, Tyr-6: 2: 5: 1 (Poly-AEKY, Sigma P1152). The reaction was stopped by the addition of 10 μL of 250 mM EDTA, and 30 μL of the reaction mixture was transferred to an Immobilon-PVDF membrane (Millipore, Bedford, MA, USA) previously soaked in methanol for 5 minutes, rinsed with water, and then 5 minutes at 0. Immerse in 5% H ₃ PO ₄ and mount in a vacuum manifold with an unconnected vacuum source. After spotting all samples, vacuum is connected and rinsed well with 200 μL 0.5% H ₃ PO ₄ each. Remove the membrane and wash on a shaker with 0.5% H ₃ PO ₄ (4 times) and once with ethanol. Are dried at ambient temperature, mounted on a Packard TopCount 96 well frame and counted after addition of 10 μL / well Microscint ™ (Packard).

Using this test system, compounds of formula (I) exhibit IC ₅₀ values in the range of 0.002 to 100 μM, usually 0.002 to 5 μM, for inhibition of c-Abl inhibition.

The effect of the compounds of the present invention as inhibitors of KDR protein-tyrosine kinase activity can be demonstrated as follows: inhibition of VEGF-induced receptor autophosphorylation, permanent inhibition of human VEGF-R2 receptor (KDR). cells such as transfected CHO cells expressing, seeded in complete culture medium of 6 well cell culture plates (with 10% fetal calf serum = FCS), under 5% CO _2, about 80% confluent at 37 ° C. This can be confirmed by further in vitro experiments, incubating until fluency is shown. The compound to be tested is then diluted in culture medium (no FCS, with 0.1% bovine serum albumin) and added to the cells. (Control consists of medium without test compound). After incubation for 2 hours at 37 ° C., recombinant VEGF is added; the final VEGF concentration is 20 ng / ml. After an additional 5 minutes incubation at 37 ° C., the cells are washed twice with ice-cold PBS (phosphate buffered saline) and immediately lysed in 100 μl lysis buffer / well. The lysate is then centrifuged to remove nuclei and the protein concentration of the supernatant is determined using a commercial protein assay (BIORAD). The lysate can either be used immediately or stored at −20 ° C. if necessary.

A sandwich ELISA is performed to measure VEGF-R2 phosphorylation: Monoclonal antibodies against VEGF-R2 (eg Mab 1495.12.14; ProQinase, Freiburg, Germany) are immobilized on a black ELISA plate (Packard OptiPlate ™ HTRF-96). The plate was then washed and the remaining free protein binding sites were extracted with phosphate buffered saline and Tween 20® (polyoxyethylene (20) sorbitan monolaurate, ICI / Uniquema) (PBST). % Saturated with TopBlock® (Juro, Cat. # TB232010). Cell lysates (20 μg protein / well) are then incubated in these plates overnight at 4 ° C. with anti-phosphotyrosine antibody conjugated to alkaline phosphatase (PY20: AP from Zymed). Binding of the anti-phosphotyrosine antibody to the capture phosphorylated receptor is then demonstrated using a luminescent AP substrate (CDP-Star, ready-to-use, Emerald II; Applied Biosystems). Luminescence is measured with a Packard Top Count Microplate Scintillation Counter. The difference in signal between positive control (stimulated with VEGF) and negative control (not stimulated with VEGF) corresponds to VEGF-induced VEGF-R2 phosphorylation (= 100%). The activity of the test substance is calculated as the percent inhibition of VEGF-induced VEGF-R2 phosphorylation, where the concentration of the substance that induces half of the maximum inhibition is defined as IC ₅₀ (inhibitory dose of 50% inhibition). The compounds of formula (I) here exhibit an IC ₅₀ for KDR inhibition in the range of 0.005 to 20 μM, preferably between 0.005 and 1 μM.

Flt3 kinase inhibition is determined as follows: The baculovirus donor vector pFbacG01 (GIBCO) is used to produce a recombinant baculovirus that expresses amino acid region 563-993 of the cytoplasmic kinase domain of human Flt-3. The coding sequence of the cytoplasmic domain of Flt-3 is amplified by PCR from a human c-DNA library (Clontech). The amplified DNA fragment and pFbacG01 vector are made compatible for ligation by digestion with BamH1 and HindIII. Ligation of these DNA fragments results in the baculovirus donor plasmid Flt-3 (1.1). Virus production, protein expression in Sf9 cells and purification of the GST-fusion protein are performed as follows:
Production of virus: A transfer vector containing the Flt-3 kinase domain (pFbacG01-Flt-3) is transfected into the DH10Bac cell line (GIBCO) and the transfected cells are seeded on selective agar plates. Colonies without insertion of the fusion sequence into the viral genome (carried by bacteria) are blue. S single, white colonies are picked and viral DNA (bacmid) is isolated from bacteria by standard plasmid purification methods. Sf9 cells or Sf21 (American Type Culture Collection) cells are then transfected into the flasks with viral DNA using cellfectin reagent.

Determination of small scale protein expression in Sf9 cells: Virus-containing media is recovered from the transfected cell culture and used for infection to increase its titer. Virus-containing media obtained after two rounds of infection is used for large-scale protein expression. For large-scale protein expression, 100 cm ² round tissue culture plates are seeded at 5 × 10 ⁷ cells / plate and infected with 1 mL of virus-containing medium (approximately 5 MOI). After 3 days, the cells are scraped from the plate and centrifuged at 500 rpm for 5 minutes. Cell pellets from 10-20 100 cm ² plates were added to 50 mL ice cold lysis buffer (25 mM Tris-HCl, pH 7.5, 2 mM EDTA, 1% NP-40, 1 mM DTT, 1 mM PMSF). Resuspend. The cells are agitated on ice for 15 minutes and then centrifuged at 5,000 rpm for 20 minutes.

  Purification of GST-labeled protein: The centrifuged cell lysate was loaded onto a 2 mL glutathione-Sepharose column (Pharmacia), 3 times 10 mL 25 mM Tris-HCl, pH 7.5, 2 mM EDTA, 1 mM DTT, 200 mM NaCl. Wash with. The GST-labeled protein is then eluted by 10 applications (1 mL each) of 25 mM Tris-HCl, pH 7.5, 10 mM reduced glutathione, 100 mM NaCl, 1 mM DTT, 10% glycerol and stored at −70 ° C.

Measurement of enzyme activity: (depending on the specific activity) Tyrosine protein kinase assays with GST-Flt-3 were purified enzyme protein 200-1800ng, 20mM Tris-HCl, pH7.6,3mM MnCl 2, 3mM MgCl 2 Perform in a final volume of 30 μL containing 1 mM DTT, 10 μM Na ₃ VO ₄ , 3 μg / mL poly (Glu, Tyr) 4: 1, 1% DMSO, 8.0 μM ATP and 0.1 μCi [γ ³³ P] ATP. Activity is assayed by measuring the incorporation of ³³ P from [γ ³³ P] ATP into a poly (Glu, Tyr) substrate in the presence or absence of inhibitors. The assay (30 μL) is performed in 96-well plates at ambient temperature for 20 minutes under the following conditions and stopped by the addition of 20 μL of 125 mM EDTA. Subsequently, 40 μL of the reaction mixture is transferred to an Immobilon-PVDF membrane (Millipore, Bedford, MA, USA) previously soaked in methanol for 5 minutes, rinsed with water, and then soaked in 0.5% H ₃ PO ₄ for 5 minutes. And mounted on a vacuum manifold having an unconnected vacuum source. After spotting all samples, vacuum is connected and each well rinsed with 200 μL 0.5% H ₃ PO ₄ . Remove membrane and wash on shaker 4 times with 1.0% H ₃ PO ₄ and once with ethanol. Membranes are dried at ambient temperature, mounted on a Packard TopCount 96 well frame and counted after the addition of 10 μL / well Microscint ™ (Packard). IC ₅₀ values are calculated by linear regression analysis of percent inhibition at 4 concentrations (usually 0.01, 0.1, 1 and 10 μM) in duplicate for each compound. One unit of protein kinase activity is defined as 1 nmole of ³³ P ATP transferred from [γ ³³ P] ATP to substrate protein / min / mg protein at 37 ° C. Compounds of formula (I) exhibit IC ₅₀ values in the range of 0.01 to 100 μM, preferably 0.05 to 10 μM, for Flt-3 inhibition.

The compounds of formula (I) also inhibit other tyrosine protein kinases, such as c-Src kinase, c-Kit, VEGF-R and / or FGFR; all of these, animals, especially mammalian cells (human cells Have a role in the growth of A suitable assay is described in Andrejauskas-Buchdunger et al., Cancer Res. 52, 5353-8 (1992). Using this test system, compounds of formula (I) exhibit IC ₅₀ values in the range of 0.005 to 100 μM, usually 0.005 to 5 μM, for inhibition of c-Src. Compounds of formula (I) also exhibit IC ₅₀ values in the range of 0.005 to 10 μM for c-kit inhibition, usually 0.005 to 5 μM; and for FGFR-1 inhibition up to 95% inhibition at 10 μM is there.

Inhibition of IGF-1R and Ins-R can be determined as follows: The baculovirus donor vector pfbgx3IGF1Rcd is used to produce a recombinant baculovirus that expresses the amino acid region 950-1337 of the mature peptide cytoplasmic domain of human IGF-IR. . PC5hInsR is used to produce a cDNA fragment encoding the amino acid region 919-1343 of the cytoplasmic kinase domain of the human insulin receptor. Human IGF-IR and Ins-R fragments were cloned as a factor Xa cleavable glutathione-S-transferase (GST) -fusion protein using the recombinant Baculovirus-produced Bac-to-Bac ^TM system (GIBCO BRL). Expressed and small-scale purified. Virus-containing media is collected from the transfected cell culture and used for infection to increase its titer. Virus-containing media obtained after two rounds of infection is used for large-scale protein expression. A cell extract is prepared and loaded onto a glutathione-Sepharose (Pharmacia) column. After washing, the GST-labeled protein is then eluted with a glutathione-containing buffer. The purified protein is stored at -70 ° C in elution buffer. Tyrosine protein kinase assays with purified GST-IGF-1R and GST-Ins-R were performed using 20 mM Tris-HCl, pH 7.6, 10 mM MgCl ₂ , 0.01 mM Na ₃ VO ₄ , 1% DMSO, 1 mM DTT, 3 μg. / Ml Poly (Glu, Tyr) 4: 1 and 10 μM ATP (γ- [ ³³ P] -ATP 0.1 μCi) in a final volume of 30 μL. The assay is performed in a 96 well plate at ambient temperature for 20 minutes and stopped by the addition of 25 μl 0.05M EDTA, pH 7.0. An aliquot of 40 μl is spotted with a multichannel dispenser onto Whatman P81 membrane mounted on a Millipore Microtiter filter manifold connected to a low vacuum source. After liquid removal, the membrane is transferred to a series of 4 0.5% H ₃ PO ₄ and 1 EtOH wash baths (10 minutes each shaking incubation), dried and mounted on a Hewlett Packard TopCount manifold 10 μl Microscint® is added and counted. Compounds of formula (I) show up to 90% inhibition of Ins-R, preferably 60-90% inhibition at 10,000 nM.

  Inhibition of Tek can be determined as follows: Methods for expression, purification and assay of these kinases have been described. Fabbro et al., Pharmacol. Ther. 82 (2-3) 293-301 (1999). Briefly, the glutathione S-transferase (GST) gene from the pAcG1 vector (Pharmingen) was excised with EcoRV and EcoRI, inserted into the cloning site of the Fast-Bac baculovirus vector (GIBCO), and the pAcG1 fusion vector (FBG0). A 5530 bp vector with an N-terminal cloning site from is created. The C-terminal cloning site can be any cloning site (from the Fast-Bac vector) downstream of the N-terminal cloning site used. N-terminal GST-fused (pAcG1, Pharmingen) KDR, Flt-1, Flk-1, Tek and PDGFR-β kinase domains are obtained from ProQinase, Freiburg, Germany. Tek is recloned into the FBG1 vector by EcoRI excision and ligation to EcoRI digested FBG1 (FBG1-Tek). The entire cytoplasmic domains of c-Kit (aa 544-976) and c-Fms (aa 538-972) are amplified by PCR from human uterus and human bone marrow cDNA libraries (Clontech), respectively. Amplified DNA fragments are fused with GST by cloning them into FBG1 as a BamHI-EcoRI insert to produce FBG1-c-Kit and FBG1-c-Fms. Tek is recloned into the FBG0 transfer vector by EcoRI excision and ligation to EcoRI digested FBG0 (FBG-Tie2 / Tek). FGFR-1 and c-met kinase domains are obtained by PCR from human A431 cells. The N-terminal primer contains an overhanging EcoRI site, while the C-terminal primer contains an XhoI site to aid in cloning into the transfer vector. After digestion of both the PCR fragment and FBG0, the cleavage product is gel purified and ligated together to form a kinase construct (FBG-Met, FBG-FGFR-1).

Virus for each kinase is performed according to the protocol provided by GIBCO. Briefly, the kinase domain-containing transfer vector is transfected into the DH10Bac cell line (GIBCO) and seeded on agar plates containing the recommended concentrations of Blue-Gal, IPTG, kanamycin, tetracycline, and gentamicin. Colonies without insertion of the fusion sequence into the viral genome (carried by bacteria) are blue. Single white colonies are usually picked and viral DNA (bacmid) is isolated from bacteria by standard plasmid mini prep method. Sf9 cells or High Five cells (GIBCO) are then transfected into 25 cm ² flasks with viral DNA using the protocol provided with the cellfectin reagent and the Bac-to-Bac kit (GIBCO). Virus-containing media is collected from the transfected cell culture and used for infection to increase its titer. Virus-containing media obtained after two rounds of infection is used for large-scale protein expression. For large-scale protein expression, 100 cm ² round tissue culture plates are seeded at 5 × 10 ⁷ cells / plate and infected with 1 ml of virus-containing medium (approximately 5 MOI). After 3 days, the cells are scraped from the plate and centrifuged at 500 rpm for 5 minutes.

Cell pellets from 10-20 100 cm ² plates were resuspended in 50 mL ice cold lysis buffer (25 mM Tris-HCl, pH 7.5, 2 mM EDTA, 1% NP-40, 1 mM DTT, 1 mM PMSF). It becomes cloudy. The cells are agitated on ice for 15 minutes and then centrifuged at 5,000 rpm for 20 minutes. The supernatant is loaded onto a 2 ml glutathione-Sepharose column and washed 3 times with 10 ml of 25 mM Tris-HCl, pH 7.5, 2 mM EDTA, 1 mM DTT, 200 mM NaCl. The GST-labeled protein is then eluted by 10 applications (1 mL each) of 25 mM Tris-HCl, pH 7.5, 10 mM reduced glutathione, 100 mM NaCl, 1 mM DTT, 10% glycerol and stored at -70 ° C.

The assay (30 μl) consists of 200-1800 ng enzyme protein (depending on specific activity), 20 mM Tris-HCl, pH 7.6, 3 mM MnCl ₂ , 3 mM MgCl _2, 1 mM DTT, 10 μM Na ₃ VO ₄ , 3 μg / ml poly ( Glu, Tyr) 4: 1, 8 [mu] M ATP ([gamma]-[< ³³ > P] -ATP 0.1 [mu] Ci). The reaction is incubated for 20 minutes at ambient temperature and stopped with 25 μl 0.25 M EDTA (pH 7.0). An aliquot of 40 μl is spotted with a multichannel dispenser onto an Immobilon P membrane mounted on a Millipore Microtiter filter manifold connected to a low vacuum source. After liquid removal, the membrane is transferred to a series of 4 0.5% H ₃ PO ₄ and 1 EtOH wash baths (10 minutes each shaking incubation), dried and mounted on a Hewlett Packard TopCount manifold 10 μl Microscint® is added and counted. The compound of formula (I) exhibits an IC ₅₀ value of about 0.1-100 μM for Tek inhibition, calculated by linear regression analysis.

Inhibition of Cdk1 can be determined as follows: Cdk1 / cycB: Cdk1 / cycB is obtained from ProQinase, Freiburg, Germany. Starfish oocytes are induced to enter the M phase of the cell cycle with 10 μM 1-methyladenine, frozen in liquid nitrogen and stored at −80 ° C. When necessary, the oocytes are homogenized and centrifuged as described (Arion et al., Cell 55: 371-378 (1988) and Rialet et al., AntiCancer Res. 11: 1581-1590 (1991 )). Cdk1 / cycB kinase is purified on ^{p9 CKShs} -Sepharose beads as described and eluted with recombinant human ^{p9 CKShs} (Azzi et al., Eur. J. Biochem. 203: 353-360. (1992)). Briefly, the supernatant from the oocyte is equilibrated with ^{p9 CKShs} -Sepharose beads for 30 minutes at 4 ° C. under constant rotation. The beads are washed thoroughly and the activated cdk1 / cycB kinase is eluted with purified p9CKShs (3 mg / ml). The activity of Cdk1 / cycB is measured as described (Arion et al., Cell 55: 371-378 (1988), Meijer et al., EMBO J. 1989; 8: 2275-2282 and Meijer et al., EMBO J. 1991; 8: 2275-2282). The assay is performed for 20 minutes at ambient temperature in a 96 well plate with minor modifications. The final volume of 30 μl is 0.1-0.3 U Cdk1 / cycB, 1 mg / ml histone H1, 60 mM β-glycerophosphatase, 30 mM nitrophenyl phosphate, 25 mM MOPS, 5 mM EGTA, 15 mM MgCl ₂ , 1 mM DTT as substrate. Contains 0.1 mM Na ₃ VO _4, 15 μM ATP and 0.1 μCi γ- ³³ P-ATP (75 μM, 8800 cpm / pmole). The reaction is stopped by the addition of 25 μl 0.05M EDTA pH 7.0. An aliquot of 40 μl is spotted with a multichannel dispenser onto an Immobilon P membrane mounted on a Millipore Microtiter filter manifold connected to a low vacuum source. After liquid removal, the membrane is transferred to a series of 4 0.5% H ₃ PO ₄ and 1 EtOH wash baths (10 minutes each shaking incubation), dried and mounted on a Hewlett Packard TopCount manifold 10 μl Microscint® is added and counted. The compounds of formula (I) show up to 100% Cdk1 inhibition at 10,000 nM.

Inhibition of c-Raf-1 can be determined as follows: the product of recombinant c-Raf-1 protein can be used to produce Sf21 cells with GST-c-Raf-1 recombinant baculovirus and active c-Raf-1 kinase. Obtained by triple infection of the required v-Src and v-Ras recombinant baculovirus together (Williams et al., PNAS 1992; 89: 2922-2926). Active Ras (v-Ras) recruits c-Raf-1 to the cell membrane and v-Src to phosphorylated c-Raf-1 and fully activates it (Williams et al., PNAS 1992; 89 : 2922-2926). Cells were seeded in 2.5 × 10 ⁷ cells / 150 mm dishes and allowed to attach to 150 mm dishes for 1 hour at RT. The medium (SF900II containing 10% FBS) is aspirated and recombinant baculovirus; GST-C-Raf-1, v-Ras and v-Src at a MOI of 3.0, 2.5 and 2.5 respectively. Add in a total volume of -5 mL. Cells are incubated for 1 hour at RT and then 15 mL of medium is added. Infected cells are incubated for 48-72 hours at 27 ° C. Infected Sf21 cells are scraped, collected in a 50 mL tube, and centrifuged at 1100 g at 4 ° C. for 10 minutes in a Sorvall centrifuge. The cell pellet is washed once with ice cold PBS and lysed with 0.6 mL lysis buffer / 2.5 × 10 ⁷ cells. Complete lysis of the cells is achieved by placing on ice for 10 minutes with occasional pipetting. The cell lysate is centrifuged in a Sorvall centrifuge for 10 minutes in an SS-34 rotor at 14,500 g at 4 ° C. and the supernatant is transferred to a new tube and stored at −80 ° C. c-Raf-1 is purified from cell lysates using 100 μL packed glutathione-Sepharose 4B beads equilibrated with ice-cold PBS per 2.5 × 10 ⁷ cells. GST-c-Raf-1 was bound to the beads with shaking at 4 ° C. for 1 hour. Bound GST-c-Raf-1 and beads were transferred to the column. The column is washed once with lysis buffer and twice with ice cold Tris buffered saline. Ice-cold elution buffer is added to stop column flow and free glutathione disrupts the interaction between GST-c-Raf-1 and glutathione sepharose beads. Fractions (1 mL) are collected in pre-frozen test tubes. Each tube contains 10% glycerol (final concentration) to maintain kinase activity during the freeze-thaw cycle. The purified fraction of GST-c-Raf-1 kinase protein is stored at -80 ° C.

IκB was used as a substrate for c-Raf-1 kinase. IκB is expressed in the relapse as a His-tagged protein (cloned and kindly provided by Dr. Eder; ABM, Novartis, Basel). BL21 LysS bacteria containing IκB plasmid were grown to OD ₆₀₀ of 0.6 in LB medium and then induced with IPTG (1 mM final concentration) for 3 hours at 37 ° C. to express kb, then bacteria Is dissolved by sonication (microchip setting limit, 3 times, 1 minute, each in ultrasonic buffer [50 mM Tris pH 8.0, 1 mM DTT, 1 mM EDTA]) and centrifuged at 10,000 g for 15 minutes. The supernatant is mixed with ammonium sulfate to a final concentration of 30%. The mixture is shaken for 15 minutes at 4 ° C. and then spun at 10,000 g for 15 minutes. The pellet is resuspended in binding buffer (Novagen) containing 10 mM BSA. This solution is applied to Ni-agarose (Novagen) according to the Novagen manual and washed. IκB is eluted from the column using elution buffer (0.4 M imidazole, 0.2 M NaCl, 8 mM Tris pH 7.9). The protein containing fraction is dialyzed in 50 mM Tris pH 8, 1 mM DTT.

The activity of c-Raf-1 protein kinase is assayed by ³³ P incorporation from [γ ³³ P] ATP to IB in the presence or absence of inhibitors. The assay is performed in a 96 well plate for 60 minutes at ambient temperature. It contains (30 μl total volume) including: c-rafl1 kinase (400 ng), 25 mM Tris · HCl, pH 7.5, 5 mM MgCl ₂ , 5 mM MnCl ₂ , 10 μM Na ₃ VO ₄ , 1 mM DTT and 1% DMSO. 0.3 μCi / assay [γ ³³ P] -ATP (10 μM ATP) using 600 ng IB. The reaction was stopped by the addition of 10 μL of 250 mM EDTA, and 30 μL of the reaction mixture was transferred to an Immobilon-PVDF membrane (Millipore, Bedford, MA, USA) previously soaked in methanol for 5 minutes, rinsed with water, then 5 minutes, 0 minutes. soaked with _.5% H 3 PO _4, and mounted on vacuum manifold with disconnected vacuum source. After spotting all samples, vacuum is connected and each well rinsed with 200 μL 0.5% H ₃ PO ₄ . Remove the membrane, 4 times on a shaker with 0.5% H ₃ PO ₄ and once with ethanol. Wash with membrane. Membranes are dried at ambient temperature, mounted on a Packard TopCount 96 well frame and counted after the addition of 10 μL / well Microscint ™ (Packard).

  The compounds of formula (I) exhibit c-Raf-1 inhibition in the range of 0.1-50 μM, preferably 0.1-10 μM.

In vivo experiments to demonstrate the antitumor activity of compounds of formula (I): For example, testing whether compounds of formula (I) such as those of Example 1 below inhibit VEGF-mediated angiogenesis in vivo To test its effect on VEGF-induced angiogenic response in a growth factor implant model in mice: a porous Teflon chamber (volume 0.5 mL) contains growth factor (2 μg / ml human VEGF) or Non-containing, heparin (0.8% w / v agar containing 20 units / ml is implanted subcutaneously on the dorsal flank of C57 / C6 mice. Mice are treated with test compounds (eg 25, 50 or 100 mg / kg p o. Once a day) or vehicle and start on the day of chamber implantation and continue for 4 consecutive days, at the end of treatment the mice are killed and the chamber is removed The angiogenic tissue grown around the chamber is carefully removed, weighed, and the blood content is assessed by immediate knowledge of the hemoglobin content in the tissue (Drabkins method; Sigma, Deisenhofen, Germany). This response induces a dose-dependent increase in tissue weight and blood content (characterized histologically by the inclusion of fibroblasts and small blood vessels) that grows around the chamber, and this response specifically neutralizes VEGF It has been shown to be blocked by antibodies (Wood JM et al., Cancer Res. 60 (8), 2178-2189, (2000); and Schlaeppi et al., J. Cancer Res. Clin. Oncol. 125 336-342 (1999)) This model can show inhibition in the case of compounds of formula (I).

の２Ｈ−ピラゾル−３−イルアミンを形成し、
(ｄ)置換されたニトリルを、エタノレートおよびギ酸エチルエステルの存在下でホルミル化して、式(II)：

の３−オキソ−プロピオニトリルを形成し、
(ｃ)式(II)の３−オキソ−プロピオニトリルおよび式(III)の２Ｈ−ピラゾル−３−イルアミンを有機溶媒の存在下で縮合して、式(Ｉ)の化合物を形成する
ことにより製造する。 The compound of synthetic formula (I) is prepared according to the method described in Alicade, E; De Mendoza, J; Garcia-Marquina, JM; Almera, C; J. Heterocycl. Chem. 11, 423 (1974):
(a) reacting a nitrile, A—CH ₂ —C≡N, ethyl formate in the presence of an organic solvent to form a substituted 3-oxo-propionitrile;
(b) The substituted 3-oxo-propionitrile of step (a) is condensed with hydrazine monohydrate in an organic solvent to give a compound of formula (III):

Of 2H-pyrazol-3-ylamine,
(d) The substituted nitrile is formylated in the presence of ethanolate and formic acid ethyl ester to give a compound of formula (II):

The 3-oxo-propionitrile of
(c) by condensing 3-oxo-propionitrile of formula (II) and 2H-pyrazol-3-ylamine of formula (III) in the presence of an organic solvent to form a compound of formula (I) To manufacture.

  Specifically, the compound of formula (I) is prepared by condensing 3-oxo-propionitrile (II) and the corresponding 2H-pyrazol-3-ylamine (III) in the presence of ethanolic HCl (FIG. 2). 2H-pyrazol-3-ylamine (III) is prepared by dissolving hydrazine monohydrate and the corresponding 3-oxo-propionitrile in an organic solvent such as EtOH, dioxane or AcOH at high temperature (preferably 100 ° C.). It is produced by condensation by heating for several hours. A preferred method for preparing the pyrazolo moiety of the title compound is to stir hydrazine monohydrate and the corresponding 3-oxo-propionitrile in acetic acid at 100 ° C. for 2-3 hours, then add aqueous HCl, The reaction mixture was refluxed for an additional 20 minutes. If R1 is not H, the corresponding substituted hydrazine is used. 3-Oxo-propionitrile (I) and (II) were synthesized from the corresponding nitrile by a classical formylation reaction using freshly prepared sodium ethanolate and formic acid ethyl ester (refluxed in EtOH for 1 hour). To do. Alternatively, instead of performing a condensation reaction with 3-oxo-propionitrile, the corresponding 3,3-dialkoxy-propionitrile (Seneci, P., Nicola, M., Inglesi, M., Vanotti, E. , Resnati, G. Synth. Commun. 29 (2), 311-341 (1999)) or 3-dimethylamino-acrylonitrile.

Alternatively, a compound of formula (I) can be prepared by first synthesizing a pyrazolo [1,5-a] pyrimidin-7-ylamine core skeleton carrying a corresponding functional group (X, see FIG. 3); Here, each of the residues A, R ₂ , or R ₃ can be produced by a known method as shown in FIG.

〔式中、Ｒ_１、Ｒ_２、Ｒ_３、およびＸは式(Ｉ)の化合物について定義の通りである。〕
そして、望むのであれば、反応(ａ)、(ｂ)または(ｃ)の後に、得られる式(Ｉ)の化合物を異なる式(Ｉ)の化合物に変換する；得られる式(Ｉ)の化合物の塩を遊離化合物または異なる塩に、または得られる遊離の式(Ｉ)の化合物を塩に変換する；および／または式(Ｉ)の化合物の得られる異性体混合物を個々の異性体に分離する；
ここで、記載の全反応について、反応に参加すべきではない出発物質中の官能基は、必要であれば、容易に除去できる任意の保護基により保護された形で存在し、そして全ての保護基をその後除去する。

[Wherein R ₁ , R ₂ , R ₃ , and X are as defined for the compound of formula (I). ]
And if desired, after reaction (a), (b) or (c), the resulting compound of formula (I) is converted to a different compound of formula (I); the resulting compound of formula (I) Converting the salt of to a free compound or a different salt, or converting the resulting free compound of formula (I) to a salt; and / or separating the resulting mixture of isomers of a compound of formula (I) into individual isomers ;
Here, for all reactions described, functional groups in the starting material that should not participate in the reaction are present in protected form by any protecting group that can be easily removed, if necessary, and all protection The group is then removed.

The following reaction conditions are each preferred:
Within this specification, unless otherwise to be construed from the context, only easily removable groups that are not constituents of a particular desired end product of formula (I) are referred to as “protecting groups”. Protection of functional groups by such protecting groups, protecting groups themselves, and their cleavage reactions are described, for example, by JFW McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973, TW Greene and PGM Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999, “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, “Methoden der organischen Chemie” ”(Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974, H.-D.Jakubke and H. Jeschkeit,“ Aminosaeuren, Peptide, Proteine ”(Amino acids, Peptides, Standard citations such as Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide und Derivate” (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974 It is described in. A characteristic of protecting groups is that they can be easily removed (ie without the occurrence of unwanted secondary reactions), for example by solvolysis, reduction, photolysis or alternatively by physiological conditions (eg enzymatic cleavage).

  The salts of the compounds of formula (I) having at least one salt-forming group can be prepared in a manner known per se. For example, a salt of a compound of the formula (I) having an acidic group is, for example, an organic alkali metal such as a compound of an alkali metal salt of a suitable organic carboxylic acid, such as a sodium salt of 2-ethylhexanoic acid. Or alkaline earth metal compounds, such as sodium or potassium hydroxide, carbonates or bicarbonates, corresponding hydroxides, carbonates or bicarbonates, corresponding calcium compounds or ammonia or suitable organic amines Can be formed preferably using a stoichiometric amount or a slight excess of salt-forming agent. Acid addition salts of the compounds of formula (I) are obtained in a conventional manner, for example by treating the compound with an acid or a suitable anion exchange reagent. Intramolecular salts of compounds of formula (I) containing acidic and basic salt-forming groups such as free carboxy and free amino groups, for example salts such as acid addition salts, at the isoelectric point, for example with weak bases. It can be formed by adding or by treatment with an ion exchanger.

  Salts can be converted to the free compounds in a conventional manner; metal and ammonium salts can be converted, for example, by treatment with a suitable acid and acid addition salts, for example, by treatment with a suitable basic reagent.

  The mixture of isomers obtained according to the invention can be separated into the individual isomers in a manner known per se; diastereoisomers can be obtained, for example, by partitioning between multiphasic solvent mixtures, recrystallization and / or, for example, on silica gel. Or can be separated by chromatographic separation, for example by medium pressure liquid chromatography, on a reverse phase column, and racemates can be obtained in this way, for example by forming salts with optically pure salt-forming reagents. A mixture of diastereoisomers can be separated, for example, by separation by fractional crystallization or chromatographic means on an optically active column material.

  Intermediates and final products can be worked up and / or purified by standard methods, eg, using chromatographic methods, distribution methods, (re) crystallization, and the like.

General process conditions The following generally apply to all of the above and below, but the reaction conditions specifically described above and below are preferred:
All the above process steps are carried out under reaction conditions known per se, preferably under the reaction conditions specifically described, preferably solvents or diluents (preferably solvents which are inert to the solvent used and dissolve them. Or in the customary presence, in the presence or absence of a catalyst, condensing agent or neutralizing agent, for example an ion exchanger, for example in the H ⁺ form, for example a cation exchanger. And / or depending on the nature of the reactants, low temperature, normal temperature or high temperature, such as about −100 ° C. to about 190 ° C., preferably about −80 ° C. to about 150 ° C., eg −80 to −60 ° C., room temperature, − It can be carried out at 20 to 40 ° C. or reflux temperature under atmospheric pressure or in a sealed container, if appropriate under pressure and / or under an inert atmosphere, for example under an argon or nitrogen atmosphere.

  At all stages of the reaction, the mixture of isomers formed, for example diastereoisomers or enantiomers, into individual isomers, or any desired mixture of isomers, for example racemic or diastereomeric mixtures. For example, according to the method described under “Additional process steps”.

  Solvent groups from which a suitable solvent for any particular reaction can be selected include, for example, water, esters, such as lower alkyl-lower alkanoates, such as ethyl acetate, ethers, unless otherwise specified in the process description. For example aliphatic ethers such as diethyl ether, or cyclic ethers such as tetrahydrofuran or dioxane, liquid aromatic hydrocarbons such as benzene or toluene, alcohols such as methanol, ethanol or 1- or 2-propanol, nitriles such as acetonitrile, halogen Hydrocarbons such as methylene chloride or chloroform, acid amides such as dimethylformamide or dimethylacetamide, bases such as heterocyclic nitrogen bases such as pyridine or N-methylpyrrolidin-2-one, carvone Anhydrides, such as lower alkanoic acid anhydrides include, for example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, or mixtures of these solvents, for example aqueous solutions. Such solvent mixtures can also be used for work-up, for example by chromatography or distribution.

  The compounds containing the salts can also be obtained in the form of hydrates, or the crystals can contain, for example, the solvent used for crystallization. Different crystal forms can exist.

  The invention can be carried out by using the compound obtained as an intermediate at any stage of the process as a starting material for the rest of the process steps, or by forming the starting material under reaction conditions or by a derivative such as protected. Or in the form of a process wherein the compound obtained by the process of the present invention is prepared under the process conditions and further processed in situ. In the process of the present invention, these starting materials are preferably used which can obtain the compounds of the new formula (I) which are initially described as particularly valuable. Particularly preferred are reaction conditions identical or similar to those described in the examples.

Preferred embodiments of the present invention:
In the preferred embodiments described below, the general expression can be replaced by the corresponding more specific definitions described above and below, thus producing a stronger preferred embodiment of the invention.

  Preferred is a compound of formula (I), a tautomer thereof or a pharmaceutical thereof, wherein the tyrosine protein kinase dependent disease to be treated is a proliferative disease dependent on one or more of the following tyrosine protein kinases: Use of salts that are acceptable: c-Abl, Bcr-Abl, c-Kit, c-Raf, Flt-1, Flt-3, KDR, Her-1, PDGFR-kinase, c-Src, among others RET-receptor kinase, FGF-R1, FGF-R2, FGF-R3, FGF-R4, Ephrin receptor kinase (eg, EphB2 kinase, EphB4 kinase and related Eph kinase), casein kinase (CK-1, CK-2) , G-CK), Pak, ALK, ZAP70, Jak1, Jak2, Axl, Cdk1, cdk4, cdk5 Like Met, FAK, Pyk2, Syk, insulin receptor kinase, Tie-2 or Bcr-Abl, c-Kit, cdk1, c-Raf, Flt-3, FGF-R3, PDGF-receptor, RET, and Met A constitutively activated variant of an active kinase (activated kinase).

  More preferably, the compound of formula (I) may be used for the treatment of proliferative diseases dependent on the following kinases: c-abl, Flt-3, KDR, c-Src, RET, EphB4, c-kit, cdk1 , FGFR-1, c-raf, Her-1, Ins-R and Tek.

〔式中、
Ｒ_２はＨ；置換または非置換アリール；置換または非置換ヘテロアリール；置換または非置換脂肪族残基；官能基；またはピラゾロ[１,５ａ]ピリミジニル環に１個の連結基もしくは原子により連結している置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールまたは置換もしくは非置換脂肪族残基であり；
Ｒ_３はＨ、置換または非置換アリール、置換または非置換ヘテロアリール、置換または非置換脂肪族残基、官能基、またはピラゾロ[１,５ａ]ピリミジニル環に連結基もしくは原子により連結している脂肪族残基であり得て、
Ｒ_２またはＲ_３の少なくとも一方は置換または非置換アリール；置換または非置換ヘテロアリール；またはピラゾロ[１,５ａ]ピリミジニル環に１個の連結基もしくは原子により連結している置換もしくは非置換ヘテロアリールまたは置換もしくは非置換アリール残基であり；
ＡはＨ、ハロゲン(例えばブロモ)、脂肪族部分、官能基、置換または非置換アリールまたは置換または非置換ヘテロアリールであり；そして
Ｒ_１はＨ、ハロゲンまたは低級アルキルである。〕
の化合物またはその薬学的に許容される塩、およびキナーゼ依存性疾患の処置におけるまたはキナーゼ依存性疾患処置用医薬製剤の製造のための式(Ｉ)の化合物の使用に関する。 The present invention especially relates to formula (I)

[Where,
R ₂ is H; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted aliphatic residue; functional group; or a pyrazolo [1,5a] pyrimidinyl ring linked by one linking group or atom. Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted aliphatic residue;
R ₃ is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aliphatic residue, functional group, or a fat linked to a pyrazolo [1,5a] pyrimidinyl ring by a linking group or atom Can be a family residue,
At least one of R ₂ or R ₃ is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or substituted or unsubstituted heteroaryl linked to the pyrazolo [1,5a] pyrimidinyl ring by one linking group or atom Or a substituted or unsubstituted aryl residue;
A is H, halogen (eg bromo), aliphatic moiety, functional group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and R ₁ is H, halogen or lower alkyl. ]
Or a pharmaceutically acceptable salt thereof, and the use of a compound of formula (I) in the treatment of a kinase dependent disease or for the manufacture of a pharmaceutical formulation for the treatment of a kinase dependent disease.

〔式中、
Ｒ_２はＨ；置換または非置換アリール；置換または非置換ヘテロアリール；置換または非置換脂肪族残基；官能基；またはピラゾロ[１,５ａ]ピリミジニル環に１個の連結基もしくは原子により連結している置換もしくは非置換アリール、置換もしくは非置換ヘテロアリールまたは置換もしくは非置換脂肪族残基であり；
Ｒ_３はＨ、置換または非置換アリール、置換または非置換ヘテロアリール、置換または非置換脂肪族残基、官能基、またはピラゾロ[１,５ａ]ピリミジニル環に連結基もしくは原子により連結し得る置換もしくは非置換脂肪族残基であり得て、
Ｒ_２またはＲ_３の少なくとも一方は置換または非置換アリール；置換または非置換ヘテロアリール；またはピラゾロ[１,５ａ]ピリミジニル環に１個の連結基もしくは原子により連結している置換もしくは非置換ヘテロアリールまたは置換もしくは非置換アリール残基である；
ただし、Ｒ_２およびＡの両方が同時に非置換フェニルではなく；
ＡはＨ、ハロゲン(例えばブロモ)、脂肪族部分、官能基、置換または非置換アリールまたはヘテロアリールであり；そして
Ｒ_１はＨ、ハロゲンまたは低級アルキルである。〕
の化合物、またはその薬学的に許容される塩、およびキナーゼ依存性疾患の処置における、またはキナーゼ依存性疾患処置用医薬製剤の製造のための式(Ｉ)の化合物の使用に関する。 The invention further relates to a compound of formula (I)

[Where,
R ₂ is H; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted aliphatic residue; functional group; or a pyrazolo [1,5a] pyrimidinyl ring linked by one linking group or atom. Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted aliphatic residue;
R ₃ is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aliphatic residue, functional group, substituted or optionally linked to a pyrazolo [1,5a] pyrimidinyl ring by a linking group or atom Can be an unsubstituted aliphatic residue,
At least one of R ₂ or R ₃ is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or substituted or unsubstituted heteroaryl linked to the pyrazolo [1,5a] pyrimidinyl ring by one linking group or atom Or a substituted or unsubstituted aryl residue;
Provided that both R ₂ and A are not simultaneously unsubstituted phenyl;
A is H, halogen (eg bromo), aliphatic moiety, functional group, substituted or unsubstituted aryl or heteroaryl; and R ₁ is H, halogen or lower alkyl. ]
Or a pharmaceutically acceptable salt thereof, and the use of a compound of formula (I) in the treatment of a kinase dependent disease or for the manufacture of a pharmaceutical formulation for treating a kinase dependent disease.

More preferred is
Linking atom or group: alkyl (e.g., -CH ₂ -); oxy -O-; keto -CO-; thio -S-; sulphonyl -SO ₂ -; sulphoxide -SO-; amine -NH- or -NR-; carboxylic acid; alcohols; esters (-COO-); amides (--CONR -, - CONHR'-); sulfonamide _{(-SO 2 NH -, - SO} 2 NR '-); (- SO 3 -); sulfoxides (—SO—); amino-group; urea (—NH—CO—NH—, —NR—CO—NH—, —NH—CO—NR—, —NR—CO—NR—); ether (—O—) ); Carbamate (—NH—CO—O—, —NR—CO—O—); or reverse amide, sulfonamide and ester (—NH—CO—, —NR—CO—, —NH—SO ₂ —, — Selected from the group consisting of (NR—SO ₂ —, —OOC—) Alkyl (e.g., -CH ₂ -); oxy -O-; keto -CO-; sulfonyl -SO ₂ -; sulfonamide _{(-SO 2 NH -, - SO} 2 NR '-); (- SO 3 -); and Urea (-NH-CO-NH-, -NR-CO-NH-, -NH-CO-NR-, -NR-CO-NR-) are particularly preferred),
The functional groups: carboxylic acid; hydroxyl; halogen; cyano (-CN); ether (-OR); ketones (-CO-R); esters (-COOR); amides _(-CONH 2, -CONHR, -CONRR '); Thioether (—SR); sulfonamide (—SO ₂ NH ₂ , —SO ₂ NHR, —SO ₂ NRR ′); sulfone (—SO ₂ —R); sulfoxide (—SO—R); amine (—NHR) , NR′R); urea (—NH—CO—NH ₂ , —NH—CO—NHR); ether (—O—R); halogen; carbamate (—NH—CO—OR); aldehyde-functional group (— CHO); then also reverse amides; sulfonamides and esters (—NH—CO—R, —NH—SO ₂ —R, —OOC—R) (halogen; hydroxyl; ether (—OR)) Amide (-C _{NH 2, -CONHR, -CONRR ')} ; sulfonamide _{(-SO 2 NH 2, -SO 2} NHR, -SO 2 NRR'); amines (-NHR, NR'R); and urea (-NH-CO- _{NH 2, -NH-CO-NHR} ) is especially preferred),
A compound of formula (I) or a pharmaceutically acceptable salt thereof per se, or in particular for use in pharmaceutical compositions, or for use in the diagnostic or therapeutic treatment of warm-blooded animals, especially humans. is there.

Especially preferred is
A is H; halo (eg Br); or aryl (eg phenyl or benzyl) or heterocyclyl (eg pyridinyl, indolyl or benzothiophenyl);
Here, an aryl or heterocyclyl may be unsubstituted or substituted with up to 4, preferably up to 2, substituents, wherein the substituents are the same or different and are independently halo (e.g. Cl; Br); hydroxy; amino; amino lower alkyl (eg dimethylamino); amino lower alkoxy (eg ethoxyamine); lower alkyl (eg methyl); lower alkoxy (eg methoxy); substituted or unsubstituted sulfonamides (eg benzo Sulfonamide, chlorobenzenesulfonamide or dichlorobenzenesulfonamide); carbamate; R ₄ R ₅ (wherein R ₄ and R ₅ are the same or different and independently H; lower alkyl (eg methyl, ethyl or propyl)) there are a; or _{R 4} and _{R 5} together with N atom, 1-4 Nitrogen, oxygen or sulfur atom to form a 3- to 8-membered heterocyclic ring (e.g. piperazinyl or lower alkyl piperazinyl) where heterocyclic R ₄ and R ₅ together with N When forming a ring, the ring is substituted with one, two or more of the substituents described herein, preferably an alkyl such as piperazinyl, pyrrolidinyl, methyl, or a hydroxyalkyl such as ethanyl. Examples of heterocycles in which R ₄ and R ₅ together form N are morpholinyl which can be unsubstituted or substituted with methyl or dimethyl; unsubstituted or 1, 2 or 3 substituents, preferably Piperazinyl which can be substituted by methyl, oxy or ethanol; or unsubstituted or 1, 2 or 3 substituents, preferably pyrrolidinyl, amine Selected from alkylamine, methylamine, dialkylamine, dimethylamine or piperazinyl which can be substituted with diethylamine;

R ₂ is H, C ₁ -C ₃ lower alkyl (eg methyl) or aryl (eg phenyl or benzyl) or heterocyclyl (eg pyridyl, indolyl, thiophenyl, thiazolyl or benzothiophenyl), wherein aryl or heterocyclyl is , Unsubstituted, or substituted with up to 4, preferably up to 2, substituents, which are the same or different and independently halo (eg Cl, F or Br); hydroxy; Amino; amino lower alkyl; C ₁ -C ₃ lower alkyl; alkoxy (eg, methoxy and benzyloxy, wherein the benzyl ring can be substituted or unsubstituted, eg, 3,4-dichlorobenzyloxy); Sulfoamino; substituted or unsubstituted benzosulfonamides (eg 2,3-dichlorobenzene) Substituted or unsubstituted sulfonates (eg chloro-phenyl sulfonate); substituted or unsubstituted ureas (eg 3-trifluoro-methyl-phenyl urea or 4-morpholin-4-yl-3-trifluoromethyl-phenyl) -Urea) or carbamates (eg ethyl-N-phenylcarbamate);
R ₃ is H; C ₁ -C ₃ alkyl, methyl; phenyl; pyridinyl or oxazo-5-yl;
A compound of formula (I) or a pharmaceutically acceptable salt thereof per se, or in particular for use in pharmaceutical compositions, or for use in the diagnostic or therapeutic treatment of warm-blooded animals, especially humans. is there.

  Particularly preferred is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical formulation for the treatment of kinase dependent diseases.

  Also preferred is a kinase-dependent disease, especially the kinase and the kinase-dependent disease (especially abnormally highly expressed or activated) or a disease dependent on the activity of the kinase pathway or the kinase A compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof, for use in the treatment of any two or more dependent diseases.

  In a broad sense of the invention, kinase-dependent diseases are leukemia, hyperplasia, fibrosis (especially lung but also other types of fibrosis such as kidney fibrosis), angiogenesis, psoriasis, atheromatous arteries. It can be a proliferative disease, including hyperproliferative conditions such as vascular smooth muscle proliferation such as sclerosis and stenosis or restenosis after angioplasty.

  Highly preferred is a method of treating a kinase-dependent disease comprising administering a compound of formula (I), wherein the disease to be treated is a proliferative disease, preferably a benign or especially malignant tumor, more preferably the brain. , Kidney, liver, adrenal gland, bladder, breast, stomach (especially stomach tumor), ovary, colon, rectum, prostate, pancreas, lung (especially SCLC), vagina, thyroid carcinoma, sarcoma, glioblastoma, multiple bone marrow A tumor or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, or a head and neck tumor, epithelial hyperproliferation, especially psoriasis, prostatic hypertrophy, especially epithelial characteristics, abnormal growth, preferably breast carcinoma, or leukemia. It is also for the treatment of atherosclerosis, thrombosis, psoriasis, scleroderma and fibrosis.

  The compounds of formula (I) can lead to tumor remission, prevention of the formation of tumor metastases and the growth of metastases (including microscopic). In addition, they can be used for epithelial hyperproliferation (eg psoriasis), prostate hypertrophy and for the treatment of abnormal growth, eg of breast cancer, especially of epithelial character. Compounds of formula (I) can also be used for the treatment of diseases of the immune system if several or, inter alia, individual tyrosine protein kinases are involved; It can also be used to treat diseases of the central or peripheral nervous system involving signaling by at least one tyrosine protein kinase, selected from those specifically described.

  KDR inhibitors are therefore particularly suitable for the treatment of diseases associated with VEGF receptor tyrosine kinase overexpression. Among these diseases, inter alia retinopathy, age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory diseases such as rheumatoid or rheumatic inflammatory diseases, especially arthritis such as rheumatism Osteoarthritis, or other chronic inflammatory diseases, such as chronic asthma, arterial or post-transplant atherosclerosis, endometriosis, and especially neoplastic diseases such as so-called solid tumors (especially gastrointestinal tract, pancreas, breast, Stomach, neck, bladder, kidney, prostate, ovary, endometrium, lung, brain cancer, melanoma, Kaposi's sarcoma, squamous cell carcinoma of the head and neck, malignant pleural mesothelioma, lymphoma or multiple myeloma) and Humoral tumors (eg leukemia) are of particular importance.

Flt3 (FMD-like tyrosine kinase) is expressed, inter alia, in hematopoietic progenitor cells and the lymphoid and myeloid systems. Abnormal expression of the Flt3 gene is expressed in AML (acute myeloid leukemia), AML with thrombocytic myelodysplasia (AML / TMDS), ALL (acute lymphoblastic leukemia), CML (chronic myeloid leukemia) and bone marrow It has been reported in both living and childhood leukemia, including dysplasia syndrome (MDS), and is therefore a preferred disease to be treated with compounds of formula (I). Activating mutations in Flt3 are found in about 25-30% of AML patients. Thus, evidence for the role of Flt3 in human leukemia has accumulated and pyrazolo [1,5a] pyrimidin-7-ylamine derivatives, particularly compounds of formula (I), useful as Flt3 inhibitors according to the present invention are Particularly useful in the treatment of types of diseases (Tse et al., Leukemia 15 (7), 1001-1010 (2001); Tomoki et al., Cancer Chemother. Pharmacol. 48 (Suppl. 1), S27-S30 ( 2001); Birkenkamp et al., Leukemia 15 (12), 1923-1921 (2001); Kelly et al., Neoplasia 99 (1), 310-318 (2002)).

  In chronic myeloid leukemia (CML), reciprocally balanced chromosomal translocations in hematopoietic stem cells (HSCs) form the BCR-ABL hybrid gene. The latter encodes an oncogenic Bcr-Abl fusion protein. ABL encodes a tightly regulated protein tyrosine kinase that has an important role in the control of cell proliferation, adhesion and apoptosis, whereas the BCR-ABL fusion gene is encoded as a constitutively activated kinase, which Transform HSCs to produce a phenotype that exhibits deregulated clonal growth, reduced ability to adhere to bone marrow substrate, and reduced apoptotic response to mutagenic stimuli, which accumulates progressively more malignant transformations it can. The resulting granulocytes cannot develop into a mature new class and are released into the circulation, leading to a lack of mature cells and increased susceptibility to infection. ATP competitive inhibitors of Bcr-Abl have been described, which can prevent kinases from kinase-activated mitogenic and anti-apoptotic pathways (eg P-3 kinase and STAT5) -Leads to death of ABL phenotype cells, thereby providing an effective treatment for CML. As Bcr-Abl inhibitors, pyrazolo [1,5a] pyrimidin-7-ylamine derivatives useful according to the present invention, especially compounds of formula (I), are useful for diseases associated with their overexpression, particularly leukemias such as CML or ALL. Suitable for the treatment of such leukemia.

  Compounds of formula (I) that inhibit the tyrosine kinase activity of EGF-R or other protein tyrosine kinases described are therefore useful, for example, in the treatment of benign or malignant tumors. The compounds of formula (I) are capable of simultaneously inhibiting tumor growth, for example with deregulated EGF-R and / or ErbB-2 activity, and inhibiting angiogenesis of solid tumors triggered by VEGF. is there. This combined activity leads to an improved antitumor effect (see also WO02 / 41882). Furthermore, the use of dual inhibitors reduces the risk of drug-drug interactions and further reduces the total drug load compared to combination therapy. Compounds of formula (I) can slow tumor growth or provide tumor regression and can prevent tumor metastasis formation and micrometastasis growth. They treat solid tumors such as non-small cell lung cancer, squamous cell carcinoma (head and neck), breast, stomach, ovary, colon and prostate cancer and glioma, especially in case of epithelial hyperproliferation (psoriasis) And for the treatment of leukemias such as acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), among others. In addition, compounds of formula (I) can be used for the treatment of immune system disorders involving several, especially individual protein tyrosine kinases and / or serine / threonine protein kinases; ) Compounds may also be used to treat central or peripheral nervous system disorders involving signaling by several or, inter alia, single protein tyrosine kinases and / or (and) serine / threonine protein kinases.

  Angiogenesis is considered an absolute prerequisite for tumors that grow beyond a maximum diameter of about 1-2 mm; up to this limit, oxygen and nutrients can be supplied to the tumor cells by nucleic acids. All tumors, regardless of their origin and cause, depend on angiogenesis for growth after it reaches a certain size.

  Three main mechanisms have an important role in the activity of angiogenesis inhibitors against tumors: 1) inhibition of the growth of blood vessels, especially capillaries, into avascular resting tumors, resulting in apoptosis and proliferation There is no net tumor growth due to the balance achieved between; 2) inhibition of tumor cell migration by lack of blood flow to and from the tumor; and 3) inhibition of endothelial cell proliferation comprising: Therefore, avoid the stimulation of paracrine proliferation that is normally exerted on the surrounding tissue by endothelial cells that line the inside of blood vessels.

  The invention also includes psoriasis; Kaposi's sarcoma; restenosis, eg, stent-induced restenosis; endometriosis; Crohn's disease; Hodgkin's disease; leukemia; arthritis such as rheumatoid arthritis; Eye diseases such as retinopathy and neovascular glaucoma; kidney diseases such as glomerulonephritis; diabetic nephropathy; malignant nephrosclerosis; thrombotic microangiopathic syndrome; transplant rejection and glomerulopathy; Mesangial cell proliferative disease; arteriosclerosis; for prevention or treatment of diseases induced by persistent angiogenesis such as nerve tissue injury; and inhibition of vascular reocclusion after balloon catheter treatment Mechanical devices for maintaining vascular prosthesis or vascular opening, such as wound healing as an immunosuppressive agent for use after stent insertion As adjuvants, and it can be used to treat age spots and contact dermatitis.

  Most preferred is the use according to the invention of a compound of formula (I), as exemplified in the “Examples” below, or a pharmaceutically acceptable salt thereof.

Pharmaceutical compositions The invention also relates to pharmaceutical compositions comprising a compound of formula (I), in the treatment (also in the broad aspect of the invention) treatment of kinase-dependent diseases, in particular the preferred diseases mentioned above, or in methods of treatment , The compounds for the use and, in particular, the preparation of pharmaceutical formulations for the use.

  The present invention also relates to prodrugs of compounds of formula (I) that convert in vivo to compounds of formula (I) themselves. It is to be understood that all references to compounds of formula (I) also refer to the corresponding prodrugs of compounds of formula (I), where appropriate and expected.

  A pharmacologically acceptable compound of the invention can be, for example, a substantial amount of one or more inorganic or pharmaceutically active compounds with an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. It can be used in the manufacture of pharmaceutical formulations, including organic, solid or liquid, pharmaceutically acceptable carriers or in admixture.

  The present invention also provides a therapeutically effective amount of a compound of formula (I) or a pharmaceutical thereof for the treatment of a disease responsive to inhibition of kinase activity or, in a broad aspect of the invention, for prevention (= protection). Administration to a warm-blooded animal, particularly a human (or a warm-blooded animal, especially a human-derived cell or cell line, eg, a lymphocyte) comprising a pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier It is related with the pharmaceutical composition suitable for.

  The pharmaceutical composition of the present invention comprises a pharmacologically active ingredient alone or in combination with a pharmaceutically acceptable carrier in a warm-blooded animal (particularly human) enterally, for example, nasally, rectally or orally. Or for parenteral, eg, intramuscular or intravenous administration. The dose of the active ingredient depends on the species of warm-blooded animal, body weight, age and individual condition, individual pharmacokinetic data, the disease to be treated and the form of administration.

  The present invention also requires a prophylactically or especially therapeutically effective amount of a compound of formula (I) of the present invention (for the described diseases), especially for one of the described diseases, requiring such treatment. The present invention relates to a method for treating a disease responsive to kinase inhibition, including administration to a warm-blooded animal such as a human.

  The dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof to be administered to a warm-blooded animal weighing about 70 kg, such as a human, is preferably about 3 mg to about 10 g, more preferably about 10 mg to about 1. 5 g, most preferably from about 100 mg to about 1000 mg / human / day, preferably divided into 1-3 single doses, which may for example be the same size. Children usually receive half the amount of an adult.

  The pharmaceutical compositions contain about 1% to about 95%, preferably about 20% to about 90%, of the active ingredient. The pharmaceutical composition of the present invention may be in unit dosage form such as ampoules, vials, suppositories, dragees, tablets or capsules.

  The pharmaceutical compositions according to the invention are prepared in a manner known per se, for example by means of conventional lysis, freeze-drying, mixing, granulating or sugar-coating processes.

  Solutions of the active ingredient, and also suspensions, and in particular isotonic aqueous solutions or suspensions are preferably used, for example in the case of lyophilized compositions comprising the active ingredient alone or with a carrier such as mannitol. Such solutions or suspensions can be prepared before use. The pharmaceutical composition may be sterilized and / or contain excipients such as preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, osmotic pressure adjusting salts and / or buffers, It is prepared in a manner known per se, for example by means of conventional lysis or lyophilization. The solution or suspension may contain thickening substances such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

  Suspensions in oil contain vegetable, synthetic or semi-synthetic oils customary for injection purposes as oil components. In particular, long-chain fatty acids having 8-22, especially 12-22 carbon atoms as the acid component, such as lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid Or the corresponding unsaturated acids, such as liquid fatty acid esters, including oleic acid, elaidic acid, erucic acid, brassic acid or linoleic acid, and if desired, antioxidants such as vitamin E, β- Add carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is mono- or poly-hydroxy, such as mono-, di- or tri-hydroxy, alcohols such as methanol, ethanol, propanol, butanol or pentanol. Or not only their isomers, but also glycol and glycerol, among others. The following examples of fatty acid esters can be mentioned accordingly: ethyl oleate, isopropyl myristate, isopropyl palmitate, “Labrafil M 2375” (polyoxyethylene glycerol trioleate, Gattefosse, Paris), “Miglyol 812” (C8 to C12 chain length) Saturated fatty acid triglycerides, Huels AG, Germany) as well as vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and more especially peanut oil.

  Injectable compositions are prepared conventionally in sterile conditions; the same applies to filling the composition into ampoules or vials as well as sealing the container.

  Pharmaceutical compositions for oral administration combine the active ingredient with a solid carrier, granulate the resulting mixture if desired, and use the resulting mixture with suitable excipients if desired or necessary. After the addition, it can be obtained by processing into tablets, dragee cores or capsules. They can also be included in a plastic carrier that allows the active ingredients to diffuse or be released in certain amounts.

  Suitable carriers are inter alia bulking agents such as sugars such as lactose, saccharose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate, and binders such as corn, wheat, rice Or potato starch, such as starch paste, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or a disintegrant, if desired, such as starch and / or carboxy Methyl starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate. Excipients are inter alia flow control agents and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. Dragee cores may be provided with suitable, optionally enteric coatings, such as concentrated sugar solutions, which may include, inter alia, gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, or coatings in suitable organic solvents. For solution or enteric coating, suitable cellulose preparations such as ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate are used. Capsules are dry-filled capsules made of gelatin and sealed soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Dry-filled capsules contain the active agent in the form of granules, for example with a bulking agent such as lactose, a binder such as starch, and / or a glidant such as talc or magnesium stearate and, if desired, a stabilizer. obtain. In soft capsules, the active ingredients are preferably dissolved or suspended in suitable oily excipients such as fatty oils, paraffin oil or liquid polyethylene glycols, and stabilizers and / or antimicrobial agents can be added. is there. Dyestuffs or pigments may be added to the tablets or dragee coatings or capsule shells, for example for identification purposes or to indicate different amounts of active ingredient.

The compounds of combination formula (I) may also be used to benefit in combination with other antiproliferative agents. Such antiproliferative agents include aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule activators; alkylating agents; histone deacetylase inhibitors; compounds that induce cell differentiation processes; Cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-neoplastic antimetabolites; platinum compounds; compounds that target / reduce protein or lipid kinase activity and additional anti-angiogenic compounds; target and decrease activity of protein or lipid phosphatase Or inhibiting compounds; gonadorelin agonists; antiandrogens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; Proteasaw Inhibitors; agents for use in the treatment of hematological malignancies; compounds that target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors; temozolomide (TEMODAL®); and leucovorin However, it is not limited to these.

  The term “aromatase inhibitor” as used herein relates to compounds which inhibit estrogen production, ie the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term refers to steroids, especially atamestan, exemestane and formestane, and especially non-steroids, especially aminoglutethimide, logretimide, pyridoglutethimide, trirostan, test lactone, ketoconazole, borozole, fadrazole, anastrozole and letrozole Including, but not limited to. Exemestane can be administered, eg, in the form as it is marketed, eg under the trademark AROMASIN. Formestane can be administered, eg, in the form as it is marketed, eg under the trademark LENTARON. Fadrozole can be administered, eg, in the form as it is marketed, eg under the trademark AFEMA. Anastrozole can be administered, eg, in the form as it is marketed, eg under the trademark ARIMIDEX. Letrozole can be administered, eg, in the form as it is marketed, eg under the trademark FEMARA or FEMAR. Aminoglutethimide can be administered, eg, in the form as it is marketed, eg under the trademark ORIMETEN. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, eg breast tumors.

  The term “antiestrogens” as used herein relates to compounds that antagonize the action of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestland, raloxifene and raloxifene hydrochloride. Tamoxifen can be administered, eg, in the form as it is marketed, eg under the trademark NOLVADEX. Raloxifene hydrochloride can be administered, eg, in the form as it is marketed, eg under the trademark EVISTA. Fulvestland can be formulated as described in US 4,659,516, or it can be administered, eg, in the form as it is marketed, eg under the trademark FASLODEX. A combination of the invention comprising a chemotherapeutic agent that is an anti-estrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.

  The term “antiandrogen” as used herein refers to all substances capable of inhibiting the biological action of androgen, including for example bicalutamide (CASODEX) which can be formulated as described in US Pat. No. 4,636,505. It is not limited to.

  The term “gonadorelin agonist” as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin is described in US 4,100,274 and can be administered, eg, in the form as it is marketed, eg under the trademark ZOLADEX. Abarelix can be formulated, for example, as described in US 5,843,901.

  As used herein, the term “topoisomerase I inhibitor” includes topotecan, gimatecan, irinotecan, camptothecin and analogs thereof, 9-nitrocamptothecin and macromolecular camptothecin-binding PNU-166148 (compound A1 of WO 99/17804). However, it is not limited to these. Irinotecan can be administered, eg, in the form as it is marketed, eg under the trademark CAMPTOSAR. Topotecan can be administered, eg, in the form as it is marketed, eg under the trademark HYCAMTIN.

  As used herein, the term “topoisomerase II inhibitor” refers to doxorubicin (including liposomal formulations such as CAELYX), anthracyclines such as daunorubicin, epirubicin, idarubicin and nemorubicin, anthraquinones mitoxantrone and rosoxanthrone, and poxanthrone. The dophilotoxins include, but are not limited to, etoposide and teniposide. Etoposide can be administered, eg, in the form as it is marketed, eg under the trademark ETOPOPHOS. Teniposide can be administered, eg, in the form as it is marketed, eg under the trademark VM 26-BRISTOL. Doxorubicin can be administered, eg, in the form as it is marketed, eg under the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can be administered, eg, in the form as it is marketed, eg under the trademark FARMORUBICIN. Idarubicin can be administered, eg, in the form as it is marketed, eg under the trademark ZAVEDOS. Mitoxantrone can be administered, eg, in the form as it is marketed, eg under the trademark NOVANTRON.

  The term “microtubule activator” relates to microtubule stabilizers, microtubule destabilizers and microtubule polymerization inhibitors, and taxanes such as paclitaxel and docetaxel, vinca alkaloids such as vinblastine, especially vinblastine sulfate, Vincristine, especially vincristine sulfate, and vinorelbine, discodermride, colchicine and epothilone and derivatives thereof such as, but not limited to, epothilone B or D or derivatives thereof. Paclitaxel can be administered, eg, in the form as it is marketed, eg, TAXOL. Docetaxel can be administered, eg, in the form as it is marketed, eg under the trademark TAXOTERE. Vinblastine sulfate can be administered, eg, in the form as it is marketed, eg under the trademark VINBLASTIN R.P. Vincristine sulfate can be administered, eg, in the form as it is marketed, eg under the trademark FARMISTIN. Discodemolide can be obtained, for example, as described in US 5,010,099. Also included are the epothilone derivatives described in WO 98/10121, US 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247. Particularly preferred is epothilone A and / or B.

  The term “alkylating agent” as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide can be administered, eg, in the form as it is marketed, eg under the trademark CYCLOSTIN. Ifosfamide can be administered, eg, in the form as it is marketed, eg under the trademark HOLOXAN.

  The term “histone deacetylase inhibitor” or “HDAC inhibitor” relates to a compound that inhibits histone deacetylase and has anti-proliferative activity. This is the case with compounds described in WO 02/22577, in particular N-hydroxy-3- [4-[[(2-hydroxyethyl) [2- (1H-indol-3-yl) ethyl] -amino] methyl] phenyl] -2E-2-propenamide, N-hydroxy-3- [4-[[[2- (2-methyl-1H-indol-3-yl) -ethyl] -amino] methyl] phenyl] -2E-2- Including propenamide and pharmaceutically acceptable salts thereof. Also included among others are suberoylanilide hydroxamic acid (SAHA).

  The term “anti-neoplastic antimetabolite” includes folate antagonists such as 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating agents such as 5-azacytidine and decitabine, methotrexate and edatrexate, and pemetrexed However, it is not limited to these. Capecitabine can be administered, eg, in the form as it is marketed, eg under the trademark XELODA. Gemcitabine can be administered, eg, in the form as it is marketed, eg under the trademark GEMZAR. Also included is the monoclonal antibody trastuzumab, which can be administered, eg, in the form as it is marketed, eg under the trademark HERCEPTIN.

  The term “platinum compound” as used herein includes, but is not limited to, carboplatin, cisplatin, cisplastin and oxaliplatin. Carboplatin can be administered, eg, in the form as it is marketed, eg under the trademark CARBOPLAT. Oxaliplatin can be administered, eg, in the form as it is marketed, eg under the trademark ELOXATIN.

As used herein, the term “protein or lipid kinase activity; or compound that targets / reduces protein or lipid phosphatase activity; or additional anti-angiogenic compound”: protein tyrosine kinase and / or serine and / or threonine kinase inhibitor Or lipid kinase inhibitors, including but not limited to:
a) a compound that targets, decreases or inhibits the activity of platelet derived growth factor-receptor (PDGFR), eg a compound which targets, decreases or inhibits the activity of PDGFR, in particular a compound which inhibits the PDGF receptor, eg N-phenyl- 2-pyrimidine-amine derivatives such as imatinib, SU101, SU6668, and GFB-111;
b) a compound that targets, decreases or inhibits the activity of fibroblast growth factor-receptor (FGFR);
c) a compound which targets, decreases or inhibits the activity of insulin-like growth factor receptor I (IGF-IR), eg a compound which targets, decreases or inhibits the activity of IGF-IR, in particular a compound which inhibits the IGF-IR receptor For example, compounds described in WO02 / 092599;
d) a compound that targets, decreases or inhibits the activity of the Trk receptor tyrosine kinase family;
e) a compound that targets, decreases or inhibits the activity of the Axl receptor tyrosine kinase family;
f) a compound that targets, decreases or inhibits the activity of the c-Met receptor;
g) a compound that targets, decreases or inhibits the activity of the Kit / SCFR receptor tyrosine kinase;
h) compounds that target, decrease or inhibit the activity of C-kit receptor tyrosine kinase- (part of the PDGFR family), for example compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular c A compound that inhibits the Kit receptor, eg imatinib;
i) compounds that target, decrease or inhibit the activity of members of the c-Abl family and their gene fusion products (eg, BCR-Abl kinase), eg, target the activity of c-AbI family members and their gene fusion products, Compounds that reduce or inhibit, for example, N-phenyl-2-pyrimidin-amine derivatives such as imatinib; PD180970; AG957; NSC680410; or ParkeDavis PD173955;
j) Raf family members of protein kinase C (PKC) and serine / threonine kinases, MEK, SRC, JAK, FAK, PDK members and Ras / MAPK family members, or PI (3) kinase family, or PI (3) A compound that targets, decreases or inhibits the activity of a member of the kinase-related kinase family and / or the member of the cyclin-dependent kinase family (CDK), in particular a staurosporine derivative as described in US 5,093,330, for example midostaurin; Examples of compounds are for example UCN-01, Safingor, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO318220 and RO320432; GO6976; Isis3521; LY333531 / LY 379196; isoquinoline compounds as described in WO 00/09495; including FTIs; PD184352 or QAN697 (P13K inhibitor);

k) A compound that targets, decreases or inhibits the activity of a protein-tyrosine kinase inhibitor, including, for example, imatinib mesylate (GLEEVEC) or tyrophostin. Tyrophostin is preferably a low molecular weight (Mr <1500) compound, or a pharmaceutically acceptable salt thereof, especially a compound selected from benzylidene malonitrile class or S-arylbenzene malonitrile or a bisubstrate quinoline class compound, Tyrophostin A23 / RG-50810; AG99; Tyrophostin AG213; Tyrophostin AG1748; Tyrophostin AG490; Tyrophostin B44; Tyrophostin B44 (+) enantiomer; Tyrophostin AG555; AG494; Tyrophostin AG556, AG957 and adaphostin (4-{[ Dihydroxyphenyl) methyl] amino} -benzoic acid adamantyl ester; NSC680410, adaphostin) any compound selected from the group; and l) acceptor Compounds that target, decrease or inhibit the activity of the epidermal growth factor family of tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as mono- or heterodimers), eg target, decrease or inhibit the activity of the epidermal growth factor receptor family Compounds, proteins or antibodies, in particular WO 97/02266 (eg Example 39) that inhibit compounds, especially members of the EGF receptor tyrosine kinase family, such as EGF receptors, ErbB2, ErbB3 and ErbB4, or bind to EGF or EGF related ligand Compound), or EP 0564409, WO99 / 03854, EP0520722, EP0566226, EP0787722, EP0837063, US5,747,498, WO98 / 10767 Commonly and specifically in WO97 / 30034, WO97 / 49688, WO97 / 38983 and in particular WO96 / 30347 (eg a compound known as CP358774), WO96 / 33980 (eg compound ZD1839) and WO95 / 03283 (eg compound ZM105180) Compounds, proteins or monoclonal antibodies described for example; trastuzumab (HERCEPTIN), cetuximab, Iressa, Tarceva, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5 , E6.2, E6.4, E2.11, E6.3 or E7.6.3 and the 7H-pyrrolo- [2,3-d] pyrimidine derivatives described in WO03 / 013541.

  Additional anti-angiogenic compounds include, for example, compounds with other mechanisms of activity that are not associated with protein or lipid kinase inhibition, such as thalidomide (THALOMID) and TNP-470.

  Compounds that target, decrease or inhibit the activity of protein or lipid phosphatases are, for example, inhibitors of phosphatase 1, phosphatase 2A, PTEN or CDC25, such as okadaic acid or derivatives thereof.

  Compounds that induce the cell differentiation process are, for example, retinoic acid, α-, γ- or δ-tocopherol or α-, γ- or δ-tocotrienol.

  As used herein, the term cyclooxygenase inhibitor includes, for example, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoroxixib, valdecoxib or 5 -Alkyl-2-arylaminophenylacetic acid, including but not limited to, 5-methyl-2- (2'-chloro-6'-fluoroanilino) phenylacetic acid, lumiracoxib.

The term “bisphosphonate” as used herein includes, but is not limited to, etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid and zoledronic acid. “Etridonic acid” can be administered, eg, in the form as it is marketed, eg under the trademark DIDRONEL. “Clodronic acid” can be administered, eg, in the form as it is marketed, eg under the trademark BONEFOS. “Tiludronic acid” can be administered, eg, in the form as it is marketed, eg under the trademark SKELID. “Pamidronic acid” can be administered, eg, in the form as it is marketed, eg under the trademark AREDIA ^™ . “Alendronic acid” can be administered, eg, in the form as it is marketed, eg under the trademark FOSAMAX. “Ibandronic acid” can be administered, eg, in the form as it is marketed, eg under the trademark BONDRANAT. “Risedronic acid” can be administered, eg, in the form as it is marketed, eg under the trademark ACTONEL. “Zoledronic acid” can be administered, eg, in the form as it is marketed, eg under the trademark ZOMETA.

The term “mTOR inhibitor” refers to compounds that inhibit the mammalian target of rapamycin (mTOR) and have anti-proliferative activity, such as sirolimus (Rapamune®), everolimus (Certican ^™ ), CCI-779 and ABT578. About.

  The term “heparanase inhibitor”, as used herein, relates to a compound which targets, decreases or inhibits heparin sulfate degradation. The term includes, but is not limited to, PI-88.

  The term “biological response modifier” as used herein relates to lymphokines or interferons, eg interferon γ.

  As used herein, the term “inhibitor of Ras oncogenic isoform”, eg, H-Ras, K-Ras, or N-Ras, is a compound that targets, decreases or inhibits the oncogenic activity of Ras, eg, “ Farnesyltransferase inhibitors ", for example L-744832, DK8G557 or P115777 (Zarnestra).

  The term “telomerase inhibitor”, as used herein, relates to a compound which targets, decreases or inhibits the activity of telomerase. Compounds that target, decrease or inhibit the activity of telomerase are especially compounds that inhibit the telomerase receptor, such as telomestatin.

  The term “methionine aminopeptidase inhibitor” as used herein is a compound that targets, decreases or inhibits the activity of methionine aminopeptidase. A compound that targets, decreases or inhibits the activity of methionine aminopeptidase is, for example, benamide or a derivative thereof.

  The term “proteasome inhibitor”, as used herein, relates to a compound which targets, decreases or inhibits the activity of the proteasome. Compounds that target, decrease or inhibit the activity of the proteasome include, for example, PS-341 and MLN341.

  As used herein, the term “matrix metalloproteinase inhibitor” or (“MMP inhibitor”) refers to collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives such as the hydroxamate peptidomimetic inhibitor batimastat and Its oral bioavailable analogs include marimastat (BB-2516), purinomastert (AG3340), metastat (NSC683551) BMS-279251, BAY12-9566, TAA211, MMI270B or AAJ996.

  As used herein, the term “agent for use in the treatment of a hematological malignancy” targets, decreases or reduces the activity of an FMS-like tyrosine kinase inhibitor, eg, FMS-like tyrosine kinase receptor (Flt-3R). Compounds that inhibit; interferon, 1-bD-arabinofuranylcytosine (ara-c) and bisulfan; and compounds that target, decrease or inhibit ALK inhibitors such as anaplastic lymphoma kinase Not.

  Compounds that target, decrease or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) include, inter alia, compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine Derivatives, SU11248 and MLN518.

  As used herein, the term “HSP90 inhibitor” includes a compound that targets, decreases or inhibits the endogenous ATPase activity of HSP90; a compound that degrades, targets, decreases or inhibits the HSP90 client protein via the ubiquitin proteasome pathway. However, it is not limited to these. Compounds that target, decrease or inhibit the endogenous ATPase activity of HSP90 include inter alia compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives Other geldanamycin-related compounds; radicicol and HDAC inhibitors.

As used herein, the term “anti-proliferative antibody” refers to trastuzumab (Herceptin ^™ ), trastuzumab-DM1, erlotinib (Tarceva ^™ ), bevacizumab (Avastin ^™ ), rituximab (Rituxan®), PRO64553 (anti-CD40). ) And 2C4 antibodies. Antibody refers to, for example, fully monoclonal antibodies, polyclonal antibodies, multispecific antibodies produced from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.

  For acute myeloid leukemia (AML), the compound of formula (I) can be used in combination with standard leukemia therapy, especially in combination with the therapy used to treat AML. In particular, the compounds of the formula (I) are for example farnesyltransferase inhibitors and / or other agents useful for the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin And can be administered in combination with PKC412.

  The term “anti-leukemic compound” includes, for example, Ara-C, a pyrimidine analog that is a 2′-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are purine analogs of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate.

  Compounds that target, decrease or inhibit the activity of histone deacetylase (HDAC) inhibitors, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of an enzyme known as histone deacetylase. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), trichostatin A and the compounds described in US 6,552,065, in particular N-hydroxy-3- [4-[[[2- (2 -Methyl-1H-indol-3-yl) -ethyl] -amino] methyl] phenyl] -2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-3- [4-[( 2-hydroxyethyl) {2- (1H-indol-3-yl) ethyl] -amino] methyl] phenyl] -2E-2-propenamide, or a pharmaceutically acceptable salt thereof, particularly lactate.

  Compounds that target, decrease or inhibit the activity of serine / threonine mTOR kinase are, inter alia, compounds, proteins or antibodies that inhibit members of the mTOR kinase family, such as RAD, RAD001, CCI-779, ABT578, SAR543, rapamycin and derivatives thereof; Ariad AP23573; everolimus (CERTICAN); and sirolimus.

  As used herein, somatostatin receptor antagonists relate to agents that target, treat or inhibit somatostatin receptors, such as octreoride and SOM230.

  Tumor cytotoxicity approaches relate to approaches such as ionizing radiation. The term “ionizing radiation” means ionizing radiation generated above and below as either electromagnetic radiation (eg X-rays and gamma rays) or particles (eg alpha and beta particles). Ionizing radiation is provided by, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1, pp. 248-275 (1993).

  The term EDG binding agent as used herein relates to a class of immunosuppressive agents that regulate lymphocyte recirculation, such as FTY720.

  CERTICAN (everolimus, RAD) is a novel proliferation signal inhibitor in clinical trials that prevents proliferation of T-cells and vascular smooth muscle cells.

  The term ribonucleotide reductase inhibitor includes fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL) and It relates to pyrimidine or purine nucleoside analogues including but not limited to pentostatin. Ribonucleotide reductase inhibitors are inter alia hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives, such as Nandy et al., Acta Oncologica, Vol. 33, No. 8, pp. 953-961. (1994), PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8.

  The term “S-adenosylmethionine decarboxylase inhibitor” as used herein includes, but is not limited to, the compounds described in US Pat. No. 5,461,076.

  Also included are in particular WO 98/35958 (eg 1- (4-chloroanilino) -4- (4-pyridylmethyl) phthalazine or pharmaceutically acceptable salts thereof such as succinate), or WO 00/09495. , WO00 / 27820, WO00 / 59509, WO98 / 11223, WO00 / 27819 and EP0769947; monoclonal antibody of protein or VEGF; Pretwett et al, Cancer Res, Vol. 59, pp. 5209-5218 (1999); Yuan et al., Proc Natl Acad Sci USA, Vol. 93, pp. 14765-14770 (1996); Zhu et al., Cancer Res, Vol. 58, pp. 3209-3214 (1998); and Mordenti et al. , Toxicol Pathol, Vol. 27, No. 1, pp. 14-21 (1999); as described in WO 00/37502 and WO 94/10202; O'Reilly et al., Cell, Vol. 79, pp. 315 -328 (1994) described by Angiostatin; O'Reilly et al , Cell, Vol. 88, pp. 277-285 (1997) according to the group cyanoendostatin; anthranilic amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF or anti-VEGF receptor antibodies such as rhuMAb and RHUFab, VEGF aptamers such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibodies, Angiozyme (RPI 4610) and Avastan.

  Photodynamic therapy as used herein relates to therapy that uses certain chemicals known as photosensitizers to treat or prevent cancer. Examples of photodynamic therapy include treatment with drugs such as, for example, VISUDYNE and porfimer sodium.

  As used herein, angiostatic steroids include, for example, anecoltab, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone. And agents that block or inhibit angiogenesis, such as testosterone, estrone and dexamethasone.

  Corticosteroid-containing implants relate to about dia, for example flucinolone, dexamethasone.

  Other chemotherapeutic agents include plant alkaloids, hormone agents and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; or other drugs or other or unknown mechanisms of action Including, but not limited to, about an agent having

  The structure of the active agent identified by code number, generic name or trade name can be taken from the current edition of the standard introduction “The Merck Index” or from a database such as Patents International (eg IMS World Publications).

  The above compounds that can be used in combination with a compound of formula (I) can be prepared and administered as described in the literature, such as those cited above.

  The compounds of formula (I) can be used to benefit from known therapies, for example in combination with administration of hormones or especially radiation.

  The compounds of formula (I) can be used in particular as radiosensitizers, in particular in the treatment of tumors that are poorly sensitive to radiotherapy.

  “Combination” refers to a fixed combination in a single dosage unit form, or a compound of formula (I) and a combination partner independently simultaneously, or in particular, the combination partner exhibits a cooperative, eg synergistic effect. Means either a kit for combination administration that is administered separately within a time interval, or any combination thereof.

温度を記載していないとき、反応は環境(室)温度で行う。
例えば、溶離剤または溶媒混合物における溶の比率は容量／容量(^ｖ／_ｖ)で記載する。 EXAMPLES The following examples are provided to illustrate the present invention without limiting its scope:

When no temperature is stated, the reaction is carried out at ambient (room) temperature.
For example, the dissolution ratio in an eluent or solvent mixture is described as volume / volume ( ^v / _v ).

Synthetic flash chromatography is performed using silica gel (Merck; 40-63 μm). For thin layer chromatography, precoated silica gel (Merck 60 F254) plates are used. The component is detected by UV light (254 nm). Using HPLC on a Nucleosil 100-3 C ₁₈ HD 125 × 4.0 mm column [1 mL / min; 20-100% NeCN / 0.1% TFA, 7 min) (Method A) on an Agilent HP 1100; Nucleosil Chromalith Speed ROD on a SpectraSystem SP8800 / UV2000 using a 100-5 C ₁₈ AB 250 × 4.6 mm column (2 mL / min; 2-100% MeCN / 0.1% TFA at 10 minutes) (Method B); Using a RP18 50-4.6 mm column (Merck) (2 mL / min; 2-100% MeCN / 0.1% TFA, 2 min) (Method C); or C8 2.1-50 mm 3 μm column ( Waters) (2 mL / min; 5-95% MeCN / 0.1% TFA, 2 min) (Method D). ¹ H-NMR was measured with a Varian Gemini 400 or Bruker DRX 500 spectrometer. Perform using tetraethylsilane as internal standard. Chemical shifts are expressed in ppm in the downfield from tetraethylsilane and coupling constants (J) are expressed in hertz (Hz). Electrospray mass spectra are obtained with Fisons Instruments VG Platform II. Melting points are measured with a Buechi 510 melting point apparatus. Commercially available solvents and chemicals are used for the synthesis.

Analytical HPLC conditions:
System 1
Linear gradient 20-100% CH ₃ CN (0.1% TFA) and H ₂ O (0.1% TFA) 7 min + 2 min 100% CH ₃ CN (0.1% TFA); detected at 215 nm, flow rate 1 mL / min at 30 ° C. Column: Nucleosil 100-3 C18HD (125 × 4 mm).

System 2
Linear gradient 2-100% CH ₃ CN (0.1% TFA) and H ₂ O (0.1% TFA) 7 min + 2 min 100% CH ₃ CN (0.1% TFA); detected at 215 nm, flow rate 1 mL / min at 30 ° C. Column: Nucleosil 100-3 C18HD (125 × 4 mm).

Example 1
3- {7-amino-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol dissolved in THF (6 mL) 6- (3-Benzyloxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine (stage 1.1) (25 mg, 0.051 mmol) is hydrogenated in the presence of Pd / C (10% Engelhard 4505, 6 mg) for 13 hours. After filtration and evaporation of the solvent under reduced pressure, the residue is subjected to flash chromatography (silica gel, CH ₂ Cl ₂ / MeOH / NH ₃ = 95: 5: 0.1) to give the compound of Example 1 as white Obtained as a solid (14 mg, 0.035 mmol; 70%): ES-MS: M + H = 401.1, R _f (CH ₂ Cl ₂ / MeOH / NH ₃ = 90: 10: 0.1) = 0.33 ^HPLC: A _{t Ret} = 2.77 min.

¹ H-NMR (400 MHz, DMSO-d ₆ ): 9.59 (s, 1H, OH), 8.58 / 8.18 (s / s, 1H / 1H, pyrazolopyrimidinyl), 8.01 (d, 9.0 Hz, 2H, phenyl ), 7.48 (s, 2H, NH 2), 7.32 (t, 8.5 Hz, 1H, phenyl -OH), 6.99 (d, 9.0 Hz, 2H, phenyl), 6.96 (d, 8.5 Hz , 1H, phenyl -OH ), 6.93 (s, 1H, phenyl-OH), 6.80 (d, 8.5 Hz, 1H, phenyl-OH), 3.17 / 2.48 (m / m, 4H / 4H, piperazinyl), 2.24 (s, 3H, CH ₃ ).

Stage 1.1 6- (3-Benzyloxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine EtOH ( 4- (4- (4-Methyl-piperazin-1-yl) -phenyl) -2H-pyrazol-3-ylamine (stage 1.2) (100 mg, 0.388 mmol), 2- (3 -Benzyloxy-phenyl) -3-oxo-propionitrile (Stage 1.3) (98 mg, 0.388 mmol), HCl (2.5 mM in EtOH; 1.55 mmol, 0.9 mL) for 17 h at RT Stir with. After addition of H ₂ O (4 mL) and K ₂ CO ₃ (250 mg), the reaction mixture is extracted with CH ₂ Cl ₂ (20 mL, 2 ×). The combined organic phases were washed with H ₂ O (10 mL), dried (Na ₂ SO ₄ ), concentrated under reduced pressure, and flash chromatography (silica gel, 2.5 × 15 cm, CH ₂ Cl ₂ / MeOH = 9: 1) to give the compound of stage 1.1 as a white solid (60 mg, 0.122 mmol; 32%); ES-MS: M + H = 491.0, R _f (CH ₂ Cl ₂ / MeOH / NH ₃ = 90: 10: 0.1) = 0.42; HPLC: A t Ret = 4.69 min.

¹ H-NMR (400 MHz, DMSO-d ₆ ): 8.79 / 8.21 (s / s, 1H / 1H, pyrazolopyrimidinyl), 8.03 (d, 9.0 Hz, 2H, phenyl), 7.53 (s, 2H, NH ₂ ), 7.44 (m, 5H, benzyl), 7.32 (t, 8.5 Hz, 1H, phenyl-OH), 7.29 (s, 1H, phenyl-OH), 7.13 (d, 8.5 Hz, 1H, phenyl-OH) , 7.06 (d, 8.5 Hz, 1H, phenyl-OH), 6.97 (d, 9.0 Hz, 2H, phenyl), 5.19 (s, 2H, benzyl), 3.17 / 2.48 (m / m, 4H / 4H, piperazinyl) , 2.24 (s, 3H, CH ₃ ).

Stage 1.2 4- [4- (4-Methyl-piperazin-1-yl) -phenyl) -2H-pyrazol-3-ylamine 2- [4- (4-Methyl-piperazin-1-yl) dissolved in AcOH ) -Phenyl] -3-oxo-propionitrile (Stage 1.4) (370 mg, 1.52 mmol), hydrazine monohydrate (0.185 mL, 3.8 mmol) is stirred at 98 ° C. for 3 h. After cooling to RT, H ₂ O (8 mL) and concentrated HCl (0.8 mL) are added and the reaction mixture is stirred at reflux for 20 minutes. After cooling to RT, the reaction mixture is adjusted by slowly adding NH ₃ (25%) to alkaline pH. The precipitated material is filtered off and kept for further purification. The reaction solution is extracted with CH ₂ Cl ₂ (50 mL, 3 ×), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The precipitated and extracted material were combined and subjected to flash chromatography (silica gel, 3.0 × 18 cm, CH ₂ Cl ₂ / MeOH / NH ₃ = 9: 1: 01) to give the compound of stage 1.2 as a white solid (277 mg, 1.08 mmol; 71%); ES-MS: M + H = 258.1, R _f (CH ₂ Cl ₂ / MeOH / NH ₃ = 90: 10: 0.1) = 0.28; HPLC : ^A t _Ret = 4.33 min.

¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.55 (s / broad, 1H, NH), 7.55 (s, 1H, pyrrolyl), 7.35 (d, 9.0 Hz, 2H, phenyl), 6.91 (d, 9.0 Hz, 2H, phenyl), 4.55 (s / broad, 2H, NH 2), 3.10 / 2.46 (m / m, 4H / 4H, piperazinyl), 2.23 (s, 3H, CH 3).

Stage 1.3 2- (3-Benzyloxy-phenyl) -3-oxo-propionitrile Na (260 mg, 11.3 mmol) is dissolved in absolute EtOH (11 mL) under Ar for 20 min. After addition of (3-benzyloxy-phenyl) -acetonitrile (1.9 g, 8.68 mmol) and ethyl formate (1.05 mL, 13.0 mmol), the reaction mixture is stirred at reflux for 2 hours. The solvent is evaporated under reduced pressure, H ₂ O (20 mL) is added and after adjusting pH = 4.0 by addition of AcOH, the reaction suspension is extracted with CH ₂ Cl ₂ (30 mL, 2 ×). The combined organic phases were washed with H ₂ O (10 mL), dried (Na ₂ SO ₄ ), concentrated under reduced pressure, and flash chromatography (silica gel, 4.5 × 25 cm, CH ₂ Cl ₂ / MeOH = 98: 2) to give the compound of stage 1.3 as a white solid (780 mg, 3.11 mmol; 36%); ES-MS: MH = 25.0, R _f (CH ₂ Cl ₂ / MeOH = 95: 5) = 0.49; HPLC : A t Ret = 6.07 min.

¹ H-NMR (400 MHz, DMSO-d ₆ ): 7.45-7.25 / 6.98-6.88 (m / m, 8 H, aryl), 5.09 (s, 2H, CH ₂ ), 3.98 (s, 2H, CH ₂ ).

Stage 1.4 2- [4- (4-Methyl-piperazin-1-yl) -phenyl] -3-oxo-propionitrile Na 160 mg (7.0 mmol) in absolute EtOH (6 mL) under Ar 10 Dissolve in minutes. After [4- (4-methyl-piperazin-1-yl) -phenyl] -acetonitrile (stage 1.5) (1 g, 4.64 mmol) and ethyl formate (0.56 mL, 7.0 mmol), the reaction mixture was added. Stir at reflux for 1 hour. After washing the reaction pulp with ether (50 mL, 3 ×), the solid residue is dissolved in H ₂ O (60 mL) and adjusted to pH = 3.9 by addition of AcOH. The aqueous solution is extracted with CH ₂ Cl ₂ (50 mL, 3 ×). The combined organic phases are washed with H ₂ O (50 mL). Both aqueous phases are combined and lyophilized. The resulting residue was crystallized from MeOH / _CH 2 Cl _2, to give a compound of Stage 1.4 as white crystals (721mg, 3.0mmol; 64%) ; ES-MS: M + H = 244.1; HPLC: A t _Ret = 2.43 minutes.

¹ H-NMR (400 MHz, DMSO-d ₆ ): the compound forms a tautomeric equilibrium in the solvent: 7.87 / 7.77 (s / s, 1H, CH = / CH-OH), 7.53 / 7.17 ( d / d, 9.0 Hz, 2H, phenyl), 7.84 / 7.82 (d / d, 9.0 Hz, 2H, phenyl), 3.10 (m, 4H, piperazinyl), 2.57 / 2.51 (m / m, 4H, piperazinyl), 2.29 / 2.26 (s, 3H, CH 3).

Stage 1.5 [4- (4-Methyl-piperazin-1-yl) -phenyl] -acetonitrile (4-Bromo-phenyl) -acetonitrile (5 g, 25.5 mmol) dissolved in 1,2-dimethoxyethane (70 mL) ), 1-methyl-piperazine (3.4 mL, 30.6 mmol), K ₂ CO ₃ (7.68 g, 35.7 mmol), Pd (AcO) ₂ (280 mg, 1.275 mmol), 2- (di-tert -Butylphosphino) -biphenyl (1.14 g, 3.825 mmol) is stirred at 85 ° C. under Ar for 20 hours. After addition of H ₂ O (100 mL), the reaction mixture is extracted with CH ₂ Cl ₂ (100 mL, 3 ×). The combined organic phases were washed with H ₂ O (100 mL), dried (Na ₂ SO ₄ ), concentrated under reduced pressure, and flash chromatography (silica gel, 4.5 × 34 cm, CH ₂ Cl ₂ / MeOH = 95: 5) to give the compound of stage 1.5 as a white solid (2.8 g, 13 mmol; 51%); ES-MS: M + H = 216.1; R _f (CH ₂ Cl ₂ / MeOH = 9: ^{1) = 0.47; HPLC: A} t Ret = 2.24 min.

¹ H-NMR (400 MHz, DMSO-d ₆ ): 7.14 / 6.91 (d / d, 9.5 Hz, 2H / 2H, phenyl), 7.53 (s, 2H, NH ₂ ), 7.44 (m, 5H, benzyl) , 7.32 (t, 8.5 Hz, 1H, phenyl-OH), 7.29 (s, 1H, phenyl-OH), 3.84 (s, 2H, benzyl), 3.09 / 2.42 (t / t, 5.0 Hz, 4H / 4H, piperazinyl), 2.18 (s, 3H, CH 3).

Example 2
6- (3-Methoxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine 6- (3-methoxy- Phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine and the compound of stage 1.2 and 2- (3 Synthesized by condensation in a manner analogous to the preparation of the compound of Example 1 of -methoxy-phenyl) -3-oxo-propionitrile (stage 2.1). Yield: 48%, solid powder; ES-MS: M + H = 415.1; HPLC: A t Ret = 3.45 min.

¹ H-NMR (400 MHz, DMSO-d ₆ ): 8.59 / 8.23 (s / s, 1H / 1H, pyrazolopyrimidinyl), 8.06 (d, 9.0 Hz, 2H, phenyl), 7.55 (s, 2H, NH ₂ ), 7.43 (t, 8.5 Hz, 1H, phenyl-OMe), 7.10 (d, 8.5 Hz, 1H, phenyl-OMe), 7.08 (s, 1H, phenyl-OMe), 6.80 (d, 8.5 Hz, 1H , Phenyl-OMe), 6.98 (d, 9.0 Hz, 2H, phenyl), 3.83 (s, 3H, CH ₃ -O), 3.16 / 2.47 (m / m, 4H / 4H, piperazinyl), 2.25 (s, 3H , CH ₃ ).

Stage 2.1 2- (3-Methoxy-phenyl) -3-oxo-propionitrile 2- (3-Methoxy-phenyl) -3-oxo-propionitrile according to the preparation of the compound of Stage 1.3 synthesizing Te: yield: 76%; white powder; ES-MS: M-H = 174.0; HPLC: A t Ret = 4.75 min.

¹ H-NMR (400 MHz, DMSO-d ₆ ): The compound forms a tautomeric equilibrium in the solvent: 8.09 / 7.67 (s / s, 1H, CH = / CH-OH), 7.38-7.23 ( m, 2H, phenyl), 7.01-6.97 (m, 1H, phenyl), 6.88-6.79 (m, 1H, phenyl), 3.74 (s / broad, 3H, CH 3 -O).

Example 3
6- (3,5-Dimethoxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine 6- (3, 5-dimethoxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine with the compound of stage 1.2; Synthesized by condensation of 2- (3,5-dimethoxy-phenyl) -3-oxo-propionitrile (stage 3.1) in a manner analogous to the preparation of the compound of Example 1. Yield: 44%, solid powder; ES-MS: M + H = 445.0; HPLC: A t Ret = 3.77 min.

¹ H-NMR (400 MHz, DMSO-d ₆ ): 8.59 / 8.23 (s / s, 1H / 1H, pyrazolopyrimidinyl), 8.06 (d, 9.0 Hz, 2H, phenyl), 7.55 (s, 2H, NH ₂ ), 7.43 (t, 8.5 Hz, 1H, phenyl-OMe), 7.10 (d, 8.4 Hz, 1H, phenyl-OMe), 7.57 (s, 2H, NH ₂ ), 7.01 (d, 9.0 Hz, 2H, Phenyl), 6.89 (s, 2H, phenyl-OMe), 6.54 (s, 1H, phenyl-OMe), 3.83 (s, 6H, CH ₃ -O), 3.16 / 2.47 (m / m, 4H / 4H, piperazinyl ), 2.24 (s, 3H, N-CH ₃ ).

Stage 3.1 2- (3,5-Dimethoxy-phenyl) -3-oxo-propionitrile 2- (3,5-Dimethoxy-phenyl) -3-oxo-propionitrile It is synthesized according to the production of Yield: 48%; white powder; ES-MS: M + H = 206.0; HPLC: A t Ret = 4.79 min.

¹ H-NMR (400 MHz, DMSO-d ₆ ): the compound forms a tautomeric equilibrium in the solvent: 8.11 / 7.68 (s / s, 1H, CH = / CH-OH), 6.85 / 6.54 ( s / s, 2H, phenyl), 6.44 / 6.38 (s / s, 1H, phenyl), 3.74 (s / broad, 6H, CH 3 -O).

Example 4
6- (3-Benzyloxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine in stage 1.1 Manufactured by the described process.

Example 5-69
The following examples listed in Table 1 are synthesized according to the production of Example 1. Intermediates for the preparation of the commercially available compounds of Example 5-69 are listed in Table 1 below. When the title compound has a free amino group (Examples 52-54), the final products are taken from their corresponding nitro functional group-supported precursors in the presence of Pd / C (10%) in THF / MeOH for several hours. Produced by hydrogenation at

Stage 5.1 : 2- (4-Chloro-phenyl) -3-oxo-propionitrile 2- (4-Chloro-phenyl) -3-oxo-propionitrile According to the preparation of stage 1.3 compound manufacturing: 89%; ES-MS [ M-1] - = 177.9 / 179.9; HPLC A t Ret = 5.67 min.

Stage 6.1 : 2- (3-Chloro-phenyl) -3-oxo-propionitrile According to the preparation of the compound of 2- (3-Chloro-phenyl) -3-oxo-propionitrile Stage 1.3 manufacturing: 89%; ES-MS [ M-1] - = 177.9 / 179.9; HPLC A t Ret = 5.60 min.

Stage 8.1 3-oxo-2-phenyl-butyronitrile Prepared according to the preparation of the compound of 3-oxo-2-phenyl-butyronitrile stage 1.3: 62%, white crystals, m.p.> 215 ° C .; ES-ES-MS MH = 157.9, R _f (hexane / AcOEt = 1: 1) = 0.57.

¹ H-NMR (400 MHz, DMSO-d ₆ ): 7.84 (d, 9.0 Hz, 2H), 7.04 (t, 9.0 Hz, 2H), 6.68 (t, 9.0 Hz, 1H), 3.21 (s / broad, 1H, CH), 2.03 (s , 3H, CH 3).

Stage 9.1 2-Methyl-3-oxo-3-phenyl-propionitrile 2-Methyl-3-oxo-3-phenyl-propionitrile was synthesized from Yoo et al., Tetrahedron Lett., Vol. 43, No. 27, pp. 4813-4815 (2002). 2-Bromo-propionitrile (0.965 mL, 11.05 mmol) and In powder (975 mg, 8.5 mmol) are stirred in THF (15 mL) under Ar for 1 h. After adding benzoylnitrile (735 mg, 5.6 mmol) over 2 minutes, the reaction mixture is heated at 60 ° C. in a microwave oven (Emrys optimizer, personal chemistry, Sweden) for 30 minutes. After filtration through Hyflo and washing with THF (5 mL), the reaction solution is concentrated under reduced pressure and partitioned between ether (150 mL) and phosphate buffer (pH = 7, 150 mL). After separation of the organic phase, the aqueous phase is extracted with ether (150 mL). The combined organic phases were washed with brine (30 mL), dried (Na ₂ SO ₄ ), concentrated under reduced pressure, subjected to flash chromatography (silica gel, 2 × 18 cm, hexane / AcOEt = 3: 1), stage 9.1 is obtained as a slightly yellowish oil (300 mg, 1.9 mmol; 34%); ES-MS: MH = 157.9; R _f (hexane / AcOEt = 1: 1) = 0.60.

¹ H-NMR (400 MHz, DMSO-d ₆ ): 8.06 (d, 8.5 Hz, 2H), 7.74 (t, 8.5 Hz, 1H), 7.62 (t, 8.5 Hz, 2H), 5.17 (q, 8.5 Hz , 1H, CH), 1.52 (s, 3H, CH ₃ ).

  The compound of Example 10 is 2,3-dichloro-N- [4- (cyano-formyl-methyl) -phenyl] -benzenesulfonamide (stage 10.1) and 4- (4-dimethylamino-phenyl). It is synthesized according to the production of the compound of stage 1.1 by condensing -2H-pyrazol-3-ylamine (stage 10.3).

Stage 10.1 2,3-dichloro-N-[4-(Cyano - formyl - methyl) - phenyl] - benzenesulfonamide N ₂ atmosphere, sodium freshly cut (total 2.3 g, 100 mmol), EtOH Add to anhydrous (230 mL) in small portions within 15 minutes, which is slightly exothermic (up to 43 ° C.). After all sodium has dissolved (about 1 hour), 2,3-dichloro-N- (4-cyanomethyl-phenyl) -benzene-sulfonamide (stage 10.2) (26.27 g, 77 mmol) and formic acid ethyl ester (11 .2 mL, 139 mmol) is added to the colorless solution at RT. The mixture is heated at reflux temperature for 2 hours. After cooling to RT, the solvent is removed under reduced pressure and the residue is dissolved in H ₂ O (20 mL) followed by the addition of AcOH (200 mL; pH 4). The aqueous layer is extracted with CH ₂ Cl ₂ (2 ×, 500 mL) and the combined organics are washed with H ₂ O and dried over Na ₂ SO ₄ . Purification is carried out by repeated chromatography (silica gel, EtOAc and CH ₂ Cl ₂ / MeOH = 98: 2) and 2,3-dichloro-N- [4- (cyano-formyl-methyl) -phenyl] -benzenesulfonamide (233 mg, 1% yield) is obtained as beige crystals: mp 88-102 ° C .; (CH ₂ Cl _{2 /} MeOH = 95: 5): 0.22; ES-MS [M + 1] ⁺ = 368 HPLC ^B t _Ret = 5.61 min.

Stage 10.2, 2,3-Dichloro-N- (4-cyanomethyl-phenyl) -benzenesulfonamide 4-aminobenzylcyanide (12 g, 90.8 mmol) in pyridine (11 mL) at RT with a few -A solution of dichlorobenzene-sulfonyl chloride (22.29 g, 90.8 mmol) in THF (80 mL) is added within 20 min. The reaction is stirred at reflux temperature for 2 hours. After cooling, the solvent is removed under reduced pressure and the remaining solid is suspended in 10% HCl (200 mL). The crude crystalline product is filtered off, washed with H ₂ O and dried at 60 ° C. Final purification is performed by dissolving the crude compound in MeOH (250 mL), heating to reflux temperature, filtering and drying. 2,3-Dichloro-N- (4-cyanomethyl-phenyl) -benzenesulfonamide (26.54 g, 86%) is obtained as orange crystals: m.p: 202-206 ° C .; (CH ₂ Cl ₂ / MeOH). 98: 2): 0.54; ES-MS [M-1] ⁻ = 338.8; HPLC ^B t _Ret = 5.85 min.

Stage 10.3 4- (4-Dimethylamino-phenyl) -2H-pyrazol-3-ylamine 4- (4-Dimethylamino-phenyl) -2H-pyrazol-3-ylamine is converted to 2- (4-dimethylamino- Prepared from phenyl) -3-oxo-propionitrile (stage 10.4) and hydrazine hydrate as described in US Pat. No. 2,989,539 (20.6.61; Anderson and Reiff; Example 18) . 4- (4-Dimethylamino-phenyl) -2H-pyrazol-3-ylamine: mp 173-176 ° C .; (CH ₂ Cl ₂ / MeOH / NH ₃ = 90: 10: 1): 0.37; ES-MS [M + 1] + = 203; HPLC B t Ret = 1.40 min.

Stage 10.4 2- (4-Dimethylamino-phenyl) -3-oxo-propionitrile 2- (4-Dimethylamino-phenyl) -3-oxo-propionitrile is converted into (4-Dimethylamino-phenyl) Prepared from acetonitrile, ethyl formate and sodium as described in US Pat. No. 2,989,539 (Example 18).
. 2- (4-dimethylamino - phenyl) -3-oxo - propionitrile: m.p 175-178 ℃; ES-MS [M + 1] + = 189; HPLC B t Ret = 2.00 min.

  The compound of Example 11 was converted to 4- (4-dimethylamino-phenyl) -2H-pyrazol-3-ylamine (stage 10.3) and 4-chloro-benzenesulfonic acid 4- (cyano-formyl-methyl) -phenyl. Prepared according to the synthesis of the compound of Example 10 using ester (stage 11.1).

Stage 11.1 4-Chloro-benzenesulfonic acid 4- (cyano-formyl-methyl) -phenyl ester 4-Chloro-benzenesulfonic acid 4- (cyano-formyl-methyl) -phenyl ester was prepared in Example 10 (Stage 10 Prepared as described in .1) using commercially available 4- (cyanomethyl) phenyl-4-chlorobenzene-1-sulfonate instead.
4-Chloro-benzenesulfonic acid 4- (cyano-formyl-methyl) -phenyl ester (162 mg); yellowish solid; (CH ₂ Cl _{2 /} MeOH = 95: ₂ ): 0.32; ES-MS [M + 1 ] ⁺ = 335; HPLC ^B t _Ret = 6.23 min.

Stage 12.1 2- (4-Methoxy-phenyl) -3-oxo-butyronitrile 2- (4-Methoxy-phenyl) -3-oxo-butyronitrile was prepared according to Smith, Breen, Hajek and Awang, J. Org. Chem. , Vol. 35, No. 7, pp. 221-2221 (1970).

Stage 14.1 2- (4-Bromo-phenyl) -3-oxo-butyronitrile 2- (4-Bromo-phenyl) -3-oxo-butyronitrile was prepared according to the method of Rau, Ger. Offen., DE 3001266 (1980). Synthesize according to

Stage 16.1 1,2- (2,6-dichloro-phenyl) -3-oxo-propionitrile 1,2- (2,6-dichloro-phenyl) -3-oxo-propionitrile was converted to Menzer, Lankau And Unverferth, Ger. Offen., DE 19521822 (1996).

Stage 17.1 4- (3-Methoxy-phenyl) -2H-pyrazol-3-ylamine 4- (3-methoxy-phenyl) -2H-pyrazol-3-ylamine and stage 22.2 were prepared according to Bruni et al., Hetelocyclic. Chem., Vol. 32, No. 1, pp. 291-298 (1995).

Stage 19.1 2-Benzo [b] thiophen-3-yl-3-oxo-propionitrile 2-Benzo [b] thiophen-3-yl-3-oxo-propionitrile is converted to a compound of Stage 1.3. synthesized analogously to the preparation: yield: 56%; white powder; ES-MS: M-H = 123.9; HPLC: a t Ret = 2.20 min.
¹ H-NMR (300 MHz, DMSO-d ₆ ): 12.0 (s / broad, 1H), 8.00-7.70 (m, 3H), 7.45-7.35 (m, 2H).

Stage 21.1 3-oxo-2-thiophen-3-yl-propionitrile 3-oxo-2-thiophen-3-yl-propionitrile is synthesized analogously to the preparation of the compound of stage 1.3: yield: 51%; white powder, ES-MS: M-H = 112.9; HPLC: A t Ret = 2.03 min.
This compound forms a tautomeric equilibrium in solution: ¹ H-NMR (300 MHz, DMSO-d ₆ ): 7.95 / 7.55 (s / s, 1H, CH = / CH-OH), 7.55-7.50 (m, 2H), 7.30-7.20 (m, 1H).

Stage 22.1 4-Benzo [b] thiophen-3-yl-1H-pyrazol-3-ylamine 4-Benzo [b] thiophen-3-yl-1H-pyrazol-3-ylamine is compound of Stage 1.2 Embedded image: Yield: 80%; white powder; ES-MS: M + H = 216.0.
¹ H-NMR (300 MHz, DMSO-d ₆ ): 12.0 (s / broad, 1H), 8.00-7.80 (m, 2H), 7.75 (s / broad, 1H), 7.60 (s / broad, 1H), 7.40-7.30 (m, 2H).

Stage 22.2 (2- (3-methoxy-phenyl) -3-oxo-propionitrile)
(2- (3-methoxy-phenyl) -3-oxo-propionitrile) according to Bruni et al., Heterocyclic. Chem., Vol. 32, No. 1, pp. 291-298 (1995). Produce as street.

Stage 23.1 2-Formyl-3-phenyl-propionitrile 2-Formyl-3-phenyl-propionitrile is synthesized according to the preparation of the compound of Stage 1.3: Yield: 77%; oil ES-MS: MH = 158.0.
The compound forms a tautomeric equilibrium in solution: ¹ H-NMR (300 MHz, DMSO-d ₆ ): 7.40-7.15 (m, 5H), 2.85-2.75 (m, 2H).

Stage 24.1 4- [3- (4-Methyl-piperazin-1-yl) -phenyl] -acetonitrile 4- [3- (4-Methyl-piperazin-1-yl) -phenyl] -acetonitrile was replaced with stage 1 Synthesized according to the preparation of the compound of .5: Yield: 55%; brown solid; ES-MS: M + H = 216.7; HPLC: ^C t _Ret = 1.65 min.
¹ H-NMR (300 MHz, CDCl ₃ ): 7.30-7.25 (m, 1H), 6.90-6.82 (m, 2H), 6.80-6.75 (m, 1H), 3.70 (s, 2H), 3.25-3.15 ( m, 4H), 2.60-2.50 (m, 4H), 2.35 (s, 3H).

Stage 24.2 2- [3- (4-Methyl-piperazin-1-yl) -phenyl] -3-oxo-propionitrile 2- [3- (4-Methyl-piperazin-1-yl) -phenyl] -3-Oxo-propionitrile is synthesized analogously to the preparation of the compound of stage 1.3: yield: 100%; brown solid; ES-MS: M + H = 244.1; HPLC: ^C t _Ret = 1 .67 minutes.

Stage 24.3 4- [3- (4-Methyl-piperazin-1-yl) -phenyl] -1H-pyrazol-3-ylamine 4- [3- (4-Methyl-piperazin-1-yl) -phenyl] -1H-pyrazol-3-ylamine is synthesized according to the preparation of the compound of stage 1.2: yield: 36%; yellow foam; ES-MS: M + H = 258.2; HPLC: ^C t _Ret = 1.46 minutes.
^{1 H-NMR (300 MHz,} CDCl 3): 7.45 (s, 1H), 7.30-7.25 (m, 1H), 7.05-7.00 (m, 1H), 6.95-6.90 (m, 1H), 6.85-6.80 ( m, 1H), 4.00 (s / broad, 2H), 3.30-3.20 (m, 4H), 2.65-2.58 (m, 4H), 2.35 (s, 3H).

Stage 25.1 2- (1-Methyl-1H-indol-3-yl) -3-oxo-propionitrile 2- (1-Methyl-1H-indol-3-yl) -3-oxo-propionitrile Is synthesized according to the preparation of the compound of stage 1.3: Yield: 59%; oil; ES-MS: M + H = 199.1.
The compound forms a tautomeric equilibrium in solution: ¹ H-NMR (300 MHz, CDCl ₃ ): 8.00 / 7.95 (s / s, 1H), 7.60-7.20 (m, 5H), 3.75 (s , 3H).

Stage 26.1 2- (4-Methoxy-phenyl) -3-oxo-propionitrile 2- (4-Methoxy-phenyl) -3-oxo-propionitrile according to the preparation of the compound of Stage 1.3 Yield: 80%; white solid; ES-MS: MH = 174.3.
The compound forms a tautomeric equilibrium in solution: ¹ H-NMR (300 MHz, DMSO-d ₆ ): 7.80 / 7.58 (s / s, 1H), 7.55-7.50 (m, 1H), 7.30 -7.20 (m, 1H), 6.90-6.80 (m, 2H), 3.73 / 3.70 (s / s, 3H).

Stage 27.1 2- (2-Methoxy-phenyl) -3-oxo-propionitrile 2- (2-Methoxy-phenyl) -3-oxo-propionitrile according to the preparation of the compound of Stage 1.3 Yield: 40%; brown oil; ES-MS: MH = 174.3; HPLC ^C t _Ret = 2.01 min.

Stage 28.1 3-oxo-2-pyridin-3-yl-propionitrile 3-oxo-2-pyridin-3-yl-propionitrile is synthesized analogously to the preparation of the compound of stage 1.3: yield: 71%; brown solid; ES-MS: M + H = 147.2; HPLC C t Ret = 1.31 min.

Stage 28.2 4-Pyridin-3-yl-1H-pyrazol-3-ylamine 4-Pyridin-3-yl-1H-pyrazol-3-ylamine is synthesized according to the preparation of the compound of Stage 1.2: yield: 68%; brown solid; ES-MS: M + H = 161.2; HPLC C t Ret = 0.50 min.

Stage 30.1 [2-Methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -acetonitrile
[2-Methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -acetonitrile is synthesized according to the preparation of the compound of stage 1.5: yield: 51%; brown solid; ES- MS: M + H = 246.6; HPLC: C t Ret = 1.72 min.
¹ H-NMR (300 MHz, CDCl ₃ ): 7.00-6.95 (m, 1H), 6.85-6.75 (m, 2H), 3.80 (s, 3H), 3.65 (s, 2H), 3.15-3.05 (m, 4H), 2.60-2.55 (m, 4H), 2.35 (s, 3H).

Stage 30.2 2- [2-Methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -3-oxo-propionitrile 2- [2-Methoxy-5- (4-methyl-piperazine) -1-yl) -phenyl] -3-oxo-propionitrile is synthesized analogously to the preparation of the compound of stage 1.4: yield: 100%; brown solid; ES-MS: M + H = 274.1 ; ^HPLC: C _{t Ret} = 1.62 min.

Stage 30.3 4- [2-Methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -2H-pyrazol-3-ylamine 4- [2-methoxy-5- (4-methyl-piperazine) -1-yl) -phenyl] -2H-pyrazol-3-ylamine is synthesized according to the preparation of the compound of stage 1.2: yield: 32%; brown solid; ES-MS: M + H = 288.2. ; ^HPLC: C _{t Ret} = 1.46 min.
¹ H-NMR (300 MHz, CDCl ₃ ): 7.50 (s, 1H), 7.00-6.95 (m, 1H), 6.90-6.80 (m, 2H), 3.80 (s, 3H), 3.20-3.10 (m, 4H), 2.65-2.55 (m, 4H), 2.35 (s, 3H).

Stage 32.1 2- (2-Benzyloxy-phenyl) -3-oxo-propionitrile 2- (2-Benzyloxy-phenyl) -3-oxo-propionitrile was prepared to produce the compound of Stage 1.3 According to: Yield: 85%; white solid; ES-MS: M + H = 252.6; HPLC: ^C t _Ret = 2.35 min.
This compound forms a tautomeric equilibrium in solution: ¹ H-NMR (300 MHz, DMSO-d ₆ ): 11.6 / 7.78 (s, 1H), 7.55-7.45 (m, 2H), 7.40-7.20 (m, 5H), 7.15-7.05 (m, 1H), 7.00-6.90 (m, 1H), 5.15 (s, 2H).

Stage 34.1 2- (4-Benzyloxy-phenyl) -3-oxo-propionitrile 2- (4-Benzyloxy-phenyl) -3-oxo-propionitrile was prepared to produce the compound of Stage 1.3 Synthesize according to: Yield: 95%; white solid; ES-MS: MH = 250.3; HPLC: ^C t _Ret = 2.41 min.
This compound forms a tautomeric equilibrium in solution: ¹ H-NMR (300 MHz, DMSO-d ₆ ): 12.0 / 11.7 (s, 1H), 7.90-7.80 and 7.60-7.50 (m, 1H) 7.40-7.25 (m, 6H), 7.05-6.95 (m, 2H), 5.10 (s, 2H).

Stage 44.1 4- (1-Methyl-1H-indol-3-yl) -2H-pyrazol-3-ylamine 4- (1-Methyl-1H-indol-3-yl) -2H-pyrazol-3-ylamine Is synthesized according to the preparation of the compound of stage 1.2: Yield: 10%; brown foam; ES-MS: M + H = 213.2; HPLC: ^C t _Ret = 1.66 min.
¹ H-NMR (300 MHz, DMSO-d ₆ ): 7.70 (d, 1H), 7.60 (s, 1H), 7.35 (d, 1H), 7.30-7.25 (m, 1H), 7.20-7.10 (m, 2H), 3.80 (s, 3H).

Stage 47.1 2- (2-Methoxy-phenyl) -3-oxo-propionitrile 2- (2-Methoxy-phenyl) -3-oxo-propionitrile according to the preparation of the compound of Stage 1.3 Yield: 59%; white solid; ES-MS: M + H = 175.3; HPLC: ^C t _Ret = 2.01 min.

Stage 47.2 4- (2-Methoxy-phenyl) -2H-pyrazol-3-ylamine 4- (2-methoxy-phenyl) -2H-pyrazol-3-ylamine is prepared according to the preparation of the compound of Stage 1.2. Yield: 35%; white solid; ES-MS: M + H = 19.11; HPLC: ^C t _Ret = 1.40 min.
¹ H-NMR (300 MHz, DMSO-d ₆ ): 11.5 (bs, 1H), 7.50 (bs, 1H), 7.30 (bs, 1H), 7.20-7.05 (m, 1H), 7.00-6.85 (m, 2H), 4.30 (bs, 2H), 3.75 (s, 3H).

Stage 51.1 3-oxo-2-pyridin-4-yl-propionitrile 3-oxo-2-pyridin-4-yl-propionitrile is synthesized analogously to the preparation of the compound of stage 1.3: Yield: 59%; orange solid; ES-MS: M + H = 147.2; HPLC: ^C t _Ret = 1.00 min.
This compound forms a tautomeric equilibrium in solution: ¹ H-NMR (300 MHz, DMSO-d ₆ ): 13.1 / 9.60 (bs, 1H), 9.10 (bs, 1H), 8.20-8.00 (m , 2H), 7.95-7.80 (m, 1H).

Stage 52.1 (Z) -3-Dimethylamino-2- (3-nitro-phenyl) -acrylonitrile
A solution of (3-nitro-phenyl) -acetonitrile (1.51 g, 9.31 mmol), dimethoxymethyl-dimethyl-amine (6.2 mL, 46.5 mmol) in xylene (30 mL) is stirred at reflux temperature for 1 hour. After the addition of hexane (20 mL), the reaction mixture is cooled to 0 ° C. The precipitated material is collected by filtration to give stage 52.1 compound as a brown solid (1.76 g, 8.19 mmol; 88%); ES-MS: M + H = 218.1; HPLC: ^C t _Ret = 2 .24 minutes.
¹ H-NMR (300 MHz, DMSO-d ₆ ): 8.10-8.05 (m, 1H), 7.90-7.85 (m, 1H), 7.75-7.72 (m, 1H), 7.70 (s, 1H), 7.65- 7.60 (m, 1H), 3.30 (s, 6H).

Stage 52.2 3- [3- (4-Methyl-piperazin-1-yl) -phenyl] -6- (3-nitro-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine AcOH (10 mL ) And BuOH (10 mL) 4- [3- (4-Methyl-piperazin-1-yl) -phenyl] -1H-pyrazol-3-ylamine (stage 24.3) (305 mg, 1.18 mmol), (Z) -3-Dimethylamino-2- (3-nitro-phenyl) -acrylonitrile (stage 52.1) (335 mg, 1.54 mmol) is stirred at reflux temperature for 16 hours. After addition of saturated aqueous NaHCO ₃ solution, the reaction mixture is extracted with EtOAc (50 mL, 2 ×). The combined organic phases were washed with H ₂ O (10 mL), dried (Na ₂ SO ₄ ), concentrated under reduced pressure, and flash chromatography (silica gel, 2.5 × 15 cm, CH ₂ Cl ₂ / MeOH = 9: Subject to 1) to obtain the compound of stage 52.2 as an orange solid (224 mg, 0.52 mmol; 44%); ES-MS: M + H = 430.1; HPLC: ^C t _Ret = 1.91 min.
¹ H-NMR (300 MHz, DMSO-d ₆ ): 8.70 (s, 1H), 8.35-8.30 (m, 1H), 8.25 (s, 1H), 8.22-8.18 (m, 1H), 7.98-7.95 ( m, 1H), 7.90 (bs, 2H), 7.80-7.70 (m, 2H), 7.65-7.60 (m, 1H), 7.25-7.18 (m, 1H), 6.80-6.75 (m, 1H), 3.20- 3.10 (m, 4H), 2.50-2.40 (m, 4H), 2.20 (s, 3H).

Stage 53.1 3- [4- (4-Methyl-piperazin-1-yl) -phenyl] -6- (3-nitro-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine 3- [ 4- (4-Methyl-piperazin-1-yl) -phenyl] -6- (3-nitro-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine is prepared as a compound of stage 52.2 Synthesize according to: Yield: 30%; red solid; ES-MS: M + H = 430.0.
¹ H-NMR (300 MHz, DMSO-d ₆ ): 8.60 (s, 1H), 8.35-8.30 (m, 1H), 8.22 (s, 1H), 8.20-8.10 (m, 1H), 8.00 (d, 2H, J = 7.9Hz), 7.95-7.90 (m, 1H), 7.85 (bs, 2H), 7.80-7.75 (m, 1H), 6.95 (d, 1H, J = 7.9Hz), 3.20-3.10 (m , 4H), 2.50-2.40 (m, 4H), 2.20 (s, 3H).

Stage 54.1 (Z) -3-Dimethylamino-2- (2-nitro-phenyl) -acrylonitrile
(Z) -3-Dimethylamino-2- (2-nitro-phenyl) -acrylonitrile is synthesized according to the preparation of the compound of stage 52.1: yield: 97%; brown solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ): 7.82-7.78 (m, 1H), 7.62-7.55 (m, 1H), 7.45-7.35 (m, 2H), 7.20 (s, 1H), 3.15 ( s, 6H).

Stage 54.2 3- [4- (4-Methyl-piperazin-1-yl) -phenyl] -6- (2-nitro-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine 3- [ 4- (4-Methyl-piperazin-1-yl) -phenyl] -6- (2-nitro-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine is prepared as a compound of stage 55.2 Synthesize according to: Brown solid l; ES-MS: M + H = 430.0; HPLC: ^D t _Ret = 1.61 min.
¹ H-NMR (300 MHz, DMSO-d ₆ ): 8.55 (s, 1H), 8.20-8.15 (m, 1H), 8.05-7.95 (m, 3H), 7.82-7.60 (m, 5H), 7.00- 6.95 (m, 2H), 3.15-3.05 (m, 4H), 2.45-2.40 (m, 4H), 2.20 (s, 3H).

Stage 55.1 (E) -3-Dimethylamino-2- (4-methyl-thiazol-2-yl) -acrylonitrile
(E) -3-Dimethylamino-2- (4-methyl-thiazol-2-yl) -acrylonitrile is synthesized according to the preparation of the compound of stage 52.1: yield: 74%; black solid; ES -MS: M + H = 194.2; HPLC: C t Ret = 1.57 min.
¹ H-NMR (300 MHz, DMSO-d ₆ ): 7.76 (s, 1H), 6.60 (s, 1H), 3.25 (bs, 6H), 2.35 (s, 3H).

Example 61
3- {7-amino-2-methyl-3- [4- (4-methyl-piperazin-1-yl) phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol 3- {7 -Amino-2-methyl-3- [4- (4-methyl-piperazin-1-yl) phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol for the preparation of Example 1 Accordingly, it is synthesized using methylhydrazine instead of hydrazine during pyrazole ring formation: ES-MS: M + H = 415.2; HPLC: ^D t _Ret = 1.45 min.
¹ H-NMR (300 MHz, DMSO-d ₆ ): 9.53 (s, 1H, OH), 2.56 (s, 3H CH ₃ ), 2.24 (s, 3H CH ₃ ).

Example 62
(4- {7-amino-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenyl) -carbamic acid ethyl ester 4- (4- (4-Methyl-piperazin-1-yl) -phenyl) -2H-pyrazol-3-ylamine (Stage 1) dissolved in EtOH (4 mL) and ethanolic HCl (1.6 mL, 2.5 N) .2) (200 mg, 0.81 mmol) and [4- (2-cyano-1-formyl-ethyl) -phenyl] -carbamic acid ethyl ester (Stage 62.1) (275 mg, 0.04 mmol) under reflux Stir for 17 hours under Ar. After addition of H ₂ O (4 mL) and K ₂ CO ₃ (250 mg), the reaction mixture is extracted with CH ₂ Cl ₂ (20 mL, 2 ×). The combined organic phases were washed with H ₂ O (10 mL), dried (Na ₂ SO ₄ ), concentrated under reduced pressure, and flash chromatography (silica gel, 2.5 × 15 cm, CH ₂ Cl ₂ / MeOH / NH ₃ = 95: 5: 0.5) to give Example 62 as a white solid (58 mg, 0.123 mmol; 15%); ES-MS: M + H = 472.0; R _f (CH ₂ Cl _{2 / MeOH / NH 3 = 90} : 10: 0.1) = 0.42; HPLC: A t Ret = 4.26 min.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 8.75 / 8.58 (s / s, 1H / 1H, pyrazolopyrimidinyl), 8.03 (d, 9.0 Hz, 2H, phenyl), 7.61 (d, 9 Hz, 2H, phenyl), 7.53 (s, 2H, NH ₂ ), 7.46 (d, 9 Hz, 2H, phenyl), 7.00 (d, 9 Hz, 2H, phenyl), 4.17 (q, 7.5 Hz, 2H, CH ₂ - ethyl), 3.17 / 2.48 (m / m, 4H / 4H, piperazinyl), 2.24 (t, 7.5 Hz , 3H, CH 3).

Stage 62a.1 [4- (Cyano-1-formyl-methyl) -phenyl] -carbamic acid ethyl ester
[4- (Cyano-methyl) -phenyl] -carbamic acid benzyl ester (stage 62a.2) (1 g, 3.76 mmol) is formylated according to the preparation of stage 1.3 and the corresponding carbamic acid ethyl ester is obtained. Obtained (which also converts the benzyl ester functionality to the ethyl ester functionality): colorless crystals (654 mg, 2.66 mmol, 70%). ES-MS: M + H = 233.0.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 4.12 (q / broad, 7.5 Hz, 2H, CH ₂ -ethyl), 1.23 (t / broad, 7.5 Hz, 3H, CH ₃ -ethyl).

Stage 62.2 [4- (Cyano-methyl) -phenyl] -carbamic acid benzyl ester (4-amino-phenyl) -acetonitrile (2 g, 15.1 mmol) and dibenzyl dicarbonate (4 .33 g, 15.1 mmol) is stirred for 1 h at RT. After solvent evaporation, the product is isolated by flash chromatography (silica gel, 4.5 × 25 cm, CH ₂ Cl ₂ / MeOH = 99: 1): white solid (3.82 g, 14.4 mmol; 95%); ES-MS: M-H = 265.0; R f (CH 2 Cl 2 /MeOH=95:5)=0.49;HPLC: A t Ret = 6.32 min.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 9.82 (s, 1H, NH), 7.51-7.35 (m, 7H, aryl), 7.26 (d, 8.5 Hz, 2H, aryl), 5.15 (s, _{2H, CH 2), 3.95 (} s, 2H, CH 2).

(Z-) 3-Dimethylamino-2-thiazol-4-yl-acrylonitrile
(Z-) 3-Dimethylamino-2-thiazol-4-yl-acrylonitrile is synthesized according to the preparation of the compound of stage 52.1: ES-MS [M + 1] ⁺ = 180.1; HPLC: ^C t _Ret = 1.91 minutes

  Reaction of compounds 61, 62, 64, 67, and 68 carrying the sulfonamide and acetylamide functional groups (compounds 63, 65 and 69) with the amino precursor and the corresponding sulfonic acid chloride or acetic anhydride in the presence of pyridine. To make it.

Examples 70 and 71
The compounds in Table 2 and Table 3 are prepared according to Example 1.

Example 72
6- (3-Chloro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine 4- [ 3- (4-Methyl-piperazin-1-yl) -phenyl] -1H-pyrazol-3-ylamine (stage 72.2) (1.29 g, 5 mmol) was dissolved in EtOH (25 mL) and then 2- ( 3-Chloro-phenyl) -3-oxo-butyronitrile (Stage 72.3) (0.97 g, 5 mmol) and HCl (1.25 M in EtOH; 20 mmol, 16 mL) are added at RT. The yellowish solution is refluxed for 20 hours with stirring. After cooling to RT, H ₂ O (80 mL) as well as K ₂ CO ₃ (2.5 g) are added to make the mixture basic. The aqueous layer is extracted with CH ₂ Cl ₂ (200 mL, 2 ×). The combined organic phases were washed with H ₂ O (50 mL, 2 ×), dried (Na ₂ SO ₄ ), concentrated under reduced pressure, and chromatographed (silica gel, 120 g RediSep, ISCO Sg-100 CH ₂ Cl ₂ / MeOH). / NH ₃ = 95: 5: 0,1) to give the title compound 72 as white crystals (1.03 g, 2.38 mmol; 48%); mp. 110-115 ° C .; MS (ESI +): m / z = 433 (M + H ) +; HPLC: A tRet = 3.72 min (system 1).

Stage 72.1 : 2- (3-Chloro-phenyl) -3-oxo-butyronitrile.
355 ml of ethanol is heated to 55 ° C. under N ₂ . To this solution is added sodium (3.91 g; 0.17 mol) within 30 minutes and stirred for 1.5 hours until all the metal is dissolved. 3-Chlorobenzyl cyanide (15.31 g; 0.1 mol) and ethyl acetate (28.53 mL; 0.29 mol) are added to the colorless solution and then stirred at reflux for 5 hours. After the reaction is complete, the yellow mixture is cooled to rt and evaporated under reduced pressure. The crude material is taken up in water (200 mL) and neutralized by addition of 25 g of citric acid. Extract the aqueous layer with CH ₂ Cl ₂ (2 × 250 mL). The combined organic phases were washed with H ₂ O (2 × 150 mL), dried (Na ₂ SO ₄ ), concentrated under reduced pressure, chromatographed (silica gel, 1 kg, Merck 60 (0.040-0.063), Elution EtOAc / Hexane 1: 1) gives the title compound 72.1 as yellowish crystals (9.7 g, 0.05 mol; 50%); mp. 92-97 ° C .; MS (ESI +): m _{^{/z=302.9(M+H) +; HPLC: A tRet}} = 5.67 min (system 1).

Stage 72.2 : 4- [3- (4-Methyl-piperazin-1-yl) -phenyl] -1H-pyrazol-3-ylamine The title compound is described in Example 24; Stages 24.1-24.3. Manufacture as follows.

Example 73
6- (3-Chloro-phenyl) -5-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine Prepared as described in Example 72; 4- [4- (4-Methyl-piperazin-1-yl) -phenyl] -2H-pyrazol-3-ylamine (Example 1; Stage 1.2) and 2 -(3-Chloro-phenyl) -3-oxo-butyronitrile (Example 73, Stage 73.1) is used instead. . Beige crystals; mp 113-115 ℃; MS (ESI +): m / z = 433 (M + H) +; HPLC: A tRet = 3.56 min (System 1).

Example 74
6- (3-Chloro-phenyl) -3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidine-7- Ilamine The title compound is prepared as described in Example 72; 4- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -2H-pyrazol-3-ylamine and 2- ( 3-Chloro-phenyl) -3-oxo-butyronitrile (Example 72, Stage 72.1) is used instead. . Beige crystals; mp 116-121 ℃; MS (ESI +): m / z = 463 (M + H) +; HPLC: A tRet = 3.68 min (System 1).

Stage 74.1: 4- [2-Methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -2H-pyrazol-3-ylamine The title compound was obtained in Example 1 (Stage 1.2; Stage 1). .4 and 1.5); 5-bromo-2-methoxy-phenylacetonitrile and N-methylpiperazine are used instead. Foam ^{yellowish; MS (ESI +): m} / z = 288.2 (M + H) +; HPLC: A tRet = 3.53 min (System 2).

Example 75
6- (3-Chloro-phenyl) -3- [2-methoxy-4- (4-methyl-piperazin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidine-7- Ilamine The title compound is prepared as described in Example 72; 4- [2-methoxy-4- (4-methyl-piperazin-1-yl) -phenyl] -2H-pyrazol-3-ylamine and 2- ( 3-Chloro-phenyl) -3-oxo-butyronitrile (Example 72, Stage 72.1) is used instead. . Beige crystals; mp 215-217 ℃; MS (ESI +): m / z = 463 (M + H) +; HPLC: A tRet = 3.63 min (System 1).

Stage 75.1: 4- [2-Methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -2H-pyrazol-3-ylamine The title compound was obtained in Example 1 (Stage 1.2; Stage 1). .4 and 1.5); 4-bromo-2-methoxy-phenylacetonitrile and N-methylpiperazine are used instead. . Green - brown crystals; mp 173.7-178.1 ℃; MS (ESI +): m / z = 288.1 (M + H) +; HPLC: A tRet = 3.40 min (System 2).

Example 76
3- {7-amino-3- [2-methoxy-4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol 6- (3-Benzyloxy-phenyl) -3- [2-methoxy-4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine Dissolve in methanol and subject it to catalytic hydrogenation in the presence of Pd / C as described in Example 1: beige crystals; mp. 217-220 ° C .; MS (ESI +): m / z = 431.0 ( ^{M + H) +; HPLC:} A tRet = 2.65 min (system 1).

Stage 76.1: 6- (3-Benzyloxy-phenyl) -3- [2-methoxy-4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine- The 7-ylamine title compound is prepared as described in Example 1 (stage 1.2; stages 1.4 and 1.5); 4-bromo-2-methoxy-phenylacetonitrile and N-methylpiperazine are used instead. To do. Yellowish ^{solid; MS (ESI +): m} / z = 521 (M + H) +; HPLC: A tRet = 4.38 min (System 1).

Example 77
6- (2-Chloro-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound was prepared in Example 72. 4- [4- (4-Methyl-piperazin-1-yl) -phenyl] -2H-pyrazol-3-ylamine and (Z) -2- (2-chloro-phenyl) -3 -Dimethylamino-acrylonitrile is used instead. . Yellow solid; mp 197-200 ℃; MS (ESI +): m / z = 419 (M + H) +; HPLC: A tRet = 3.33 min (System 1).

Stage 77.1: (Z) -2- (2-chloro-phenyl) -3-dimethylamino-acrylonitrile.
N, N-dimethylformamide-dimethylacetal (9.06 mL; 64.3 mMol) and 2-chlorobenzyl cyanide (1.95 g; 12.86 mMol) are stirred and heated to 100 ° C. under an argon atmosphere. After cooling to RT, the mixture was concentrated under reduced pressure and purified by chromatography (silica gel, 120 g RediSep, ISCO Sg-100, elution EtOAc / hexane 1: 1) to give the title compound as a yellow thick oil (2.44 g). , 11.8 mmol; 92%); MS (ESI +): m / z = 207 (M + H) ⁺ ; TLC (EtOAc / hexane 1: 1) R _f = 0.38.

Example 78
6- (2-Chloro-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound was prepared in Example 72. (Z) -2- (2-Chloro-phenyl) -3-dimethylamino-acrylonitrile (Example 77, Stage 77.1) is used instead. . Crystals yellowish; mp 200-203 ℃; MS (ESI +): m / z = 419.0 (M + H) +; HPLC: A tRet = 3.65 min (System 1).

Example 79
6- (4-Fluoro-phenyl) -5-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine Prepared as described in Example 72; 4- [4- (4-Methyl-piperazin-1-yl) -phenyl] -2H-pyrazol-3-ylamine and 2- (4-fluoro-phenyl) -3 -Oxo-butyronitrile is used instead. . White crystals; mp 289-291 ℃; MS (ESI +): m / z = 417.1 (M + H) +; HPLC: A tRet = 3.21 min (System 1).

Stage 79.1: 2- (4-Fluoro-phenyl) -3-oxo-butyronitrile.
The title compound is prepared as described in Example 72 Stage 72.1 using (4-fluoro-phenyl) -acetonitrile instead. . Beige crystals; mp 77-83 ℃; MS (ESI +): m / z = 176.9 (M + H) +; HPLC: A tRet = 5.15 min (System 1).

Example 80
6- (4-Fluoro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine 2- (4-fluoro-phenyl) -3-oxo-butyronitrile (Example 79, Stage 79.1) is used instead. . White crystals; mp 204-206 ℃; MS (ESI +): m / z = 417.1 (M + H) +; HPLC: A tRet = 3.34 min (System 1).

Example 81
6- (3-Chloro-phenyl) -5-methyl-3- {3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-yl] -phenyl} -pyrazolo [1,5- a] Pyrimidin-7-ylamine The title compound is prepared as described in Example 72; 4- {3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-yl] -phenyl} -2H-pyrazol-3-ylamine is used instead. . Beige crystals; mp 180-185 ℃; MS (ESI +): m / z = 516.0 (M + H) +; HPLC: A tRet = 4.96 min (System 1).

Stage 81.1: 4- {3- [4- (1-Methyl-piperidin-4-yl) -piperazin-1-yl] -phenyl} -2H-pyrazol-3-ylamine.
The title compound is prepared as described in Example 1 (stages 1.2 and 1.4 and 1.5); (3-bromo-phenyl) -acetonitrile and 1- (1-methyl-piperidin-4-yl) ) -Piperazine is used instead. . Crystals yellowish; mp 213-220 ℃; MS (ESI +): m / z = 341.18 (M + H) +; HPLC: A tRet = 3.57 min (System 1).

Example 82
6- (3-Chloro-4-fluoro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound is prepared as described in Example 72; 2- (3-chloro-4-fluoro-phenyl) -3-oxo-butyronitrile is used instead. . White crystals; mp 224-226 ℃; MS (ESI +): m / z = 451 (M + H) +; HPLC: A tRet = 3.86 min (System 1).

Stage 82.1: 2- (3-Chloro-4-fluoro-phenyl) -3-oxo-butyronitrile The title compound was prepared in an example using (3-chloro-4-fluoro-phenyl) -acetonitrile instead. 72, manufactured as described in stage 72.1. . White crystals; mp 133-134 ℃; MS (ESI -): m / z = 209.9 (M-H) -; HPLC: A tRet = 5.79 min (System 1).

Example 83
6- (3-Chloro-4-fluoro-phenyl) -5-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine-7- Ilamine The title compound was prepared as described in Example 72 using 4- [4- (4-methyl-piperazin-1-yl) -phenyl] -2H-pyrazol-3-ylamine and 2- (3-chloro-4- Fluoro-phenyl) -3-oxo-butyronitrile (Example 82; Stage 82.1) is used instead. . White crystals; mp 264-265 ℃; MS (ESI +): m / z = 451 (M + H) +; HPLC: A tRet = 3.72 min (System 1).

Example 84
6- (3-Bromo-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine , 2- (3-Bromo-phenyl) -3-oxo-butyronitrile is used instead, as described in Example 72, Stage 72.1. . White crystals; mp 107-113 ℃; MS (ESI +): m / z = 477 (M + H) +; HPLC: A tRet = 4.90 min (System 1).

Stage 84.1: 2- (3-Bromo-phenyl) -3-oxo-butyronitrile.
The title compound is prepared as described in Example 72, Stage 72.1, using (3-bromo-phenyl) -acetonitrile instead. . White crystals; mp 96-100 ℃; MS (ESI -): m / z = 235.9 (M-H) -; HPLC: A tRet = 5.76 min (System 1).

Example 85
6- (3-Bromo-benzyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound is obtained in Example 72. Prepared as described; 3- (3-bromo-phenyl) -2-formyl-propionitrile is used instead. . White crystals; mp 170-171 ℃; MS (ESI +): m / z = 477.0 (M + H) +; HPLC: A tRet = 3.84 min (System 1).

Stage 85.1: 3- (3-Bromo-phenyl) -2-formyl-propionitrile.
3- (3-Bromophenyl) propionitrile (0.703 mL; 4.66 mMol) and ethyl formate (1499 mL; 18.64 mMol) were dissolved in anhydrous THF (12.5 mL) and then NaH (60 in mineral oil). %; 670 mg) is added at rt. After 17 h at rt, more NaH (448 mg) and ethyl formate (0.765 mL) are added. Since this results in a strong exothermic reaction, more solvent is added (15 mL of THF). After completion (3 days), the reaction mixture is cooled to 0 ° C. and treated with several small ice cubes, then 6N HCl (3 mL) is added to acidify the mixture. After addition of water (50 mL), the mixture is extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with H ₂ O (50 mL, 2 ×), brine, dried (Na ₂ SO ₄ ), concentrated under reduced pressure, and chromatographed (silica gel, 40 g RediSep, ISCO Sg-100, eluted EtOAc / hexane. 1: 1) to give the title compound as a brownish oil (220 mg; 20%); MS (ESI−): m / z = 235.9 (M−H) −; TLC EtOAc / hexane 1 1) Rf = 0.28.

Example 86
6- (3-Bromo-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound was prepared in Example 72. (Z) -2- (3-bromo-phenyl) -3-dimethylamino-acrylonitrile is used instead. . White crystals; mp 195.3-197.2 ℃; MS (ESI +): m / z = 463.0 (M + H) +; HPLC: A tRet = 4.05 min (System 1).

Stage 86.1: (Z) -2- (3-Bromo-phenyl) -3-dimethylamino-acrylonitrile is prepared as described in Example 77, Stage 77.1: golden brown crystals; mp. 102- ^{105 ℃; MS (ESI +)} : m / z = 251.0 (M + H) +; HPLC: A tRet = 6.45 min (system 1).

Example 87
6- (3-Chloro-phenyl) -5-methyl-3- (3-morpholin-4-yl-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound is described in Example 72. 4- (3-morpholin-4-yl-phenyl) -2H-pyrazol-3-ylamine is used instead. . Off-white crystals; mp 165-167 ℃; MS (ESI +): m / z = 420 (M + H) +; HPLC: A tRet = 4.49 min (System 1).

Stage 87.1: 4- (3-morpholin-4-yl-phenyl) -2H-pyrazol-3-ylamine The title compound is described in Example 1 (Stage 1.2; Stages 1.4 and 1.5). (3-bromo-phenyl) -acetonitrile and morpholine are used instead. . Off-white crystals; mp 166-168 ℃; MS (ESI +): m / z = 245.1 (M + H) +; HPLC: A tRet = 1.79 min (System 1).

Example 88
6- (3-Chloro-phenyl) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound is prepared as described in Example 72. 4- (4-methoxy-phenyl) -2H-pyrazol-3-ylamine is used instead. . White crystals; mp 171-172 ℃; MS (ESI +): m / z = 365 (M + H) +; HPLC: A tRet = 4.96 min (System 1).

Stage 88.1: 4- (4-Methoxy-phenyl) -2H-pyrazol-3-ylamine The title compound is prepared as described in Example 1 (Stages 1.4 and 1.2); -Phenyl) -acetonitrile is used instead. . White crystals; mp 198-201 ℃; MS (ESI +): m / z = 190 (M + H) +; HPLC: A tRet = 2.85 min (System 1).

Example 89
6- (3-Chloro-phenyl) -3- [3-((2R, 6S) -2,6-dimethyl-morpholin-4-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] Pyrimidin-7-ylamine The title compound is prepared as described in Example 72; 4- [3-((2R, 6S) -2,6-dimethyl-morpholin-4-yl) -phenyl] -2H-pyrazole -3-ylamine is used instead. . White crystals; mp 165-167 ℃; MS (ESI +): m / z = 448 (M + H) +; HPLC: A tRet = 5.14 min (SYSTEM1).

Stage 89.1: 4- [3-((2R, 6S) -2,6-Dimethyl-morpholin-4-yl) -phenyl] -2H-pyrazol-3-ylamine The title compound was prepared in Example 1 (Stage 1 .2 and 1.4 and 1.5); (3-bromo-phenyl) -acetonitrile and (2R, 6S) -2,6-dimethyl-morpholine are used instead. . White crystals; mp 158-160 ℃; MS (ESI +): m / z = 273.1 (M + H) +; HPLC: A tRet = 3.02 min (System 1).

Example 90
2- (4- {3- [7-Amino-6- (3-chloro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-3-yl] -phenyl} -piperazin-1-yl ) -Ethanol The title compound is prepared as described in Example 72; 2- {4- [3- (5-amino-1H-pyrazol-4-yl) -phenyl] -piperazin-1-yl} -ethanol Is used instead. . Off-white crystals; mp 108-116 ℃; MS (ESI +): m / z = 463 (M + H) +; HPLC: A tRet = 3.62 min (System 1).

Stage 90.1: 2- {4- [3- (5-Amino-1H-pyrazol-4-yl) -phenyl] -piperazin-1-yl} -ethanol The title compound was prepared in Example 1 (stage 1.2). And 1.4 and 1.5); (3-bromo-phenyl) -acetonitrile and 2-piperazin-1-yl-ethanol are used instead. . Foam yellowish; mp 40-48 ℃; MS (ESI +): m / z = 288.1 (M + H) +; HPLC: A tRet = 3.45 min (System 1).

Example 91
6-Benzyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound is prepared as described in Example 72. 2-formyl-3-phenyl-propionitrile (Example 23; Stage 23.1) is used instead. . Crystals yellowish; mp 72-75 ℃; MS (ESI +): m / z = 399.1 (M + H) +; HPLC: A tRet = 3.30 min (System 1).

Example 92
6- (3-Chloro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-fluoromethyl-pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound is described in Example 72. 4- (3,4-dimethoxy-phenyl) -2H-pyrazol-3-ylamine (Example 93; stage 93.1) and 2- (3-chloro-phenyl) -4-fluoro-3- Oxo-butyronitrile is used instead. . Yellow crystals; mp 228-230 ℃; MS (ESI +): m / z = 413 (M + H) +; HPLC: A tRet = 6.65 min (System 1).

Stage 92.1: 2- (3-Chloro-phenyl) -4-fluoro-3-oxo-butyronitrile The title compound is described in Example 72, Stage 72.1 using fluoro-acetic acid ethyl ester instead. Produce as street. . Beige crystals; mp 90-96 ℃; MS (ESI -): m / z = 209.9 (M-H) -; HPLC: A tRet = 5.66 min (System 1).

Example 93
6- (3-Chloro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound is as described in Example 72. Prepare; 4- (3,4-dimethoxy-phenyl) -2H-pyrazol-3-ylamine is used instead. . Off-white solid; mp 223-226 ℃; MS (ESI +): m / z = 395.0 (M + H) +; HPLC: A tRet = 4.69 min (System 1).

Stage 93.1: 4- (3,4-Dimethoxy-phenyl) -2H-pyrazol-3-ylamine The title compound is prepared as described in Example 1 (Stages 1.4 and 1.2); , 4-dimethoxy-phenyl) -acetonitrile is used instead. . White crystals; mp 143-146 ℃; MS (ESI +): m / z = 220.1 (M + H) +; HPLC: A tRet = 2.28 min (System 1).

Example 94
6- (3-Chloro-4-fluoro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound was prepared in Example 72. 4- (3,4-dimethoxy-phenyl) -2H-pyrazol-3-ylamine (Example 93; Stage 93.1) and 2- (3-Chloro-4-fluoro-phenyl) -3-Oxo-butyronitrile (Example 82; Stage 82.1) is used instead. . Off-white solid; mp 235-238 ℃; MS (ESI +): m / z = 413.0 (M + H) +; HPLC: A tRet = 4.83 min (System 1).

Example 95
6- (3-Chloro-4-fluoro-phenyl) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound is described in Example 72. 4- (4-Methoxy-phenyl) -2H-pyrazol-3-ylamine (Example 88; Stage 88.1) and 2- (3-Chloro-4-fluoro-phenyl) -3-oxo -Butyronitrile (Example 82; Stage 82.1) is used instead. . White crystals; mp 224-227 ℃; MS (ESI +): m / z = 383 (M + H) +; HPLC: A tRet = 5.08 min (System 1).

Example 96
6- (4-Fluoro-phenyl) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound is prepared as described in Example 72. 4- (4-methoxy-phenyl) -2H-pyrazol-3-ylamine (Example 88, Stage 88.1) and 2- (4-Fluoro-phenyl) -3-oxo-butyronitrile (Example 79; Stage); Use 79.1) instead. . White crystals; mp 243-244 ℃; MS (ESI +): m / z = 349,1 (M + H) +; HPLC: A tRet = 4.56 min (System 1).

Example 97
2- (4- {3- [7-Amino-6- (4-fluoro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-3-yl] -phenyl} -piperazin-1-yl ) -Ethanol The title compound is prepared as described in Example 72; 2- {4- [3- (5-amino-1H-pyrazol-4-yl) -phenyl] -piperazin-1-yl} -ethanol (Example 90, Stage 90.1) and 2- (4-Fluoro-phenyl) -3-oxo-butyronitrile (Example 79; Stage 79.1) are used instead. . Off-white crystals; mp 209-212 ℃; MS (ESI +): m / z = 447.1 (M + H) +; HPLC: A tRet = 3.24 min (System 1).

Example 98
6- (3,4-Difluoro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine The compound is prepared as described in Example 72; 2- (3,4-difluoro-phenyl) -3-oxo-butyronitrile is used instead. . White solid; mp 216-219 ℃; MS (ESI +): m / z = 435 (M + H) +; HPLC: A tRet = 3.30 min (SYSTEM1).

Stage 98.1: 2- (3,4-Difluoro-phenyl) -3-oxo-butyronitrile The title compound is prepared as described in Example 1 (Stages 1.4 and 1.2); -Difluoro-phenyl) -acetonitrile is used instead. . White crystals; mp 147-152 ℃; MS (ESI +): m / z = 195 (M + H) +; HPLC: A tRet = 5.39 min (System 1).

Example 99
6- (3,4-Difluoro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound is described in Example 72. 4- (3,4-dimethoxy-phenyl) -2H-pyrazol-3-ylamine (Example 93; stage 93.1) and 2- (3,4-difluoro-phenyl) -3-oxo -Butyronitrile (Example 98; Stage 98.1) is used instead. . Off-white solid; mp 230-235 ℃; MS (ESI +): m / z = 397.0 (M + H) +; HPLC: A tRet = 4.53 min (System 1).

Example 100
2- (4- {3- [7-Amino-6- (3-chloro-4-fluoro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-3-yl] -phenyl} -piperazine -1-yl) -ethanol The title compound is prepared as described in Example 72; 2- {4- [3- (5-amino-1H-pyrazol-4-yl) -phenyl] -piperazine-1- IL} -ethanol (Example 90, Stage 90.1) and 2- (3-Chloro-4-fluoro-phenyl) -3-oxo-butyronitrile (Example 82; Stage 82.1) are used instead. . Off-white crystals; mp 104-107 ℃; MS (ESI +): m / z = 481 (M + H) +; HPLC: A tRet = 4.00 min (System 1).

Example 101
2- (4- {3- [7-amino-6- (3,4-difluoro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-3-yl] -phenyl} -piperazine-1 -Yl) -ethanol The title compound is prepared as described in Example 72; 2- {4- [3- (5-Amino-1H-pyrazol-4-yl) -phenyl] -piperazin-1-yl} -Ethanol (Example 90, Stage 90.1) and 2- (3,4-Difluoro-phenyl) -3-oxo-butyronitrile (Example 98; Stage 98.1) are used instead. . Off-white crystals; mp 172-174 ℃; MS (ESI +): m / z = 465 (M + H) +; HPLC: A tRet = 3.71 min (System 1).

Example 102
6- (3-Chloro-phenyl) -5-methyl-3- [3- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine-7- Ilamine The title compound is prepared as described in Example 72; 4- [3- (4-Pyrrolidin-1-yl-piperidin-1-yl) -phenyl] -1H-pyrazol-3-ylamine is used instead. To do. . Yellow crystals; mp 188-193 ℃; MS (ESI +): m / z = 487.0 (M + H) +; HPLC: A tRet = 4.21 min (System 1).

Stage 102.1: 4- [3- (4-Pyrrolidin-1-yl-piperidin-1-yl) -phenyl] -1H-pyrazol-3-ylamine The title compound was prepared in Example 1 (stages 1.2 and 1). .4 and 1.5); (3-bromo-phenyl) -acetonitrile and 4-pyrrolidin-1-yl-piperidine are used instead. . Yellow crystals; mp 214-216 ℃; MS (ESI +): m / z = 312.1 (M + H) +; HPLC: A tRet = 3.71 min (System 1).

Example 103
6- (4-Fluoro-phenyl) -5-methyl-3- [3- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine-7- Ilamine The title compound is prepared as described in Example 72; 4- [3- (4-Pyrrolidin-1-yl-piperidin-1-yl) -phenyl] -1H-pyrazol-3-ylamine (Example 102) Stage 102.1) and 2- (4-fluoro-phenyl) -3-oxo-butyronitrile (Example 79; Stage 79.1) are used instead. . White crystals; mp 244-249 ℃; MS (ESI +): m / z = 471.0 (M + H) +; HPLC: A tRet = 3.82 min (System 1).

Example 104
6- (3-Chloro-phenyl) -3- [3- (4-diethylamino-piperidin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine Prepared as described in Example 72; {1- [3- (3-amino-1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -diethyl-amine is used instead. . White crystals; mp 163-168 ℃; MS (ESI +): m / z = 489.0 (M + H) +; HPLC: A tRet = 4.02 min (System 1).

Stage 104.1: {1- [3- (3-Amino-1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -diethyl-amine The title compound was prepared in Example 1 (stage 1.2). And 1.4 and 1.5); (3-bromo-phenyl) -acetonitrile and diethyl-piperidin-4-yl-amine are used instead. Beige solid, ^{amorphous; MS (ESI +): m} / z = 314.2 (M + H) +; HPLC: A tRet = 3.75 min (System 1).

Example 105
3- [3- (4-Diethylamino-piperidin-1-yl) -phenyl] -6- (4-fluoro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine Prepared as described in Example 72; {1- [3- (3-Amino-1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -diethyl-amine (Example 104, Stage) 104.1) and 2- (4-fluoro-phenyl) -3-oxo-butyronitrile (Example 79; Stage 79.1) are used instead. . White crystals; mp 208-210 ℃; MS (ESI +): m / z = 473.1 (M + H) +; HPLC: A tRet = 3.63 min (System 1).

Example 106
6- (4-Fluoro-phenyl) -5-methyl-3- [3- (4-methyl-4-oxy-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine-7- Ilamine 6- (4-Fluoro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine Example 80) (50 mg; 0.12 mMol) was dissolved in CH ₂ Cl ₂ (10 mL) and treated with 3-chloroperbenzoic acid (31.1 mg; 0.126 mMol) at 0 ° C. for 1 hour, followed by 2 at rt. Stir for hours. After removal of the solvent under reduced pressure, the crude mixture is purified by chromatography (silica gel, 12 g RediSep, ISCO Sg-100 CH ₂ Cl ₂ / MeOH / NH ₃ = 80: 20: 1) to give the title compound as beige crystals. . (44mg); mp 210-223 ℃ ; MS (ESI +): m / z = 449 (M + H) +; HPLC: A tRet = 3.31 min (system 1).

Example 107
6- (4-Fluoro-phenyl) -5-methyl-3- [3- (4-methyl-1,4-dioxy-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine- 7-ylamine The title compound is isolated from the same reaction described in Example 106: beige crystals (20 mg); mp. 161-169 ° C .; MS (ESI +): m / z = 433 (M + H) +; HPLC: : ^A _tRet = 3.89 min (system 1).

Example 108
6- (3-Chloro-phenyl) -3- [3- (4-dimethylamino-piperidin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine Title compound Is prepared as described in Example 72; {1- [3- (5-amino-1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -dimethyl-amine is used instead. .

Stage 108.1 {1- [3- (5-Amino-1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -dimethyl-amine The title compound was prepared according to Example 1 (stage 1.2 and 1.4 and 1.5); (3-bromo-phenyl) -acetonitrile and dimethyl-piperidin-4-yl-amine are used instead.

Example 109
6- (3,4-Difluoro-phenyl) -3- [3- (4-dimethylamino-piperidin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound is prepared as described in Example 72; {1- [3- (5-Amino-1H-pyrazol-4-yl) -phenyl] -piperidin-4-yl} -dimethyl-amine (Example 108; Stage 108.1) and 2- (3,4-Difluoro-phenyl) -3-oxo-butyronitrile (Example 98; Stage 98.1) are used instead.

Example 110
6- (3-Chloro-phenyl) -5-methyl-3- (3,4,5-trimethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound is described in Example 72. 4- (3,4,5-trimethoxy-phenyl) -2H-pyrazol-3-ylamine is used instead.

Stage 110.1: 4- (3,4,5-Trimethoxy-phenyl) -2H-pyrazol-3-ylamine The title compound is prepared as described in Example 1 (Stages 1.4 and 1.2); (3,4,5-Trimethoxy-phenyl) -acetonitrile is used instead.

Example 111
6- (3,4-Difluoro-phenyl) -5-methyl-3- (3,4,5-trimethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound was prepared in Example 72. 4- (3,4,5-trimethoxy-phenyl) -2H-pyrazol-3-ylamine (Example 110; Stage 110.1) and 2- (3,4-difluoro-phenyl) -3-Oxo-butyronitrile (Example 98; Stage 98.1) is used instead.

Example 112
6- (3-Chloro-phenyl) -3- (3-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound is prepared as described in Example 72. 4- (3-methoxy-phenyl) -2H-pyrazol-3-ylamine is used instead.

Stage 112.1: 4- (3-Methoxy-phenyl) -2H-pyrazol-3-ylamine The title compound is prepared as described in Example 1 (Stages 1.4 and 1.2); -Phenyl) -acetonitrile is used instead.

Example 113
6- [7-Amino-3- (3,4-dimethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-6-yl] -pyridin-2-ol The title compound is prepared as described in Example 1. 2- (6-hydroxy-pyridin-2-yl) -3-oxo-propionitrile and 4- (3,4-dimethoxy-phenyl) -2H-pyrazol-3-ylamine (Example 93; Stage 96) Use 1) instead.

Example 114
6-Benzyl-3- (3,4-dimethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound is prepared as described in Example 93; 4- (3,4-dimethoxy -Phenyl) -2H-pyrazol-3-ylamine (Example 93; Stage 93.1) is used instead.

Example 115
3- (3,4-Dimethoxy-phenyl) -6- (3-fluoro-benzyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine The title compound is prepared as described in Example 114; (3-Fluoro-benzyl) -3-oxo-propionitrile is used instead.

Example 116
Tablet 1 containing a compound of formula (I)
A tablet of the following composition containing 50 mg of any of the compounds of formula (I) described in Example 1-115 above as an active ingredient is prepared in a conventional manner:

Production : The active ingredient is combined with a portion of wheat starch, lactose and colloidal silica, and the mixture is sieved. A further portion of the wheat starch is mixed with 5 times the amount of water on a water bath to make a paste, and the initially made mixture is kneaded with this paste until a weak plastic mass is formed.
The dried granules are passed through a sieve having a mesh size of 3 mm, mixed with the remaining premixed mixture of corn starch, magnesium stearate and talc (1 mm sieve) and compressed to form a slightly biconvex tablet.

製造：活性成分を担体物質と混合し、打錠機(Korsch EKO, Stempeldurchmesser 10mm)の手段により圧縮する。 Example 117
Tablet 2 containing a compound of formula (I)
A tablet containing 100 mg of any one of the compounds of formula (I) described in Example 1-115 above as active ingredient is prepared according to standard methods with the following composition:

Production : The active ingredient is mixed with the carrier material and compressed by means of a tableting machine (Korsch EKO, Stempeldurchmesser 10 mm).

製造は、成分を混合し、それらをサイズ１のゼラチンカプセルに充填することにより行う。 Example 118
Capsules Capsules of the following composition containing 100 mg of any of the compounds of formula (I) described in Example 1-115 above as active ingredients are prepared according to standard methods:

Manufacture is performed by mixing the ingredients and filling them into size 1 gelatin capsules.

Example 119
Kinase inhibition by the compounds of the present invention The activity of the compounds of the above examples was measured using the test methods described above, and the activities of the compounds of the following formula (I) against the following kinases are shown in Table 4 ("x" , Showing activity against the kinase). “Activity” as used herein is defined as the IC ₅₀ value for kinase inhibition of 10 μM or less:

Claims (14)

Formula (I) for the treatment of protein kinase dependent diseases:

[Where,
R ₂ is H; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted aliphatic residue; functional group; or a pyrazolo [1,5a] pyrimidinyl ring linked by one linking group or atom. Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted aliphatic residue;
R ₃ is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aliphatic residue, functional group, substituted or optionally linked to a pyrazolo [1,5a] pyrimidinyl ring by a linking group or atom Can be an unsubstituted aliphatic residue,
At least one of R ₂ or R ₃ is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or substituted or unsubstituted heteroaryl linked to the pyrazolo [1,5a] pyrimidinyl ring by one linking group or atom Or a substituted or unsubstituted aryl residue;
A is H, halogen (eg bromo), aliphatic moiety, functional group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and R ₁ is H, halogen or lower alkyl. ]
Or a pharmaceutically acceptable salt thereof. For the treatment of protein kinase dependent diseases,
R ₂ is H; lower alkyl; cycloalkyl; benzyl; benzothienyl, indyl substituted with lower alkyl, pyridyl or thiazolyl optionally substituted with lower alkyl; unsubstituted phenyl or; halo, hydroxy, alkoxy, benzyl With phenyl substituted with one or two substituents selected from the group consisting of oxy, cycloalkyl, amino, acetylamino, lower alkylsulfonamide and benzenesulfonamide substituted with one or two halo Yes;
R ₃ is H; lower alkyl optionally substituted with halo; phenyl, pyridyl, or oxazolyl;
A is
(a) H; halo; benzothienyl; pyridyl; methylpiperazinylphenoxyl; indolyl substituted with lower alkyl;
(b) one selected from unsubstituted or mono-, di- or tri-lower alkoxy, di-lower alkylaminyl, morpholinyl, which may optionally be disubstituted by alkyl Or phenyl substituted with more substituents,
Piperazinyl substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkyl piperazinyl, pyrrolidinyl, dialkylaminyl and lower alkanol; and R ₁ is H is there,
The compound according to claim 1, or a pharmaceutically acceptable salt thereof.   Kinase dependent diseases are c-Abl, Bcr-Abl, c-Kit, c-Raf, Flt-1, Flt-3, Her-1, KDR, PDGFR-kinase, c-Src, RET-receptor kinase, FGF -R1, FGF-R2, FGF-R3, FGF-R4, Ephrin receptor kinase (eg, EphB2 kinase, EphB4 kinase and related Eph kinase), casein kinase (CK-1, CK-2, G-CK), Pak , ALK, ZAP70, Jak1, Jak2, Axl, Cdk1, cdk4, cdk5, Met, FAK, Pyk2, Syk, insulin receptor kinase, Tie-2 or Bcr-Abl, c-Kit, c-Raf, Flt-3, Constitutives of kinases such as FGF-R3, PDGF-receptor, RET, and Met Dependent on activated mutants (activated kinases), and (especially abnormally highly expressed or activated) kinase-dependent diseases or diseases dependent on activation of the kinase pathway, or described immediately above Use according to claim 1 or 2, wherein the disease is dependent on two or more of any of the kinases.   Kinase-dependent diseases that depend on c-abl, Flt-3, KDR, c-Src, RET, EphB4, c-kit, cdk1, FGFR-1, c-raf, Her-1, Ins-R or Tek Use according to any of claims 1 to 3, wherein   The disease to be treated is a proliferative disease, preferably a benign or especially malignant tumor, more preferably brain, kidney, liver, adrenal gland, bladder, breast, stomach (especially stomach tumor), ovary, colon, rectum, prostate, pancreas, lung , Vaginal, thyroid carcinoma, sarcoma, glioblastoma, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, or head and neck tumor, epithelial hyperproliferation, especially psoriasis, prostate enlargement, especially epithelial Use according to any of claims 1 to 4, which is of characteristic overgrowth, preferably breast cancer or leukemia.   Diseases to be treated include psoriasis; Kaposi's sarcoma; restenosis, eg, stent-induced restenosis; endometriosis; Crohn's disease; Hodgkin's disease; leukemia; arthritis such as rheumatoid arthritis; angioma; Eye diseases such as retinopathy and neovascular glaucoma; kidney diseases such as glomerulonephritis; diabetic nephropathy; malignant nephrosclerosis; thrombotic microangiopathy syndrome; transplant rejection and glomerulopathy; Fibrous diseases such as; mesangial cell proliferative diseases; arteriosclerosis; induced by persistent angiogenesis such as nerve tissue injury; and for inhibition of vascular reocclusion after balloon catheterization Wound healing as an immunosuppressive agent, for use after insertion of mechanical devices such as stents, for maintaining vascular prosthesis or vascular opening As adjuvants, as well as for the treatment of senile plaques and contact dermatitis, use according to any of claims 1 to 5. Formula (I):

[Where,
R ₂ is H; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; aliphatic residue; functional group; or substituted or attached to the pyrazolo [1,5a] pyrimidinyl ring by one linking group or atom Unsubstituted aryl, substituted or unsubstituted heteroaryl or an aliphatic residue;
R ₃ can be H, substituted or unsubstituted aryl, heteroaryl, aliphatic residue, functional group, or an aliphatic residue linked to a pyrazolo [1,5a] pyrimidinyl ring by a linking group or atom;
At least one of R ₂ or R ₃ is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or substituted or unsubstituted heteroaryl linked to the pyrazolo [1,5a] pyrimidinyl ring by one linking group or atom Or a substituted or unsubstituted aryl residue. Provided that both R ₂ and A are not simultaneously unsubstituted phenyl;
A is H, halogen (eg bromo), aliphatic moiety, functional group, substituted or unsubstituted aryl or heteroaryl; and R ₁ is H, halogen or lower alkyl. ]
Or a pharmaceutically acceptable salt thereof. R ₂ is H; lower alkyl; cycloalkyl; benzyl; benzothienyl, indyl substituted with lower alkyl, pyridyl or thiazolyl optionally substituted with lower alkyl; unsubstituted phenyl or; halo, hydroxy, alkoxy, benzyl With phenyl substituted with one or two substituents selected from the group consisting of oxy, cycloalkyl, amino, acetylamino, lower alkylsulfonamide and benzenesulfonamide substituted with one or two halo Yes;
R ₃ is H; lower alkyl optionally substituted with halo; phenyl, pyridyl, or oxazolyl;
A is
(a) H; halo; benzothienyl; pyridyl; methylpiperazinylphenoxyl; indolyl substituted with lower alkyl;
(b) one selected from unsubstituted or mono-, di- or tri-lower alkoxy, di-lower alkylaminyl, morpholinyl, which may optionally be disubstituted by alkyl Or phenyl substituted with more substituents,
Piperazinyl substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkyl piperazinyl, pyrrolidinyl, dialkylaminyl and lower alkanol; and R ₁ is H is there;
Provided that both R ₂ and A are not simultaneously unsubstituted phenyl,
8. A compound according to claim 7. 3- {7-amino-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (3-Benzyloxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl} -phenol;
6- (3-methoxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3,5-dimethoxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Benzyloxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (4-Chloro-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- [4- (4-Methyl-piperazin-1-yl) -phenyl] -6-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
5-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -6-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -5-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
N- {4- [7-amino-3- (4-dimethylamino-phenyl) -pyrazolo [1,5-a] pyrimidin-6-yl] -phenyl} -2,3-dichloro-benzenesulfonamide;
4-chloro-benzenesulfonic acid 4- [7-amino-3- (4-dimethylamino-phenyl) -pyrazolo [1,5-a] pyrimidin-6-yl] -phenyl ester;
6- (4-Methoxy-phenyl) -5-methyl-3-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- (4-methoxy-phenyl) -5-methyl-6-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (4-Bromo-phenyl) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (4-Bromo-phenyl) -5-methyl-3-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (2,6-dichloro-phenyl) -3-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- (3-methoxy-phenyl) -6-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
3-bromo-5-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6-benzo [b] thiophen-3-yl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- (4-bromo-phenyl) -5-phenyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- [4- (4-Methyl-piperazin-1-yl) -phenyl] -6-thiophen-3-yl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
3-benzo [b] thiophen-3-yl-6- (3-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6-benzo-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-methoxy-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (1-methyl-1H-indol-3-yl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (4-methoxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (2-methoxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-methoxy-phenyl) -3-pyridin-3-yl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- {7-amino-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (3-Benzyloxy-phenyl) -3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- {7-amino-3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (2-Benzyloxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
2- {7-amino-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (4-Benzyloxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
4- {7-amino-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (2-Benzyloxy-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
2- {7-amino-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (4-Benzyloxy-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
4- {7-amino-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (2-Benzyloxy-phenyl) -3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
2- {7-amino-3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (4-Benzyloxy-phenyl) -3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
4- {7-amino-3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (3-Benzyloxy-phenyl) -3- [1-methyl-1H-indol-3-yl) -pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- [7-amino-3- (1-methyl-1H-indol-3-yl) -pyrazolo [1,5-a] pyrimidin-6-yl] -phenol;
3- [7-amino-3-pyridin-3-yl-pyrazolo [1,5-a] pyrimidin-6-yl] -phenol;
6- (3-Benzyloxy-phenyl) -3- (2-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- [7-amino-3- (2-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-6-yl] -phenol;
3- [3- (4-Methyl-piperazin-1-yl) -phenyl] -6-thiophen-3-yl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- (2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -6-thiophen-3-yl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- [4- (4-Methyl-piperazin-1-yl) -phenyl] -6-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-amino-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-amino-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (2-amino-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- [4- (4-Methyl-piperazin-1-yl) -phenyl] -6- (4-methyl-thiazol-2-yl) -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6-benzo [b] thiophen-3-yl-3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6-benzo [b] thiophen-3-yl-3- [4-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- (3-methoxy-phenyl) -6-thiophen-3-yl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Benzyloxy-phenyl) -3- (3-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- [7-amino-3- (3-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-6-yl] -phenol;
(4- {7-amino-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenyl) -carbamic acid ethyl ester 6- (3-Chloro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-phenyl) -5-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-phenyl) -3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidine-7- Ilamine;
6- (3-Chloro-phenyl) -3- [2-methoxy-4- (4-methyl-piperazin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidine-7- Ilamine;
3- {7-amino-3- [2-methoxy-4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol;
6- (2-Chloro-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (2-Chloro-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (4-Fluoro-phenyl) -5-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (4-Fluoro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-phenyl) -5-methyl-3- {3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-yl] -phenyl} -pyrazolo [1,5- a] pyrimidin-7-ylamine;
6- (3-Chloro-4-fluoro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] pyrazolo [1,5-a] pyrimidin-7-ylamine ;
6- (3-Chloro-4-fluoro-phenyl) -5-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine-7- Ilamine;
6- (3-Bromo-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Bromo-benzyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Bromo-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-phenyl) -5-methyl-3- (3-morpholin-4-yl-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine; 6- (3-chloro-phenyl) ) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-phenyl) -3- [3-((2R, 6S) -2,6-dimethyl-morpholin-4-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] Pyrimidine-7-ylamine;
2- (4- {3- [7-Amino-6- (3-chloro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-3-yl] -phenyl} -piperazin-1-yl ) -Ethanol;
6-benzyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-fluoromethyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-4-fluoro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-4-fluoro-phenyl) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (4-Fluoro-phenyl) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
2- (4- {3- [7-Amino-6- (4-fluoro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-3-yl] -phenyl} -piperazin-1-yl ) -Ethanol;
6- (3,4-difluoro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3,4-difluoro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
2- (4- {3- [7-Amino-6- (3-chloro-4-fluoro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-3-yl] -phenyl} -piperazine -1-yl) -ethanol;
2- (4- {3- [7-amino-6- (3,4-difluoro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-3-yl] -phenyl} -piperazine-1 -Yl) -ethanol;
6- (3-Chloro-phenyl) -5-methyl-3- [3- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine-7- Ilamine;
6- (4-Fluoro-phenyl) -5-methyl-3- [3- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine-7- Ilamine;
6- (3-Chloro-phenyl) -3- [3- (4-diethylamino-piperidin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
3- [3- (4-diethylamino-piperidin-1-yl) -phenyl] -6- (4-fluoro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (4-Fluoro-phenyl) -5-methyl-3- [3- (4-methyl-4-oxy-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine-7- Ilamine;
6- (4-Fluoro-phenyl) -5-methyl-3- [3- (4-methyl-1,4-dioxy-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine- 7-ylamine;
6- (3-Chloro-phenyl) -3- [3- (4-dimethylamino-piperidin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3,4-Difluoro-phenyl) -3- [3- (4-dimethylamino-piperidin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine ;
6- (3-Chloro-phenyl) -5-methyl-3- (3,4,5-trimethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine; 6- (3,4-difluoro -Phenyl) -5-methyl-3- (3,4,5-trimethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- (3-Chloro-phenyl) -3- (3-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-ylamine;
6- [7-amino-3- (3,4-dimethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-6-yl] -pyridin-2-ol;
6-benzyl-3- (3,4-dimethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine; and 3- (3,4-dimethoxy-phenyl) -6- (3-fluoro- A compound selected from the group consisting of (benzyl) -pyrazolo [1,5-a] pyrimidin-7-ylamine.   Use of a compound according to claim 7, 8 or 9 in the manufacture of a pharmaceutical composition.   A pharmaceutical composition comprising the compound according to claim 7, 8 or 9.   A pharmaceutical composition comprising a compound according to claim 7, 8 or 9 and an acceptable pharmaceutical carrier.   Use of a compound according to claim 1 or 2 for the manufacture of a pharmaceutical composition for the treatment of kinase dependent diseases. A process for producing a compound according to claim 7, 8 or 9, comprising:
(a) reacting a nitrile, A—CH ₂ —C≡N, with ethyl formate in the presence of an organic solvent to form a substituted 3-oxo-propionitrile;
(b) The substituted 3-oxo-propionitrile of step (a) is condensed with hydrazine monohydrate in an organic solvent to give a compound of formula (III):

Of 2H-pyrazol-3-ylamine,
(d) The substituted nitrile is formylated in the presence of ethanolate and formic acid ethyl ester to give a compound of formula (II):

The 3-oxo-propionitrile of
(c) condensing 3-oxo-propionitrile of formula (II) and 2H-pyrazol-3-ylamine of formula (III) in the presence of an organic solvent to form a compound of formula (I). Including.