MXPA06008303A - Pyrazolo[1,5-a]pyrimidin-7-yl-amine derivatives for use in the treatment of protein kinase dependent diseases - Google Patents

Abstract

The invention relates to the use of pyrazolo[1,5a]pyrimidin-7-yl amine compounds and salts thereof in the treatment of kinase dependent diseases and for the manufacture ofpharmaceutical preparations for the treatment of said diseases, novel pyrazolo[1,5a]pyrimidin-7-yl amine compounds, and a process for the preparation of the novel pyrazolo[1,5a]pyrimidin-7-yl amine compounds.

Description

DERIVATIVES OF PIRAZOLO [1, 5-A] PYRIMIDIN-7-IL-A INA FOR USE IN THE TREATMENT OF DEPENDENT DISEASES OF THE PROTEI NA QUINASA FIELD OF THE INVENTION The invention relates to the use of pyrazolo [1, 5-a] pyrimidin-7-M-amine derivatives in the treatment of kinase protein dependent diseases, or for the manufacture of pharmaceutical compositions to be used in the treatment of these diseases, methods of using the pyrazolo [1, 5-a] pyrimidin-7-yl-amine derivatives in the treatment of these diseases, pharmaceutical preparations comprising pyrazolo derivatives [1, 5] a] pyrimidin-7-α-amine for the treatment of these diseases, novel pyrazolo [1, 5-a] pyrimidin-7-yl-amine derivatives, processes for the manufacture of the novel pyrazolo derivatives [1, 5] a] pyrimidin-7-yl-amine, and pharmaceutical preparations, to the use or methods of use of the pyrazolo [1, 5-a] pyrimidin-7-yl-amine derivatives as mentioned above , and / or to these pyrazolo [1, 5-a] pyrimidin-7-α-amino derivatives for use in the treatment of the animal or human body.

BACKGROUND OF THE INVENTION Pirazolo [1, 5-a] pyrimidin-7-yl-amine derivatives have been reported in the literature as legandos of benzodiazepine receptors (eg, S. Sellen et al., Bioorg. Med. Chem. 7 (12), 2705-1 1 (1999)), as antagonists of the factor of release of corticotropin (European Patent Number EP 1097709), as angiotensin II receptor antagonists (eg, S. Takeshi et al., Japan Pharm. Bull. 47 (7), 928-38 (1999)), as inhibitors of monoxide synthase (Japanese Patent Number JP 10101671), as analgesics (International Publication Number WO) 9535298), as fungicides (European Patent Number EP 071792), or as anti-inflammatory reagents (International Publication Number WO 9218504). We have now found that the pyrazolo [1, 5-ajpyrimidin-7-yl-amine residue can also be used as a template for the design of potent kinase inhibitors. In view of the large number of protein kinase inhibitors, and the multitude of proliferative diseases and other protein kinase related diseases, there is an ever-existing need to provide novel classes of compounds that are useful as protein kinase inhibitors, and therefore both, in the treatment of related diseases.

What is desirable from the point of view of the possible treatments of prolific diseases, is to have a large number of classes of compounds, each tailored for specific protein kinases or protein kinase classes, thus allowing to reach to specific treatments. Therefore, there is a strong need to find new classes of compounds that allow these specific inhibitory effects to occur.

BRIEF DESCRIPTION OF THE INVENTION Surprisingly, it has been found that the class of pyrazolo [1, 5-a] pyrimidin-7-yl-amine compounds described herein, especially the novel compounds that fall under this class , have pharmaceutically convenient properties, which allow the inhibition of specific types or classes or groups of kinases, especially c-Abl, Bcr-Abl, c-Kit, c-Raf, Flt-1, Flt-3, KDR, Her- 1, PDGFR-quinase, c-Src, RET receptor kinase, FGF-R1, FGF-R2, FGF-R3, FGF-R4, ephrin receptor kinases (e.g., 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 constitutively activating mutations of kinases (activating kinases), such as Bcr-Abl, c-Kit, c-Raf, Flt-3, FGF-R3, PDGF, RET, and Met receptors. The class of pyrazolo [1, 5-a] pyrimidin-7-yl-amine compounds described herein, further inhibit mutants of such kinases. In addition to this established activity, the pyrazolo [1, 5-a] pyrimidin-7-yl-amino derivatives have the advantage that their base structure allows having a large number of substitution patterns that offer a wide possibility of achieving a tuning of the interaction specific with the binding site of the kinase or targeted kinases, opening up this new perspective, and providing kinase inhibitors of different degrees of specificity. In view of these activities, the compounds can be used for the treatment of diseases related to a especially aberrant or excessive activity of these types of kinases, especially those mentioned.

DETAILED DESCRIPTION OF THE INVENTION In one embodiment, the invention relates to the use of a compound of the formula (I): wherein: R2 is H; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; a substituted or unsubstituted aliphatic residue; a functional group; or a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted aliphatic residue which is connected by a linking group or atom to the pyrazolo [1,5-a] pyrimidine ring; and R3 may be H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted aliphatic residue, a functional group, or an unsubstituted or substituted aliphatic residue which may be connected by a group or connecting atom to the pyrazolo ring [ 1, 5-a] pyrmidine, at least one of R 2 or R 3 is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or substituted or unsubstituted heteroaryl, or a substituted or unsubstituted aryl residue that is connects by a group or connecting atom with the pyrazolo [1,5-a] pyrimidinyl ring; A is H, halogen (such as bromine), an aliphatic moiety, a functional group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and Ri is H, halogen, or lower alkyl; or pharmaceutically acceptable salts thereof, for the treatment of a protein kinase dependent disease. A preferred embodiment is the use of a compound according to the above, wherein: R2 is H; lower alkyl; cycloalkyl; benzyl; benzothienyl, indilyl substituted by lower alkyl, pyridyl or thiazolyl optionally substituted by lower alkyl; unsubstituted phenyl or phenyl substituted by 1 or 2 substituents selected from the group consisting of: halogen, hydroxyl, alkoxy, benzyloxy, cycloalkyl, amino, acetylamino, lower alkyl-sulfonamide, and benzenesulfonamide substituted by 1 or 2 halogens; R3 is H; lower alkyl optionally substituted by halogen; phenyl, pyridyl, or oxazolyl; A is: (a) H; halogen; benzothienyl; pyridyl, methyl-piperazinyl-phenoxy; indolyl substituted with lower alkyl; (b) phenyl which is substituted or unsubstituted with one or more of the substituents selected from the group consisting of: mono-, di-, or tri-lower alkoxy, lower alkyl-amino, morpholinyl which is optionally di-substituted by alkyl, piperazinyl which is substituted with one or more of the substituents selected from the group consisting of: lower alkyl, lower alkoxy, lower alkyl-piperazinyl, pyrrolidinyl, dialkyl-aminyl, and lower alkanol; Y or pharmaceutically acceptable salts thereof, for the treatment of a protein kinase dependent disease. A protein kinase dependent disease is preferably one that depends on 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 kinases (e.g., 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 constitutively activating mutations of kinases (activating kinases), such as Bcr-Abl, c-Kit, c-Raf, Flt- 3, FGF-R3, PDGF, RET, and Met receptors, and a kinase dependent disease (especially highly expressed or activated in an aberrant form), or a disease dependent on the activation of kinase pathways, or a disease dependent on any two or more of the kinases just mentioned. A protein kinase dependent disease is more preferably one that depends on c-abl, Flt-3, KDR, c-Src, RET, EphB4, c-kit, cdk-1, FGFR-1, c-raf, Her-1, Ins-R, or Tek. More preferably, the disease to be treated is a proliferative disease, preferably a benign or especially malignant tumor, more preferably carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach (especially tumors gastric), ovaries, colon, rectum, prostate, pancreas, lung, vagina, thyroid, sarcoma, glioblastomas, multiple myeloma, or gastrointestinal cancer, especially carcinoma of the colon or colo-rectal adenoma, or a tumor of the neck and head, epidermal hyperproliferation, especially psoriasis, prostate hyperplasia, a neoplasm, especially of epithelial character, preferably mammary carcinoma, or a leukemia. In a further embodiment, the disease to be treated is a disease that is triggered by persistent angiogenesis, such as psoriasis.; Kaposi's sarcoma; restenosis, for example stent-induced restenosis (vascular implant); endometriosis; Crohn's disease; Hodgkin's disease; leukemia, arthritis, such as rheumatoid arthritis; hemangioma; angiofibroma; diseases of the eyes, such as diabetic retinopathy and neovascular glaucoma; kidney diseases, such as glomerulonephritis; diabetic nephropathy, malignant nephrosclerosis; thrombotic mycroangiopathic syndromes; transplant rejections and glomerulopathy; fibrotic diseases, such as cirrhosis of the liver; proliferative diseases of mesangial cells; arteriosclerosis; nerve tissue injuries. The compounds of the present invention can also be used to inhibit reocclusion of vessels after balloon catheter treatment, for use in vascular prostheses, or after inserting mechanical devices to keep vessels open, such as, for example, stents (vascular implants), as immunosuppressants, as an auxiliary in the healing of wounds without a scar, and for the treatment of age spots and contact dermatitis. In a further embodiment, the invention relates to a compound of the formula I: wherein: R2 is H; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; an aliphatic residue; a functional group; or a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or aliphatic residue which is connected by a group or connecting atom to the pyrazolo [1, 5a] pyrimidinyl ring; R3 can be H, substituted or unsubstituted aryl, heteroaryl, an aliphatic residue, a functional group or an aliphatic residue which can be connected by a group or connecting atom to the pyrazolo [1, 5a] pyrimidinyl ring. at least one of R2 or R3 is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or a substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl residue it is connected by a group or connecting atom to the pyrazolo [1, 5a] pyrimidinyl ring, and in the understanding that both R 2 and A can not both be unsubstituted phenyl; A is H, halogen (such as bromine), an aliphatic moiety, a functional group, aryl or substituted or unsubstituted heteroaryl; and R is H, halogen, or lower alkyl; or a pharmaceutically acceptable salt thereof. A preferred embodiment is a compound according to the above, wherein: R2 is H; lower alkyl; cycloalkyl; benzyl; benzothienyl; indyl substituted by lower alkyl, pyridyl or thiazolyl optionally substituted by lower alkyl; n-substituted phenyl or phenyl substituted by 1 or 2 substituents selected from the group consisting of: halogen, hydroxy, alkoxy, benzyloxy, cycloalkyl, amino, acetylamino, lower alkyl-sulfonamide, and benzenesulfonamide substituted by 1 or 2 halogens; R3 is H; lower alkyl optionally substituted by halogen; phenyl; pyridyl, or oxalyl; A is: (a) H; halogen, benzothienyl; pyridyl; methyl-piperazinyl-phenoxy; indolyl substituted with lower alkyl; (b) phenyl which is substituted or unsubstituted with one or more of the substituents selected from the group consisting of: mono-, di-, or tri-lower alkoxy, di-lower alkyl-amino, morpholinyl which is optionally -replaced by alkyl, piperazinyl which is substituted with one or more of the substituents selected from the group consisting of: lower alkyl, lower alkoxy, lower alkyl-piperazinyl, pyrrolidinyl, dialkyl-aminyl, and lower alkanol; Y and with the understanding that both R2 and A can not both be unsubstituted phenyl. More preferably, the compound is selected from the group consisting of: 3-. { 7-amino-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -prazorazo- [1,5-a] -pyridin-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) -4- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3,5-d-methoxy-f-enyl) -3- [4- (4-methyl-piperazin-1-M) -phenyl] -p -razolo [1, 5-a] pyrimidin-7-yl-amine; 6- (3-benzyloxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-ajpyrimidin-7-yl-amine; 6- (4-chloro-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-Chloro-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -prazolo [1, 5-a] pyrimid-7-yl- Amy 3- [4- (4-methyl-piperazin-1-yl) -phenyl] -6-phenyl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; -methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -6-phenyl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6-methyl-3- [4- (4-methyl-piperazin-1-l) -phenyl] -5-phenyl-pyrazolo [1, 5a] pyrimidin-7-yl-amine; N-. { 4- [7-amino-3- (4-dimethylamino-phenyl) -pyrazolo [1,5-a] pyrimidin-6-yl] -phenyl] -2,3-dichloro-benzenesulfonamide; 4-Chloro-benzenesulfonic acid ester of 4- [7-amino-3- (4-dimethylamino-phenyl) -pyrazolo [1,5-a] pyrimidin-6-yl] -phenyl ester; 6- (4-methoxy-f enyl) -5-methyl-3-f in i-pyrazolo [1,5-a] pyrimidin-7-i-amine; 3- (4-methoxy-phenyl) -5-methyl-6-phenyl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (4-Bromo-phenyl) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1, 5-a] pyrimidin-7-yl-amine; 6- (4-bromo-phenyl) -5-methyl-3-phenyl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (2,6-dichloro-phenyl) -3-phenyl-pyrrazolo [1,5-a] pyrimidin-7-yl-amine; 3- (3-methoxy-phenyl) -6-phenyl-pyrrazolo [1,5-a] pyrimidin-7-yl-amino; 3-bromo-5-phenyl-pyrazolo [1, 5-a] pyrimidin-7-yl-amine; 6-benzo [b] thiophen-3-yl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1, 5-a] pyrimidin-7-yl-amine; 3- (4-bromo-phenyl) -5-phenyl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; 3- [4- (4-methyl-piperazin-1-yl) -phenyl] -6-thiophen-3-yl-p -razolo- [1, 5-a] pyrimidin-7-yl-amine; 3-benzo [b] thiophen-3-yl-6- (3-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6-Benzo-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimid-7-yl-amine; 6- (3-methoxy-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (1-methy1-1 H-indol-3-yl) -3- [4- (4-methyl-piperazin-1-l) -phenyl] -pyrrazolo [1, 5 a] pyrimidin-7-yl-amine; 6- (4-methoxy-phenyl) -3- [4- (4-methyl-piperazin-1-y) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (2-methoxy-phenyl) 3- [4- (4-methyl-piperazin-1-l) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-methoxy-phenyl) -3-pyrimidin-3-yl-pyrrazolo [1, 5-a] pyrimidin-7-yl-amine; 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-i-amine; 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-l) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 2-. { 7-amino-3- [4- (4-methyl-piperazin-1 -yl) -phenyl] -pyrazolo [1,5-a] pyrmidin-6-l} -fenoI; 6- (4-benzyloxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 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] -prazora [1,5-a] pyrimidin-7-yl-amine; 2-. { 7-amino-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -p -razolo [1,5-a] pyridin-6-yl} -phenol; 6- (4-benzyloxy-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 4-. { 7-amino-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -p -razolo [1,5-a] pyridin-6-yl} -phenol; 6- (2-benzyloxy-phenyl) -3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 2-. { 7-amino-3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -p -razolo [1,5-a] pyrimidin-6-yl} -phenol; 6- (4-benzyloxy-phenyl) -3- [2-methoxy-5- (4-methyl-p-eperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl -amine; 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-1 H-indol-3-yl) -prazora [1,5-a] pyrmidin-7-yl-amine; 3- [7-amino-3- (1-methyl-1 H -indoI-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-yl-amine; 3- [7-amino-3- (2-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-6-yl] -f-enol; 3- [3- (4-methyl-p-piperazin-1-yl) -phenyl] -6-thiophen-3-yl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; 3- (2-methoxy-5- (4-methyl-piperazin-1-l) -phenyl] -6-thiophen-3-yl-pyrazolo [1,5-a] pyrimidin-7-yl -amine; 3- [4- (4-methyl-piperazin-1-yl) -phenyl] -6-pyridin-4-yl-p -razolo [1, 5-a] pyridm-d-n-7- I-amine; 6- (3-Amino-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -prazolo [1,5-ajpyrimid-n-7-i-amine]; 6- (3-amino-phenyI) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -prazora [1,5-a] pyrimidin-7-yl-amine; 6- (2-Amino-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 3- [4- (4-Methy1-piperazin-1-yl) -phenyl] -6- (4-methyl-thiazol-2-yl) -pyrazolo [1,5-a] pyrimidine-7- i I amine; 6-benzo [b] thiophen-3-yl-3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine-7 -I-amine; 6-benzo [b] thiophen-3-yl-3- [4-methoxy-phenyl) -pyrazolo [1, 5-a] pyrimidin-7-yl-amine; 3- (3-methoxy-phenyl) -6-thiophen-3-yl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-benzyloxy-phenyl) -3- (3-methoxy-phenyl) -pyrazolo [1, 5-a] pyrimidin-7-yl-amine; 3- [7-amino-3- (3-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-6-yl] -phenoyl; [4- {7-amino-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl] ethyl ester. .phenyl) -carbamic; 6- (3-Chloro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine-7-yl- amine; 6- (3-chloro-phenyl) -5-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-ami na 6- (3-Chloro-phenyl) -3- [2-methoxy-5- (4-methyl-p-pperazin-1-yl) -phenyl] -5-methyl-pyrrazolo [1-5 a] pyridin-7-yl-amine; 6- (3-chloro-phenyl) -3- [2-methoxy-4- (4-methyl-p-piperazin-1-l) -phenyl] -5-methyl- pyrazolo [1,5-a] pyrimidin-7-i-amine; 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-yl-amine; 6- (2-Chloro-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (4-Fluoro-phenyl) -5-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl -amina; 6 (4-fluoro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-chloro-phenyl) -5-metii-3-. { 3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-yl] -pheni} - pyrazolo [1,5-a] pyrimidn-7-α-amino; 6- (3-Chloro-4-fluoro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7 -am-amine; 6- (3-Chloro-4-fluoro-phenyl) -5-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -prazora [1,5-a] pyrimidine- 7-yl-amine; 6- (3-bromo-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1 -yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-i-amine; 6- (3-bromo-benzyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-bromo-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-Chloro-phenyl) -5-methyl-3- (3-morpholin-4-yl-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-Chloro-pheny!) -3- (4-methoxy-phenyl) -5-methyl-p-arazoo [1,5-a] pipmindin-7-ylamine; 6- (3-Chloro-phenyl) -3- [3 - ((2R, 6S) -2,6-dimethyl-morpholin-4-yl) -phenyl] -5-methyl-pyrazoic [1, 5-a] pyrimidin-7-yl-amine; 2- (4- { 3- [7-amino-6- (3-chloro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-3-yl] -pheni}. -piperazin -1-yl) -ethanol; 6-benzyl-3- [3- (4-meth1I-piperazin-1-l) -phenyl] -pyrazolo [1, 5-a] pyrimidin-7-yl-amine; 6- (3-chloro-phenyl) -3- (3,4-d-methoxy-f-enyl) -5-f-Ioromethyl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-chloro-phenyl) 3- (3,4-dimethoxy-phenyl) -5-methyl-p -razolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-chloro-4-fluoro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-methyl-pyrazoo [1,5-a] pyrimidin-7-yl-amine; 6- (3-Chloro-4-fluoro-phenyl) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimid i n-7-i-amine; 6- (4-fluoro-phenyl) -3- (4-methoxy-phenyl) -5-methy1-pyrazolo [1, 5-a] p1pmdin-7-yl-amine; 2- (4-. {3- [7-amino-6- (4-fluoro-phenyl) -5-methyl-pyrazolo [1, 5-a] pyrimidin-3-yl] -phenyl] -piperazine -1-yl) -ethanol; 6- (3,4-difluoro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl- amine; 6- (3,4-difluoro-phenyl) -3- (3,4-dimethoxyphenyl) -5-methylene-pyrazolo [1,5-a] pyrimidin-7-yl-amino; 2- (4-. {3- [7-amino-6- (3-chloro-4-fluoro-phenyl) -5-methyl-p-arazoo [1, 5 a] pyrimidin-3-yl] -phenyl} -piperazin-1-yl) -ethanol; 2- (4-. {3- [7-amino-6- (3,4-difluoro-phenyl) -5-methyl-pyrazolo [1, 5-a] pyrimidin-3-yl] -phenyl}. -piperazin-1 -iI) -ethane; 6- (3-Chloro-phenyl) -5-methyl-3- [3- (4-pyrroidin-1-yl-piperidin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7- il-amine; 6- (4-fluoro-phenyl) -5-methyI-3- [3- (4-pyrroliin-1-yl-p -peridin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine -7-i I-amine; 6- (3-chloro-phenyl) -3- [3- (4-diethylamino-piperidin-1-l) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; 3- [3- (4-diethyl-amino-piperidin-1-yl) -phenyl] -6- (4-fluoro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-yl- amine; 6- (4-fluoro-phenyl) -5-methyl-3- [3- (4-methyl-4-oxy-piperazin-1-yl) -phenyl] -prazora [1,5-a] pyrimidine-7- i I amine; 6- (4-fluoro-phenyl) -5-methyl-3- [3- (4-methyl-1,4-dyoxy-p-piperazin-1-yl) -phenyl] -pyrazolo [1, 5-a] pyrimidin-7-α-amine; 6- (3-Chloro-phenyl) -3- [3- (4-dimethylamino-piperidin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidin- 7-il-amine; 6- (3,4-difluoro-phenyl) -3- [3- (4-dimethylamino-piperidin-1-l) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidin-7-yl -amine; 6- (3-chloro-phenyl) -5-methyl-3- (3,4,5-trimethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3,4-difluoro-phenyl) -5-methyl-3- [3,4,5-trimethoxy-phenyl) -pyrazolo [1,5-a] pyridin-7-yl-amine; 6- (3-chloro-phenyl) -3- (3-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; 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-yl-amine; and 3- (3,4-dimethoxy-phenyl) -6- (3-fluoro-benzyl) -pyrazolo [1,5-a] pyrimidin-7-yl-amine. Still another embodiment is the use of a compound according to the above, in the preparation of a pharmaceutical composition. Still another embodiment is a pharmaceutical composition comprising a compound according to the foregoing. The pharmaceutical composition preferably comprises a compound according to the above, and an acceptable pharmaceutical carrier. In another embodiment, the use of a compound according to the foregoing is provided in the preparation of a pharmaceutical composition for use in the treatment of a kinase dependent disease. An additional embodiment is a process for preparing a compound according to the foregoing, which comprises: (a) reacting a nitrile, A-CH2-C = N, with ethyl formate in the presence of an organic solvent, to form a substituted 3-oxo-propionitrile, (b) condensing the 3-oxo-propionitriles of step (a) with hydrazine monohydrate in an organic solvent, to form a 2H-pyrazol-3-yl-amine of the formula (III): (d) forming a substituted nitrile in the presence of ethanolate and ethylester of formic acid, to prepare a 3-oxo-propionitrile of the formula (I I): (c) condensing the 3-oxo-propionitrile of the formula (I I) and the 2H-pyrazol-3-yl-amines of the formula (11) in the presence of an organic solvent, to form a compound of the formula (I). The invention relates in particular to pyrazolo [1,5-a] pyrimidin-7-yl-amine compounds of the formula (I): wherein: R2 is H; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; a substituted or unsubstituted aliphatic residue; a functional group; or a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted aliphatic residue that is connects by a group or connecting atom with the pyrazolo [1,5-a] pyrimidinyl ring; R3 is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted aliphatic residue, a functional group, or an aliphatic residue which may be connected by a protecting group or atom to the pyrazolo [1, 5-a ring ] pyrimidinyl, at least one of R2 or R3 is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or a substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl residue which is connected by a linking group or atom to the pyrazoo [1,5-a] pyrimidinyl ring; A is H; halogen (such as bromine), an aliphatic moiety, a functional group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R-, is H; halogen or lower alkyl, or pharmaceutically acceptable salts thereof, in the treatment of protein kinase-dependent diseases (especially protein tyrosine kinase), or for the manufacture of pharmaceutical compositions for use in the treatment of these diseases, methods of use of the compounds of the formula (I) in the treatment of such diseases, or pharmaceutical preparations comprising the compounds of the formula (I) for the treatment of these diseases. The present invention relates in particular to a compound of the formula (I), wherein R2 is H; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; a substituted or unsubstituted aliphatic residue; a functional group; or a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted aliphatic residue that is connected by a linking group or atom to the pyrazolo [1,5-a] pyrimidinyl ring; R3 is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted aliphatic residue, a functional group, or an aliphatic residue that can be connected by a group or connecting atom to the pyrazolo [1, 5-a ring ] pyrimidinyl, at least one of R2 or R3 is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or a substituted or unsubstituted heteroaryl or substituted or unsubstituted residue that is connected by a group or connecting atom to the pyrazolo [1,5-a] pyrimidinyl ring, and in the understanding that both R 2 and A can not both be phenyl unsubstituted A is H, halogen (such as bromine), an aliphatic moiety, a functional group, aryl or substituted or unsubstituted heteroaryl; and Ri is H, halogen or lower alkyl, or pharmaceutically acceptable salts thereof, in the treatment of protein kinase dependent diseases (especially protein tyrosine kinase), or for the manufacture of pharmaceutical compositions for use in the treatment of these diseases, methods of using the compounds of the formula (I) in the treatment of such diseases, pharmaceutical preparations comprising the compounds of the formula (I) for the treatment of These diseases, compounds of the formula (I) for use in the treatment of such diseases. The present invention also relates to a method for the treatment of kinase-dependent diseases, which comprises administering pyrazolo [1,5-a] pyrimidin-7-yl-amine compounds of the formula (I) to a blood animal. hot, especially a human being. The present invention also relates to pharmaceutical preparations comprising a pyrazole compound or [1], 5-a] pyrimidin-7-yl-amine of the formula (I), especially for the treatment of a kinase dependent disease, to novel pyrazolo [1,5-a] pyrimidin-7-yl-amine compounds of the formula (I), to a process for the manufacture of the pyrazolo [1, 5-a] pyrimidin-7-yl-amine compounds of the formula (I), and to novel starting materials and intermediates for their manufacture. The present invention also relates to the use of a compound of the formula I in the manufacture of a pharmaceutical preparation for the treatment of a kinase dependent disease. The general terms used hereinbefore and hereinafter, preferably within the context of this disclosure, have the following meanings, unless otherwise indicated: "Aryl" is an aromatic radical having 6 to 14 carbon atoms, especially phenyl, naphtyl, indenyl, azulenyl, or anthryl, and is unsubstituted or substituted by one or more, preferably 1 or 2 substituents, wherein the substituents are selected from any of the functional groups defined below, and including: halogen, lower alkyl, substituted alkyl, halo-lower alkyl, for example trifluoromethyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower alkoxy, hydroxy, other aryl, etherified or esterified hydroxy , amino, mono- or di-substituted amino, lower aminoalkyl, amino-lower alkoxy; acetyl-amino; amide, halogen, nitro, cyano, cyano-lower alkyl, carboxyl, esterified carboxyl, especially lower alkoxycarbonyl, for example methoxycarbonyl, n-propoxycarbonyl, or iso-propoxycarbonyl, alkanoyl, benzoyl, carbamoyl, Carbamoyl N-mono- or N, N-di-substituted, carbamates, esters of alkyl-carbamic acid, amidino, guanidino, urea, ureido, mercapto, sulfo, lower thioalkyl, sulfoamino, sulfonamide, benzosulfonamide, sulfonate, phenyle, benzyl, phenoxy, benzyloxy, thiophenyl, phenyl-thioalkyl, alkylthiophenyl, alkylthiophenyl, phenyl-sulfinyl, phenyl-lower alkyl-sulfinyl, alkylphenyl-sulfinyl, lower alkane-sulfonyl, phenyl-sulfonyl, phenyl-lower alkyl- sulfonyl, alkyl-phenyl-sulfonyl, halo-lower-mercaptoalkyl, lower-sulfonyl-haloalkyl, such as in particular trifluoromethanesulfonyl, dihydroxyboron (-B (OH) 2), heterocyclyl, and lower alkylenedioxyl bonded to the adjacent carbon of the ring or, such as methylenedioxyl, phosphono (- P (= O) (OH) 2), hydroxy-lower alkoxy-phosphoryl, or di-lower alkoxy-phosphoryl, carbamoyl, mono- or di-alkyl-carbamoyl, mono- or di-hydroxy-lower alkyl) -carbamoyl, or -NR R5, wherein R4 and R5 may be the same or different, and are independently H; lower alkyl (for example methyl, ethyl, or propyl); or R4 and R5, together with the N atom they form a 3- to 8-membered heterocyclic ring containing from 1 to 4 nitrogen, oxygen or sulfur atoms (eg, piperazinyl, lower alkyl-piperazinyl, azetidinyl, pyrrolidinyl, piperidino, morpholinyl, imidazolinyl). Aryl is more preferably phenyl which is unsubstituted or independently substituted by one or two substituents selected from a solubilizing group selected from the group consisting of: halogen (such as Cl, Br or F); hydroxyl; lower alkyl (such as lower alkyl of 1 to 3 carbon atoms or methyl); aryl (such as phenyl or benzyl); Not me; amino-lower alkyl (such as dimethyl amino); acetyl-amino; amino-lower alkoxy (such as ethoxy-amine); lower alkyl substituted (such as fluoro-ethyl); alkoxy (such as methoxy or benzyloxy, wherein the benzyl ring may be substituted or unsubstituted, such as 3,4-dichloro-benzyloxy); sulfoamino; substituted or unsubstituted sulfonamide (such as benzo-sulfonamide, chlorobenzenesulfonamide, or 2,3-dichloro-benzenesulfonamide); substituted or unsubstituted sulfonate (such as chlorophenyl sulfonate); substituted urea (such as 3-trifluoromethyl-phenyl-urea or 4-morpholin-4-yl-3-trifluoromethyl-phenyl-urea); alkylcarbamic acid ester or carbamates (such as ethyl-N-phenyl carbamate) or -R R5, wherein R4 and R5 may be equal or different, and are independently H; lower alkyl (e.g., methyl, ethyl, or propyl); or R and R5, together with the N atom form a 3- to 8-membered heterocyclic ring containing from 1 to 4 nitrogen, oxygen or sulfur atoms (eg, piperazinyl, lower alkyl-piperazinyl, pyridyl, indolyl, thiophenyl, thiazolyl, morpholinyl-N-methyl-piperazinyl, benzothiophenyl, azetidinyl, pyrrolinyl, piperidino or imidazolinyl), wherein, when R4 and R5, together with N form a heterocyclic ring, this ring may be substituted with 1, 2 or more of any of the substituents described herein, preferably piperazinyl, pyrrolidinyl, alkyl such as methyl, or hydroxy-alkyl such as ethanyl. Examples of the hetero ring formed by R4 and R5 together with N include morpholinyl, which may be substituted or unsubstituted with methyl or dimethyl, piperazinyl which may be unsubstituted or substituted with 1, 2, or 3 substituents, preferably methyl, oxy, or ethanol; or piperidinyl which may be unsubstituted or substituted with 1, 2, or 3 substituents, preferably pyrrolidinyl, amine, alkyl amine, methyl amine, dialkyl amine, dimethylamine or diethylamine; A heteroaryl group is preferably monocyclic, but may be bi- or tri-cyclic, and comprises from 3 to 24, preferably from 4 to 16 ring atoms, wherein at least one or more, preferably from 1 to 4, atoms of the ring carbon are replaced by a heteroatom selected from O, N, or S. Preferably, the heteroaryl group is selected from pyridyl, indolyl, pyrimidyl, pyrazolyl, oxazolyl, thiophenyl, benzothiophenyl, 2H-pyrrolyl, pyrrolyl , Midazolyl, benzimidazolyl, pyrazolyl, iodazolyl, purinyl, pyrazinyl, pyridazinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinoxylin, indolizinyl, 3H-indolyl, isoindolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolole, tetrazolyl, furazanil, and benzo [d] pyrazole. More preferably, the heteroaryl group is selected from the group consisting of pyridyl, n-dyl, pyrimidyl, pyrazolyl, oxazolyl, thiophenyl, or benzothiophenium. The heteroaryl group may be unsubstituted or substituted by one or more substituents selected from the group defined above as substituents for aryl, more preferably by hydroxyl, halogen, lower alkyl, such as methyl or lower alkoxy, such as methoxy or ethoxy. "Aliphatic", as used herein, refers to any non-aromatic carbon-based residue. Examples of the aliphatic residues include substituted or unsubstituted alkyl, cycloalkyl, alkenyl, and alkynyl. Alkyl includes lower alkyl, preferably alkyl with up to 7 carbon atoms, preferably 1 up to and including 5, and is linear or branched; Preferably, lower alkyl is pentyl, such as normal pentyl, butyl, such as normal butyl, secondary butyl, isobutyl, tertiary butyl, propyl, such as normal propyl, or isopropyl, ethyl or methyl. Preferably, lower alkyl is methyl, propyl, or tertiary butyl. A cycloalkyl group is preferably cyclopentyl, cyclohexyl, or cycloheptyl, and may be unsubstituted or substituted by one or more, especially 1 or 2 substituents selected from the group defined above as the substituents for aryl, more preferably by lower alkyl, such as methyl, lower alkoxy, such as methoxy or ethoxy, or hydroxyl. Alkenyl and alkynyl preferably have up to 7 atoms carbon, preferably from 1 up to and including 5, and can be linear or branched. Alkyl, cycloalkyl, alkenyl, and alkynyl can be substituted or unsubstituted, and, when substituted, they can be substituted with up to 3 substituents, including another alkyl, cycloalkyl, alkenyl, alkynyl, any of the substituents defined above for aryl, or any of the functional groups defined below. Halo or halogen is preferably fluorine, chlorine, bromine, or iodine, more preferably fluorine, chlorine or bromine. The term "atom or linking group", as used herein, includes alkyl (such as -CH 2 -); oxy -O-; keto -CO-; thio -S-sulfonyl -SO2-; sulfoxides -SO-; amines -NH- or -NR-; carboxylic acid alcohol; esters (-COO-); amides (-CONR-, -CONHR'-) sulfonamides (-SO2NH-, -SO2NR'-); sulfones (-SO2-); sulfoxides (-SO-) amino group; ureas (-NH-CO-NH-, -NR-CO-NH-, -NH-CO-NR-, -NR-CO-NR-); ethers (-O-); carbamates (-NH-CO-O-, -NR-CO-O-); or reversed amides, sulfonamides, and esters (-NH-CO-, -NR-CO-, -NH-SO2-, -NR-SO2-, -OOC-). The term "functional group" as used herein, includes: carboxylic acid; hydroxyl; halogen; cyano (-CN); ethers (-OR); ketones (-CO-R); esters (-COOR); amides (-CONH2, -CONHR, -CONRR '); thioethers (-SR); sulfonamides (-SO2NH2, -SO2NHR, -SO2NRR '); sulfones (-SO2-R); sulfoxides (-SO-R); amines (-NHR, NR'R); ureas (-NH-CO-NH2, -NH-CO-NHR); ethers (-O-R); halogens; carbamates (-NH-CO-OR); aldehyde function (-CHO); then also inverse amides; sulfonamides and esters (-NH-CO-R, -NH-SO2-R, -OOC-R); R and R 'are the same or different, and can be H, or are any aliphatic aryl or heteroaryl moiety, as defined above. When the plural form is used for compounds, salts, pharmaceutical preparations, diseases, and the like, it is also intended to mean a single compound, salt, or the like. The salts are in particular the pharmaceutically acceptable salts of the compounds of the formula I. These salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of the formula (I) with a basic nitrogen atom, especially the 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, phosphonic, sulphonic or sulphamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid , azelaic acid, mellic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymeleic acid, methylmaleic acid, cyclohexane carboxylic acid, adamantane carboxylic acid, benzoic acid, salicylic acid, -amino-salicylic acid, phthalic acid phenyl acetic acid, mandelic acid, cinnamic acid, methano- or ethanesulfonic acid, 2-hydroxy-ethane-2-sulphonic acid, ethane-1,2-di-phonic acid, benzenesulfonic acid, 2-naphthalene-2-acid sulfonic acid, 1,5-naphthalene-disulfonic acid, 2-, 3-, or 4-methylbenzenesulfonic acid, methyl sulfuric acid, ethyl sulfuric acid, dodecyl sulfuric acid, N-cyclohexyl sulfamic acid, N- acid methyl, N-ethyl, or N-propyl-sulfamic, or other organic protonic acids, such as ascorbic acid. In the presence of negatively charged radicals, such as carboxyl or sulfo, salts can also be formed with bases, for example metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium salts, magnesium, or calcium, or ammonium salts with ammonia or with suitable organic amines, such as tertiary monoamines, for example triethylamine or tri (2-hydroxyethyl) -amine, or heterocyclic bases, for example N-ethylpiperidine or N , N'-dimethyl-piperazine. When a basic group and an acid group are present in the same molecule, a compound of the formula (I) can also form internal salts. For purposes of isolation or purification, it is also possible to use pharmaceutically unacceptable salts, for example picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds (where applicable, in the form of pharmaceutical preparations) are employed, and accordingly, these are preferred. In view of the close relationship between the compounds in free form and those in the form of their salts, including salts that can be used as intermediates, for example in the purification or identification of the compounds, tautomers or tautomeric mixtures and their salts, any reference to the compounds hereinbefore and hereinafter, in particular to the compounds of the formula I, it is to be understood also to refer to the corresponding tautomers of these compounds, in particular of the compounds of the formula I, tautomeric mixtures of these compounds, in particular of the compounds of the formula I, or salts of any of them, as appropriate and convenient, and if not mentioned otherwise. When "a compound ..., a tautomer thereof, or a salt thereof," or the like, is mentioned, this means "a compound ..., a tautomer thereof, or a salt of the compound or tautomer". Any asymmetric carbon atom may be present in the (R), (S), or (R, S) configuration, preferably in the (R) or (S) configuration. If possible, substituents on a ring, on atoms with saturated bonds, if possible, may be present in the cis (= Z-) or trans (= E-) form. Accordingly, the compounds may be present as mixtures of isomers, or preferably as pure isomers, preferably as pure diastereomers of enantiomers, or as pure enantiomers. The present invention also relates to prodrugs of a compound of the formula (I) which is converted in vivo into the compound of the formula (I) as such. Any reference to a compound of the formula (I), therefore, should be understood to also refer to the corresponding prodrugs of the compound of the formula (I), as appropriate and convenient. The compounds of the formula (I) have valuable pharmacological properties, and are useful in the treatment of kinase-dependent diseases, for example as drugs for treating proliferative diseases. The term "treatment of protein tyrosine kinase-dependent diseases" refers to the prophylactic or preferably therapeutic (including palliative and / or curative) treatment of these diseases, especially the diseases mentioned below. Subsequently, when the term "USE" is mentioned, it includes any one or more of the following embodiments of the invention, respectively: use in the treatment of protein kinase dependent diseases (especially tyrosine), the use for the manufacture of pharmaceutical compositions for use in the treatment of these diseases, methods of use of the pyrazolo [1,5-a] pyrimidin-7-yl-amine derivatives in the treatment of these diseases, preparations Pharmaceuticals comprising the derivatives of prazrazolo [1,5-a] pyrimidin-7-ylamine for the treatment of such diseases, and pyrazolo [1,5-a] pyrimidin-7-ylamine derivatives to be used in the treatment of these diseases, as appropriate and convenient, if not mentioned otherwise. In particular, the diseases that are going to be treated, and therefore, are the Preferred for the USE of a compound of the formula (1), are selected from the protein kinase dependent diseases (especially tyrosine) (meaning "dependent" also "supported", and not only "exclusively dependent") mentioned further further, especially the corresponding proliferative diseases, more especially the diseases that depend on c-Abl, Bcr-Abl, c-Klt, 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 kinases (e.g., EphB2 kinase, EphB4 kinase, and related Eph kinases), casein kinases (CK) -1, CK-2, G-CK), Pak, ALK, ZAP70, Jak1, Jak2, AxI, Cdk1, cdk4, cdk5, Met, FAK, Pyk2, Syk, insulin receptor kinase, Tie-2, or constitutively mutations activators of kinases (activating kinases), such as Bcr-Abl, c-Kit, c-Raf, Flt-3, FGF-R3, PDGF, RET, and Met receptors (hereinafter "such kinases") , therefore, can be used in the treatment of kinase-dependent diseases, in particular diseases dependent on such kinases, and diseases dependent on such kinases (especially highly expressed in an aberrant or constitutively activated manner), or diseases dependent on the activation of the pathways of such kinases, or any combination of two or more of the aforementioned kinases. More preferred is the use of a compound of the formula (I) for the treatment of dependent diseases of c-Abl, Flt-3, KDR, c-Src, RET, EphB4, c-kit-cdkl, FGFR-1, c -raf, Her-1, Ins-R, and Tek, and the use of a compound of the formula (I) as an inhibitor of c-abl, Flt-3, KDR, c-Src, RET, EphB4, c-kit, FGFR-1, c-raf, cdk-1, Her- 1, Ins-R, and Tek. There are also experiments to demonstrate the anti-tumor activity of the compounds of formula (I) in vivo. The compounds of formula (I) have valuable pharmacological properties, and are useful in the treatment of protein kinase dependent diseases, for example as drugs for treating proliferative diseases. The inhibition of RET is measured as follows: The baculovirus donor vector pFB-GSTX3 is used to generate a recombinant baculovirus expressing the amino acid region 658-1072 (Swiss prot. Q9BTB0) of the intra-cytoplasmic kinase domain of the RET -Men2A human corresponding to the wild-type kinase domain of RET (wtRET) and RET-Men2B, which differs from the wtRET by the activating mutation in the M918T activation cycle. The coding sequences for the cytoplasmic domain of wtRET and RET-Men2B are amplified by polymerase chain reaction from the pBABEpuro RET-Men2A and pBABEpuro RET-Men2B plasmids. The amplified DNA fragments and the pFB-GSTX3 vector are made compatible for binding by digestion with Sali and Kpnl. Ligation of these DNA fragments results in the baculovirus donor plasmid pFB-GX3-RET-Men2A and pFB-GX3-RET-Men2B, respectively. Virus production: vectors are transfected transfer containing the kinase domains, in the DHI OBac cell line (GIBCO), and applied on selective agar plates. The colonies without the insertion of the fusion sequence in the viral genome (carried by the bacteria) are blue. Individual white colonies are collected, and viral DNA (bacmid) is isolated from the bacteria by standard plasmid purification procedures. The Sf9 cells or Sf21 cells (American Type Culture Collection) are then transfected in 25 cm3 flasks with the viral DNA using the Cellfectin reagent. Determination of the expression of the protein on a small scale in Sf9 cells: The medium containing the virus is harvested from the transfected cell culture, and used for infection, in order to increase its titration. The virus-containing medium obtained after two rounds of infection is used for large-scale expression of the protein. For large-scale protein expression, round tissue culture plates of 100 cm 2 are seeded with 5 x 10 7 cells / plate, and infected with 1 milliliter of the virus-containing medium (approximately 5 MOIs). After 3 days, the cells are scraped off the plate, and centrifuged at 500 revolutions per minute for 5 minutes. The cell granules from 10 to 20 100 cm2 plates are resuspended in 50 milliliters of ice cold lysis buffer (25 mM tris-HCl, pH 7.5, 2 mM EDTA, 1% NP-40, 1 mM DTT, P MSF 1 mM). The cells are shaken on ice for 15 minutes, and then centrifuged at 5,000 revolutions per minute for 20 minutes. Purification of proteins marked with GST: El The centrifuged cell lysate is loaded onto a 2 milliliter column of glutathione-sepharose (Pharmacia), and washed three times with 10 milliliters of 25 mM tris-HCl, pH 7.5, 2 mM EDTA, 1 mM DTT, 200 mM NaCl. The proteins labeled with GST are then eluted by 10 applications (1 milliliter each) of 25 mM tris-HCl, pH of 7.5, reduced glutathione 10 mM, 100 mM NaCl, 1 mM DTT, 10 percent glycerol, and they are stored at -70 ° C. Measurement of enzymatic activity: tyrosine protein kinase assays are carried out with either the purified GST-wtRET or GST-RET-Men2B protein, in a final volume of 30 microliters containing 15 nanograms of the GST-wtRET or GST-protein RET-Men2B, 20 mM tris-HCl, pH 7.5, 1 mM MnCl2, 10 mM MgCl2, 1 mM DTT, 3 micrograms / milliliter of poly (Glu, Tyr) 4: 1, 1% dimethyl sulfoxide, ATP 2.0 μM (? - [33P] -ATP 0.1 μCi). The activity is assayed in the presence or in the absence of inhibitors, measuring the incorporation of 33P from [? 33P] ATP in poly (Glu, Tyr) 4: 1. The assay is carried out in 96-well plates at room temperature for 15 minutes under the conditions described below, and is terminated by the addition of 20 microliters of 125 mM EDTA. Subsequently, 40 microliters of the reaction mixture Immobilon-PVDF (Millipore) previously soaked for 5 minutes with ethanol is transferred, rinsed with water, then soaked for 5 minutes with H3PO4 at 0.5, and mounted on a vacuum manifold with the vacuum source disconnected. After staining all the samples, the vacuum is connected, and each well is rinsed with 200 microliters of H3PO4 at 0.5 hundred. The membranes are removed and washed four times on a shaker with 1.0% H3PO, and once with ethanol. The membranes are counted after drying at room temperature, mounted in a 96-well Packard TopCount frame, and 10 microliters / well of Microscint ™ (Packard) are added. The IC 50 values are calculated by linear regression analysis of the percentage of inhibition of each compound in duplicate, in four concentrations (usually 0.01, 0.1, 1 and 10 μM). One unit of protein kinase activity is defined as 1 nanomol of 33P ATP transferred from [? 33P] ATP to the protein substrate / min / milligram protein at 37 ° C. IC50 calculation. Insertion of a 3 x 4 microterm sealed assay on Immobilon membrane, not washed. Bottom test (3 wells) with H2O instead of enzyme. Positive control (4 wells) of 3 percent dimethylsulphoxide instead of the compound. Bath control (1 well) without reaction mixture. The IC 50 values are calculated by logarithmic regression analysis of the percent inhibition of each compound in four concentrations (usually a 3 or 10 fold dilution series starting at 10 μM). In each experiment, the actual inhibition by the reference compound is used for the normalization of the IC50 values based on an average value of the reference inhibitor: Standardized IC5o = measured IC50, average reference IC50 / measured IC50 of reference.

Example: Reference inhibitor in the experiment 0.4 μM, average 0.3 μM. Test compound in the experiment .0 μM, normalization: 0.3 / 0.4 = 0.75 μM. For example, staurosporine or a synthetic derivative of staurosporine is used as a reference compound. Using this protocol, it is found that the compounds of formula I show IC 50 values for network inhibition in the range of 0.005 to 100 μM, preferably in the range of 0.01 to 2 μM. The efficacy of the compounds of the invention as inhibitors of the kinase tyrosine c-Abl protein activity can be demonstrated as follows: An in vitro enzymatic assay is carried out in 96 well plates, as a filter binding assay, as described by Geissler et al. in Cancer Res. 1992; 52: 4492-4498, with the following modifications. The His-tagged kinase domain of c-Abl is cloned and expressed in the baculovlrus / Sf9 system as described by Bhat et al., In J. Biol. Chem. 1997; 272: 16170-16175. A 37 kD protein (c-Abl quinase) is purified by a two-step procedure on a cobalt metal chelate column, followed by an anion exchange column, with a yield of 1 to 2 milligrams / liter of Sf9 cells (Bhat et al., cited reference). The purity of the c-Abl kinase is > 90 percent, as judged by SDS-PAGE after staining with Coomassie blue. The assay contains (total volume of 30 microliters): c-Abl kinase (50 nanograms), 20 mM tris-Hcl, pH 7.5, 10 mM MgCl 2, 1 μM Na3VO 4, 1 mM DTT and 0.06 μCi / assay [? 33P] ] -ATP (5 μM ATP) using 30 micrograms / milliliter of poly-Ala, Glu, Lys, Tyr-6: 2: 5: 1 (Poly-AEKY, Sigma P1 1 52) in the presence of dimethyl sulfoxide at 1 percent. The reactions are terminated by the addition of 10 microliters of 250 mM EDTA, and 30 microliters of the reaction mixture are transferred to the Immobilon-PVDF membrane (Milllpore, Bedford, MA, USA) previously soaked for 5 minutes with methanol, rinsed with water, then soaked for 5 minutes with 0.5 percent H3PO4, and mounted on a vacuum manifold with the vacuum source disconnected. After staining all the samples, the vacuum is connected, and each well is rinsed with 200 microliters of 0.5% H3PO4. The membranes are removed and washed and washed on a shaker with 0.5% H3PO4 (4 times), and once with ethanol. The membranes are counted after being dried at room temperature, mounted in the 96-well Packard TopCount well, and 10 micro-wells / well of Microscint TM (Packard) are added. Using this test system, the compounds of formula I show IC50 inhibition values for the inhibition of c-Abl in the range of 0.002 to 1 00 μM, usually between 0.002 and 5 μM.

The efficacy of the compounds of the invention as inhibitors of KDR tyrosine protein kinase activity can be demonstrated as follows: Inhibition of VEGF-induced receptor autophosphorylation can be confirmed with additional in vitro experiments on cells such as transfected CHO cells , which permanently express the human VEGF-R2 receptor (KDR), which are seeded in a complete culture medium (with 10 percent fetal calf serum = FCS) in 6-well cell culture plates, and incubated at 37 ° C under CO5 at 5 percent until they show a confluence of about 80 percent. The compounds to be tested are then diluted in the culture medium (without fetal calf serum, with 0.1 percent bovine serum albumin) and added to the cells. (The controls comprise the medium without test compounds). After 2 hours of incubation at 37 ° C, the recombinant VEGF is added; The final concentration of VEGF is 20 nanograms / milliliter. After an additional 5 minutes of incubation at 37 ° C, the cells are washed twice with ice cold PBS (phosphate-buffered serum), and immediately lysed in 100 milliliters of lysis buffer per well. The lysates are then centrifuged to remove the cell nuclei, and the protein concentrations of the supernatants are determined using a commercial protein assay (BIORAD). Then the lysates can be used immediately, or if necessary, they can be stored at -20 ° C. A sandwich ELISA is carried out to measure the phosphorylation of VEGF-R2: A monoclonal antibody for VEGF-R2 (for example, Mab 1495, 12.14; ProQinase, Freiburg, Germany) is immobilized on black ELISA plates (OptiPlate ™ HTRF-96 from Packard). The plates are then washed, and the remaining free protein binding sites are saturated with 3 percent TopBlock® (Juro, Cat. # TB232010) in phosphate buffer with Tween 20® (polyoxyethylene sorbitan monolaurate (20)). , ICI / Uniquema) (PBST). The cell lysates (20 micrograms of protein per well) are then incubated in these plates overnight at 4 ° C, together with an anti-phosphotyrosine antibody coupled with alkaline phosphatase (PY20: AP from Zymed). The plates are washed again, and then the binding is demonstrated by the anti-phosphotyrosine antibody with the captured phosphorylated receptor using a luminescent AP substrate (CDP-Star, ready for use, with Emerald I I; Applied Biosystems). Luminescence is measured on a Packard Top Count Microplate Cintment Counter. The difference between the positive control signal (stimulated with VEGF) and that of the negative control (not stimulated with VEGF) corresponds to the VEGF-R2 phosphorylation induced by VEGF (= 1 00 percent). The activity of the substances tested is calculated as the percentage of inhibition of the VEGF-induced phosphorylation of VEGF-R2, where the concentration of the substance that induces half of the maximum inhibition is defined as the IC50 (inhibitory dose for an inhibition of the 50 percent). The compounds of the formula I here show an IC 50 in the range of 0.005 to 20 μM, preferably between 0.005 and 1 μM for the inhibition of KDR. The inhibition of Flt3 kinase is determined as follows: baculovirus vector donor pFbacGOl (GIBCO) is used to generate a recombinant baculovirus that expresses the amino acid region 563-993 of the cytoplasmic domain kinase Flt-3 human. The coding sequence for the cytoplasmic domain of Flt-3 is amplified by polymerase chain reaction from human c-DNA libraries (Clontech). The amplified DNA fragments and the pFbacGOl vector are made compatible for ligation by digestion with BamH 1 and Hindl 1. Ligation of these DNA fragments results in the baculovirus donor plasmid Flt-3 (1.1). The production of the viruses, the expression of proteins in the Sf9 cells, and the purification of the proteins fused with GST, are carried out as follows: Production of the virus: The transfer vector (pFbacG01 -Flt-3) which contains the domain of Kinase Flt-3 is transfected into the DH I OBac cell line (GI BCO), and the transfected cells are applied onto selective agar plates. Colonies without insertion of the fusion sequence into the viral genome (carried by the bacteria) are blue. Individual white colonies are collected, and viral DNA (bacmid) is isolated from the bacteria by standard plasmid purification procedures. Then the Sf9 cells are transfected or Sf21 (American Type Culture Collection) in flasks with the viral DNA, using the Cellfectin reagent. Determination of small-scale protein expression in Sf9 cells: The medium containing the virus is harvested from the transfected cell culture, and used for infection, in order to increase your degree. The virus-containing medium obtained after two rounds of infection is used for large-scale protein expression. For large-scale protein expression, round 100 cm2 tissue culture dishes are seeded with 7 x 10 7 cells / dish, and infected with 1 milliliter of the virus-containing medium (approximately 5 MOIs). After 3 days, the cells are scraped off the dish, and centrifuged at 500 revolutions per minute for 5 minutes. The cell granules from 10 to 20 plates of 1 00 cm2 are resuspended in 50 milliliters of ice cold lysis buffer (25 mM tris-HCl, pH 7.5, 2 mM EDTA, 1 percent NP-40, 1 mM DTT , 1 mM PMSF). The cells are shaken on ice for 15 minutes, and then centrifuged at 5,000 revolutions per minute for 20 minutes. Purification of GST-tagged proteins: The cell lysate centrifuged loaded onto a 2 ml glutathione-Sepharose (Pharmacia) and washed three times with 10 ml of tris-HCI 25 mM, pH 7.5, 2 mM EDTA , 1 mM DTT, 200 mM NaCl. The GST-tagged protein is then eluted by 10 applications (1 ml each) of tris-HCI 25 mM, pH 7.5, 10 mM reduced glutathione, 100 mM NaCI, 1 mM DTT, glycerol 10 percent, and stored at -70 ° C. Measurement of enzyme activity: Kinase Assays tyrosine protein GST-Flt-3 purified are carried out in a final volume of 30 microliters containing 200 to 1, 800 nanograms of enzyme protein (depending on the specific activity), ( 20 mM tris-HCl, pH 7.6, 3 mM MnCl2, 3 mM MgCl2, 1 mM DTT, Na3VO4 10 μM, 3 micrograms / milliliter of poly (Glu, Tyr) 4: 1, dimethyl sulfoxide 1 percent, ATP 8.0 μM and 0.1 μCi [? 33P] ATP). The activity is assayed in the presence or in the absence of inhibitors, by measuring the incorporation of 33P from [? 33P] -ATP into the poly (Glu, Tyr) substrate. The assay (30 microliters) is carried out in 96-well plates at room temperature for 20 minutes under the conditions described below, and is terminated by the addition of 20 microliters of 125 mM EDTA. Subsequently, 40 microliters of the reaction mixture to Immobilon PVDF membrane (Millipore, Bedford, MA, USA) previously soaked for 5 minutes with ethanol, rinsed with water, then soaked for 5 minutes with 0.5 percent H3PO4 transferred, and mounted on a vacuum manifold with the vacuum source disconnected. After staining all the samples, the vacuum is connected, and each well is rinsed with 200 microliters of 0.5% H3PO4. The membranes are removed and washed four times on a shaker with 1.0% H3PO, and once with ethanol. The membranes are counted after drying at room temperature, mounted in a 96-well Packard Top Count frame, and 10 micripoles / well of Microscint ™ (Packard) are added. The IC 50 values are calculated by linear regression analysis of the percent inhibition of each compound in triplicate, in four concentrations (usually 0.01, 0.1, 1 and 10 μM). One unit of protein kinase activity is defined as 1 nanomol of 33P ATP transferred from [? 33P] ATP to the substrate protein per minute per milligram of protein at 37 ° C. The compounds of the formula I show IC50 values for the inhibition of Flt-3 in the range between 0.01 and 100 μM, preferably between 0.05 and 1.0 μM. The compounds of the formula I also inhibit other tyrosine protein kinases, such as in particular the c-Src kinase, c-kit, VEGF-R and / or FGFR; all of which have a part in the regulation of growth and transformation in animal cells, especially mammals, including human cells. An appropriate assay is described in Andrejauskas-Buchdunger et al., Cancer Res. 52, 5353-8 (1992). Using this test system, the compounds of the formula I show IC 50 values for the inhibition of c-Src in the range of 0.005 to 100 μM, usually between 0.005 and 5 μM. The compounds of the formula I also show IC 50 values for the inhibition of c-kit in the range of 0.005 to 10 μM, usually between 0.005 and 5 μM; and for the inhibition of FGFR-1, an inhibition of up to 95 percent with 1 0 μM. Inhibition of IGF-1 R and Ins-R can be determined as follows: The baculovirus donor vector pfbgx3IGFIRcd is used to generate a recombinant baculovirus that expresses the amino acid region 950-1337 of the cytoplasmic domain of the mature peptide of IGF-IR human In order to generate the cDNA fragment encoding amino acid region 91 9-1 343 of the intra-cytoplasmic kinase domain of the human insulin receptor, pCdhlnsR is used. The fragments of IGF-IR and human Ins-R are cloned, expressed, and purified on a small scale as a fusion protein of glutathione S-transferase (GST) dissociable by factor Xa using the Bac-to-BacMR system (GIBCO BRL) of the baculovirus generation recombinant. The virus-containing medium is harvested from the transfected cell culture, and used for infection, in order to increase its titration. The virus-containing medium obtained after two rounds of infection is used for large-scale expression of the protein. Cell extracts are prepared, and loaded onto a glutathione-Sepharose column (Pharmacia). After washing, the proteins labeled with GST are then eluted with a regulator containing glutathione. The purified protein is stored at -70 ° C in the elution buffer. Tyrosine protein kinase assays are carried out with purified GST-IGF-IR and GST-Ins-R in a final volume of 30 microliters containing 20 mM tris-Hcl, pH of 7.6, 10 mM MgCl2, 0.01 mM Na3VO4, sulfoxide of dimethylated at 1 percent, 1 mM DTT, 3 micrograms / milliliter of poly (Glu, Tyr) 4: 1 and 10 μM ATP (? - [33P] -ATP 0.1 μCi). The assay is carried out in 96-well plates at room temperature for 20 minutes, and is terminated by the addition of 25 microliters of 0.05 M EDTA, pH 7.0. An aliquot of 40 milliliters is stained with a multi-channel dispenser on Whatman P81 membranes mounted on a Millipore microtiter filter manifold connected to a low vacuum source. After liquid removal, the membrane is transferred to a sequence of four wash baths containing 0.5 percent H3PO4, and one with EtOH (incubation with stirring for 10 minutes each), dried, mounted on a manifold Hewlett Packard Top Count, add 10 microliters of Microscint®, and count. The compounds of the formula (I) show an inhibition of up to 90 percent of Ins R with 10,000 nM, preferably an inhibition of between 60 and 90 percent. The inhibition of Tek can be determined as follows: The procedure of the expression, purification, and assay of these kinases has already been described. Fabbro et al., Pharmacol. Ther. 82 (2-3) 293-301 (1999). Briefly, the glutathione S-transferase (GST) gene is separated from the pAcG 1 vector (Pharmingen) with EcoRV and EcoRI, and inserted into the cloning site of the Baculoviral Fast-Bac vector (G IBCO) creating a vector of 5,530 base pairs, with the N-terminal cloning sites derived from the fusion vector pAcG1 (FBG0). The C-terminal cloning site can be any cloning site (of the Fast-Bac vector) upstream of the N-terminal cloning site used. The kinase domains KDR, Flt-1, Flk-1, Tek and PDGFR-β N-terminally fused with GST (pAcG1, Pharmingen) are obtained from ProQinase, Freiburg, Germany. The Tek is cloned back into the vector FBG 1 by separation with EcoRI and ligation in FBG1 digested with EcoRI (FBG 1 -Tek). The coding sequences for the entire cytoplasmic domain of c-Kít (aa 544-976) and c-Fms (aa 538-972) are amplified by polymerase chain reaction from human uterus and marrow cDNA libraries human bone (Clontech) respectively. The amplified DNA fragments are fused with GST by their cloning into FBG1 as BamHI-EcoRI insertions, to produce FBG1 -c-Kit and FBG 1 -c-Fms. The Tek is re-cloned into the transfer vector FBG0 by EcoRI separation and ligation in the EcoRI-digested FBG0 (FBG-Tie2 / Tek). The kinase domains FGFR-1 and c-met are obtained by polymerase chain reaction from human A431 cells. The N-terminal primers contain a pendant EcoRI site, whereas the C-terminal primers contain an XhoI site to aid cloning in the transfer vectors. After digestion of both fragments of the polymerase chain reaction and FBGO, the cleavage products are gel purified, and ligated together to form the kinase constructs (FBG-Met, FBG-FGFR-1) . The viruses for each of the kinases are made according to the protocol provided by GIBCO. In brief, transfer vectors containing the kinase domains are transferred to the cell line DH I obac (GIBCO), are applied on agar plates containing the recommended concentrations Biue-Gal, IPTG, Kanamycin, Tetracycline, and Gentamycin. Colonies without insertion of the fusion sequence into the viral genome (carried by the bacteria) are blue. Normally a single white colony is collected, and the viral DNA (bacmid) is isolated from the bacteria by means of mini-prep procedures of conventional plasmids. The High Five cells (GIBCO) are then transfected into 25 cm3 flasks with the viral DNA, using the Cellfectin reagent and the protocol supplied with the Bac-to-Bac kit.

(GIBCO) The virus-containing medium is harvested from the transfected cell culture, and used for infection, in order to increase its titration. The virus-containing medium obtained after two rounds of infection is used for large-scale expression of the protein. For the expression of the protein on a large scale, they are sown round tissue culture dishes of 100 cm2 with 5 x 10 7 cells / dish, and infected with 1 milliliter of the virus-containing medium (approximately 5 MOIs). After 3 days, the cells are scraped off the dish, and centrifuged at 500 revolutions per minute for 5 minutes. The cell granules from 10 to 20 plates of 100 cm2 are resuspended in 50 milliliters of ice cold lysis buffer (25 mM tris-HCl, pH 7.5, 2 mM EDTA, 1 percent NP-40, 1 mM DTT, PMSF 1 M). The cells are shaken on ice for 15 minutes, and then centrifuged at 5,000 revolutions per minute for 20 minutes. The supernatant is loaded onto a 2 milliliter column of glutathione-Sepharose, and washed three times with 10 milliliters of 25 mM tris-HCl, pH 7.5, 2 mM EDTA, 1 mM DTT, 200 mM NaCl. The proteins are then eluted with GST by 10 applications (1 milliliter each) of 25 mM tri-HCl, pH 7.5, reduced glutathione 10 mM, 100 mM NaCl, 10 percent glycerol, and stored at -70 ° C. C. Assays (30 microliters) contain 200-1800 ng of enzyme protein (depending on the specific activity), tris-HCI 20 mM, pH 7.6, MnCI3 3 mM, MgCl2 3 mM, 1 mM DTT, Na3VO 10 uM, 3 micrograms / milliliter of poly (Glu, Tyr) 4: 1, ATP 8 μM (? - [33P] -ATP 0.1 μCi). The reactions are incubated for 20 minutes at room temperature, and then stopped by the addition of 25 microliters of EDTA (pH 7.0). An aliquot of 40 microliters is stained with a multi-channel feeder on Immobilon P membranes mounted on a microtiter filter manifold Millipore connected to a low vacuum source. After the elimination of the liquid, the membrane is transferred to a sequence of four wash baths containing 0.5% H3PO4, and one with EtOH (incubation with shaking for 10 minutes each), dried, mounted on a Hewlett Packard TopCount manifold, 10 microliters of Microscint® and counted. The compounds of the formula (I) show IC 50 values, calculated by linear regression analysis, for Tek inhibition, of about 0.1 to 100 μM. The inhibition of Cdk1 can be determined as follows: Cdk1 / cycB: Cdk1 / cycB are obtained in ProQinase, Freiburg, Germany. Starfish oocytes are induced to introduce the M phase of the cell cycle with 1 μM methladenin 1, and frozen in liquid nitrogen, and stored at -80 ° C. When required, the oocytes are homogenized and centrifuged as described (Arion et al., Cell 55: 371-378 (1988) and Rialet et al., Anticancer Res. 1 1: 1581-1590 (1991)). The qulphan Cdk1 / cycB is purified on beads of p9CKShs-sepharose, and eluted with recombinant human p9CKShs as described (Azzi et al., Eur. J. Biochem. 203: 353-360 (1992)). Briefly, the oocyte supernatant is equilibrated for 30 minutes at 4 ° C under constant rotation with the beads of p9CKShs-sepharose. The beads are extensively washed, and the activated cdkl / cycB kinase is eluted with purified c9CKSsh (3 milligrams / milliliter). 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. 1 991; 8: 2275-2282). The assay is carried out with slight modifications in 96-well plates at room temperature for 20 minutes. The final volume of 30 microliters contains 0.1 to 0.3 Units of Cdk1 / cycB, 1 milligram / milliliter of histone H1 as a substrate, 60 mM β-glycerophosphate, 30 mM nitrophenyl phosphate, 25 mM MOPS, 5 mM EGTA, MgCl2 15 mM, 1 mM DTT, 0.1 mM Na3VO4, 15 μM ATP, and 0.1 μCi? -33 P-ATP (75 μM, 8800 cpm / piccomol). The reaction is terminated by the addition of 25 microliters of 0.05 M EDTA, pH 7.0. An aliquot of 40 milliliters is stained with a multi-channel dispenser on Immobilon P membranes in a Millipore microtiter filter manifold connected to a low vacuum source. After removal of the liquid, the membrane is transferred to a sequence of four wash baths containing 0.5 percent H3PO4, and one with EtOH (incubation with stirring for 10 minutes each), dried, mounted on a manifold Hewlett Packard TopCount, 10 microliters of Microscint® are added and counted. The compounds of the formula (I) show an inhibition of Cdk1 of up to 100 percent with 1 0,000 nM. The inhibition of c-Raf-1 can be determined as follows: The production of the recombinant c-Raf-1 protein is obtained by triple infection of Sf21 cells with recombinant baculovirus GST-Raf-1 together with the recombinant baculoviruses v-Src and v-Ras that are required for the production of active c-Raf-1 kinase (Williams et al., PNAS 1992; 89: 2922-2926). Active ras (v-Ras) is required to recruit c-Raf-1 in the cell membrane, and v-Src for phosphorylate c-Raf-1 in order to fully activate it (Williams et al., PNAS 1992; 89: 2922-2926). Cells were seeded at 2.5 x 1 07 cells per 150-millimeter dish, and allowed to attach to a 1 50 millimeter dish for 1 hour at room temperature. The medium (SF900II containing 10 percent fetal calf serum) is aspirated, and the recombinant baculovirus; GST-C-Raf-1, v-Ras and v-Src are added in an MOI of 3.0, 2.5, and 2.5 respectively, in a total volume of 4 to 5 milliliters. The cells are incubated for 1 hour at room temperature, and then 15 milliliters of medium are added. The infected cells are incubated for 48 to 72 hours at 27 ° C. The cells Infected Sf21 are scraped and collected in a 50 milliliter tube, and centrifuged for 10 minutes at 4 ° C at 1, 100 g in a Sorvall centrifuge. The cell granule is washed once with ice-cold phosphate-regulated serum, and is smoothed with 0.6 milliliter with lysis buffer by 2.5 x 10 7 cells. Complete lysis of the cells is achieved after 10 minutes on ice with occasional pipetting. The cell lysates are centrifuged for 10 minutes at 4 ° C at 14,500 g in a Sorvall centrifuge with the SS-34 rotor, and the supernatant is transferred to a clean tube, and stored at -80 ° C. C-Raf-1 is purified from cell lysates using 100 microliters of packed gelatin-Sepharose 4B beads equilibrated in ice-cold phosphate buffered serum by 2.5 x 10 7 cells. The GST-c-Raf-1 was allowed to bind to the beads at 4 ° C for 1 hour with rocking. The GST-c-Raf-1 linked to the beads was transferred to a column. The column is washed once with a lysis regulator, and twice with serum regulated with ice-cold tris. HE add ice-cold elution regulator, and flow off the column to allow the flow of free glutathione to disrupt the interaction of GST-c-Raf-1 with glutathione-Sepharose beads. The fractions (1 milliliter) are collected in previously frozen tubes. Each tube contains 10 percent glycerol (final concentration) to maintain the activity of the kinase during freeze-thaw cycles. The purified fractions of the kinase protein GST-c-Raf-1 are stored at -80 ° C. I KB was used as substrate for the c-Raf-1 kinase. l B is expressed in bacteria as a His-tagged protein (cloned and kindly provided by Dr. Eder, ABM, Novartis, Basel). The BL21 LysS bacteria containing the plasmid L? B are grown to an OD60o of 0.6 in an LB medium, then induced to express the kb with IPTG (final concentration of 1 mM) for 3 hours at 37 ° C, and then The bacteria are lysed by sonication (limit position of the microtip for three times of 1 minute each in the sonication buffer) [50 mM Tris, pH 8.0, 1 mM DTT, 1 mM EDTA] and centrifuged at 10,000 g for 15 minutes. minutes The supernatant is mixed with ammonium sulfate to give a final concentration of 30 percent. This mixture is swung for 15 minutes at 4 ° C, then centrifuged at 1 0,000 g for 15 minutes. The granule is resuspended in the binding buffer (Novagen) containing 10 mM bovine serum albumin. This solution is applied to Ni-agarose (Novagen), and washed according to the Novagen manual. The L? B is eluted from the column using an elution buffer (0.4 M imidazole, NaCl 0. 2 M, Tris 8 mM, pH 7.9). The fractions containing the protein are dialyzed in 50 mM Tris, pH 8, 1 mM DTT. The activity of protein kinase c-Raf-1 is tested in the presence or in the absence of inhibitors, measuring the incorporation of 33P from [? 33P] ATP in IB. The assay is carried out in 96-well plates at room temperature for 60 minutes. Contains (total volume of 30 microliters): c-rafl 1 kinase (400 nanograms), 25 mM Tris-HCl, pH 7.5, 5 mM MgCl 2, 5 mM MnCl 2, 10 μM Na3VO 4, 1 mM DTT, and 0.3 μCi / assay [? 33P] -ATP (10 μ ATP) using 600 nanograms of IB in the presence of 1 percent dimethyl sulfoxide. The reactions are terminated by the addition of 1.0 microliters of 250 mM EDTA, and 30 microliters of the reaction mixture is transferred to an Immobilon PVDF membrane (Millipore, Bedford, MA, USA) previously soaked for 5 minutes with methanol, rinsed with water, then soaked for 5 minutes with 0.5 percent H3PO4, and mounted on a vacuum manifold with the vacuum source disconnected. After staining all the samples, the vacuum is connected, and each well is rinsed with 200 microliters of 0.5% H3PO4. The membranes are removed and washed four times on a shaker with 0.5% H3PO4, and once with ethanol. The membranes are counted after drying at room temperature, mounted in a 96 well Packard TopCount frame, and 10 microliters / well of Microscint ™ (Packard) are added. The compounds of the formula (I) show an inhibition of c-Raf-1 in the range between 0.1 and 50 μM, preferably between 0.1 and 10 μM.

Experiments to demonstrate the anti-tumor activity of the compounds of the formula (I) in vivo: For example, in order to test whether a compound of the formula (I), for example that of Example 1 given below, inhibits mediated angiogenesis by VEGF in vivo, its effect on the angiogenic response induced by VEGF in a model of growth factor implant in mice is tested: a porous Teflon chamber (volume of 0.5 milliliters) is filled with 0.8 weight percent agar / volume containing heparin (20 units / milliliter) with or without growth factor (2 micrograms / milliliter of human VEGF), and implanted subcutaneously on the dorsal flank of C57 / C6 mice. The mice are treated with the test compound (e.g., 25, 50, or 100 milligrams / kilogram orally once a day) or with the vehicle, starting on the day of implantation of the camera, and continuing for 4 days afterwards. At the end of the treatment, the mice are sacrificed, and the chambers are removed. The vascularized tissue that grows around the chamber is carefully removed and weighed, and the blood content is evaluated by measuring the hemoglobin content of the tissue (Drabkins method).; Sigma, Deisenhofen, Germany). It has previously been shown that these growth factors induce dose-dependent increases in the weight and in the blood content of this growing tissue (histologically characterized by containing fibroblasts and small blood vessels) around the chambers, and that this response is blocked by antibodies that specifically neutralize VEGF (see Wood JM et al., Cancer Res. 60 (8), 2178-2189, (2000); and Schlaeppi et al., J.

Cancer Res. Clin. Oncol. 125. 336-342, (1999)). With this model, inhibition can be demonstrated in the case of the compounds of the formula (I).

Synthetic Process The compounds of the formula (I) are prepared in a manner analogous to the procedure described by Alicade, E; From Mendoza, J; Garcia-Marquina, JM; Almera, C; J. Heterocycl. Chem. 1 1, 423 (1974), by: (a) reacting a nitrile, A-CH2-C = N, with ethyl formate in the presence of an organic solvent to form a 3-oxo-propionitrile, (b) ) condensing the substituted 3-oxo-propionitriles of step (a) with hydrazine monohydrate in an organic solvent, to form a 2H-pyrazol-3-yl-amine of the formula (III): (c) forming a substituted nitrile in the presence of ethanolate and ethylester of formic acid to prepare a 3-oxo-propionitrile of the formula (I I): (II) (d) condensing the 3-oxo-propionitrile of the formula (I I) and the 2H-pyrazol-3-yl-amines of the formula (I I) in the presence of an organic solvent, to form a compound of the formula (I). In a specific manner, the compounds of the formula (I) are prepared by the condensation of the corresponding 3-oxo-propionitriles (II) and the corresponding 2H-pyrazol-3-yl-amines (III), in the presence of ethanolic HCl (reaction diagram 2). The 2H-pyrazol-3-yl-amines (III) are prepared by the condensation of hydrazine monohydrate with the corresponding 3-oxopropionitriles dissolved in an organic solvent, such as EtOH, dioxane, or AcOH, and heated at elevated temperatures ( preferably at 1 00 ° C) for several hours. The preferred procedure for the preparation of the pyrazolo moiety of the title compounds was to stir the hydrazine monohydrate with the corresponding 3-oxo-propionitriles in acetic acid at 100 ° C for 2 to 3 hours, followed by the addition of aqueous HCl. , and further refluxing the reaction mixture for an additional 20 minutes. In the case where R-, is not H, the corresponding substituted hydrazines are used. The 3-oxo-propionitriles (I) and (I I) are synthesized from the corresponding nitriles by a classical formylation reaction, using freshly prepared sodium ethanolate and formic acid ethyl ester (reflux for 1 hour in EtOH). In an alternative way, instead of carrying out the condensation reactions with the 3-oxo-propionitriles, the 3,3-dialkoxy-propionitriles can be used (in analogy to the procedure described by Seneci.P., Nícola, M. , Inglesi, M., Vanotti, E., Resnati, G. Synth, Commun. 29 (2), 31 1-341 (1999)), or the 3-dimethylamino-acrylonitriles.

EtOH, Ethanolic HCl, reflux III Diagram of Reaction 2 Alternatively, the compounds of the formula (I) can be prepared by first synthesizing the scaffolding of the pyrazolo [1, 5-a] pyridin-7-yl-amine nucleus bearing corresponding functional groups (X, see reaction diagram 3), where residues A, R2, or R3, respectively, can be introduced by known reactions, as indicated in reaction diagram 3.

X = functional group for additional chemical modifications AY? X Diagram of Reaction 3 wherein R, R2, R3, and X are as defined for compounds of formula (I), and if desired, after reaction (a), (b), or (c), transform a compound which can be obtained from the formula (I) in a compound different from the formula (I); transforming a salt of a compound obtainable from the formula (I) into the free compound or into a different salt, or a free compound obtainable from the formula (I) into a salt; and / or separating the mixture of isomers obtainable from the compounds of the formula (I) into the individual isomers; where, for all the reactions mentioned, the functional groups mentioned in the starting materials do not take part in the reaction, if required, are present in a form protected by easily removable protective groups, and subsequently any protective groups are removed. The following reaction conditions are preferred, respectively: Within the scope of this text, only an easily removable group that is not a constituent of the particular desired end product of formula (I) is designated as a "protecting group", unless the context indicates it in another way. The protection of the functional groups by these protecting groups, the protecting groups themselves, and their dissociation reactions, are described, for example, in conventional reference works, such as J. F.W. McOmie, "Protectíve Groups in Organic Chemistry", Plenum Press, London and New York, 1973, in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Third Edition, Wiley, New York, 1999, in "The Peptides", Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York, 1981, in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4a. Edition, Volume 1 5/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jeschkeit, "Amínosáuren, Peptide, Proteine" (Amino Acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basilea 1 982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monossacharide und Derivate" (Carbohydrate chemistry: monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic of protective groups is that they they can be easily removed (i.e., without the presentation of undesired side reactions), for example by solvolysis, reduction, photolysis, or alternatively under physiological conditions (eg, by enzymatic dissociation).

The salts of the compounds of the formula (I) having at least one salt-forming group can be prepared in a manner known per se. For example, salts of the compounds of the formula (I) having acidic groups can be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of the suitable organic carboxylic acids, for example the sodium salt of 2-ethylhexanoic acid, with alkali metal or organic alkaline earth metal compounds, such as the corresponding hydroxides, carbonates, or acid carbonates, such as sodium, potassium hydrogen carbonate, carbonate or acid carbonate, with the compounds of corresponding calcium, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt forming agent. The acid addition salts of the compounds of the formula (I) are obtained in the customary manner, for example by treating the compounds with an appropriate acid or anion exchange reagent. The internal salts of the compounds of the formula (I) containing acidic and basic salt-forming groups, for example a free carboxyl group and a free amino group, can be formed, for example, by neutralization of the salts, such as the acid addition salts, up to the isoelectric point, for example with weak bases, or by their treatment with ion exchangers. The salts can be converted in the customary way in the free compounds; the metal or ammonium salts can be converted, for example, by their treatment with suitable acids, and the acid addition salts, for example, by their treatment with a suitable basic agent.

The mixtures of isomers obtainable according to the invention can be separated in a manner known per se from the individual isomers; the diastereoisomers can be separated, for example, by dividing the mixtures of polyphase solvents, separation by recrystallization and / or chromatography, for example on silica gel, or, for example, by medium pressure liquid chromatography on a reverse phase column. , and the racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents, and the separation of the diastereomer mixture which can thus be obtained, for example by means of fractional crystallization, or by chromatography on optically active column materials. Intermediates and final products can be processed and / or purified according to conventional methods, for example using chromatographic methods, distribution methods, (re-) crystallization, and the like.

General process conditions The following applies in general to all the processes mentioned hereinabove and hereinafter, while the reaction conditions specifically mentioned above or below are preferred: All the above-mentioned process steps can be carry out under reaction conditions that are known per se, of. preferably those mentioned in a specific manner, in the absence, or by custom, in the present of solvents or diluents, preferably solvents or diluents that are inert toward the reagents used and dissolve them, in the absence or in the presence of catalysts, condensing or neutralizing agents, for example ion exchangers, such as cation exchangers, for example in the H + form, depending on the nature of the reaction and / or the reactants, at a reduced, normal, or elevated temperature, for example in a temperature range from about -100 ° C to about 190 ° C, preferably from about -80 ° C to about 150 ° C, for example from -80 ° C at -60 ° C, at room temperature, from -20 ° C to 40 ° C, or at reflux temperature, under atmospheric pressure or in a closed vessel, when appropriate under pressure, and / or in an inert atmosphere, example under an argon or nitrogen atmosphere. In all the steps of the reactions, the mixtures of isomers that are formed can be separated into the individual isomers, for example diastereomers or enantiomers, or in any desired mixtures of isomers, for example racemates or mixtures of diastereomers, for example in a manner analogous to the methods described under "additional process steps". Solvents from which solvents can be selected that are suitable for any particular reaction include those specifically mentioned, or, for example, water, esters, such as lower alkyl lower alkanoates, for example ethyl acetate, ethers, such as as aliphatic ether, for example diethyl ether, or cyclic ethers, for example 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, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethylformamide or dimethylacetamide, bases, such as heterocyclic nitrogen bases, for example pyridine or N-methyl-plrrolydin-2-one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane, or isopentane, or mixtures of these solvents, for example aqueous solutions, unless otherwise indicated in the description of the processes. These solvent mixtures can also be used in the process, for example by chromatography or division. The compounds, including their salts, may also be obtained in the form of hydrates, or their crystals, for example, may include the solvent used for crystallization. There may be different crystalline forms present. The invention also relates to the forms of the process where a compound that can be obtained as an intermediate at any stage of the process is used as the starting material, and the remaining steps of the process are carried out, or where a material is formed starting under the reaction conditions or is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound that can be obtained by the process according to the invention is produced under the process conditions and is further processed in situ. In the process of the present invention, the starting materials are preferably used which result in novel compounds of the formula (I) described at the beginning as being especially valuable. A special preference is given to reaction conditions that are identical or analogous to those mentioned in the Examples. Preferred embodiments according to the invention: In the following preferred embodiments, the general expression may be replaced by the corresponding more specific definitions provided above and below, thereby producing stronger preferred embodiments of the invention. Preferred is the use of compounds of the formula (I), tautomers thereof, or pharmaceutically acceptable salts thereof, wherein the tyrosine protein kinase-dependent disease to be treated is a proliferative disease. dependent on any one or more of the following tyrosine protein kinases: in particular, 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 kinases (e.g., EphB2 kinase, EphB4 qulase, and related Eph kinases), casein kinases ( CK-1, CK-2, G-CK), Pak, ALK, ZAP70, Jak1, Jak2, Axl, Cdk1, cdk4, cdkd, Met, FAK, Pyk2, Syk, insulin receptor kinase, Tie-2, or mutations constitutively activating kinases (activating kinases), such as Bcr-Abl, c-Kit, cdkl, c-Raf, Flt-3, FGF-R3, PDGF, RET, and Met receptors. More preferably, the compounds of the formula (I) can be used to treat a proliferative disease dependent on the following kinases: c-abl, Flt-3, KDR, c-Src, RET, EphB4, c-kit, cdkl, FGFR-1, c-raf, Her-1, Ins-R and Tek. The invention relates in particular to a compound of the formula (I): wherein: R2 is H; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; a substituted or unsubstituted aliphatic residue; a functional group; or a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aliphatic residue which is connected by a group or connecting atom with the pyrazolo ring [1, 5 a] pyrimidinyl; R3 can be H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted aliphatic residue, a functional group, an aliphatic residue that can be connected by a group or connecting atom to the pyrazolo [1, 5-a ring ] pyrimidinyl, at least one of R2 or R3 is substituted or unsubstituted aryl; substituted or insubstituted heteroaryl; or a substituted or unsubstituted heteroaryl residue or substituted or unsubstituted aryl which is connected by a group or connecting atom to the pyrazolo [1,5-a] pyrimidinyl ring; A is H, halogen (such as bromine), an aliphatic moiety, a functional group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R-1 is H, halogen, or lower alkyl, or pharmaceutically acceptable salts thereof, and to the use of the compounds of the formula (I) in the treatment of kinase-dependent diseases, or for the manufacture of pharmaceutical preparations for the treatment of kinase-dependent diseases. The invention also relates to a compound of the formula (I): (i) wherein: R2 is H; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; a substituted or unsubstituted aliphatic residue; a functional group; or a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aliphatic residue that is connected by a group or connecting atom to the pyrazolo [1,5-ajpyrimidinyl; R3 can be H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted aliphatic residue, a functional group, or a substituted or unsubstituted aliphatic residue that can be connected by a group or connecting atom to the pyrazolo ring [1, 5-a] pyrimide, at least one of R2 or R3 is substituted or unsubstituted aryl; substituted or insituted heteroaryl; or a substituted or insubstituted or substituted or unsubstituted heteroaryl residue that is connected by a linking group or atom to the pyrazolo [1,5-a] pyrimidinyl ring; and with the understanding that R2 and A can not both be unsubstituted phenyl; A is H, halogen (such as bromine), an aliphatic moiety, a functional group, or substituted or unsubstituted aryl or heteroaryl; and R-i is H, halogen, or lower alkyl, or pharmaceutically acceptable salts thereof, and to the use of the compounds of the formula (I) in the treatment of kinase dependent diseases or for the manufacture of pharmaceutical preparations for the treatment of kinase-dependent diseases. More preferred is a compound of the formula (I), wherein: the atom or linking group is selected from the group consisting of: alkyl (such as -CH 2 -); oxy -O-; keto -CO-; uncles-; sulfonyl -SO2-; sulfoxides -SO-; amines -NH-, ó. -NR-; carboxylic acid; alcohol; esters (-COO-); amides (-CONR-, -CONHR'-); sulfonamides (-SO2NH-, -SO2NR'-); (-SO3-); sulfoxides (-SO-); amino group; ureas (-NH-CO-NH-, -NR-CO-NH-, -NH-CO-NR-, -NR-CO-NR-); ethers (-O-); carbamates (-NH-CO-O-, -NR-CO-O-); or reversed amides, sulfonamides, and esters (-NH-CO-, -NR-CO-, -NH-SO2-, -NR-SO2-, -OOC-); alkyl being preferred (such as -CH2-); oxy -O-; keto -CO-; sulfonyl -SO2-; sulfonamides (-SO2NH-, -SO2NR'-); (-SO3-); and ureas (-NH-CO-NH-, -NR-CO-NH-, -NH-CO-NR-, -NR-CO-NR-), are especially preferred and the functional group is selected from the group that consists of: carboxylic acid; hydroxyl; halogens; cyano (-CN); ethers (-OR); ketones (-CO-R); esters (-COOR); amides (-CONH2, -CONHR, -CONRR '); thioethers (-SR); sulfonamides (-SO2NH2, -SO2NHR, -SO2NRR '); sulfones (-SO2-R); sulfoxides (-SO-R); amines (-NHR, NR'R); ureas (-NH-CO-NH2, -NH-CO-NHR); ethers (-O-R); halogens; carbamates (-NH-CO-OR); aldehyde function (-CHO); then also inverse amides; sulfonamides and esters (-NH-CO-R, -NH-SO2-R, -OOC-R); halogens being preferred; hydroxyl; ethers (-OR); amides (-CONH2, -CONHR, -CONRR '); sulfonamides (-SO2NH2, -SO2NHR, - SO2NRR '), amines (-NHR, NR'R); and ureas (-NH-CO-NH2, -NH-CO-NHR), are especially preferred, or a pharmaceutically acceptable salt thereof, as such or especially for use in the preparation of a pharmaceutical composition, or for use in the diagnosis or therapeutic treatment of a warm-blooded animal, especially a human being. Especially preferred is a compound of the formula (I), wherein: A is H; a halogen (such as Br); or aryl (such as phenyl or benzyl), or heterocyclyl (such as pyridinyl, indolyl, or benzothiophenyl), wherein the aryl or heterocyclyl can be substituted or unsubstituted with up to 4, preferably up to 2 substituents, wherein the substituents are the same or different, and are independently selected from halogen (such as Cl or Br); hydroxyl; Not me; amino-lower alkyl (such as dimethylamino); amino-lower alkoxy (such as ethoxy-amine); lower alkyl (such as methyl); lower alkoxy (such as methoxy); substituted or unsubstituted sulfonamide (such as benzo-sulfonamide, chlorobenzenesulfonamide, or dichlorobenzenesulfonamide); carbamates; R R5, wherein R and R5 may be equal or different, and are independently H; lower alkyl (for example methyl, ethyl or propyl); or R4 and R5, together with the N atom, form a 3- to 8-membered heterocyclic ring containing from 1 to 4 nitrogen, oxygen, or sulfur atoms (for example, piperazinyl or lower alkyl-piperazinyl), wherein, when R4 and R5, together with N form a heterocyclic ring, this ring may be substituted with 1, 2, or more of any of the substituents described herein, preferably piperazinyl, pyrrolidinyl, alkyl such as methyl, or hydroxyalkyl such as ethanyl. Examples of the hetero ring formed by R 4 and R 5 together with N include morpholinyl, which may be unsubstituted or substituted with methyl or dimethyl; piperazinyl which may be unsubstituted or substituted with 1, 2, or 3 substituents, preferably methyl, oxy, or ethanol; or piperidinyl which may be unsubstituted or substituted with 1, 2, or 3 substituents, preferably pyrrolidinyl, amine, alkylamine, methylamine, dialkylamine, dimethylamine, or diethylamine; R 2 is H, lower alkyl of 1 to 3 carbon atoms (such as methyl), or aryl (such as phenyl or benzyl), or heterocyclyl (such as pyridyl, indolyl, thiophenyl, thiazolyl, or benzothiophenyl), wherein the aryl or the heterocyclyl can be substituted or unsubstituted with up to 4, preferably up to 2 substituents, wherein the substituents are the same or different, and are independently selected from halogen (such as Cl, F, or Br); hydroxyl, amino; amino-lower alkyl; lower alkyl of 1 to 3 carbon atoms; alkoxy (such as methoxy and benzyloxy, wherein the benzyl ring may be substituted or unsubstituted, such as 3,4-dichlorobenzyloxy); sulfoamino; substituted or unsubstituted benzosulfonamide (such as 2,3-dichlorobenzenesulfonamide); substituted or unsubstituted sulfonate (such as chlorophenyl sulfonate); substituted or unsubstituted ureas (such as 3-trifluoromethyl-phenyl-urea or 4-morpholin-4-yl-3-trifluoromethyl-phenyl-urea) or carbamates (such as ethyl-N-phenyl-carbamate); R3 is H; alkyl of 1 to 3 carbon atoms, methyl; phenyl; pyridinyl; or oxaz-5-yl; or a pharmaceutically acceptable salt thereof, as such or especially for use in the composition of a pharmaceutical preparation, or for use in the diagnosis or therapeutic treatment of a warm-blooded animal, especially a human being. Especially preferred is the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical preparation for the treatment of a kinase dependent disease. Also preferred is a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as shown above, for use in the treatment of a kinase-dependent disease., especially one dependent on such kinases, and of a disease dependent on such kinases (especially highly expressed in an aberrant or constitutively activated manner) on the activation of the pathways of such kinases, or a disease dependent on any two or more of these kinases. In a broader sense of the invention, a kinase-dependent disease can be a proliferative disease, including a hyperproliferative condition, such as leukemia, hyperplasias, fibrosis (especially puary, but also other types of fibrosis, such as renal fibroses), angiogenesis, psoriasis, atherosclerosis, and smooth muscle proliferation in blood vessels, such as stenosis or restenosis following angioplasty. A method for the treatment of a kinase dependent disease, which comprises administering a compound of the formula (I), wherein the disease to be treated is a proliferative disease, preferably a benign or especially malignant tumor, more preferably carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach (especially gastric tumors), ovaries, colon, rectum, prostate, pancreas, lung (especially SCLC), vagina, thyroid, sarcoma, glioblastomas, multiple myeloma, or gastrointestinal cancer, special carcinoma of the colon or colo-rectal adenoma, or a tumor of the neck and head, an epidermal hyperproliferation, especially psoriasis, prostate hyperplasia, a neoplasm, especially of epithelial character, preferably mammary carcinoma, or a leukemia. Also for the treatment of atherosclerosis, thrombosis, psoriasis, scleroderma, and fibrosis. The compounds of the formula (I) are capable of causing tumor regression and of preventing the formation of tumor metastasis and the growth of (also micro) metastasis. In addition, they can be used in epidermal hyperproliferation (for example, psoriasis), in prostate hyperplasia, and in the treatment of neoplasms, especially of epithelial character, for example mammary carcinoma. It is also possible to use the compounds of the formula (I) in the treatment of diseases of the immune system, up to where several, or especially, individual tyrosine protein kinases are involved; in addition, the compounds of the formula (I) can also be used in the treatment of diseases of the central or peripheral nervous system, when the transmission of signals is involved by at least a protein tyrosine kinase, especially selected from those mentioned in a specific manner. Accordingly, KDR inhibitors are especially suitable for the therapy of diseases related to overexpression of the receptor VEGF tyrosine kinase. Among these diseases, retinopathies, age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory diseases, such as rheumatoid or rheumatic inflammatory diseases, especially arthritis, such as rheumatoid arthritis, or other chronic inflammatory disorders, are especially important. such as chronic asthma, arterial atherosclerosis or after transplantation, endometriosis, and especially neoplastic diseases, for example so-called solid tumors (especially cancers of the gastrointestinal tract, pancreas, breast, stomach, cervix, bladder, kidney, prostate, ovaries, endometrium, lung, brain, melanoma, Kaposi's sarcoma, squamous cell carcinoma of the head and neck, malignant pleural mesothelioma, lymphoma or multiple myeloma), and fluid tumors (eg, leukemias). Flt3 (tyrosine kinase type FMD) is expressed especially in hematopoietic progenitor cells and progenitors of the lymphoid and myeloid series. Aberrant expression of the Flt3 gene has been documented in both adult and child leukemias, including AML (acute myelogenous leukemia), AML with triple-line myelodysplasia (AML / TMDS), ALL (acute lymphoblastic leukemia), CML (leukemia) chronic myelogenous), and myelodysplastic syndrome (MDS), which, therefore, are the preferred diseases to be treated with the compounds of the formula (I). Activating mutations have been found in Flt3 in approximately 25 to 30 percent of patients with acute myelogenous leukemia. Accordingly, there is cumulative evidence of the role of Flt3 in human leukemias, and pyrazoic [1,5-a] pyrimidin-7-yl-amine derivatives useful according to the invention, especially the compounds of Formula (I), as inhibitors of Flt3, are especially useful in the therapy of this type of diseases (see Tse et al., Leukemia 15. (7), 1 001 -1 01 0 (2001); Tomoki et al., Cancer Chemother. Pharmacol. 48_ (Supplement 1), S27-S30 (2001); Birkenkamp et al., Leukemia 15 (12), 1 923-1921 (2001); Kelly et al., Neoplasia 99 (1), 31 0-318 (2002)). In chronic myelogenous leukemia (CML), a reciprocally balanced chromosomal translocation in totipotent hematopoietic cells (HSCs), produces the hybrid BCR-ABL gene. The latter encodes the oncogenic fusion protein Bcr-Abl. Although ABL encodes a tightly regulated protein tyrosine kinase, which plays a key role in the regulation of cell proliferation, adhesion, and apoptosis, the BCR-ABL fusion gene encodes a constitutively activated kinase, which transforms totipotent hematopoietic cells to produce a phenotype that exhibits a dysregulated clonal proliferation, a reduced ability to adhere to the bone marrow stroma, and a reduced apoptotic response to mutagenic stimuli, which cause him to progressively accumulate more malignant transformations. The resulting granulocytes fail to develop into mature lymphocytes, and are released into the circulation, leading to a deficiency in mature cells and an increased susceptibility to infection. Competitive inhibitors of Bcr-Abl with ATP have been described, which prevent the kinase from activating the mitogenic and anti-apoptotic pathways (for example, kinase P-3 and STAT5), leading to the death of the cells of the BCR-ABL phenotype, and thus providing an effective therapy against chronic myelogenous leukemia. The pyrazolo [1, 5-a] pyrimid-7-ylamine derivatives useful in accordance with the present invention, especially the compounds of the formula I, as Bcr-Abl inhibitors, Consequently, they are especially suitable for the therapy of diseases related to their overexpression, especially leukemias, such as leukemias, for example chronic myelogenous leukemia or acute lymphoblastic leukemia. The compounds of the formula (I) which inhibit the tyrosine kinase activity of EGF-R or of the other tyrosine protein kinases mentioned, are therefore useful, for example, in the treatment of malignant or benign tumors. The compounds of the formula (1), for example, are capable of simultaneously inhibiting the growth of tumors with a deregulated activity of EGF-R and / or ErbB2, as well as of inhibiting the vascularization of solid tumors triggered by VEGF. This combined activity leads to a better antitumor effect (see also International Publication Number WO 02/41882). Moreover, the use of a double inhibitor reduces the risk of drug-drug interactions, and also reduces the total drug load, compared to a combination therapy. The compounds of the formula (I) are capable of slowing tumor growth and of tumor regression, and of preventing the formation of tumor metastases and the growth of micrometastases. They can be used especially in the case of epidermal hyperproliferation (psoriasis), in the treatment of solid cancers such as, for example, non-small-cell lung cancer, squamous cell carcinoma (head and neck), breast, gastric, ovaries, colon, and prostate, as well as gliomas, and in the treatment of leukemias, such as especially acute myeloma leukemia (AML) and chronic myeloid leukemia (CML). In addition, the compounds of the formula (I) can be used in the treatment of disorders of the immune system in which several are involved, or especially the individual tyrosine protein kinases and / or (in addition) protein kinases. serine / threonine; The compounds of the formula (I) can also be used in the treatment of disorders of the central or peripheral nervous system in which the transmission of signals by several is involved, or special a single protein tyrosine kinase and / or (in addition) kinases of protein serine / threonine. Angiogenesis is considered as an absolute prerequisite for tumors that grow beyond a maximum diameter of approximately 1 to 2 millimeters; up to this limit, it can be supply oxygen and nutrients to the tumor cells by diffusion. Each tumor, regardless of its origin and its cause, therefore, depends on angiogenesis for its growth after it has reached a certain size. Three main mechanisms have an important part in the activity of inhibitors of angiogenesis against tumors: 1) the inhibition of the growth of vessels, especially capillaries, in avascular resting tumors, with the result that there is no net tumor growth due to that the balance between apoptosis and proliferation is reached; 2) the prevention of migration of tumor cells due to the absence of blood flow to and from the tumors; and 3) the inhibition of endothelial cell proliferation, thereby avoiding the stimulating effect of paracrine growth on the surrounding tissue by the endothelial cells that normally coat the vessels. The present invention can also be used to prevent or treat diseases that are triggered by a persistent angiogenesis, such as psoriasis.; Kaposi's sarcoma; restenosis, for example restenosis induced by stent (vascular implant); endometriosis; Crohn's disease; Hodgkin's disease; leukemia; arthritis, such as rheumatoid arthritis; hemangioma; angiofibroma; diseases of the eyes, such as diabetic retinopathy and neovascular glaucoma; vascular diseases, such as glomerulonephritis; diabetic nephropathy; malignant nephrosclerosis; microangiopathic thrombotic syndromes; transplant rejections and glomerulopathy; fibrotic diseases, such as cirrhosis of the liver; proliferative diseases of mesangial cells; arteriosclerosis; nerve tissue injuries; and to inhibit the reocclusion of the vessels after a balloon catheter treatment, to be used in vascular prostheses, or after inserting mechanical devices to keep the vessels open, such as, for example, stent (vascular implants), as immunosuppressants, as an aid in the healing of wounds without a scar, and to treat age spots and contact dermatitis. More preferred is the use according to the present invention, of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as exemplified hereinbelow under "examples". Pharmaceutical Compositions The invention also relates to pharmaceutical compositions comprising a compound of the formula (I), to its use in the therapeutic treatment (in a broader aspect of the invention, also prophylactic), or to a method of treating a disease kinase-dependent, especially the preferred diseases mentioned above, to the compounds for this use, and to the preparation of pharmaceutical preparations, especially for such uses. The present invention also relates to prodrugs of a compound of the formula (I) which is converted in vivo into the compound of the formula (I) as such. Any reference to a compound of the formula (I), therefore, should be understood to also refer to the corresponding prodrugs of the compound of the formula (I), as appropriate and convenient. The pharmacologically acceptable compounds of the present invention can be used, for example, for the preparation of pharmaceutical compositions comprising an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as an active ingredient, together or in admixture with a significant amount of one or more inorganic or organic, solid or liquid, pharmaceutically acceptable vehicles. The invention also relates to a pharmaceutical composition which is suitable for administration to a warm-blooded animal, especially a human (or to cells or cell lines derived from a warm-blooded animal, especially a human being, for example lymphocytes) , for the treatment, or, in a broader aspect of the invention, for the prevention of (= prophylaxis against) a disease that responds to the inhibition of kinase activity, which comprises an amount of a compound of the formula ( I) or a pharmaceutically acceptable salt thereof, which is effective for said inhibition, especially together with at least one pharmaceutically acceptable carrier. The pharmaceutical compositions according to the invention are those for enteral administration, such as nasal, rectal or oral, or parenteral, such as intramuscular or intravenous, to warm-blooded animals (especially a human being), which they comprise an effective dose of the pharmacologically active ingredient, alone or together with a significant amount of a pharmaceutically acceptable carrier. The dose of the active ingredient depends on the species of warm-blooded animal, the body weight, the age, and the individual condition, the individual pharmacokinetic data, the disease to be treated, and the mode of administration. The invention also relates to a method of treatment for a disease that responds to the inhibition of a kinase; which comprises administering a prophylactically or especially therapeutically effective amount (against the aforementioned disease) of a compound of the formula (I) according to the invention, in particular to a warm-blooded animal, for example a human being, which , on account of one of the mentioned diseases, requires such treatment. The dose of a compound of the formula (1) or a pharmaceutically acceptable salt thereof to be administered to warm-blooded animals, for example humans of a body weight of about 70 kilograms, is preferably about 3 milligrams to about 10 grams, more preferably from about 10 milligrams to about 1.5 grams, most preferably from about 100 milligrams to about 1000 milligrams / person / day, preferably divided into 1 to 3 individual doses, which, for example, may be of the same size. Usually, children receive half the dose for adults.

The pharmaceutical compositions comprise from about 1 percent to about 95 percent, preferably from about 20 percent to about 90 percent of the active ingredient. The pharmaceutical compositions according to the invention can be, for example, in a unit dosage form, such as in the form of ampoules, flasks, suppositories, dragees, tablets, or capsules. The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional processes of dissolution, lyophilization, mixing, granulation, or confectionery. Preferably, solutions of the active ingredient, and also suspensions, and especially isotonic aqueous solutions or suspensions are used, possibly, for example, in the case of lyophilized compositions comprising the active ingredient alone or together with a vehicle, for example mannitol , that these solutions or suspensions produce before being used. The pharmaceutical compositions can be sterilized and / or can comprise excipients, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or pH regulators, and are prepared in a manner known per se same, for example by means of conventional dissolution or lyophilization processes. These solutions or suspensions may comprise viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone. or gelatin. Suspensions in oil include, as the oil component, the vegetable, synthetic or semi-synthetic oils customary for injection purposes. As such, in particular the esters of liquid fatty acids containing, as the acid component, a long-chain fatty acid having from 8 to 22, in particular from 12 to 22, carbon atoms, for example lauric acid, can be mentioned. tridecylic acid, myristic acid, pentadecyl acid, palmic acid, margaric acid, stearic acid, arachidic acid, behenic acid or the corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brasidic acid, or linoleic acid, if it desires with the addition of antioxidants, for example vitamin E, β-carotene, or 3,5-diterbutyl-4-hydroxy-toluene. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms, and is a mono- or polyhydroxy-, for example a mono-, di-, or tri-hydroxy-alcohol, for example methanol, ethanol, propanol, butanol, or pentanol, or the isomers thereof, but especially glycol and glycerol. Accordingly, the following examples of fatty acid esters are mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethylene glycerol trioleate, Gattefossé, Paris), "Migiyol 812" (triglyceride of saturated fatty acids with a chain length of 8 to 12 carbon atoms, Hüls AG, Germany), but especially vegetable oils, such as oil of cottonseed, almond oil, olive oil, castor oil, sesame oil, seed oil soy, and more especially peanut oil. The compositions for injection are prepared in the customary manner under sterile conditions; the same applies also to the introduction of the compositions in ampoules or flasks, and the sealing of the containers. Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired the resulting mixture is granulated, and the mixture is processed, if desired or necessary, after the addition of appropriate excipients, in tablets, dragee cores, or capsules. It is also possible that they are incorporated in plastic vehicles that allow the active ingredients to diffuse or be released in measured quantities. Suitable carriers are in particular fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example calcium triphosphate or calcium acid phosphate, and binders, such as pastes of starch using, for example, corn, wheat, rice, or potato starch, gelatin, tragacanth, methylcellulose, hydroxy-propyl-methyl-cellulose, sodium carboxy-methyl-cellulose, and / or poly-vinyl-pyrrolidone , and / or, if desired, disintegrants, such as the above-mentioned starches, and / or carboxy-methyl starch, cross-linked polyvinyl-pyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. The excipients are in particular flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts of the same, such as magnesium or calcium stearate, and / or polyethylene glycol. The dragee cores are provided with suitable, optionally enteric coatings, using, inter alia, concentrated sugar solutions, which may comprise gum arabic, talc, poly-vinyl-pyrrolidone, polyethylene glycol and / or titanium dioxide, or solutions of coating in suitable organic solvents, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as ethyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. Capsules are dry filled capsules made of gelatin and soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The dry filled capsules may comprise the active ingredient in the form of granules, for example with fillers, such as lactose, binders, such as starches, and / or skimmers, such as talc or magnesium stearate, and if desired, with stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable oily excipients, such as fatty oils, paraffin oil, or liquid polyethylene glycols, it also being possible for stabilizers and / or antibacterial agents to be added. Dyes or pigments may be added to tablets or dragee coatings or capsule shells, for example, for identification purposes, or to indicate different doses of the active ingredient. Combinations A compound of the formula (I) can also be used with advantage in combination with other antiproliferative agents. These antiproliferative agents include, but are not limited to, aromatase inhibitors; antiestrogens; Topoisomerase I inhibitors; topoisomerase II inhibitors; active microtubule agents; alkylating agents; inhibitors of histone deacetylase; compounds that induce cellular differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platinum compounds; steering compounds / reduction of a protein kinase or lipid activity, and other anti-angiogenic compounds; compounds that direct, reduce, or inhibit the activity of a protein or lipid phosphatase; Gonadrelin agonists; anti-androgens; inhibitors of methionine aminopeptidase; bisphosphonates; biological response modifiers, antiproliferative antibodies; heparanase inhibitors; inhibitors of the Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; agents used in the treatment of hematological malignancies; compounds that direct, reduce, or inhibit the activity of Flt-3; Hsp90 inhibitors; Temozolomide (TEMODAL®); and leucovorin. The term "aromatase inhibitor", as used herein, refers to a compound that inhibits the production of estrogen, ie, the conversion of the substrates of androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, especially atamestane, exemestane, and formestane, and in partar, to non-steroids, especially aminoglutethimide, rogletimide, pyridoglutetimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane can be administered, for example, in the form as it is traded, for example under the registered trademark AROMASIN. The formestane can be administered, for example, in the form as it is traded, for example under the registered trademark LENTARON. Fadrozole can be administered, for example in the form as it is traded, for example under the registered trademark AFEMA. Anastrozole can be administered, for example in the form as it is traded, for example, under the registered trademark ARIMIDEX. The letrozole can be administered, for example, in the form as it is traded, for example under the registered trademark FEMARA or FEMAR. The amino-glutethimide can be administered, for example in the way it is traded, for example under the trademark registered ORIMETEN. A combination of the invention comprising a chemotherapeutic agent that is an aromatase inhibitor, is particularly useful for the treatment of tumors positive for the hormone receptor, for example breast tumors. The term "antiestrogen", as used herein, refers to a compound that antagonizes the effect of estrogen at the level of the estrogen receptor. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen can be administered, for example, in the form as it is traded, for example under the registered trademark NOLVADEZ. Raloxifene hydrochloride can be administered, for example, in the form how it is traded, for example under the registered trademark EVISTA. The fulvestrant can be formulated as disclosed in US Pat. No. 4,659,516, or it can be administered, for example, in the form as it is traded, for example under the registered trademark FASLODEX. A combination of the invention comprising a chemotherapeutic agent that is antiestrogenic, is particularly useful for the treatment of tumors positive for the estrogen receptor, for example breast tumors. The term "anti-androgen", as used herein, refers to any substance that is capable of inhibiting the biological effects of androgenic hormones, including, but not limited to, bicalutamide (CASODEX), which it can be formulated, for example as disclosed in US Pat. No. 4,636,505. The term "gonadirelin agonist", as used herein, includes, but is not limited to, avarelix, goserelin, and goserelin acetate. Goserelin is disclosed in U.S. Patent Number US 4, 100,274, and may be administered, for example, in the form as it is traded, for example under the registered trademark ZOLADEX. Abarelix can be formulated, for example, as disclosed in U.S. Patent No. 5,843,901. The term "topoisomerase I inhibitor", as used herein, includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin, and their analogues, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148 (compound A1 in International Publication No. WO99 / 17804). The irinotecan can be administered, for example, in the way it is traded, for example under the trademark registered CAMPTOSAR. The topotecan can be administered, for example, in the form as it is traded, for example under the registered trademark HYCAMTIN. The term "topoisomerase II inhibitor", as used herein, includes, but is not limited to, anthracyclines, such as doxorubicin (including liposomal formulation, eg CAELYX), daunorubicin, epirubicin, idarubicin, and nemorubicin, and the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. The etoposide can be administered, for example, in the form as it is traded, for example under the registered trademark ETOPOPHOS. The teniposide can be administered, for example, in the form as it is traded, for example under the registered trademark VM 26-BRISTOL. Doxorubicin can be administered, for example, in the form as it is traded, for example under the registered trademark ADRIBLASTIN or ADRIAMICIN. The epirubicine can be administered, for example, in the form as it is traded, for example under the registered trademark FARMORUBICIN. The idarubicin can be administered, for example, in the form as it is traded, for example under the registered trademark ZAVEDOS. Mitoxantrone can be administered, for example, in the form as it is traded, for example under the trademark registered commercial NOVANTRON. The term "microtubule active agent" refers to microtubule stabilizing and microtubule destabilizing agents, and to microtubulin polymerization inhibitors, but is not limited to, taxanes, for example paclitaxel and docetaxel, vinca alkaloids, for example vinblastine , especially vinblastine sulphate, vincristine, especially vincristine sulfate, and vinorelbine, discodermolyses, colchicine, and epothilones and derivatives thereof, for example epothilone B or D or derivatives thereof. Paclitaxel can be administered, for example, in the form as it is traded, for example TAXOL. The docetaxel can be administered, for example in the form as it is traded, for example under the registered trademark TAXOTERE. Vinblastine sulfate can be administered, for example in the way it is traded, for example under the registered trademark VINBLASTIN R.R. The vincristine sulfate can be administered, for example in the form as it is traded, for example under the registered trademark FARMISTIN. The discodermolide can be obtained, for example, as disclosed in U.S. Patent No. 5,010,099. Also included are epothilone derivatives which are disclosed in Patent Numbers WO 98/10121, US 6, 194, 1 81; WO 98/25929, WO 99/43653, WO 98/22461 and WO 00/31247. Epothilone A and / or B is especially preferred. The term "alkylating agent", as used herein, includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCN U or Gliadel). Cyclophosphamide can be administer, for example in the way it is traded, for example under the registered trademark CYCLOSTIN. The phosphamide can be administered, for example, in the form as it is traded, for example under the registered trademark HOLOXAN. The term "histone deacetylase inhibitors" or "HDAC inhibitors" refers to compounds that inhibit histone deacetylase, and which possess antiproliferative activity. This includes the compounds disclosed in International Publication Number WO 02/22577, especially N-hydroxy-3- [4 - [[(2-hydroxy-ethyl) [2- (1H-indole 3-yl) etl] -amino] methylene] phenyl] -2E-2-propenamide, N-hydroxy-3- [4 - [[[2- (2-methyl-1 H-indoI-3 -l) -ethyl] -amino] -methyl] -phenyl] -2E-2-propenamide and the pharmaceutically acceptable salts thereof. It also includes, in particular, suberoylanilide hydroxamic acid (SAHA). The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluoro-uracil or 5-FU, capecitabine, gemcitabine, DNA distillation agents, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists. such as pemetrexed. Capecitabine can be administered, for example in the form as it is traded, for example under the registered trademark XELODA. Gemcitabine can be administered, for example in the form as it is traded, for example under the registered trademark GEMZAR. Also included is the monoclonal antibody trastuzumab, which can be administered, for example in the form as it is traded, for example under the registered trademark HERCEPTIN.

The term "platinum compound", as used herein, includes, but is not limited to, carboplatin, cisplatin, cisplatin, and oxaliplatine. Carboplatin can be administered, for example in the form as it is traded, for example under the registered trademark CARBOPLAT. The oxaliplatin can be administered, for example in the form as it is traded, for example under the registered trademark ELOXATIN. The term "compounds that direct / reduce the activity of the protein kinase or lipid, or the activity of protein or lipid phosphatase, or additional anti-angiogenic compounds", as used herein, includes, but is not limited to: inhibitors of protein tyrosine kinase and / or serine and / or threonine kinase, or lipid kinase inhibitors, for example: a) compounds that direct, reduce or inhibit the activity of platelet-derived growth factor receptors (PDGFR) , such as compounds that direct, reduce or inhibit the activity of PDGFR, especially compounds that inhibit the PDGF receptor, for example an N-phenyl-2-pyrimidin-2-amine derivative, for example imatinib, SU 101 , SU6668, and GFB-1 1 1; b) compounds that direct, reduce or inhibit the activity of fibroblast growth factor receptors (FGFR); c) compounds that direct, reduce or inhibit the activity of the insulin-like growth factor I (IGF-IR) receptor, such as compounds that direct, reduce or inhibit the activity of IGF-IR, especially compounds that inhibit the IGF-IR receptor, such as the compounds disclosed in International Publication Number WO 02/092599; d) compounds that direct, reduce or inhibit the activity of the Trk receptor tyrosine kinase family; e) compounds that direct, reduce or inhibit the activity of the Axl receptor tyrosine kinase family; f) compounds that direct, reduce or inhibit the activity of the c-Met receptor; g) compounds that direct, reduce or inhibit the receptor tyrosine kinase activity of Kit / SCFR; h) compounds that direct, reduce or inhibit the activity of the C-kit receptor-tyrosine kinases (part of the PDGFR family), such as compounds that direct, reduce or inhibit the activity of the receptor-receiving tyrosine kinase family. -Kit, especially compounds that inhibit the c-Kit receptor, for example imatinib; ) Compounds that direct, reduce or inhibit the activity of members of the c-Abl family and their gene fusion products (e.g., BCR-Abl kinase), such as compounds that direct, reduce or inhibit member activity of the c-Abl family and their gene fusion products, for example an N-phenyl-2-pyrimidine-amine derivative, for example imatinib; PD180970; AG957; NSC 68041 0; or PD173955 from ParkeDavis; j) compounds that direct, reduce or inhibit activity of members of the serine / threonine kinase family, protein kinase C (PKC) and Raf, members of the MEK family, SRC, JAK, FAK, PDK, and Ras / MAPK, or the kinase family Pl ( 3), or of the kinase family related to Pl (3) kinase, and / or members of the cyclin dependent kinase (CDK) family, and are especially the staurosporine derivatives disclosed in U.S. Pat. from North America Number US 5,093,330, for example midostaurin; examples of additional compounds include, for example, UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosin; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / L379196; isoquinoline compounds such as those disclosed in International Publication Number WO 00/09495; FTIs; PD1 84352 or QAN697 (a P13K inhibitor); k) compounds that direct, reduce or inhibit the activity of the tyrosine protein kinase inhibitors, such as the compounds they direct, reduce or inhibit the activity of the protein kinase tyrosine inhibitors, including imatinib mesylate (GLEEVEC) or tyrphostin. A tyrphostin is preferably a low molecular weight compound (Mr < 1500), or a pharmaceutically acceptable salt thereof, especially a compound selected from the benzylidene malonitrile class, or from the class of compounds of S- arylbenzene malonitrile or the quinoline bis substrate, more especially any compound selected from the group consisting of Tirfostin A23 / RG-50810; AG 99; Tirfostin AG 213; Tirfostin AG 1748; Tírfostina AG 490; Tyrphostin B44; enantiomer of Tyrphostin B44 (+); Tírfostina AG 555; AG 494; Thrifostin AG 556, AG957 and adamantyl ester of adafostin- (4- {[[(2,5-dihydroxy-phenyl) -methyl] -amino} -benzoic acid, NSC 680410, adafostine, and I) compounds that direct, reduce or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or hetero-dimers), such as the compounds that direct, reduce or inhibit activity of the family of epidermal growth factor receptors, and are especially compounds, proteins, or antibodies that inhibit members of the EGF receptor tyrosine kinase family, for example the EGF receptor, ErbB2, ErbB3, and ErbB4, or which bind to EGF or to EGF-related ligands, and are in particular the compounds, proteins, or monoclonal antibodies generically and specifically disclosed in International Publication Number WO 97/02266, for example the compound of Example 39, or in Patents Number s EP 0,564,409; WO 99/03854; EP 0520722; EP 0,566,226; EP 0,787,722; EP 0,837,063; US 5,747,498; WO 98/10767; WO 97/30034; WO 97/49688; WO 97/38983 and, in particular WO 96/30347 (for example the compound known as CP 358774), WO 96/33980 (for example the compound ZD 1839), and WO 95/03283 (for example the compound ZM1 05180); for example trastuzumab (HERCEPTIN), cetuximab, Iressa, Tarceva, OSI-774, Cl-1 033, EKB-569, GW-2016, E1 .1, E2.4, E2.5, E6.2, E6.4, E2.1 1, E6.3 or E7.6.3, and 7H-pyrrolo [2,3-d] pyrimidine derivatives which are disclosed in International Publication Number WO 03/013541.

Other anti-angiogenic compounds include those compounds that have another mechanism for their activity, for example unrelated to the inhibition of protein kinase or lipid, for example thalidomide (THALOMID) and TNP-470. Compounds which direct, reduce or inhibit the activity of a protein or lipid phosphatase are, for example, inhibitors of phosphatase 1, phosphatase 2B, PTEN or CDC25, for example okadaic acid or a derivative thereof. The compounds that induce cell differentiation processes are, for example, retinoic acid, a-, and-, or d-tocopherol, or a-, and-, or d-tocotrienol. The term "cyclo-oxygenase inhibitor," as used herein, includes, but is not limited to,, Cox-2 inhibitors, 2-aryl-amino-phenyl-acetic acid substituted by 5-alkyl and its derivatives, such as celecoxib (CELEBREX), rofecoxib (V1OXX), etoricoxib, valdecoxib, or a 5-alkyl-2 acid -aryl-amino-phenyl-acetic acid, for example 5-methyl-2- (2'-chloro-6'-fluoro-ani I) -f in I-acetic acid, lumiracoxib. The term "bisphosphonates", as used herein, includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, ristaedronic, and zoledronic acid. The "etidronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark DIDRONEL. The "clodronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark BONEFOS. The "tiludronic acid" can be administered, for example, in the way it is traded, for example under the registered trademark SKELID. The "pamidronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark AREDIAMR. The "alendronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark FOSAMAX. The "ibandronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark BONDRANAT. The "risedronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark ACTONEL. The "zoledronic acid" can be administered, for example, in the form as it is traded, for example under the registered trademark ZOMETA. The term "mTOR inhibitors" refers to compounds that inhibit the mammalian target of rapamycin (mTOR), and which possess an anti-pyrolymphatic activity, such as sírolimus (Rapamune®), everolimus (Certícal®), CCl-779 and ABT578 . The term "heparanase inhibitor", as used herein, refers to compounds that direct, reduce or inhibit the degradation of heparin sulfate. The term includes, but is not limited to, PI-88. The term "biological response modifier", as used herein, refers to a lymphocine or to interferons, for example interferon and. The term "inhibitor of Ras oncogenic isoforms", by example H-Ras, K-Ras, or N-Ras, as used herein, refers to compounds that direct, reduce or inhibit the oncogenic activity of Ras, for example a "farnesyl transferase inhibitor", for example L-744832, DK8G557 or P1 15777 (Zarnestra). The term "telomerase inhibitor", as used herein, refers to compounds that direct, reduce or inhibit telomerase activity. The compounds that direct, reduce or inhibit the activity of telomerase are in particular compounds that inhibit the telomerase receptor, for example telomestatin. The term "methionine aminopeptidase inhibitor", as used herein, refers to compounds that direct, reduce or inhibit the activity of methionine aminopeptidase. The compounds that direct, reduce or inhibit the activity of the methionine aminopeptidase are, for example, bengamide or a derivative thereof. The term "proteasome inhibitor", as used herein, refers to compounds that direct, reduce or inhibit proteasome activity. Compounds that direct, reduce or inhibit proteasome activity include, for example, PS-341 and MLN 341. The term "matrix metalloproteinase inhibitor" or ("MMP inhibitor"), as used herein, includes, but is not limited to, peptidomimetic and non-peptidomimetic inhibitors of collagen, tetracycline derivatives, for example the peptidomimetic inhibitor. of hydroxamate, batimastat, and its analog orally bioavailable, marmostat (BB-2516), prinomastat (AG3340), metastate (NSC 683551) BMS-279251, BAY 12-9566, TAA21 1, MMI270B, or AAJ996. The term "agents used in the treatment of hematological malignancies", as used herein, includes, but is not limited to, FMS-type tyrosine kinase inhibitors, for example compounds that direct, reduce, or inhibit the activity of tyrosine kinase receptors type FMS (FI.-3R); interferon, 1-b-D-arabino-furanosyl-cytosine (ara-c) and bisulfan; and ALK inhibitors, for example compounds that direct, reduce or inhibit anaplastic lymphoma kinase. The compounds that direct, reduce or inhibit the activity of the tyrosine kinase receptors type FMS (Flt-3R) are in particular the compounds, proteins or antibodies that inhibit the members of the family of receptor kinase FI.-3R, for example PKC412, midostaurin, a staurosporine derivative, SU 1 1248 and MLN518. The term "HSP90 inhibitors", as used herein, includes, but is not limited to, the compounds they direct, reduce or inhibit the intrinsic activity of the ATPase of HSP90.; that degrade, direct, reduce, or inhibit HSP90 client proteins through the proteasome pathway of ubiquitin. The compounds that direct, reduce or inhibit the intrinsic activity of the ATPase of HSP90 are in particular the compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, for example 17-allylamino, 17-demethoxygeldanamycin (17AAG), a derivative of geldanamycin; others compounds related to geldanamycin; radicicol and HDAC inhibitors. The term "anti-proliferative antibodies", as used herein, includes, but is not limited to, trastuzumab (Herceptin ™), Trastuzumab-DM1, erlotinib (Tarceva ™), bevacizumab (Avastin®), tiruximab (Rituxan®), PRO64553 (anti-CD40) and the antibody 2C4. Antibodies mean, for example, intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, as long as they exhibit the desired biological activity. For the treatment of acute myeloid leukemia (AML), the compounds of the formula (I) can be used in combination with conventional leukemia therapies, especially in combination with the therapies employed for the treatment of acute myeloid leukemia. In particular, the compounds of the formula (I) can be administered in combination, for example, with the farnesyl transferase inhibitors and / or other drugs useful for the treatment of acute myeloid leukemia, such as Daunorubicin, Adriamycin, Ara-C , VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatin and PKC412. The term "antileukemic compounds" includes, for example, Ara-C, a pyrimidine analogue, which is the 2'-alpha-hydroxy-ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP), and fludarabine phosphate. The compounds that direct, reduce or inhibit the activity The inhibitors of histone deacetylase (HDAC), such as sodium butyrate and suberoylanilide-hydroxamic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A, and the compounds disclosed in U.S. Patent Number US 6,552,065, in particular, N-hydroxy-3- [4- [[[2- (2-methyl-1 H-indol-3-yl) -ethyl] -amino] -methyl] -phenyl] -2-E-2-propenamide, or a pharmaceutically acceptable salt thereof, and N- hydroxy-3- [4 - [(2-hydroxyethyl). { 2- (1 H-indol-3-yl) ethyl] -amino] -methyl] -phenyl] -2 E-2-propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt. Compounds that direct, reduce or inhibit the activity of mTOR serine / threonine kinase, are especially compounds, proteins, or antibodies that inhibit members of the mTOR kinase family, eg RAD, RAD001, CCl-779 , ABT578, SAR543, rapamycin and its derivatives; AP23573 of Ariad; everolímus (CERTICAN); and sirolimus. Somatostatin receptor antagonists, as used herein, refer to agents that direct, treat or inhibit the somatostatin receptor, such as octreotide, and SOM230. The proposals for damage to tumor cells refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter, means ionizing radiation that occurs either as electromagnetic rays (such as x-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but is not limited to, radiation therapy, and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principies and Practice of Oncology, Devita et al., Eds. , 4a. edition, Volume 1, pages 248-275 (1993). The term "EDG binders", as used herein, refers to a class of immunosuppressants that modulates the recirculation of lymphocytes, such as FTY720. CERTICAN (everolimus, RAD), is an inhibitor of novel research of proliferation signals that prevents the proliferation of T-cells, and vascular smooth muscle cells. The term "ribonucleotide reductase inhibitors" refers to the nucleoside analogs of pyrimidine or purine, including, but not limited to, fludarabine and / or cytosine-arabinoside (ara-C), 6-thioguanine, 5-fluorouraine, cladribine, 6-mercaptopurine (especially in combination with ara-C against acute lymphoblastic leukemia) and / or pentostatin. Inhibitors of ribonucleotide reductase are in particular hydrodiurea or derivatives of 2-hydroxy-1 H-isoindole-1,3-dione, such as PL-1, PL-2, PL-3, PL-4, PL -5, PL-6, PL-7, or PL-8 mentioned in Nandy et al., Acta Oncológica, Volume 33, Number 8, pages 953-961 (1994). The term "S-adenosyl-methionine decarboxylase inhibitors", as used herein, includes but is not limited to, the compounds disclosed in US Pat.

North America Number US 5,461, 076. Also included in particular are the compounds, proteins, or VEGF monoclonal antibodies disclosed in International Publication Number WO 98/35958, for example 1- (4-chloroanilino) -4- (4-pyridinyl) phthalazine. or a pharmaceutically acceptable salt thereof, for example succinate, or in Patent Numbers WO 00/09495, WO 00/27820, WO 00/59509, WO 98/1 1223, WO 00/27819, and EP 0,769,947; those described by Prewett et al., Cancer Res., volume 59, page 5209-5218 (1999); Yuan et al., Proc. Nati Acad. Sci. USA, Volume 93, pages 14765-14770 (1 996); Zhu et al., Cancer Res., Volume 58, pages 3209-3214 (1998); and Mordenti et al., Toxicol Pathol, Volume 27, Number 1, pages 14-21 (1999); in International Publications Nos. WO 00/37502 and WO 94/10202; ANGIOSTATINA, described by O'Reilly et al., Cell, Volume 79, pages 315-328 (1994); ENDOSTATINE, described by O'Reilly et al., Cell, Volume 88, pages 277-285 (1997); anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, for example rhuMAb and RHUFab, the VEGF aptamer, for example Macugon; inhibitors of FLT-4, inhibitors of FLT-3, IgG1 antibody of VEGFR-2, antiozyme (RPI 461 0) and Avastan. "Photodynamic therapy", as used herein, refers to therapy that uses certain chemicals known as photosensitizing agents to treat or prevent cancers. The Examples of photodynamic therapy include treatment with agents, such as, for example, VISUDYNE and porfimer-sodium. Angiostatic steroids, as used herein, refer to agents that block or inhibit angiogenesis, such as, for example, anecortave, triamcinolone, hydrocortisone, 1 1-a-epihydrocortisol, cortexolone, 17a-hydroxy-progesterone, corticosterone, deoxy-corticosterone, testosterone, estrone and dexamethasone. Implants containing corticosteroids refer to agents, such as, for example, fluocinolone, dexamethasone. Other chemotherapeutic agents include, but are not limited to, plant alkaloids, hormonal agents and antagonists; modifiers of biological responses, preferably lymphokines or interferons; anti-sense oligonucleotides or oligonucleotide derivatives; or several agents, or agents with another mechanism of action or one unknown. The structure of the active agents identified by code numbers, generic or commercial names, can be taken from the current edition of the standard compendium "The Merck Index", or from the databases, for example Patents International (for example, IMS World Publications). The above-mentioned compounds, which can be used in combination with a compound of the formula (1), can be prepared and administered as described in the art, such as in the documents cited above.

A compound of the formula (I) can also be used advantageously in combination with known therapeutic processes, for example the administration of hormones, or in particular radiation. A compound of the formula (I) can be used in particular as a radiosensitizer, in particular for the treatment of tumors exhibiting poor sensitivity to radiotherapy. "Combination" means either a fixed combination or a unit dosage form, or a kit of parts for combined administration wherein a compound of the formula (I) and a combination component can be administered independently at the same time or separately , within time intervals that allow in particular that the components of the combination show a cooperative, for example synergistic, effect or any combination thereof. EXAMPLES The following examples serve to illustrate the invention, without limiting its scope: Abbreviations DMSO dimethyl sulfoxide ES-MS electrospray mass spectrometry EtOAc ethyl acetate HPLC high pressure liquid chromatography mL milliliter (s) NMR nuclear magnetic resonance TA temperature ambient AtRET HPLC retention time in minutes (method A) BtRET HPLC retention time in minutes (method B) ctRET HPLC retention time in minutes (method C) DtRET HPLC retention time in minutes (method D) acid TFA trifluoroacetic THF tetrahydrofuran TMSCI trismethylsilyl chloride When temperatures are not given, the reaction takes place at room temperature. The proportions of the solvents, for example in the eluents or solvent mixtures, are given in volume by volume (v / v). Synthesis The chromatography is carried out by evaporation using silica gel (Merck, 40-63 μm). For thin layer chromatography, precoated silica gel plates are used (Merck 60 F254). The detection of the components is done by ultraviolet light (254 nanometers). High pressure liquid chromatography is carried out on an Agilent HP 1 100 using a column Nucleosil 100-3 C18 HD 125 x 4.0 millimeters [1 milliliter / minute; NeCN at 20-1 00 percent / 0.1 percent TFA in 7 minutes) (Method A); SpectraSystem SP8800 / UV2000 using a Nucleosil 100-5 column C18 AB of 250 x 4.6 millimeters (2 milliliters / minute; MeCN at 2-100 per cent / 0.1% TFA in 10 minutes) (Method B); using a column Chromalith Speed ROD RP18 of 50-4.6 millimeters (Merck) (2 milliliters / minute; MeCN at 2-100 percent / 0.1 percent TFA at 2 minutes) (Method C); or a column of 3 microns C8 of 2.1 -50 millimeters (Waters) (2 milliliters / minute; MeCN at 5-95 per cent / 0.1% TFA in 2 minutes) (Method D). The 1 H-NMR measurements are carried out on a Varian Gemini 400 or Bruker DRX 500 spectrometer using tetraethylsilane as the internal standard. Chemical changes are expressed in ppm downfield from tetraethylsilane, and coupling constants (J) are expressed in Hertz (Hz). The electrospray mass spectra are obtained with a Fisons Instruments VG Platform I I. The melting points are measured with a Büchi 510 melting point apparatus. For solvents, solvents and commercially available chemicals are used.

Analytical high pressure liquid chromatography conditions: System 1 Linear gradient from 20 to 100 percent CH3CN (0.1 percent trifluoroacetic acid) and H2O (0.1 percent trifluoroacetic acid) in 7 minutes + 2 minutes, 100 percent of CH3CN (0.1 percent trifluoroacetic acid); detection at 215 nanometers, flow rate of 1 milliliter / minute at 30 ° C. Column: Nucleosil 100-3 C18HD (125 x 4 millimeters).

System 2 Linear gradient from 2 to 100 percent CH3CN (0.1 percent trifluoroacetic acid) and H2O (0.1 percent trifluoroacetic acid) in 7 minutes + 2 minutes, 100 percent CH3CN (acid) 0.1 percent trifluoroacetic); detection at 215 nanometers, flow rate of 1 milliliter / minute at 30 ° C. Column: Nucleosil 1 00-3 C1 8HD (125 x 4 mm).

Example 1 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-pperazin-1-l) -phenyl] -pyrazolo [1,5-a] pyrimidine-7-yl- amine (Stage 1 .1) (25 milligrams, 0.051 mmol) dissolved in tetrahydrofuran (6 milliliters) is hydrogenated in the presence of Pd / C (10 percent, Engelhard 4505, 6 milligrams) for 13 hours. After filtration and evaporation of the solvent under reduced pressure, the residue is passed by evaporation chromatography (silica gel, CH 2 Cl 2 / MeOH / NH 3 = 95: 5: 0.1), to give the compound of Example 1 as a solid. white (14 milligrams, 0.035 millimoles, 70 percent): ES-MS: M + H = 401 .1, Rf (CH2Cl2 / MeOH / NH3 = 90: 10: 0.1) = 0.33, HPLC: AtRet = 2.77 minutes. 1 H NMR (400 MHz, DMSO-d 6): 9.59 (s, 1 H, OH), 8.58 / 8.18 (s / s, 1 H / 1 H, pyrazolopyrimidinium), 8.01 (d, 9.0 Hz, 2 H, phenyl) , 7.48 (s, 2H, NH2), 7.32 (t, 8.5 Hz, 1 H, phenyl-OH), 6.99 (d, 9.0 Hz, 2H, phenyl), 6.96 (d, 8.5 Hz, 1 H, phenyl-OH), 6.93 (s, 1 H, phenyl-OH), 6.80 (d, 8.5 Hz, 1 H, phenyl-OH), 3.17 / 2.48 (m / m, 4H / 4H, piperazinyl), 2.24 (s, 3H, CH3). Step 1. 1 6- (3-Benzyloxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl- amine 4- (4- (4-Methyl-piperazin-1-yl) -phenyl) -2H-pyrazol-3-yl-amine (Step 1 .2) (100 milligrams, 0.388 millimoles), 2- (3-benzyloxy-phenyl) -3-oxo-propionitrile (Step 1 .3) (98 milligrams, 0.388 millimoles), HCl (2.5 mM in EtOH; 1.55 millimoles, 0.9 milliliters) dissolved in EtOH (1 milliliter), are stirred for 17 hours at room temperature. After adding H2O (4 milliliters) and K2CO3 (250 milligrams), the reaction mixture is extracted with CH2Cl2 (20 milliliters, twice). The combined organic phases are washed with H 2 O (10 milliliters), dried (Na 2 SO 4), concentrated under reduced pressure, and passed by evaporation chromatography (silica gel, 2.5 x 15 centimeters, CH 2 Cl 2 / MeOH = 9: 1). ) to give the compound of Step 1 .1 as a white solid (60 milligrams, 0.122 millimoles, 32 percent); ES-MS: M + H = 491.0, Rf (CH2Cl2 / MeOH / NH3 = 90: 10: 0.1) = 0.42; HPLC AtRet = 4.69 minutes. 1 H NMR (400 MHz, DMSO-d 6): 8.79 / 8.21 (s / s, 1 H / 1 H, pyrazolopyrimidinyl), 8.03 (d, 9.0 Hz, 2 H, phenyl), 7.53 (s, 2 H, NH 2), 7.44 (m, 5H, benzyl), 7.32 (t, 8.5 Hz, 1 H, fe? // o-OH), 7.29 (s, 1 H, phenyl-OH), 7.13 (d, 8.5 Hz, 1 H, phenyl -OH), 7.06 (d, 8.5 Hz, 1 H, 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). Step 1.2 4- (4- (4-methyl-piperazin-1-yl) -phenyl) -2H-pyrazol-3-yl-amine 2- [4- (4-methyl-piperazin-1-yl) -phenyl] -3-oxo-propy-nitril (Step 1 .4) (370 milligrams, 1.52 millimoles), and the hydrazine monohydrate (0.185 milliliters, 3.8 millimoles) dissolved in AcOH, are stirred at 98 ° C for 3 hours. After cooling to room temperature, H2O (8 milliliters) and concentrated HCl (0.8 milliliters) are added, and the mixture of reaction is stirred under reflux for 20 minutes. After cooling to room temperature, the reaction mixture is adjusted to an alkaline pH making the addition of NH3 (25 percent) slower. The material that is precipitated is filtered and stored for further purification. The reaction solution is extracted with CH2Cl2 (50 milliliters, 3 times), dried (Na2SO), and concentrated under reduced pressure. The precipitated and extracted material is combined, and passed through chromatography by evaporation (silica gel, 3.0 x 18 centimeters, CH2Cl2 / MeOH / NH3 = 9: 1: 01), to give the compound of Step 1 .2 as a solid white (277 milligrams, 1.08 millimeters, 71 percent); ES-MS: M + H = 258.1, Rf (CH2Cl2) / MeOH / NH3 = 90: 10: 0.1) = 0.28; HPLC: AtRet = 4.33 minutes. 1 H NMR (400 MHz, DMSO-d 6): 1 1 .55 s / broad, 1 H, NH), 7.55 (s, 1 H, pyrrolyl), 7.35 (d, 9.0 Hz, 2 H, phenyl), 6.91 (d , 9.0 Hz, 2H, phenyl), 4.55 (broad s, 2H, NH2), 3.10 / 2.46 (m / m, 4H / 4H, piperazinyl), 2.23 (s, 3H, CH3). Step 1 .3 2- (3-benzyloxy-phenyl) -3-oxo-propionitrile Na (260 milligrams, 11.3 millimoles) is dissolved in absolute EtOH (11 milliliters) under argon for 20 minutes. After adding (3-benzyloxy-phenyl) -acetonitrile (1.9 grams, 8.68 millimoles) and ethyl formate (1.05 milliliters, 13.0 mmol), the reaction mixture is stirred under reflux for 2 hours. After evaporation of the solvent under reduced pressure, addition of H 2 O (20 milliliters), and adjustment to pH = 4.0 by the addition of AcOH, the reaction suspension is extracted with CH 2 Cl 2 (30 milliliters, 2 times) . The combined organic phases are washed with H2O (10 milliliters), dried (Na2SO), concentrated under reduced pressure, and passed by evaporation chromatography (silica gel, 4.5 x 25 centimeters, CH2Cl2 / MeOH = 98.2), to give the compound from Step 1 .3 as a white solid (780). milligrams, 3.1 1 millimoles, 36 percent); ES-MS: M-H = 250.0, Rf (CH2Cl2 / MeOH = 95: 5) = 0.49; HPLC: AtRet = 6.07 minutes. 1 H NMR (400 MHz, DMSO-d 6): 7.45-7.25 / 6.98-6.88 (m / m, 8 H, aryl), 5.09 (s, 2 H, CH 2), 3.98 (s, 2 H, CH 2). Step 1.4: 2- [4- (4-Methyl-piperazin-1-yl) -phenyl] -3-oxo-propionitrile 160 milligrams of Na (7.0 millimoles) are dissolved in absolute EtOH (6 milliliters) under argon for 10 minutes. After adding [4- (4-methyl-piperazin-1-yl) -phenyl] -acetonitrile (Step 1.5) (1 gram), 4.64 mmol) and ethyl formate (0.56 milliliters, 7.0 mmol), the reaction mixture is stirred under reflux for 1 hour. After washing the reaction pulp with ether (50 milliliters, 3 times), the solid residue is dissolved in H2O (60 milliliters), and adjusted to a pH = 3.9 by the addition of AcOH. The aqueous solution is extracted with CH2Cl2 (50 milliliters, 3 times). The combined organic phases are washed with H2O (50 milliliters). Both aqueous phases are combined and lyophilized. The resulting residue is crystallized from MeOH / CH2Cl2 to give the compound from Step 1.4 as white crystals (721 milligrams, 3.0 millimoles; 64 percent); ES-MS: M + H = 244.1; HPLC: AtRet = 2.43 minutes. 1 H NMR (400 MHz, DMSO-d 6): the compound forms a tautomeric equilibrium in solution: 7.87 / 7.77 (s / s, 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), 3.1 0 (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 grams, 25.5 millimoles), 1-methyl-piperazine (3.4 milliliters, 30.6 millimoles), K2CO3 (7.68 grams, 35.7 millimoles), Pd (AcO) 2 (280 milligrams, 1 .275 mmol), 2- (di-tert-butyl-phosphino) -biphenyl (1.14 grams, 3.825 mmol) dissolved in 1,2-dimethoxyethane (70 milliliters), are stirred under argon at 85 ° C for 20 hours. After the addition of H2O (100 milliliters), the reaction mixture is extracted with CH2Cl2 (1000 milliliters, 3 times). The combined organic phases are washed with H 2 O (1 00 milliliters), dried (Na 2 SO 4), concentrated under reduced pressure, and passed by evaporation chromatography (silica gel, 4.5 x 34 centimeters, CH 2 Cl 2 / MeOH = 95: 5 ), to give the compound from Step 1 .5 as a white solid (2.8 grams, 13 mmol, 51 percent); ES-MS: M + H = 216.1; Rf (CH2Cl2 / MeOH = 9: 1) = 0.47; HPLC: AtRβt = 2.24 minutes. 1 H NMR (400 MHz, DMSO-d 6): 7.14 / 6.91 (d / d, 9.5 Hz, 2 H / 2 H, phenyl), 7.53 (s, 2 H, NH 2), 7.44 (m, 5 H, benzyl), 7.32 ( t, 8.5 Hz, 1 H, phenyl-OH), 7.29 (s, 1 H, phenyl-OH), 3.84 (s, 2H, benzyl), 3.09-2.42 (t / t, 5.0 Hz, 4H / 4H, piperazinyl ), 2.18 (s, 3H, CH3). Example 2 6- (3-methoxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimid i n-7-i I-amine 6- (3-Methoxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine is synthesized through condensation of the compound of Step 1 .2 and 2- (3-methoxy-phenyl) -3-oxo-propionitrile (Step 2.1), in a manner analogous to the preparation of the compound of Example 1. Yield: 48 percent, solid powder; ES-MS: M + H = 415.1; HPLC: AtRet = 3.45 minutes. 1 H NMR (400 MHz, DMSO-d 6): 8.59 / 8.23 (s / s, 1 H / 1 H, pyrazolopyrimidinyl), 8.06 (d, 9.0 Hz, 2H, phenyl), 7.55 (s, 2H, NH2), 7.43 (t, 8.5 Hz, 1 H, phenyl-OMe), 7.10 (d, 8.5 Hz, 1 H, phenyl-OMe), 7.08 (s, 1 H, phenel-OMe), 6.80 (d, 8.5 Hz, 1 H, phenyl-OMe), 6.98 (d, 9.0 Hz, 2H, phenyl), 3.83 (s, 3H, CH3-O), 3.16 / 2.47 (m / m, 4H / 4H, piperazinyl), 2.25 (s, 3H , CH3). Step 2. 1 2- (3-methoxy-phenyl) -3-oxo-propionitrile 2- (3-methoxy-phenyl) -3-oxo-propionitrile is synthesized in a manner analogous to the preparation of the compound of the invention. Stage 1 .3: Yield: 76 percent; white powder; ES-MS: M-H = 1 74.0; HPLC: AtRet = 4.75 minutes. 1 H NMR (400 MHz, DMSO-d 6): the compound forms a tautomeric equilibrium in solution: 8.09 / 7.67 (s / s, 1 H, CH = / CH-OH), 7.38-7.23 (m, 2H, phenyl) , 7.01 -6.97 (m, 1 H, phenyl), 6.88-6.79 (m, 1 H, phenyl), 3.74 (broad s, 3 H, CH 3 -O). EXAMPLE 3 6- (3,5-Dimethoxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pi ri m id i n-7 -i I-amine 6- (3,5-dimethoxy-phenyl) -3- [4- (4-methyl-piperazin-1-l) -phenyl] -pyrazolo [1,5-a] ] pyrimidin-7-yl-amine is synthesized by the condensation of the compound from Step 1 .2 and 2- (3,5-dimethoxy-phenyl) -3-oxo-propionitrile (Step 3.1) in a manner analogous to the preparation of the compound of Example 1 . Yield: 44 percent, solid powder; ES-MS: M + H = 445. 0; HPLC: AtRet = 3.77 minutes. 1 H NMR (400 MHz, DMSO-d 6): 8.59 / 8.23 (s / s, 1 H / 1 H, pyrazolopyrimidinyl), 8.06 (d, 9.0 Hz, 2H, phenyl), 7.55 (s, 2H, NH2), 7.43 (t, 8.5 Hz, 1 H, phenyl-OMe), 7.10 (d, 8.4 Hz, 1 H, phenyl-OMe), 7.57 (s, 2H, NH2), 7.01 (d, 9.0 Hz, 2H, phenyl), 6.89 (s, 2H, phenyl-OMe), 6.54 (s, 1 H, 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). Step 3. 1 2- (3,5-Dimethoxy-phenyl) -3-oxo-propionitrile 2- (3,5-D-methoxy-phenyl) -3-oxo-propionitrile is synthesized in a manner analogous to the preparation of the compound of Step 1 .3.

Yield: 48 percent; white powder; ES-MS: M + H = 206.0; HPLC: AtRet = 4.79 minutes. 1 H NMR (400 MHz, DMSO-d 6): the compound forms a tautomeric equilibrium in solution: 8.1 1 /7.68 (s / s, 1 H, CH = / CH-OH), 6.85 / 6.54 (s / s, 2H, phenyl), 6.44 / 6.38 (s / s, 1 H, phenyl), 3.74 (s / broad, 6H, CH3-O). Example 4 6- (3-benzyloxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1, 5-a] pyrimidin-7-yl-amine Prepared by the step released in the Stage eleven . Examples 5-69 The following examples listed in Table 1 are synthesized in a manner analogous to the preparation of Example 1. The The synthesis of the intermediates for the preparation of the compounds of Examples 5 to 69 which are not commercially available, are described in the text which is found after Table 1. In cases where the title compounds carry a free amino group (Examples 52 to 54), the final products are generated from their precursors bearing corresponding nitro function by hydrogenation in the presence of Pd / C (10 percent ) in THF / MeOH for several hours.

Table 1 Step 5.1 2- (4-chloro-phenyl) -3-oxo-propionitrile. The 2- (4-chloro-phenyl) -3-oxo-propionitrile is prepared in a manner analogous to the preparation of the compound of Step 1 .3: 89 percent; ES-MS (M-1] "= 177.9 / 179.9; HPLC AtRef = 5.67 minutes.

Step 6. 1 2- (3-chloro-phenyl) -3-oxo-propionitrile The 2- (3-chloro-phenyl) -3-oxo-propionitrile is prepared in a manner analogous to the preparation of the compound of Step 1 .3: 89 percent; ES-MS [M-1] "= 177.9 / 179.9; HPLC AtRef = 5.60 minutes Step 8. 1 3-Oxo-2-phenyl-butyronitrile 3-Oxo-2-phenyl-butyronitrile is prepared in a manner analogous to the preparation of the compound of Step 1: 3: 62 percent, white crystals, mp> 215 ° C; ES-ES-MS MH = 157.9, Rf (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, 1 H), 3.21 (s / broad, 1 H, CH), 2.03 (s, 3H, CH3).

Step 9.1 2-Methyl-3-oxo-3-phenyl-propionitrile 2-Methyl-3-oxo-3-phenyl-propionitrile is prepared in a manner analogous to the procedure of Yoo et al., Tetrahedron Lett. Volume 43, No. 27, pages 4813-4815 (2002). The 2-bromo-proplonitrile (0.965 milliliters, 1150 millimoles) and In powder (975 milligrams, 8.5 millimoles) are stirred under argon in tetrahydrofuran (15 milliliters) for 1 hour. After adding benzoylnitrile (735 milligrams, 5.6 millimoles) for 2 minutes, the reaction mixture is stirred at 60 ° C in a microwave oven (Emrys optimizer, personal chemistry, Sweden) for 30 minutes. After filtration on Hyflo and washing with tetrahydrofuran (5 milliliters), the reaction solution is concentrated under reduced pressure, and divided between ether (150 milliliters) and a phosphate buffer (pH = 7, 150 milliliters). After separation of the organic phase, the aqueous phase is extracted with ether (150 milliliters). The combined organic phases are washed with brine (30 milliliters), dried (Na2SO4), concentrated under reduced pressure, and passed by evaporation chromatography (silica gel, 2 x 18 centimeters, hexane / AcOEt = 3: 1). , to obtain the compound of step 9.1 as a slightly yellowish oil (300 milligrams, 1.9 millimoles, 34 percent); ES-MS: M-H = 157.9; Rf (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, 1 H), 7.62 (t, 8.5 Hz, 2H), 5.17 (q, 8.5 Hz, 1 H, CH), 1.52 (s, 3H, CH 3). The compound of Example 1 0 is synthesized in a manner analogous to the preparation of the compound of Step 1 .1, by condensation of 2,3-dichloro-N- [4-cyano-formyl-methyl) -phenyl] -benzenesulfonamide (Step 10.1) and 4- (4-dimethylamino-phenyl) -2H-pyrazol-3-yl-amine (Stage 10.3). Step 10. 1-2,3-dichloro-N- [4- (cyano-formyl-methyl) -phenyl] -benzenesulfonamide Under an N 2 atmosphere, freshly cut pieces of sodium are added in portions (2.3 grams in total, 100 millimoles) to absolute EtOH (230 milliliters) within 15 minutes, which is slightly exothermic (up to 43 ° C). After all of the sodium is dissolved (approximately 1 hour), 2,3-dichloro-N- (4-clanomethyl-phenyl) -benzenesulfonamide (Step 10.2) (26.77 grams, 77 millimoles) and acid ethyl ester are added. Formic (1.2 1 milliliters, 139 millimoles) to the colorless solution at room temperature. The mixture is refluxed for 2 hours. After cooling to room temperature, the solvent is removed under reduced pressure, and the residue is dissolved in H2O (20 milliliters), followed by the addition of AcOH (200 milliliters).; pH of 4). The aqueous layer is extracted with CH2Cl2 (500 milliliters, 2 times), the combined organics are washed with H2O and dried over Na2SO. The purification is done by repeated chromatography (silica gel, EtOAc and CH2Cl2 / MeOH = 98: 2) to obtain 2,3-dichloro-N- [4- (cyanothrylmethyl) -phenyl] -benzene-its-phosphonamide (233 milligrams, yield 1 percent) as beige crystals: pf 88-1 02 ° C; (CH2Cl2 / MeOH = 95: 5): 0.22; ES-MS [M + H] + = 368; HPLC BtRet = 5.61 minutes. Step 10.2 2-Dichloro-N- (4-cyanomethyl-phenyl) -benzenesulfonamide To the solution of 4-amino-benzyl cyanide (12 grams, 90.8 millimoles) in pyridine (1 milliliters) at room temperature, a solution of 2,3-dichloro-benzenesulfonyl chloride (22.29 grams, 90.8 mmol) in tetrahydrofuran (80 milliliters) within 20 minutes. The reaction is stirred at reflux for 2 hours. After cooling, the solvent is removed under reduced pressure, and the remaining solid is suspended in 10 percent HCl (200 milliliters). The crude crystalline product is filtered, washed with H2O, and dried at 60 ° C. The final purification is done by suspending the crude compound in MeOH (250 milliliters), heating to reflux, filtering and drying. The 2,3-dichloro- N- (4-cyanomethyl-phenyl) -benzenesulfonamide (26.54 grams, 86 percent) is obtained as orange crystals: m.p. 202-206 ° C; (CH2Cl2 / MeOH 98: 2): 0.54; ES-MS [M-1] "= 338.8; HPLC BtRet = 5.85 minutes Step 10.3 4- (4-dimethylamino-phenyl) -2H-pyrazol-3-yl-amine 4- (4-dimethylamino-phenol) ) -2H-p'razoI-3-yl-amine is prepared from 2- (4-dimethylamino-phenyl) -3-oxo-propionitrile (Step 10.4) and hydrazine hydrate, as described in the US Pat. United States of America Number 2,989,539 (20.6.61; Anderson and Reiff; Example 18) 4- (4-dimethylamino-phenyl) -2H-pyrazol-3-yl-amine: mp 173-176 ° C (CH 2 Cl 2) / MeOH / NH3 = 90: 1: 1): 0.37; ES-MS [M + 1] + = 203; HPLC BtRet = 1 -40 minutes. Step 10.4 2- (4-dimethylamino-phenyl) -3-oxo-propionitrile 2- (4-Dimethylamino-phenyI) -3-oxo-propionitrile is prepared from (4-dimethylamino-phenyl) -acetonitrile, ethyl formate, and sodium, as described in U.S. Pat. from North America Number 2,989,539 (Example 18). 2- (4-dimethylamino-phenyl) -3-oxo-propionitrile: p.f. 175-178 ° C; ES-MS [M + 1] + = 189; HPLC BtRet = 2.00 minutes. The compound of Example 1 1 is prepared in a manner analogous to the synthesis of the compound of Example 10, using 4- (4-dimethylamino-phenyl) -2H-pyrazol-3-yl-amine (Step 1 0.3) and 4- ( cyano-formyl-methyl) -phenyl ester of 4-cyclobenzenephonic acid (Step 1 1.1). Step 1 1. 1 4- (Chloro-benzenesulfonic acid 4- (cyano-formyl-methyl) -phenyl ester-ester 4-Chloro-benzenesulfonic acid 4- (cyano-formyl-methyl) -phenol-ester is prepared as described in Example 10 (Step 10.1), using commercially available 4- (cyanomethyl) phenyl-4-chlorobenzene-1-sulfonate instead. 4- (cyano-formyl-methyl) -phenyl ester of 4-chloro-benzenesulfonic acid (162 milligrams); yellowish solid; (CH2Cl2 / MeOH = 95.2): 0. 32; ES-MS [M + 1] + = 335; HPLC BtRet = 6.23 minutes. Step 12. 1 2- (4-methoxy-phenyl) -3-oxo-butyronitrile 2- (4-methoxy-phenyl) -3-oxo-butyronitrile is prepared as described by Smith, Breen, Hajek and Awang , J. Org. Chem., Volume 35, number 7, pages 2215-2221 (1 970). Step 14. 1 2- (4-Bromo-phenyl) -3-oxo-butyronitrile 2- (4-Bromo-phenyl) -3-oxo-butyronitrile is synthesized according to the procedure of Rau, Ger. Offen , DE 3001266 (1 980). Step 16. 1 1, 2- (2,6-dicyoro-phenyl) -3-oxo-proplonitrile The 1,2- (2,6-dichloro-phenyl) -3-oxo-propionitrile is prepared as is described by Menzer, Lankau and Unverferth, Ger. Offen , DE 1 9521 822 (nineteen ninety six). Step 17. 1 4- (3-Methoxy-phenyl) -2H-pyrazol-3-yl-amine The 4- (3-methoxy-phenyl) -2H-pyrazol-3-yl-amine and Step 22.2 are prepared as is described by Bruñí et al., Heterocyclic.

Chem. Volume 32, Number 1, pages 291-298 (1995). Step 19. 1 2-benzo [b] thiophen-3-yl-3-oxo-propionitrile 2-Benzo [b] thiophen-3-yl-3-oxo-propionitrile is synthesized in a manner analogous to the preparation of the compound of Step 1 .3: Yield: 56 percent; white powder; ES-MS: M-H = 123.9; HPLC: AtRet = 2.20 minutes. 1 H NMR (300 MHz, DMSO-d 6): 12.0 (broad s, 1 H), 8.00-7.70 (m, 3H), 7. 45-7.35 (m, 2H). Step 21. 1 3-Oxo-2-thiophen-3-yl-propionitrile 3-Oxo-2-thiophen-3-yl-propionitrile is synthesized in a manner analogous to the preparation of the compound of Step 1 .3: Yield: 51 percent; white powder, ES-MS: M-H = 1 12.9; HPLC AtRet = 2.03 minutes. The compound forms a tautomeric equilibrium in solution: 1 H NMR (300 MHz, DMSO-d6): 7.95 / 7.55 (s / s, 1 H, CH = / CH-OH), 7.55-7.50 (m, 2H), 7.30 -7.20 (m, 1 K). Step 22. 1 4-Benzo [b] thiophen-3-yl-1 H-pyrazol-3-yl-amine 4-Benzo [b] thiophen-3-yl-1 H-pyrazole-3-yl-amine is synthesized in a manner analogous to the preparation of the compound of Step 1 .2: Yield: 80 percent; white powder; ES-MS: M + H = 216.0. 1 H NMR (300 MHz, DMSO-d 6): 12.0 (broad s, 1 H), 8.00-7.80 (m, 2H), 7.75 (broad s, 1 H), 7.60 (broad s, 1 H) 7.40-7.30 (m, 2H). Step 22.2 (2- (3-methoxy-phenyl) -3-oxo-propionitrile) (2- (3-methoxy-phenyl) -3-oxo-propionitrile) is prepared as described by Bruni et al. , Heterocyclic. Chem. Volume 32, number 1, pages 291-298 (1,995). Step 23. 1-2-formyl-3-phenyl-propionitrile 2-formyl-3-phenylpropionitrile is synthesized in a manner analogous to the preparation of the compound of Step 1 .3: Yield: 77 percent; oil; ES-MS: M-H = 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). Step 24. 1 4- [3- (4-Methyl-piperazin-1-yl) -phenyl] -acetonyl trile 4- [3- (4-methyl-piperazin-1-yl) -phenyl] -aceto- nitrile is synthesized in a manner analogous to the preparation of the compound of Step 1 .5: Yield: 55 percent; solid chestnut; ES-MS: M + H = 21 6.7; HPLC: ctRet = 1.65 minutes. H NMR (300 MHz, CDCl 3): 7.30-7.25 (m, 1 H), 6.90-6.82 (m, 2H), 6.80-6.75 (m, 1 H), 3.70 (s, 2H), 3.25-3.15 (m , 4H), 2.60-2.50 (m, 4H), 2.35 (s, 3H). Step 24.2 2- [3- (4-Methyl-piperazin-1-yl) -phenyl] -3-oxo-propionitrile 2- [3- (4-methyl-piperazin-1-yl) -phenyl] -3-oxo -propionytryl is synthesized in a manner analogous to the preparation of the compound of Step 1 .3: Yield: 100 percent; solid chestnut; ES-MS: M + H = 244.1; HPLC: ctRet = 1.67 minutes.

Step 24.3 4- [3- (4-Methyl-piperazin-1-yl) -phenyl] -1 H -pyrazol-3-yl-amine 4- [3- (4-Methyl-piperazin-1-yl) -phenyl] -1 H -pyrazol-3-yl-amine is synthesized in a manner analogous to the preparation of the compound of the Stage 1 .2: Performance: 36 percent; yellow foam; ES-MS: M + H = 258.2; HPLC: ctRet = 1.46 minutes. 1 H NMR (300 MHz, CDCl 3): 7.45 (s, 1 H), 7.30-7.25 (m, 1 H), 7.05-7.00 (m, 1 H), 6.95-6.90 (m, 1 H), 6.85-6.80 (m, 1 H), 4.00 (s / broad, 2H), 3.30- 3.20 (m, 4H), 2.65-2.58 (m , 4H), 2.35 (s, 3H). Step 25. 1 2- (1-methyl-1 H-indol-3-yl) -3-oxo-propionitrile The 2- (1-methyl-1 H-indol-3-yl) -3-oxo-propionitrile is synthesizes in a manner analogous to the preparation of the compound from Step 1 .3: Yield: 59 percent; 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, 1 H), 7.60-7.20 (m, 5H), 3.75 (s, 3H). Step 26. 1 2- (4-methoxl-phenyl) -3-oxo-propionitrile 2- (4-methoxy-phenyl) -3-oxo-propionitrile is synthesized in a manner analogous to the preparation of the compound of the invention. Stage 1 .3: Performance: 80 percent; white solid; ES-MS: M-H = 174.3. The compound forms a tautomeric equilibrium in solution: 1 H NMR (300 MHz, DMSO-d 6): 7.80 / 7.58 (s / s, 1 H), 7.55-7.50 (m, 1 H), 7. 30-7.20 (m, 1 H), 6.90-6.80 (m, 2H), 3.73 / 3.70 (s / s, 3H). Step 27. 1 2- (2-methoxy-phenyl) -3-oxo-propionitrile 2- (2-methoxy-phenyl) -3-oxo-propionitrile is synthesized in a manner analogous to the preparation of the compound of Step 1 .3: Performance: 40 percent; chestnut oil; ES-MS: M-H = 174.3; HPLC: ctRet = 2.01 minutes. Step 28. 1 3-Oxo-2-pyridin-3-yl-propionitrile 3-Oxo-2-pyridin-3-yl-propionitrile is synthesized in a manner analogous to the preparation of the compound of the invention. Stage 1 .3; - Yield: 71 percent; solid chestnut; ES-MS: M + H = 147.2; HPLC ctRet = 1.31 minutes. Step 28.2 4-pyridin-3-yl-1 H-pyrazol-3-yl-amine The 4-pyridin-3-yl-1 H-pyrazol-3-yl-amine is synthesized in a manner analogous to the preparation of the compound of Stage 1 .2: Yield: 68 percent; solid chestnut; ES-MS: M + H = 161.2; HPLC: ctRet = 0.50 minutes. Step 30. 1 [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -acetonitrile [2-methoxy-5- (4-methyl-piperazin-1-yl) - phenol] -acetonitrile is synthesized in a manner analogous to the preparation of the compound of the Stage 1 .5: Yield: 51 percent; solid chestnut; ES-MS: M + H = 246. 6; HPLC: ctRet = 1.72 minutes. 1 H NMR (300 MHz, CDCl 3): 7.00-6.95 (m, 1 H), 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). Step 30.2 2- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -3-oxo-propionitrile 2- [2-methoxy-5- (4-methyl-piperazine-1 - il) -phenyl] -3-oxo-propionitrile is synthesized in a manner analogous to the preparation of the compound of Step 1 .4: Yield: 100 percent; solid chestnut; ES-MS: M + H = 274.1; HPLC: ctRet = 1.62 minutes.

Step 30.3 4- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -2H-pyrazol-3-yl-amine 4- [2-methoxy-5- (4-methyl) -piperazin-1-yl) -phenyl] -2H-pyrrazol-3-yl amine is synthesized in a manner analogous to the preparation of the compound of Step 1 .2: Yield: 32 percent; solid chestnut; ES-MS: M + H = 288.2; HPLC: ctRet = 1.46 minutes. 1 H NMR (300 MHz, CDCl 3): 7.50 (s, 1 H), 7.00-6.95 (m, 1 H), 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).

Step 32. 1 2- (2-Benzyloxy-phenyl) -3-oxo-propionitrile 2- (2-Benzyloxy-phenyl) -3-oxo-propionitrile is synthesized in a manner analogous to the preparation of the compound of Stage 1 .3: Yield: 85 percent; white solid; ES-MS: M + H = 252.6; HPLC: ctRet = 2.35 minutes. The compound forms a tautomeric equilibrium in solution: 1 H NMR (300 MHz, DMSO-d 6): 1 1 .6 / 7.78 (s, 1 H), 7.55-7.45 (m, 2H), 7. 40-7.20 (m, 5H), 7.15-7.05 (m, 1 H), 7.00-6.90 (m, 1 H), 5.15 (s, 2H).

Step 34. 1 2- (4-benzyloxy-phenyl) -3-oxo-propionitrile 2- (4-benzyloxy-phenyl) -3-oxo-propionitrile is synthesized in a manner analogous to the preparation of the compound of the invention. Stage 1 .3: Yield: 95 percent; white solid; ES-MS: M-H = 250.3; HPLC: ctRet = 2.41 minutes. The compound forms a tautomeric equilibrium in solution: 1 H NMR (300 MHz, DMSO-d 6): 12.0 / 1 1.7 (s, 1 H), 7.90-7.80 and 7.60-7.50. (m, 1 H), 7.40-7.25 (m, 6H), 7.05-6.95 (m, 2H), 5.10 (s, 2H). Step 44. 1 4- (1-methyl-1 H-indol-3-yl) -2H-pyrazol-3-yl-amine 4- (1-Methyl-1 H -indol-3-yl) -2H-pyrazol-3-yl-amino is synthesized in a manner analogous to the preparation of the compound of Step 1 .2: Yield: 10 percent; chestnut foam; ES-MS: M + H = 21 3.2; HPLC: ctRet = 1.66 minutes. 1 H NMR (300 MHz, DMSO-d 6): 7.70 (d, 1 H), 7.60 (s, 1 H), 7.35 (d, 1 H), 7. 30-7.25 (m, 1 H), 7.20-7.1 0 (m, 2H), 3.80 (s, 3H).

Step 47. 1 2- (2-methoxy-phenyl) -3-oxo-propionitrile 2- (2-methoxy-phenyl) -3-oxo-propionitrile is synthesized in a manner analogous to the preparation of the compound of Step 1 .3: Yield: 59 percent; white solid; ES-MS: M + H = 1 75.3; HPLC: ctRet = 2.01 minutes.

Step 47.2 4- (2-methoxy-phenyl) -2H-plrazol-3-ylamine 4- (2-methoxy-phenyl) -2H-pyrazol-3-yl-amine is synthesized in a manner analogous to the preparation of the compound of Stage 1 .2: Yield: 35 percent; white solid; ES-MS: M + H = 190.1; HPLC: ctRet = 1.40 minutes. 1 H-NMR (300 MHz, DMSO-d 6): 1 1.5 (bs, 1 H), 7.50 (bs, 1 H), 7.30 (bs, 1 H), 7.20-7.05 (m, 1 H), 7.00 -6.85 (m, 2H), 4.30 (bs, 2H), 3.75 (s, 3H).

Step 51. 1 3-Oxo-2-pyridin-4-yl-propionitrile 3-Oxo-2-pyridin-4-yl-propionitrile is synthesized in a manner analogous to the preparation of the compound of Step 1. 3: Yield: 59 percent; solid orange; ES-MS: M + H = 147.2; HPLC: ctRet = 1 -00 minutes. The compound forms a tautomeric equilibrium in solution: 1 H-NMR (300 MHz, DMSO-d 6): 13.1 / 9.60 (bs, 1 H), 9.10 (bs, 1 H), 8.20- 8.00 (m, 2H), 7.95-7.80 (m, 1 H).

Step 52. 1 (Z) -3-Dimethyl-amino-2- (3-nitro-phenyl) -acrylonitrile (3-nitro-phenyl) -acetonitrile (1.51 grams, 9.31 mmol), dimethoxymethyl-dimethyl Amine (6.2 milliliters, 46.5 millimoles) in xylene (30 milliliters) is stirred at reflux for 1 hour. After adding hexane (20 milliliters), the reaction mixture is cooled to 0 ° C. The material that precipitates is filtered to give the compound of Step 52.1 as a tan solid (1.76 grams, 8.1 9 mmol, 88 percent); ES-MS: M + H = 21 8.1; HPLC: ctRet = 2.24 minutes. 1 H-NMR (300 MHz, DMSO-d 6): 8.10-8.05 (m, 1 H), 7.90-7.85 (m, 1 H), 7.75-7.72 (m, 1 H), 7.70 (s, 1 H), 7.65-7.60 (m, 1 H), 3.30 (s, 6H).

Step 52.2 3- [3- (4-Methyl-piperazin-1-yl) -phenyl] -6- (3-n-phenyl) -pyrazolo [1,5-a] pyrimidin-5-i-amine 4- [3- (4-Methy1-piperazin-1-yl) -phenyl] -1H-pyrazol-3-yl-amine (Step 24.3) (305 milligrams, 1.18 mmol), and (Z ) -3-dimethylamino-2- (3-nitro-phenyl) -acylonitrile (Step 52.1) (335 milligrams, 1.54 millimoles) dissolved in AcOH (10 milliliters) and BuOH (10 milliliters), stirred at reflux for 16 hours. After adding a saturated aqueous solution of NaHCO3, the reaction mixture is extracted with EtOAc (50 milliliters, 2 times). The combined organic phases are washed with H2O (10 milliliters), dried (Na2SO4), concentrated under reduced pressure, and passed by evaporation chromatography (silica gel, 2.5 x 15 centimeters, CH2Cl2 / MeOH = 9: 1) for the compound of Step 52.2 as an orange solid (224 milligrams, 0.52 millimoles, 44 percent); ES-MS: M + H = 430.1; HPLC ctRet = 1.91 minutes. 1 H-NMR (300 MHz, DMSO-d 6): 8.70 (s, 1 H), 8.35-8.30 (m, 1 H), 8.25 (s, 1 H), 8.22-8.18 (m, 1 H), 7.98- 7.95 (m, 1 H), 7.90 (bs, 2H), 7.80-7.70 (m, 2H), 7.65-7.60 (m, 1 H), 7.25-7.18 (m, 1 H), 6.80-6.75 (m, 1 H), 3.20-3.10 (m, 4H), 2.50-2.40 (m, 4H), 2.20 (s, 3H).

Step 53. 1 3- [4- (4-Methyl-piperazin-1-yl) -phenyl] -6- (3-nitro-phenyl) -pyrazolo [1,5-a] pyrimidin-7-i-amine 3- [4- (4-methyl-p-perazi n-1-yl) -f-enyl] -6- (3-n -itro-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl -amine is synthesized in a manner analogous to the preparation of the compound of Step 52.2: Yield: 30 percent; solid red; ES-MS: M + H = 430.0. 1 H-NMR (300 MHz, DMSO-d 6): 8.60 (s, 1 H), 8.35-8.30 (m, 1 H), 8.22 (s, 1 H), 8.20-8.1 0 (m, 1 H), 8.00 (d, 2H, J = 7.9 Hz), 7.95-7.90 (m, 1 H), 7.85 (bs, 2H), 7.80-7.75 (m, 1 H), 6.95 (d, 1 H, J = 9Hz), 3.20-3.10 (m, 4H), 2.50-2.40 (m, 4H), 2.20 (s, 3H).

Step 54. 1 (Z) -3-Dimethylamino-2- (2-nitro-phenyl) -arylonitrile The (Z) -3-dimethy1-amino-2- (2-nitro-phenyl) - acrylonitrile is synthesized in a manner analogous to the preparation of the compound of Step 52.1: Yield: 97 percent; solid chestnut 1 H-NMR (300 MHz, DMSO-d 6): 7.82-7.78 (m, 1 H), 7.62-7.55 (m, 1 H), 7.45-7.35 (m, 2H), 7.20 (s, 1 H), 3.15 (s, 6H).

Step 54.2 3- [4- (4-Methyl-piperazin-1-yl) -phenyl] -6- (2-nitrophenol) -pyrazolo [1,5-a] pyrimidin-7-i-amine 3- [4- (4-Methyl-piperazin-1-l) -phenyl] -6- (2-nitro-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl-amine is synthesized in a manner analogous to the preparation of the compound of Step 55.2: solid chestnut; ES-MS: M + H: 430.0; HPLC: DtRet = 1.61 minutes. 1 H-NMR (300 MHz, DMSO-d 6): 8.55 (s, 1 H), 8.20-8.1 5 (m, 1 H), 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).

Step 55. 1 (E) -3-Dimethyl-amino-2- (4-methyl-thiazol-2-yl) -acrylonitrile (E) -3-dimethyl-amino-2- (4-methyl) -thiazol-2-yl) -acylonitrile is synthesized in a manner analogous to the preparation of the compound of the Stage 52.1: Performance: 74 percent; solid black; ES-MS: M + H: 194. 2; HPLC: ctRet = 1.57 minutes. 1 H-NMR (300 MHz, DMSO-d 6): 7.76 (s, 1 H), 6.60 (s, 1 H), 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] pyridin-6-yl} -phenol is synthesized in a manner analogous to the preparation of Example 1, by the use of methyl hydrazine in place of hydrazine when the pyrazole ring is formed: ES-MS: M + H = 415.2; HPLC: DtRet = 1 -45 minutes. 1 H NMR (300 MHz, DMSO-d 6): 9.53 (s, 1 H, OH), 2.56 (s, 3 H CH 3), 2.24 (s, 3H CH3).

Example 62 (4- {7-amino-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl) ethyl ester .}.-phenyl) -carbamic acid 4- (4- (4-methyl-piperazin-1 -yl) -phenyl) -2H-pyrrazol-3-yl-amine (Stage 1 .2) (200 milligrams, 0.81 mmol) and [4- (2-cyano-1-formyl-ethyl) -phenyl] -carbamic acid ethyl ester (Stage 62.1) (275 milligrams, 0.04 millimoles) dissolved in EtOH (4 milliliters) and HCl Ethanolic (1.6 milliliters, 2.5 N), stirred under reflux for 17 hours under argon. After adding H2O (4 milliliters) and K2CO3 (250 milligrams), the reaction mixture is extracted with CH2Cl2 (20 milliliters, 2 times). The combined organic phases are washed with H2O (10 milliliters), dried (Na2SO4), concentrated under reduced pressure, and passed by evaporation chromatography (silica gel, 2.5 x 15 centimeters, CH2Cl2 / MeOH / NH3 = 95: 5: 0.5) to give the compound of Example 62 as a white solid (58 milligrams, 0.123 millimoles; 15 percent); ES-MS: M + H = 472.0; Rf (CH2Cl2 / MeOH / NH3 = 90: 10: 0.1) = 0.42; HPLC: AtRet = 4.26 minutes. 1 H-NMR (400 MHz, DMSO-d 6): 8.75 / 8.58 (s / s, 1 H / 1 H, pyrazolopyrimidinyl), 8.03 (d, 9.0 Hz, 2H, phenyl), 7.61 (d, 9 Hz, 2H, phenyl), 7.53 (s, 2H, NH2), 7.46 (d, 9 Hz, 2H, phenyl), 7.00 ( d, 9 Hz, 2H, phenyl), 4.17 (q, 7.5 Hz, 2H, CH2-ethyl), 3.17 / 2.48 (m / m, 4H / 4H, piperazinyl), 2.24 (t, 7.5 Hz, 3H, CH3) .

Stage 62a. 1 [4- (Cyano-1-formyl-methyl) -pheni] -carbamic acid ethyl ester [4- (Cyano-methyl) -phenyl] -carbamic acid benzyl ester (Step 62a.2) (1 gram, 3.76 mmol) is formulated in analogy to the preparation of Stage 1 .3, giving the corresponding carbamic acid ethyl ester (thereby also transforming the benzyl ester function into the ethyl ester function): crystals colorless (654 milligrams, 2.66 millimoles, 70 percent). ES-MS: M + H = 233.0. H-NMR (400 MHz, DMSO-d6): 4.12 (q / broad, 7.5 Hz, 2H, CH2-ethyl), 1.23 (broad t, 7.5 Hz, 3H, CH3-ethyl).

Step 62.2 [4- (Cyano-methyl) -phenyl] -carbamic acid benzyl ester The (4-amino-phenyl) -acetonitrile (2 grams, 15.1 mmol) and the dibenzyl dicarbonate (4.33 grams, 15.1 mmol) dissolved in dioxane (16 milliliters) are stirred for 1 hour at room temperature. After evaporating the solvent, the product is isolated by evaporation chromatography (silica gel, 4.5 x 25 centimeters, CH 2 Cl 2 / MeOH = 99.1): white solid (3.82 grams, 14.4 mmol, 95 percent); ES-MS: M-H = 265.0; Rf (CH2Cl2 / MeOH = 95: 5) = 0.49; HPLC: AtRet = 6.32 minutes. 1 H NMR (400 MHz, DMSO-d 6): 9.82 (s, 1 H, NH), 7.51-7.35 (m, 7H, aryl), 7.26 (d, 8.5 Hz, 2H, aryl), 5.15 (s, 2H, CH2), 3.95 (s, 2H, CH2).

(Z) -3-dimethyl-amino-2-thiazole-4-yl-acrylonitrile (Z) -3-Dimethyl-amino-2-thiazol-4-yl-acrylonitrile is synthesized in a manner analogous to the preparation of the compound of Step 52.1: ES-MS [M + 1] + = 180.1; HPLC: ctRet = 1.91 minutes. Compounds 61, 62, 64, 67, and 68 which carry the functions of sulfonamide and acetylamide (compounds 63, 65, and 69) are prepared by the reaction of the amino precursor with the sulfonic acid chloride or the acetic acid anhydride corresponding, in the presence of pyridine.

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

Table 2 - Example 70 4-dimethylaryl ilo H K 4- (4-methyl-piperazin-1-yl) H 4- (4-methyl-piperazin-1-yl) H M 4- (4-methyl-piperazin-1-yl) H 4-pyridyryl N 4- (4-methyl-piperazin-1-yl) H OR 4- (4-methyl-piperazin-1-yl) H R 4- (4-methyl-piperazin-1-yl) H 4- (4-methyl-piperazin-1-yl) H V 4- (4-methyl-piperazin-l -yl) W 4- (4-methyl-piperazin-1-yl) / 2-methoxy x 4- (4-methyl-piperazin-1-yl) / 2-methoxy H 4- (4-methyl-piperazin-1-yl) H 4- (4-methyl-piperazin-1-yl) H zl 3- (4-methyl-piperazin-1-yl) H z2 3- (4-methyl-piperazin-1-yl) H z3 3- (4-methyl-piperazin-1-yl) H zll 3- (4-methyl-piperazin-1-yl) H zl2 3- (4-methyl-piperazin-1-yl) H zl3 5- (4-methyl-piperazin-1-yl) / 2-methoxy H zl4 5- (4-methyl-piperazin-1-yl) / 2-methoxy H zl5 4- (4-methyl-piperazin-1-yl) / 2-methoxy H zl6 4- (4-methyl-piperazin-1-yl) / 2-methoxy H zl7 4- (4-methyl-piperazin-1-yl) Br H zl 8 3- (4-methyl-piperazin-1-yl) H Table 3 - Example 71 Example 72 6- (3-Chloro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrim id i n -7-i I-amine 4- [3- (4-Methyl-piperazin-1-yl) -phenyl] -1H-pyrazole-3-yl-amine (Step 72.2) (1.29 grams, 5 millimoles ) is dissolved in EtOH (25 milliliters), followed by the addition of 2- (3-chloro-phenyl) -3-oxo-butyronitrile (Step 72.3) (0.97 grams, 5 mmol) and HCl (1.25 M in EtOH). 20 millimoles, 16 milliliters) at room temperature. The yellowish solution is refluxed with stirring for 20 hours. After cooling to room temperature, H2O (80 milliliters) is added, as well as K2CO3 (2.5 grams) to make the mixture basic. The aqueous layer is extracted with CH2Cl2 (200 milliliters, 2 times). The combined organic phases are washed with H2O (50 milliliters, 2 times), dried (Na2SO4), concentrated under reduced pressure, and passed by chromatography (silica gel, 120 grams of RediSep, ISCO Sg-100 CH2Cl2 / MeOH / NH3 = 95: 5: 0.1), to obtain the title compound 72 as white crystals (1.03 grams, 2.38 millimoles, 48 percent); p.f. 1 10-1 1 5 ° C; MS (ESI +): m / z = 433 (M + H) +; HPLC: AtRet = 3.72 minutes (System 1). Step 72. 1 2- (3-Chloro-phenyl) -3-oxo-butyron trile 355 milliliters of ethanol are heated to 55 ° C under N2. To this, sodium is added (3.91 grams, 0.17 moles) within 30 minutes, and it is stirred for 1.5 hours until all the metal dissolves. 3-Chlorobenzyl cyanide (15.31 grams, 0.1 moles) and ethyl acetate (28.53 milliliters, 0.29 moles) are added to the colorless solution, followed by stirring under reflux for 5 hours. After the reaction is completed, the yellow mixture is cooled to room temperature, and evaporated under reduced pressure. The crude material is recovered in water (200 milliliters), and neutralized by the addition of 25 grams of citric acid. The aqueous layer is extracted with CH2Cl2 (250 milliliters, 2 times). The combined organic phases are washed with H2O (150 milliliters, twice), dried (Na2SO), concentrated under reduced pressure, and passed through chromatography (silica gel, 1 kilogram, Merck 60 (0.040-0.063), eluting with EtOAc / hexanes 1: 1), to obtain the title compound 72.1 as yellowish crystals (9.7 grams, 0.05 moles, 50 percent); p.f. 92-97 ° C; MS (ESI *); m / z = 302.9 (M + H) +; HPLC :. AtRet = 5.67 minutes - (System 1). Step 72.2 4- [3- (4-Methyl-piperazin-1-yl) -phenyl] -1 H -pyrazol-3-yl-amine The title compound is prepared as described in Example 24; Stages 24.1 - 24.3. Example 73 6- (3-Chloro-phenyl) -5-methyl-3- [4- (4-methyl-piperazin-1-yl-phenyl] -pyrazolo [1,5-a] pyrimidine-7-yl- amine The title compound is prepared as described in Example 72, using instead 4- [4- (4-methyl-piperazin-1-yl) -phenyl] -2H-pyrazol-3-yl-amine (Example 1; Stage 1 .2) and 2- (3-chloro-phenyl) -3-oxo-butyronitrile (Example 73, Step 73.1) Beige crystals, mp 1 13-1 15 ° C; MS (ESI *): m / z = 433 (M + H) +; HPLC: AtRet = 3.56 minutes (System 1) Example 74 6- (3-chloro-phenyl) -3- [2-methoxy-5- (4-methyl-piperazin- 1 -yl) -phenyl] -5-methyl-pyrazolo [1, 5-a] pyrimidin-7-yl-amine The title compound is prepared as described in Example 72, using instead 4- [2- methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -2H-pyrazol-3-yl-amine and 2- (3-chloro-phenyl) -3-oxo-butyronitrile (Example 72, Stage 72.1). Beige crystals; p.f. 1 16-121 ° C; MS (ESI +): m / z = 463 (M + H) +; HPLC: AtRet = 3.68 minutes (System 1).

Step 74. 1 4- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -2H-pyrazol-3-yl-amine The title compound is prepared as described in Example 1 (Stage 1 .2; Stages 1 .4 and 1 .5); using instead 5-bromo-2-methoxy-phenylacetonitrile and N-methylpiperazine. Yellowish foam; MS (ESI +): m / z = 288.2 (M + H) +; HPLC: AtRet = 3.53 minutes (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 -i I-amine The title compound is prepared as described in Example 72; using instead 4- [2-methoxy-4- (4-methyl-piperazin-1-yl) -phenyl] -2H-pyrazol-3-yl-amine and 2- (3-cyoro-phenyl) -3- oxo-butyronitrile (Example 72, Stage 72.1). Beige crystals; p.f. 2215-217 ° C; MS (ESI +): m / z = 463 (M + H) +; HPLC: AtRet = 3.63 minutes (System 1). Step 75. 1 4- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -2H-pyrazol-3-yl-amine The title compound is prepared as described in Example 1 (Step 1 .2; Steps 1 .4 and 1 .5); using instead 4-bromo-2-methoxy-phenylacetonitrile and N-methylpiperazine. Chestnut-green crystals; p.f. 173.7-178.1 ° C; MS (ESI +): m / z = 288.1 (M + H) +; HPLC: AtRet = 3.40 minutes (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 The title compound is prepared by dissolving 6- (3-benzyloxy-phenyl) -3- [2-methoxy-4- (4-methyl-piperazin-1-l) -phenyl] -pyrazolo [1, 5-a] pyrimidin-7-yl-amine in methanol, and subjecting it to catalytic hydrogenation in the presence of Pd / C, as described in Example 1: beige crystals; p.f. 217-220 ° C; MS (ESI +): m / z = 431.0 (M + H) +; HPLC: AtRet = 2.65 minutes (System 1). Step 76. 1-6- (3-benzyloxy-phenyl) -3- [2-methoxy-4- (4-methyl-piperazine-1 - il) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-i-amine The title compound is prepared as described in Example 1 (Step 1 .2; Steps 1.4 and 1.5); using in its place 4-bromo-2-methoxy-phenylacetonitrile and N-methylpiperazine. Yellowish solid; MS (ESI +): m / z = 521 (M + H) +; HPLC: AtRet = 4.38 minutes (System 1).

Example 77 6- (2-chloro-f-enyl) -3- [4- (4-methyl-pi-perazi n-1 -yl) -f-enyl] -pyrazolo [1,5-a] pyrimidin-7-yl- amine The title compound is prepared as described in Example 72; using instead 4- [4- (4-methyl-piperazin-1-yl) -phenyl] -2H-pyrazol-3-yl-amine and (Z) -2- (2-chloro-phenyl) -3- dimethylamino-aclonitrile. Yellow solid; p.f. 197-200 ° C; MS (ESI +): m / z = 419 (M + H) +; HPLC: AtRβt = 3.33 minutes (System 1).

Step 77. 1 (Z) -2- (2-Chloro-phenyl) -3-d-methylamino-acrylonitrile N, N-dimethylformamide-d-methyl-acetal (9.06 milliliters, 64.3 mmol) and 2-chlorobenzyl cyanide ( 1.95 grams, 12.86 millimoles) are heated with stirring at 100 ° C under an argon atmosphere. After cooling to room temperature, the mixture is concentrated under reduced pressure, and purified by chromatography (silica gel, 120 grams of RediSep, ISCO Sg-100, eluting with EtOAc / hexanes, 1: 1), to obtain the compound of the title as a thick yellow oil (2.44 grams, 1 1 .8 millimoles, 92 percent); MS (ESI +): m / z = 207 (M + H) +; TLC (EtOAc / hexanes, 1: 1) Rf = 0.38.

Example 78 6- (2-Chloro-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine The compound of the title is prepared as described in Example 72; using (Z) -2- (2-chloro-phenyl) -3-dimethylamino-acrylonitrile (Example 77, Step 77.1). Yellowish crystals; p.f. 200-203 ° C; MS (ESI +): m / z = 419.0 (M + H) +; HPLC: AtRef = 3.65 minutes (System 1). Example 79 6- (4-Fluoro-phenyl) -5-metN-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrirnidin-7- il-amine The title compound is prepared as described in Example 72; using instead 4- [4- (4-methyl-piperazin-1-yl) -phenyl] -2H-pyrazol-3-yl-amine and 2- (4-fluoro-phenyl) -3- oxo-butyronitrile. White crystals; p.f. 289-291 ° C; MS (ESI +): m / z = 417.1 (M + H) +; HPLC: AtRßt = 3. 21 minutes (System 1). Step 79. 1 2- (4-Fluoro-phenyl) -3-oxo-butyronitrile The title compound is prepared as described for Example 72, Step 72.1, using instead (4-fluoro-phenyl) -acetonitrile. Beige crystals; p.f. 77-83 ° C; MS (ESI +): m / z = 176.9 (M + H) +; HPLC: AtRet = 5.15 minutes (System 1). Example 80 6- (4-Fluoro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7- il-amine The title compound is prepared as described in Example 72; using 2- (4-fluoro-phenyl) -3-oxo-butyronitrile instead (Example 79, Step 79.1). White crystals; p.f. 204-206 ° C; MS (ESI +): m / z = 417.1 (M + H) +; HPLC: AtRet = 3.34 minutes (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-yl-amine The title compound is prepared as described in Example 72; using instead 4-. { 3- [4- (1-methyl-piperidin-4-yl) -piperazin-1-yl] -phenyl} -2H-pyrazol-3-yl-amine. Beige crystals; p.f. 180-1 85 ° C; MS (ESI +): m / z = 516.0 (M + H) +; HPLC: AtRet = 4.96 minutes (System 1). Stage 81. 1 4-. { 3- [4- (1-methyl-p.pehdin-4-yl) -piperidin-1-l] -phenyl} -2H-pyrazol-3-yl-amine The title compound is prepared as described in Example 1 (Steps 1.2 and 1.4 and 1.5); using instead (3-bromo-phenyl) -acetonitrile and 1- (1-methyl-piperdin-4-yl) -piperazine. Yellowish crystals; p.f. 213-220 ° C; MS (ESI +): m / z = 341 .18 (M + H) +; HPLC: AtRet = 3.57 minutes (System 1). Example 82 6- (3-Chloro-4-fluoro-fem'l) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] pyrazolo [1,5-a] pyrimidine -7-yl-amine The title compound is prepared as described in Example 72; using 2- (3-chloro-4-fluoro-phenyl) -3-oxo-butyryltrile instead. White crystals; p.f. 224-226 ° C; MS (ESI +): m / z = 451 (M + H) +; HPLC: AtRet = 3.86 minutes (System 1).

Step 82. 1 2- (3-Chloro-4-fluoro-phenyl) -3-oxo-butyronitrile The title compound is prepared as described in Example 72, Step 72.1, using instead (3-chloro-4-fluoro-phenyl) -acetonitrile. White crystals; p.f. 133-134 ° C; MS (ESI "): m / z = 209.9 (M-H) -; HPLC: AtRe = 5.79 minutes (System 1) Example 83 6- (3-Chloro-4-fluoro-phenyl) -5-methyl-3 - [4- (4-methyl-piperazin-1-yl) -phenyl] -pi-razolo [1,5-a] pyrimidin-7-i-amine The title compound is prepared as described for Example 72, using instead 4- [4- (4-methyl-piperazin-1-yl) -phenyl] -2H-pyrazole-3-yl-amine and 2- (3-chloro-4-fluoro-phenyl) -3- oxo-butyronitrile (Example 82; Stage 82.1). White crystals; p.f. 264-265 ° C; MS (ESl +): m / z = 451 (M + H) +; HPLC: AtRet = 3.72 minutes (System 1). EXAMPLE 84 6- (3-Bromo-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-i I -amine The title compound is prepared as described for the Example 72, Step 72.1, using instead 2- (3-bromo-phenyl) -3-oxo-butyronitrile. White crystals; p.f. 107-1 13 ° C; MS (ESI +): m / z = 477 (M + H) +; HPLC: AtRet = 4.90 minutes (System 1). Step 84. 1 2- (3-bromo-phenyl) -3-oxo-butyronitrile The title compound is prepared as described for Example 72, Step 72.1, using instead (3-bromo-phenyl) -acetonitrile. White crystals; p.f. 96-100 ° C; MS (ESI "): m / z = 235.9 (M + H)"; HPLC: AtRet = 5.76 minutes (System 1).

Example 85 6- (3-Bromo-benzyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1, 5-a] pi rim id i-7-i I -amine The title compound is prepared as described in Example 72; using 3- (3-bromo-phenyl) -2-formyl-propionitrile instead. White crystals; p.f. 170-171 ° C; MS (ESI +): m / z = 477.0 (M + H) +; HPLC: AtRet = 3.84 minutes (System 1). Step 85. 1 3- (3-bromo-phenyl) -2-formyl-propionitrile 3- (3-Bromophenyl) propionitrile (0.703 milliliters, 4.66 millimoles) and ethyl formate (1,499 milliliters; Dissolve in anhydrous tetrahydrofuran (12.5 milliliters), followed by the addition of NaH (60 percent in mineral oil, 670 milligrams) at room temperature. After 17 hours at room temperature, additional NaH (448 milligrams) and ethyl formate (0.765 milliliters) are added. Because this results in a strong exothermic reaction, additional solvent (15 milliliters of tetrahydrofuran) is added. After completion (3 days), the reaction mixture is cooled to 0 ° C, treated with a few small ice cubes, followed by the addition of 6N HCl (3 milliliters) to acidify the mixture. After the addition of water (50 milliliters), the mixture is extracted with EtOAc (100 milliliters, 3 times). The combined organic phases are washed with H2O (50 milliliters, 2 times), brine, dried (Na2SO4), concentrated under reduced pressure, and chromatographed (silica gel, 40 grams of RediSep, ISCO Sg-100, eluting with EtOAc / hexanes, 1: 1), to obtain the title compound as a chestnut oil (220 milligrams, 20 percent); MS (ESI -): m / z = 235. 9 (M-H) -; TLC EtOAc / hexanes, 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-yl-amine The compound of title is prepared as described in the Example 72; using (Z) -2- (3-bromo-phenyl) -3-dimethylamino-acrylonitrile instead. White crystals; p.f. 195.3-197.2 ° C; MS (ESI +): m / z = 463.0 (M + H) +; HPLC: AtRet = 4.05 minutes (System 1). Step 86. 1 (Z) -2- (3-bromo-phenyl) -3-d-methylamino-acrylonitrile is prepared as described in Example 77, Step 77.1: Chestnut-golden crystals; p.f. 102-105 ° C; MS (ESI +): m / z = 251 .0 (M + H) +; HPLC: AtRet = 6.45 minutes (System 1). Example 87 6- (3-chloro-phenyl) -5-methyl-3- (3-morpholin) -4-yl-phenyl) -pyrazolo [1,5-a] p irim id i n-7-i I- amine The title compound is prepared as described in Example 72; using 4- (3-morfoin-4-yl-phenyl) -2H-pyrazol-3-yl-amine instead. White crystals; p.f. 165-167 ° C; MS (ESl +): m / z = 420 (M + H) +; HPLC: AtRet = 4.49 minutes (System 1). Step 87. 1 4- (3-morpholin-4-yl-phenyl) -2H-pyrazolo-3-yl-amine The title compound is prepared as described in Example 1 (Step 1 .2; Steps 1.4 and 1 .5); using instead (3-bromo-phenyl) -acetonitrile and morpholine. White crystals; p.f. 166-168 ° C; MS (ESI +): m / z = 445.13 (M + H) +; HPLC: AtRe, = 1.79 minutes (System 1).

EXAMPLE 88 6- (3-Chloro-phenyl) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1, 5-a] pyrimidin-7-yl-amine The title compound is prepared as described in Example 72; using 4- (4-methoxy-phenyl) -2H-pyrazol-3-yl-amine instead. White crystals; p.f. 171 -172 ° C; MS (ESI +): m / z = 365 (M + H) +; HPLC: AtRet = 4.96 minutes (System 1). Step 88. 1-4- (4-methoxy-phenyl) -2H-pyrazol-3-yl-amine The title compound is prepared as described in Example 1 (Steps 1.4 and 1.2); using instead (4-methoxy-phenyl) acetonitrile. White crystals; p.f. 198-201 ° C; MS (ESI +): m / z = 190 (M + H) +; HPLC: AtRet = 2.85 minutes (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] pyrim id i n-7-i I-amine The title compound is prepared as described in Example 72; using instead 4- [3 - ((2R, 6S) -2,6-dimethyl-morfoin-4-yl) -phenyl] -2H-pyrazol-3-yl-amine. White crystals; p.f. 165-167 ° C; MS (ESI +): m / z = 448 (M + H) +; HPLC: AtRet = 5.14 minutes (System 1). Step 89. 1 4- [3 - ((2R, 6S) -2,6-dimethyl-morpholin-4-yl) -phenyl] -2H-pyrazol-3-yl-amine The title compound is prepared as described at Example 1 (Steps 1 .2 and 1 .4 and 1 .5); using instead (3-bromo-phenyl) -acetonitrile (2R, 6S) -2,6-dimethyl-morpholm. White crystals; p.f. 158-160 ° C; MS (ESI +): m / z = 273.1 (M + H) +; HPLC: AtRet = 3.02 minutes (System 1). Example 90 2- (4-. {3- [7-amino-6- (3-chloro-phenyl) -5-methyl-pyrazolo [1, 5-a] pyrimidin-3-yl] -phenyl}. -pi perazi n-1-yl) -ethanol The title compound is prepared as described in Example 72; using instead 2-. { 4- [3- (5-amino-1 H -pyrazol-4-yl) -phenyl] -piperazin-1-yl} -ethanol. White crystals; p.f. 108-1 16 ° C; MS (ESI +): m / z = 463 (M + H) +; HPLC: AtRet = 3.62 minutes (System 1).

Stage 90. 1 2-. { 4- [3- (5-amino-1 H -pyrazol-4-yl) -phenyl] -piperazin-1-yl} Ethanol The title compound is prepared as described in Example 1 (Steps 1.2 and 1.4 and 1.5); using instead (3-bromo-phenyl) -acetonitrile and 2-piperazin-1-l-ethanol. Yellowish foam; p.f. 40-48 ° C; MS (ESI +): m / z = 288.1 (M + H) +; HPLC: AtRet = 3. 45 minutes (System 1).

Example 91 6-benzyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine The title compound is prepared as described in Example 72; using in its place 2-formyl-3-phenyl-propionitrile (Example 23, Step 23.1). Yellow crystals; p.f. 72-75 ° C; MS (ESI +): m / z = 399.1 (M + H) +; HPLC: AtRet = 3.30 minutes (System 1).

EXAMPLE 92 6- (3-Chloro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-fluorophenyl-pyrazolo [1,5- a] pyrimidin-7-yl-amine The title compound is prepared as described in Example 72; using 4- (3,4-dimethoxy-phenyl) -2H-pyrazol-3-yl-amine (Example 93; Step 93.1) and 2- (3-cyoro-phenyl) -4-fluoro-3-oxo instead -butironitriio. Yellow crystals; p.f. 228-230 ° C; MS (ESI +): m / z = 413 (M + H) +; HPLC: AtRet = 6.65 minutes (System 1). Step 92. 1 2- (3-chloro-phenyl) -4-fluoro-3-oxo-butyronitrile The title compound is prepared as described for Example 72, Step 72.1, using fluoroacetic acid ethyl ester instead. Beige crystals; p.f. 90-96 ° C; MS (ESI -): m / z = 209.9 (M-H) -; HPLC: AtRet = 5.66 minutes (System 1). Example 93 6- (3-Chloro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-i-amine The title compound is prepared as described in the Example 72; using 4- (3,4-dimethoxy-phenyl) -2H-pyrazol-3-yl-amine instead. White solid; p.f. 223-226 ° C; MS (ESI +): m / z = 463 (M + H) +; HPLC: AtRet = 3.62 minutes (System 1). Step 93. 1-4- (3,4-Dimethoxy-phenyl) -2H-pyrazol-3-yl-amine The title compound is prepared as described in Example 1 (Steps 1.4 and 1.2); using instead (3,4-dimethoxy-phenyl) -acetonitrile. White crystals; p.f. 143-146 ° C; MS (ESI +): m / z = 220.1 (M + H) +; HPLC: AtRet = 2.28 minutes (System 1).

EXAMPLE 94 6- (3-Chloro-4-fluoro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-methyl-pyrazoic [1,5-a] pi ri m id i n-7-i I-amine The title compound is prepared as described in Example 72; using 4- (3,4-dimethoxy-pheny!) -2H-pyrazol-3-yl-amine (Example 93; Step 93.1), and 2- (3-chloro-4-fluoro-phenyl) - 3-oxo-butyryltrile (Example 82, Step 82.1); White solid; p.f. 235-238 ° C; MS (ESI +): m / z = 413 (M + H) +; HPLC: AtRet = 4.83 minutes (System 1). Example 95 6- (3-chloro-4-fluoro-phenyl) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-i-amine The title compound is prepared as described in Example 72; using instead 4- (4-methoxy-phenyl) -2H-pyrazol-3-yl-amine (Example 88; Step 88.1) and 2- (3-chloro-4-fluoro-phenyl) -3-oxo-butyronitrile (Example 82, Step 82.1). White crystals; p.f. 224-227 ° C; MS (ESI +): m / z = 383 (M + H) +; HPLC: AtRet = 5.08 minutes (System 1).

Example 96 6- (4-Fluoro-f-enyl) -3- (4-methoxy-f-enyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-yl-amine The title compound is prepared as described in Example 72; using instead 4- (4-methoxy-phenyl) -2H-pyrazol-3-yl-amine (Example 88, Step 88.1) and 2- (4-fluoro-phenyl) -3-oxo-butyronityl (Example 79; Stage 79.1). White crystals; p.f. 243-244 ° C; MS (ESI +): m / z = 349.1 (M + H) +; HPLC: AtRef = 4.56 minutes (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; using instead 2-. { 4- [3- (5-amino-1 H -pyrazol-4-yl) -phenyl] -piperazin-1-yl} Ethanol (Example 90, Step 90.1) and 2- (4-fluoro-phenyl) -3-oxo-butyronitrile (Example 79, Step 79.1). White crystals; p.f. 209-212 ° C; MS (ESI +): m / z = 447.1 (M + H) +; HPLC: AtRet = 3.24 minutes (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- I-amine The title compound is prepared as described in Example 72; using 2- (3,4-difluoro-phenyl) -3-oxo-butyryltrile instead. White solid; p.f. 216-219 ° C; MS (ESl +): m / z = 435 (M + H) +; HPLC: AtRet = 3.30 minutes (System 1). Step 98. 1 2- (3,4-difluoro-phenyl) -3-oxo-butyronitrile The title compound is prepared as described in Example 1 (Steps 1 .4 and 1 .2); using in its place (3,4-difluoro-phenyl) -acetonitrile. White crystals; p.f. 147-152 ° C; MS (ESI +): m / z = 195 (M + H) +; HPLC: AtRet = 5.39 minutes (System 1). Example 99 6- (3,4-difluoro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrim id i n-7-i I-amine compound of the title is prepared as described in Example 72; using 4- (3,4-dimethoxy-phenyl) -2H-pyrazolo-3-yl-amine (Example 93; Step 93.1) and 2- (3,4-difluoro-phenyl) -3-oxo- butyronitrile (Example 98, Step 98.1). White solid; p.f. 230-235 ° C; MS (ESI +): m / z = 397.0 (M + H) +; HPLC: AtRet = 4.53 minutes (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.}. piperazin-1-yl) -ethanol The title compound is prepared as described in Example 72; using instead 2-. { 4- [3- (5-amino-1 H -pyrazol-4-yl) -phenyl] -piperazin-1-yl} -ethane I (Example 90, Step 90.1) and 2- (3-chloro-4-fluoro-phenyl) -3-oxo-butyronitrile (Example 82, Step 82.1). White crystals; p.f. 104-107 ° C; MS (ESI +): m / z = 481 (M + H) +; HPLC: AtRet = 4.00 minutes (System 1).

Example 101 2- (4-. {3- [7-amino-6- (3,4-difluoro-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-3-yl] -phen l.}. -piperazin-1-yl) -ethanol The title compound is prepared as described in Example 72; using instead 2-. { 4- [3- (5-amino-1 H -pyrazol-4-yl) -phenyl] -piperazin-1-yl} -ethane I (Example 90, Step 90.1) and 2- (3,4-difluoro-phenyl) -3-oxo-butyronitrile (Example 98, Step 98.1). White crystals; p.f. 172-174 ° C; MS (ESI +): m / z = 465 (M + H) +; HPLC: AtRet = 3.71 minutes (System 1).

EXAMPLE 102 6- (3-Chloro-phenyl) -5-methoxy-3- [3- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine- 7-yl-amine The title compound is prepared as described in Example 72; using instead 4- [3- (4-pyrrolidin-1-yl-piperidin-1-yl) -pheni] -1 H -pyrrazole-3-yl-amine. Yellow crystals; p.f. 188-193 ° C; MS (ESI +): m / z = 487.0 (M + H) +; HPLC: AtRet = 4.21 minutes (System 1).

Step 102. 1 4- [3- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenyl] -1 H -pyrazol-3-yl-amine The title compound is prepared as described in Example 1 (Stage 1 .2 and 1 .4 and 1 .5); using instead (3-bromo-phenyl) -acetonitrile and 4-pyrrolidin-1-yl-piperidine. Yellow crystals; p.f. 214-216 ° C; MS (ESI +): m / z = 312.1 (M + H) +; HPLC: AtRet = 3.71 minutes (System 1).

Example 103 6- (4-fluoro-phenyl) -5-methyl-3- [3- (4-pyrrolidn-1 -l-piperidin-1-l) -pheny] - pi razolo [1, 5-a] pyrimidin-7-i-amine The title compound is prepared as described in Example 72; using instead 4- [3- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenyl] -1 H -pyrazol-3-yl-amine (Example 102; Step 102.1) and 2- (4 Fluoro-phenyl) -3-oxo-butyronitrile (Example 79, Step 79.1). White crystals; p.f. 244-249 ° C; MS (ESI +): m / z = 471 .0 (M + H) +; H PLC: AtRet = 3.82 minutes (System 1).

EXAMPLE 104 6- (3-Chloro-phenyl) -3- [3- (4-diethylamino-piperidin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidin-7-yl- amine The title compound is prepared as described in Example 72; using instead. { 1 - [3- (3-amino-1 H -pyrazol-4-yl) -phenyl] -piperidin-4-yl} -diethyl-amine. White crystals; p.f. 163-168 ° C; MS (ESI +): m / z = 489.0 (M + H) +; HPLC: AtRet = 4.02 minutes (System 1).

Stage 104. 1. { 1 - [3- (3-amino-1 H -pyrazol-4-yl) -phenyl] -piperidin-4-yl} Diethylamine The title compound is prepared as described in Example 1 (Steps 1.2 and 1.4 and 1.5); using instead (3-bromo-phenyl) -acetonitrile and diethyl-pperidin-4-yl-amine. Solid beige, amorphous; MS (ESI +): m / z = 314.2 (M + H) +; HPLC: AtRet = 3.75 minutes (System 1).

Example 105 3- [3- (4-DiethyNamino-piperidin-1-yl) -phenyl] -6- (4-fluoro-phenyl) -5-methyl-pi-raz [1,5-a] pyrimidine-7-i I-amine The title compound is prepared as described in Example 72; using instead. { 1 - [3- (3-amino-1 H -pyrazol-4-yl) -phenyl] -piperidin-4-yl} Diethylamine (Example 104, Step 104.1) and 2- (4-fluoro-phenyl) -3-oxo-butyronitrile (Example 79, Step 79.1). White crystals; p.f.208-210 ° C; MS (ESI +): m / z = 473.1 (M + H) +; HPLC: AtRet = 3.63 minutes (System 1).

Example 106 6- (4-Fluoro-phenM) -5-methyl-3- [3- (4-methyl-4-oxy-piperazin-1-yl) -phenyl] -pi razolo [1,5-a] pirim id i n-7-i I-amine 6- (4-Fluoro-phenyl) -5-methyl-3- [3- (4-methyl-4-oxy-piperazin-1-yl) -phenyl] -pyrazolo [1, 5-a] pyrimidin-7-yl-amine (Example 80) (50 milligrams; 0.12 mmol) is dissolved in CH 2 Cl 2 (10 milliliters) and at 0 ° C, treated with 3-chloroperbenzoic acid (31 .1 milligrams; 0.126 mmol) for 1 hour, followed by stirring at room temperature for 2 hours. After removal of the solvent under reduced pressure, the crude mixture is purified by chromatography (silica gel, 12 grams of RediSep, ISCO Sg-100 CH2Cl2 / MeOH / NH3 = 80:20: 1) to obtain the title compound as beige crystals (44 milligrams); p.f. 210-223 ° C; MS (ESI +): m / z = 449 (M + H) +; HPLC: AtRet = 3.31 minutes (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] pyrim id in-7-i I-amine The title compound is isolated from the same reaction described in Example 106: beige crystals (20 milligrams); p.f. 161-169 ° C; MS (ESI +): m / z = 433 (M + H) +; HPLC: AtRet = 3.89 minutes (System 1). Example 108 6- (3-Chloro-phenyl) -3- [3- (4-dimethylamino-piperidin-1-yl) -phenyl] -5-methyl-pi-razolo [1, 5-a] pyrim id-n- 7-I-amine The title compound is prepared as described in Example 72; using instead. { 1 - [3- (5-amino-1 H -pyrazol-4-yl) -phenyl] -piperidin-4-yl} -dimethyl-amine.

Stage 108. 1. { 1 - [3- (5-amino-1 H -pyrazol-4-yl) -phenyl] -piperidin-4-yl} dimethyl amine The title compound is prepared as described in Example 1 (Steps 1.2 and 1.4 and 1.5); using instead (3-bromo-phenyl) -acetonitrile and dimethyl-piperidin-4-yl-amine.

Example 109 6- (3,4-difluoro-phenyl) -3- [3- (4-dimethylamino-piperidin-1-yl) -phenyl] -5-methyl-pyrazoo [1,5-a] pyrimidin-7 il-amine The title compound is prepared as described in Example 72; using instead. { 1 - [3- (5-amino-1 H -pyrazol-4-yl) -phenyl] -piperidin-4-yl} dimethyl amine (Example 108, Step 108.1) and 2- (3,4-difluoro-phenyl) -3-oxo-butyronitrile (Example 98, Step 98.1).

Example 1 10 6- (3-chloro-phenyl) -5-methyl-3- (3,4,5-trimethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl-amine The title compound is prepared as described in Example 72; using 4- (3,4,5-trimethoxy-phenyl) -2H-pyrazol-3-yl-amine instead. Step 110. 4- (3,4,5-trimethoxy-phenyl) -2H-pyrazol-3-l-amine The title compound is prepared as described in Example 1 (Steps 1 .4 and 1 .2); using in its place (3,4,5-trimethoxy-phenyl) -acetonitrile.

Example 11 1 6- (3,4-difluoro-phenyl) -5-methyl-3- (3,4,5-trimethoxy-phenyl) -pyrazolo [1,5-a] pi ri mid i n-7-i I-amine The title compound is prepared as described in Example 72; using instead 4- (3,4,5-trimethoxy-phenyl) -2H-pyrazol-3-yl-amine (Example 1 10, Step 1 10.1) and 2- (3,4-difluoro-phenyl) -3 -oxo-butyronitrile (Example 98, Step 98.1).

Example 112 6- (3-Chloro-f-enyl) -3- (3-methoxy-f-1) -5-methyl-pyrazolo [1,5-a] pyrim idin-7-yl-amine The title compound is prepared as described in Example 72; using 4- (3-methoxy-phenyl) -2H-pyrazol-3-yl-amine instead. Step 112. 1-4- (3-Methoxy-phenyl) -2H-pyrazol-3-yl-amine The title compound is prepared as described in Example 1 (Steps 1.4 and 1.2); using instead (3-methoxy-phenyl) -acetonitrile. 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 at Example 1; using 2- (6-hydroxy-pyridin-2-yl) -3-oxo-propionitrile and 4- (3,4-d-methoxy-phenyI) -2H-pyrazol-3-yl-amine instead (Example 93; Stage 96.1).

Example 114 6-Benzyl-3- (3,4-di methoxy-f in i I) -pyrazolo [1,5-a] p irim idin-7-i I-amine The title compound is prepared as described in Example 93; using 4- (3,4-dimethoxy-phenyI) -2H-pyrazol-3-ylamine (Example 93; Step 93.1) instead.

Example 115 3- (3,4-dimethoxy-phenyl) -6- (3-fluoro-benzyl) -pyrazolo [1,5-a] pyrimidin-7-yl-amine The title compound is prepared as described in Example 1 14; using 2- (3-fIuoro-benzyl) -3-oxo-propionitrile instead.

Example 116 Tablets comprising the compounds of the formula (1) Tablets comprising, as an active ingredient, 50 milligrams of any of the compounds of the formula (I) mentioned in the preceding Examples 1 to 15 of the following composition are prepared. , using routine methods: Manufacturing: The active ingredient is combined with part of the wheat starch, the lactose, and the colloidal silica, and the mixture is compressed through a sieve. An additional part of the wheat starch is mixed with five times the amount of water in a water bath to form a paste, and the mixture that is first made is kneaded with this paste until a weakly plastic mass is formed. The dried granules are compressed through a sieve having a mesh size of 3 millimeters, mixed with a previously sieved mixture (1 millimeter sieve) of the remaining wheat starch, magnesium stearate and talc, and compressed to form slightly biconvex tablets.

Example 117 Tablets comprising the compounds of the formula (I) Tablets comprising, as an ingredient are prepared active, 1 00 milligrams of any of the compounds of the formula (I) of Examples 1 to 1 15, with the following composition, following conventional procedures: Manufacturing: The active ingredient is mixed with the carrier materials, and compressed by means of a tablet-forming machine (Korsh, EKO, Stempeldurchmesser 10 millimeters).

Example 1 Capsules Capsules are prepared which comprise, as an active ingredient, 100 milligrams of any of the compounds of the formula (I) given in Examples 1 to 15 of the following composition, according to the conventional procedures: Manufacturing is done by mixing the components and filling them in hard gelatin capsules, size 1.

Example 119 Inhibition of kinase by the compounds of the present invention The activity determinations of the compounds of the above examples, using the test method described above, with the following test compounds of the formula (I), exhibit activity for the following kinases shown in Table 4 (an "x" indicates activity for that kinase). "Activity", as used herein, is defined as having IC 50 values for kinase inhibition of 10 μM or less: Table 4:

Claims (10)

1 . The use of a compound of the formula (I): wherein: R2 is H; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; a substituted or unsubstituted aliphatic residue; a functional group; or a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted aliphatic residue which is connected by a group or connecting atom to the pyrazolo [1,5-a] pyrimidinyl ring; and R3 can be H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a substituted or unsubstituted aliphatic residue, a functional group, or a substituted or unsubstituted aliphatic residue that can be connected by a group or connecting atom to the pyrazo ring or [1, 5-a] pyrimidinyl, at least one of R2 or R3 is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or substituted or unsubstituted heteroaryl, or a substituted or unsubstituted aryl residue that is connected by a linking group or atom to the pyrazolo [1,5-a] pyrimidinyl ring; A is H, halogen (such as bromine), an aliphatic fraction, a functional group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and Ri is H, halogen, or lower alkyl; or pharmaceutically acceptable salts thereof, for the treatment of a protein kinase dependent disease.

2. The use according to claim 1, wherein: R2 is H; lower alkyl; cycloalkyl; benzyl; benzothienyl, -dolyl substituted by lower alkyl, pyridyl or thiazolyl optionally substituted by lower alkyl; unsubstituted phenyl or phenyl substituted by 1 or 2 substituents selected from the group consisting of: halogen, hydroxyl, alkoxy, benzyloxy, cycloalkyl, amino, acetylamino, lower alkyl-sulfonamide, and benzenesulfonamide substituted by 1 or 2 halogens; R3 is H; lower alkyl optionally substituted by halogen; phenyl, pyridyl, or oxazolyl; A is: (a) H; halogen; benzothienyl; pyridyl, methyl-piperazinyl-phenoxy; indolyl substituted with lower alkyl; (b) phenyl which is substituted or unsubstituted with one or more of the substituents selected from the group consisting of: mono-, di-, or tri-lower alkoxy, lower di-lower alkylamine, morpholinyl which is optionally di- substituted by alkyl, piperazinyl which is substituted by one or more of the substituents selected from the group consisting of: lower alkyl, lower alkoxy, lower alkyl piperazinyl, pyrrolidinyl, dialkyl aminyl, and lower alkanol; Y or pharmaceutically acceptable salts thereof, for the treatment of a protein kinase dependent disease.

3. The use according to claim 1 or 2, wherein the kinase-dependent disease is one that depends on 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 kinases (e.g., EphB2 kinase, EphB4 kinase, and kinases Eph related), casein kinases (CK-1, CK-2, G-CK), Pak, ALK, ZAP70, Jak1, Jak2, Axl, Cdkl, cdk4, cdk5, Met, FAK, Pyk2, Syk, insulin receptor kinase, Tie-2, or constitutively activating mutations of kinases (activating kinases) , such as Bcr-Abl, c-Kit, c-Raf, Flt-3, FGF-R3, PDGF, RET, and Met receptors, and a kinase-dependent disease (especially highly expressed or activated in an aberrant form) , or a disease dependent on the activation of the kinase pathways, or a disease dependent on any two or more of the kinases just mentioned.

4. The use according to any of the claims 1 to 3, wherein the kinase dependent disease is one that depends on c-abi, Flt-3, KDR, c-Src, RET, EphB4, c-kt, cdk-1, FGFR-1, c-raf, Her-1, Ins-R, or Tek.

5. The use according to any of claims 1 to 4, wherein the disease to be treated is a disease proliferative, preferably a benign or especially malignant tumor, more preferably carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach (especially gastric tumors), ovaries, colon, rectum, prostate, pancreas, lung, vagina , thyroid, sarcoma, glioblastomas, multiple myeloma, or gastrointestinal cancer, especially carcinoma of the colon or colo-rectal adenoma, or a tumor of the neck and head, an epidermal hyperproliferation, especially psoriasis, prostate hyperplasia, a neoplasm, especially of epithelial character, preferably mammary carcinoma, or a leukemia.

6. The use according to any of the claims 1 to 5, wherein the disease to be treated is triggered by persistent angiogenesis, such as psoriasis; Kaposi's sarcoma; restenosis, for example restenosis induced by stent (vascular implant); endometriosis; Crohn's disease; Hodgkin's disease; leukemia, arthritis, such as rheumatoid arthritis; hemangioma; angiofibroma; diseases of the eyes, such as diabetic retinopathy and neovascular glaucoma; kidney diseases, such as glomerulonephritis; diabetic nephropathy, malignant nephrosclerosis; microangiopathic thrombotic syndromes; transplant rejections and glomerulopathy; fibrotic diseases, such as cirrhosis of the liver; mesangial cell proliferative diseases; arteriosclerosis; nerve tissue injuries; and to inhibit reocclusion of vessels after balloon catheter treatment, for use in vascular prostheses, or after inserting mechanical devices to keep vessels open, such as, for example, stents (implants) vascular), as immunosuppressants, as an aid in the healing of wounds without a scar, and for the treatment of age spots and contact dermatitis.

7. A compound of the formula I: where: 0) R2 is H; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; an aliphatic residue; a functional group; or a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or aliphatic residue that is connected by a group or connecting atom to the pyrrazolo [1, 5a] pyrimidinyl ring; R3 can be H, substituted or unsubstituted aryl, heteroaryl, an aliphatic residue, a functional group or an aliphatic residue which can be connected by a group or connecting atom with the pyrazolo [1, 5a] pyrimidinyl ring. at least one of R2 or R3 is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; or a substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl residue which is connected by a group or connecting atom to the pyrazolo [1, 5a] pyrimidinyl ring, and in the understanding that both R 2 and A can not both be unsubstituted phenyl; A is H, halogen (such as bromine), an aliphatic moiety, a functional group, aryl or substituted or unsubstituted heteroaryl; Y Ri is H, halogen, or lower alkyl; or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 7, wherein: R2 is H; lower alkyl; cycloalkyl; benzyl; benzothienyl; indicate it substituted by lower alkyl, pyridyl or thiazolyl optionally substituted by lower alkyl; unsubstituted phenyl or phenyl substituted by 1 or 2 substituents selected from the group consisting of: halogen, hydroxyl, alkoxy, benzyloxy, cycloalkyl, amino, acetylamino, lower alkyl sulfonamide, and benzenesulfonamide substituted by 1 or 2 halogens; R3 is H; lower alkyl optionally substituted by halogen; phenyl; pyridyl, or oxalyl; A is: (a) H; halogen, benzothienyl; pyridyl; methyl-piperazinyl-phenoxy; Nolyl substituted with lower alkyl; (b) phenyl which is substituted or unsubstituted with one or more of the substituents selected from the group consisting of: mono-, di-, or tri-lower alkoxy, di-lower alkyl-amino, morpholinyl which is optionally di- Substituted by alkyl, piperazinyl which is substituted with one or more of the substituents selected from the group consisting of: lower alkyl, lower alkoxy, lower alkyl-piperazinyl, pyrrolidinyl, dialkyl-aminyl, and lower alkanol; and R! it's H; and with the understanding that both R2 and A can not both be unsubstituted phenyl.

9. A compound 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-p-piperazin-1-l) -phenyl] -pyrazolo [1,5-a] pyrimidine-7-yl) -phenol; 6- (3-methoxy-phenyl) -4- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3,5-dimethoxy-phenyl) -3- [4- (4-methylpipern-1 -yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-benzyloxy-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -prazora [1,5-a] pyrimid i n-7-i I- amine; 6- (4-chloro-phenyl) -3- [4- (4-methylpiperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-chloro-phenyl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 3- [4 - (4-methyl-piperazin-1-yl) -phenyl] -6-phenyl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; 5-methyl-3- [4- (4-methyl- piperazin-1-yl) -phenyl] -6-phenyl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6-methyl-3- [4- (4-methyl-piperazin-1 - il) -phenyl] -5-phenyl-pyrazolo [1, 5a] pyrimidin-7-yl-amine; N-. {4- [7-amino-3- (4-dimethylamino-phenyl) -prazora [1, 5- a] pyrimidin-6-yl] -phenyl] -2,3-dichloro-benzenesulfonamide; 4-chloro-benzenesulfonic acid ester of 4- [7-amino-3- (4-dimethyl-phenyl) -pyrazolo [1,5-a] pyrimidin-6-yl] -phenyl ester; 6- (4-methoxy-phenyl) -5-methyl-3-f enyl-pyrazolo [1,5-a] pyrim idin-7-yl-amine; 3- (4-methoxy-phenyl) -5-methyl-6-phenyl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (4-Bromo-phenyl) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1, 5-a] pyrimidin-7-yl-amino; 6- (4-bromo-phenyl) -5-methyl-3-phenyl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (2,6-dichloro-phenyl) -3-phenyl-pyrazolo [1, 5-a] pyrimidin-7-yl-amine; 3- (3-methoxy-phenyl) -6-phenyl-pyrazolo [1, 5-a] pyrimidin-7-yl-amine; 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] -prazora [1,5-a] pyrimidin-7-yl-amine; 3- (4-bromo-phenyl) -5-phenyl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; 3- [4- (4-methyl-piperazin-1-l) -phenyl] -6-thiophen-3-yl-pyrazolo- [1, 5-a] pyrimidin-7-yl-amine; 3-benzo [b] thiophen-3-yl-6- (3-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6-Benzo-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidn-7-yl-amine; 6- (3-methoxy-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] - pyrazolo [1, 5-a] pyrimidin-7-yl-amine; 6- (1-methyl-1 H-indol-3-yl) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl -amina; 6- (4-methoxy-phenyl) -3- [4- (4-methyl-piperazin-1 -i) -phenyl] -pyrazoo or [1,5-a] pyrimidin-7-yl-amine; 6- (2-methoxy-phenyI) 3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-methoxy-phenyl) -3-pyrimidin-3-yl-pyrazolo [1, 5-a] pyrimidin-7-yl-amine; 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- il-amine; 3-. { 7-amino-3- [2-methoxy-5- (4-methyl-piperazin-1-l) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol 6- (2-benzyloxy-phenyl) -3- [4- (4-methyl-piperazin-1-l) -phenyl] -pyrazolo [1,5-a] pyrimidine-7-yl -amine; 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-yl-amine; 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-pi-perazi n-1-yl) -f in I] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 2-. { 7-amino-3- [3- (4-methyl-piperazin-1 -yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -fenoI; 6- (4-benzyloxy-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 4-. { 7-amino-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol; 6- (2-Benzylloxyphenyl) -3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine-7- i I amine; 2-. { 7-amino-3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-6-yl} -phenol; 6- (4-benzyloxyl-phenyl) -3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -prazora [1,5-a] pyrimidin-7-yl- amine; 4-. { 7-amino-3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -prazora [1,5-a] pyrim id in-6-yl} -f enol; 6- (3-benzyloxy-phenyl) -3- [1-methyl-1 H -indole-3-yl) -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 3- [7-amino-3- (1-methyl-1 H-indol-3-yl) -pyrazolo [1, 5-a] pyrimidin-6-yl] -phenol; 3- [7-amino-3-pyridin-3-yl-pyrrazolo [1, 5-a] pyrimidin-6-yl] -phenol; 6- (3-benzyloxy-phenyl) -3- (2-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 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-p-arazoo [1,5-a] pyrimidin-7-yl-amine; 3- (2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -6-thiophen-3-yl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; 3- [4- (4-methyl-piperazin-1-yl) -phenyl] -6-pyridin-4-yl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; -amino-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-amino) -phenyl) -3 [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-i-amine; 6- (2-amino-phenyl) ) -3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 3- [4- (4-methyl-piperazin- 1-yl) -phenyl] -6- (4-methyl-thiazol-2-yl) -prazoo [1,5-a] pyrimidin-7-yl-amine; 6-benzo [b] thiophen-3-yl) il-3- [2-methoxy-5- (4-methyl-piperazin-1-l) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6-benzo [b ] thiophen-3-yl-3- [4-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-i-amine; 3- (3-methoxy-phenyl) -6-thiophen-3-yl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-benzyloxy-phenyl) -3- (3-methoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 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} -prazora [1,5-a] pyrimidin-6-yl) ethyl ester. .}.-pheny1) -carbamic; 6- (3-Chloro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] - pyrazolo [1, 5-a] pyrimid i n-7-i I-amine; 6- (3-chloro-phenyl) -5-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrim id i n-7-¡ I-amine; 6- (3-Chloro-phenyl) -3- [2-methoxy-5- (4-methyl-piperazin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidine-7- il-amine; 6- (3-Chloro-phenyl) -3- [2-methoxy-4- (4-methyl-piperazin-1-yl) -phenyl] -5-methy1-pyrazolo [1,5-a] pyrimid n-7-il-ami na; 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-yl-amine; 6- (2-Chloro-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimid i n-7-i-amine; 6- (4-fIuoro-phenyl) -5-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6 (4-fluoro-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-α-ami na 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) -f-enyl] -pyrazolo [1,5-a] pyrimidin-7- il-amine; 6- (3-Chloro-4-fluoro-phenyl) -5-methyl-3- [4- (4-methyl-piperazin-1-yl) -phenyl] -prazolo [1,5-a] pyrimidine- 7-yl-amine; 6- (3-bromo-phenyl) -5-methyl-3- [3- (4-methyl-piperazin-1-yl) -phenyl] -prazora [1,5-a] pyrimidin-7-yl-amine; 6- (3-Bromo-benzyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-bromo-phenyl) -3- [3- (4-methyl-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-chloro-phenyl) -5-methyl-3- (3-morpholin-4-yl-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-chloro-phenyl) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-yl-amino; 6- (3-chloro-phenyl) -3- [3 - ((2R, 6S) -2,6-dimethyl-morpholin-4-yl) -pheni] -5-methyl-pyrazolo [1,5-a] pyrmidin-7-yl-amine; 2- (4-. {3- [7-amino-6- (3-cyoro-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-yl-amine; 6- (3-Chloro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-fIuoromethyl-pyrazoic [1,5-a] pyrimidin-7-M-amino; 6- (3-chloro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-yl-amino; 6- (3-chloro-4-fluoro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-chloro-4-fluoro-phenyl) -3- (4-methoxy-phenyl) -5-methyl-pyrazolo [1,5-a] pyrimidin-7-α-amino; 6- (4-fluoro-phenyl) -3- (4-methoxy-phenyl) -5-methyl-1-pyrazoic [1,5-a] pyrimidin-7-yl-amine; 2- (4- { 3- [7-amino-6- (4-fluoro-phenyl) -5-methyl-pyrazolo [1, 5 a] pyrimidin-3-yl] -phenyl} -piperazin-1 -iI) -ethanol; 6- (3,4-difluoro-phenyl) -5-methyl-3- [3- (4-methyI-piperazin-1-yl) -fl-l] -prazoo [1,5-a] pyrimid i n-7-il-am ¡na; 6- (3,4-difluoro-phenyl) -3- (3,4-dimethoxy-phenyl) -5-methylene- < _. pyrazolo [1, 5-a] pyrimidin-7-yl-amine; 2- (4-. {3- [7-amino-6- (3-chloro-4-fluoro-phenyl) -5-methyl-prazrazolo [1,5-a] pyrimid-n-3-yl] - f in il.}. -piperazin-1-yl) -ethanol; 2- (4-. {3- [7-amino-6- (3,4-difluoro-phenyl) -5-methyl-pyrazoic [1,5-a] pyrimidin-3-yl] -phenyl] .piperazin-1-yl) -ethanol; 6- (3-chloro-phenyl) -5-methyl-3- [3- (4-pyrrolidin-1-yl-piperidin-1-yl) -f in il] -p¡razolo [1, 5-a] pyrmidin-7-I-amine; 6- (4-fluoro-phenyl) -5-methyl-3- [3- (4-pyrrolidin-1-yl-piperidin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidi n-7-yl-amine; 6- (3-Chloro-phenyl) -3- [3- (4-diethylamino-piperidin-1-yl) -phenyl] -5-methyl-pyrazolo [1,5-a] pyrimidin-7-yl -amine; 3- [3- (4-diethylamino-piperidin-1-yl) -phenyl] -6- (4-fluoro-phenyl) -5-methy1-pyrazolo [1,5-a] pyrimidine-7-yl -amine; 6- (4-fluoro-phenyl) -5-methyl-3- [3- (4-methyl-4-oxy-piperazin-1-yl) -f in il] -pyrazolo [1,5-a] pyrimidin-7-i-amine; 6- (4-fluoro-phenyl) -5-methyl-3- [3- (4-methyl-1,4-dioxy-piperazin-1-yl) -phenyl] -pyrazolo [1,5-a] pyrimidine- 7-yl-amine; 6- (3-Chloro-pheny1) -3- [3- (4-dimethylamino-p1peridin-1-I) -phenyl] -5-methy1-pyrazoo [1,5-a] pyr Midn-7-α-amine; 6- (3,4-difluoro-phenyl) -3- [3- (4-dimethylamino-piperidn-1-yl) -phenyl] -5-methyl-prazolo [1,5-a] pyrimidine- 7-amine; 6- (3-Chloro-phenyl) -5-methyl-3- (3,4,5-trimethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3,4-difluoro-phenyl) -5-methyl-3- [3,4,5-trimethoxy-phenyl) -pyrazolo [1,5-a] pyrimidin-7-yl-amine; 6- (3-chloro-phenyl) -3- (3-methoxy-phenyl) -5-methyl-pyrazolo [1, 5-a] pyrimidin-7-yl-amine; 6-7-amino-3- (3,4-d i methoxy-f in I) -prazo Io [1,5-a] pyrimidin-6-yl] -pyridin-2-ol; 6-benzyl-3- (3,4-d-methoxy-f enyl) -pyrazolo [1,5-a] pyrimid i n-7-yl-amine; and 3- (3,4-d-methoxy-f-enyl) -6- (3-fluoro-benzyl) -pyrazolo [1,5-a] pyrimidin-7-yl-amine.

10. The use of a compound according to claim 7, 8, or 9, in the preparation of a pharmaceutical composition. eleven . A pharmaceutical composition comprising a compound according to claim 7, 8, or 9. 12. A pharmaceutical composition comprising a compound according to claim 7, 8, or 9, and an acceptable pharmaceutical carrier. 13. The use of a compound according to claim 1 or 2, in the preparation of a pharmaceutical composition for use in the treatment of a kinase dependent disease. 14. A process for preparing a compound in accordance with claim 7, 8, or 9, which comprises: (a) reacting a nitrile, A-CH2-C = N, with ethyl formate in the presence of an organic solvent, to form a substituted 3-oxo-propionitrile , (b) condensing the 3-oxo-propionitriles of step (a) with hydrazine monohydrate in an organic solvent, to form a 2H-pyrazol-3-ylamine of the formula (III): III (c) forming a substituted nitrile in the presence of ethanolate and ethylester of formic acid, to prepare a 3-oxo-propionitrile of the formula (I I): (d) condensing the 3-oxo-propionitrile of the formula (II) and the 2H-pyrazol-3-yl-amines of the formula (11) in the presence of an organic solvent, to form a compound of the formula (I).