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MXPA02003140A - Quinazolines and their use for inhibiting cyclin dependent kinase enzymes. - Google Patents

Quinazolines and their use for inhibiting cyclin dependent kinase enzymes.

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Publication number
MXPA02003140A
MXPA02003140A MXPA02003140A MXPA02003140A MXPA02003140A MX PA02003140 A MXPA02003140 A MX PA02003140A MX PA02003140 A MXPA02003140 A MX PA02003140A MX PA02003140 A MXPA02003140 A MX PA02003140A MX PA02003140 A MXPA02003140 A MX PA02003140A
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quinazolin
phenyl
cyclopentyl
methoxy
piperazin
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MXPA02003140A
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Spanish (es)
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Robert Barvian Mark
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Warner Lambert Co
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

This invention provides quinazolines that are useful for treating cell proliferative diseases and disorders, such as cardiovascular diseases, infections, cancers, autoimmune diseases, gout, kidney disease, and neurodegenerative diseases and disorders such as Alzheimer s disease. We have now discovered a group of 2 arylamino quinazolines (I) and (II) that are potent inhibitors of cyclin dependent kinases (cdks). The compounds are readily synthesized and can be administered by a variety of routes, including orally, and have sufficient bioavailability. This invention also provides pharmaceutical formulations comprising at least one of the quinazoline compounds together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. The invention further provides useful intermediates generated during the production of the quinazoline compounds.

Description

QUINAZOLINES AND THEIR USE FOR THE INHIBITATION OF CYCLIN DEPENDENT ENZYMES FIELD OF THE INVENTION This invention relates to quinazolines which inhibit the cylin-dependent kinase enzymes and so useful for treating cell proliferative diseases and disorders, such as cardiovascular diseases (ie atherosclerosis, restenosis) and cancer, infections (ie, viral and fungal), autoimmune diseases, rejections to organ transplants (ie, inflammation), gout, kidney disease and also diseases and neurodegenerative disorders.
PRIOR ART Cyclone dependent kinases and related theorine / serine protein kinases are important cellular enzymes that perform essential functions in the regulation of cell division and proliferation. The catalytic units of the cyclone-dependent clhanase, of which 9 will now be described, are activated by the regulatory subunits known as cyclins. At least 16 mammalian cyclins have been identified (Jonson D. G. and Walter C.L., Annu., Rev. Pharmacol, Toxicol, 1999; 39: 295-312). Ciclin B / Cdk1, Ciclin A / Cdk2, Ciclin E / Cdk2, Ciclin D / Cdk4, Ciclin D / Cdk6 and probably other heterodimers including Cdk3 and Cdk4 are important regulators of cell cycle progression. Additional functions of Cdk Ciclin heterodimers include regulation of transcription, DNA repair, differentiation and apoptosis (Morgan D.O., Annu, Rev. Cell, Dev. Biol. 1997; 1361-191).
Increased activity or temporarily abnormal activation of cylin-dependent kinases has been shown to result in the development of human tumors (Sherr C.J. Science 1996; 274: 1672-1677). Indeed, the development of human tumors is commonly associated with alterations in the Cdk proteins themselves or their regulators (Cord-Cardo C, Am. J. Pathol., 1995; 147: 545-560; Karp JE and Broker S. , Nat. Med. 1995; 1: 309-320; et al, Adv. Cancer Res. 1996; 68: 67-108). These and other observations have initiated an intense search for small molecule Cdk inhibitors. The strong validation for this scope is provided by studies of the inhibitors of naturally occuring proteins of Cdks (Kamb A., Curr. Top, Microbiol.Immunol., 1998; 227: 139-148). Introduction of p16 into blocked lung cancer cell lines entered the S phase and caused growth inhibition (Jin X. et al., Cancer Res. 1995; 55: 3250-3253; Chintaia SK et al., Oncogene 1997; 15: 2049-2057). Other studies demonstrated a similar effect for p27 (Craig C. et al., Oncogen 1997; 14: 2283-2289). Expression of Cdk p21 or p27 inhibitors in U937 human leukemia cells resulted in the detection of cell growth and differentiation (Liu et al., Genes Dev., 1996; 10: 142-153). Markers of differentiation were also observed in the non-small lung cancer cell line NCI-H358 followed by the expression of antisense Cdk2. The expression of the anti-sense cyclin D1 in human esophageal cancer cells resulted in the inhibition of growth (Zhou P. et al, Oncogen, 1995; 11: 571-580).
Additional support to signal Cdk2 with therapeutic agents in the work of Chen et al., Proc. Nati Acad. Sci. (USA) 1999; 96: 4325-4329, which demonstrates the selective killing of the transformed U20S cells containing the deregulated E2F using the inhibitors of the Ciclin A / Cdk2 peptide. The non-transformed cell lines were not affected by these inhibitors. In addition, Cdk inhibitors could potentially demonstrate efficacy in vivo with a useful margin of safety.
In addition to treating cancer, Cdk inhibitors may also have potential applications in the treatment of cardiovascular diseases such as restenosis and arteriosclerosis. Proliferation of vascular smooth muscle and intimal hyperplasia followed by angioplasty by inflammation is inhibited by over-expression of the ciclin-dependent p21 kinase inhibitor protein (Chang MW et al., J. Clin.Invest., 1995; 96: 2260; Yang ZY et al., Proc. Nati. Acad. Sci. (USA) 1996; 93: 9905. In addition, intraluluminal exposure of a naked rat carotid artery for the purine inhibitor Cdk2 CVT-313 (Ki = 95 nM) resulted in more than 80% 2de inhibition of neointima formation (Brooks E.E. et al., J. Biol. Chem. 1997: 29207-2911). Taken together, these observations support the use of small molecule inhibitors of cell cycle progression in the treatment of vascular diseases that are due to aberrant cell proliferation.
The neuronal kinase like Cdc2, known as Cdk5, together with its p35 / p25 brain-specific activating protein, phosphorylates the tau protein associated with the neuron-specific micro-tube (Lew J and Wang JH Trends Biochem. Sci.; 20: 33-37). The aberrant expression of Cdkd is proposed to contribute to the neurodegenerative disease Multiple System Atrophy (Nakamura S. et al., J. Neuropathol, Exp. Neurol. 1998; 57: 690) and tau hyperphosphorylation have been greatly associated with pathogenesis. of Alzheimer's Disease (AD) (Spillantini MG and Gtedert M., Trends Neurosci, 1998; 21: 428-433). In addition to amyloid plaques, neurofibrillary tangles (NTFs) are a primary marker for AD. The main component of the NFTs is the tau filaments (PHF) of double helix, which is a filamentous aggregate of the hyperphosphorylated tau. The "NFT burden" in the brains of patients with Alzheimer's Disease (AD) correlates strongly with the severity of the disease. This correlation is stronger than that observed for amyloid plaques rich in Aβ. Abnormal activation of protein kinases (cyclin-dependent kinase 5 (Cdk5), 3β glycogen kinase synthase (GSK-3β)) and protein phosphatases (type 2A and 2B) have been implicated in tau hyperphosphorylation and the pathological activation of the Cdkd is as a major contributor to the tau-PHF.
Cdk5 is an important therapeutic target because its p35 activator protein is located specifically in peripheral and central neurons (Tsai J. H. et al., Nature 1984; 371: 419-42). Indeed, the abnormal deposition of amyloid beta peptide (APP gene) and hyperphosphorylated tau can combine factors that lead to the early onset of AD (Mandelkow E.-M. and Mandelkow E., Trends Cell Biol. 1998; 8: 425 -427). There is evidence of growth that abnormally processes tau that is also associated with other CNS diseases. Recently, mutations in the tau gene on chromosome 14 have been linked to dementia ^ len ^ aIn terms of Parkinsonism (FTDP-17 = and progressive supernuclear palsy (PSP) (Spilantini M.G. and Giedert M., Trends Neurosci., 1998; 21: 428-433).
In addition, the evidence supporting the role of Cdk5 in taupathy and Alzheimer's disease includes the following observations. (1) Increased Cdk5 activity has been found in AD brains (Pei J.J. et al., Brain Res. 1998; 797: 267-77; Lee K. Y. et al., Neurosci Res. 1999; 34: 21-9). (2) The PHF-Tau found in the AD brains has 8 phosphorylation sites that overlap with the csk5 phosphorylation sites (Paudel HK et al., J. Biol. Chem. 1993; 268: 23512-23518; Baumann K. et al. al., FEBS Lett., 1993; 336: 417-424). (3) The synergy between the different tau protein kinases, ie, the Cdk5-phosphorylated tau, is more rapidly phosphorylated by GSK3 (Sengupta A., et al., Mol.Cell. Biochem., 1997; 167: 99-105. ).
Other diseases in which Cdk inhibitors might find application include those caused by a variety of infectious agents, including DNA and RNA viruses. For example, cyclin dependent kinases are required for viral replication after infection by herpes simplex virus (HSV) (Schang L.M. et al., J. Virol. 1998; 72: 5626). HSV replication was inhibited by the inhibitors roscovitin and olomoucine of the cylin-dependent kinase but not by a cell cycle inhibitor that does not inhibit cylin-dependent kinase activity. The inactivation of the p16 protein of the Cdk inhibitor by the viral Tax protein and the inactivity of the p27 by the viral E1A, have shown that it overcomes the cell cycle suppression and promotes cell immortalization and the transformed phenotype (Mal A. et al., Nature 1996; 380: 262-265; Suzuki T. et al., EMBO J. 1996; 15: 1607-1614; Parker G.A. et al., Oncogen 1996; 13: 2541-2549). Cdk2 has also been implicated in the progression of cytomegalovirus infections (Bresnahan W. A. et al., Virology 1997; 231: 239-247; Albrecht T. et al., WO 98/39007). It is expected that fungal infections are susceptible to Cdk inhibitors on the basis of the essential roles known from the Cdk homologs in yeast. to. £ LMÉH?. *. iJb & . - *. ^ Jb-.A * í- - * **. **. .- * - ». j? t *. * »* - ** It is also possible that several autoimmune diseases may succumb to treatment with selective Cdk inhibitors. Rheumatoid arthritis of chronic inflammatory disease is characterized by hyperplasia of synovial tissue; Inhibition of synovial tissue proliferation should minimize inflammation and prevent joint destruction. Consistent with this idea, the expression of the P16 protein of the Cdk inhibitor in synovial fibroblasts for growth inhibition (Taniguchi K. et al., Nati, Med 199; 760-767). Similarly, in a rat model with arthritis, joint swelling was substantially inhibited by treatment with p16 expressing the adenovirus. By extension, Cdk inhibitors can be effective against other diseases of cell proliferation including psoriasis (characterized by hyperproliferation of keratinocytes) and possibly lupus.
Different from the scope of therapy by GEN, many research groups are looking for small molecule inhibitors of cyclin-dependent kinases. The small molecule inhibitors of Cdks that have been published to date include purines such as olomoucine (Vesely et al., Eur. J. Biochem., 1994; 224: 771-786) and roscovitine (Meijer L. et al., Eur. J. Biochem, 1997; 243: 527-536), butyrolactone, staurosporine and UCN-01, suramin, 9-hydroxyelopticine and various flavonoids including flavopiridol (Garrett MD and Fattaey A., Curr Opin. Genes &Develop. 1999; 9: 104-111; Walter DH, Curr Top, Microbe, Immunol 1998, 148-165, Meijer L., Meths, In Enzymol, 1997, 223: 113-128). Of these inhibitors, most information is available for flavopiridiol.
Flavopiridol is currently in phase II of clinical trials for the treatment of metastatic renal cell carcinoma. It is a relatively non-specific inhibitor of Cdks and produces the cell cycle that is blocked in G1 and G2. However, it is a potent inhibitor of several lung and breast cancer cell lines (Sedlacek HH et al., Int. J. Oncol., 1996: 1143-1168, Kur et al., J. Nati. Cancer Inst. 1992; 84: 1436-1740; Bible KC: and Kaufman SH, Cancer Res. 1996; 56: 4856-4861) and displays the growth of inhibitory activity against tumors in vivo (Patel V. et al., J. Clin. Invest. Wright, J. et al., Oncology 1998; 12: 1018, 1023-1014; Senderowicz A.M. et al., J. Clin. Oncol. 1998; 16 2988-2999). The flavopiridol analogs have been described by Mitotix (International Patent Application WO 97/16447; US Patent No. 5,733,920) as well as by Bristol-Myers Squibb (WO 97/42949).
The purine class of Cdk inhibitors has been studied extensively in vitro, generally displaying greater potency against Cdk1, Cdk2 and Cdk5. The olomoucine analogs have been synthesized by Meijer and his collaborators (Legraverand M. et al., Bioor.Med.Chem. 1999; 7: 1281-1293 and cited references), Schultz et al. (Chang YT. Et al. , Chem. &Biol. 1999; 6: 361-375), Griffin et al. (International Patent Application WO 99/02162) and Mackman et al., (US Patent 5,866,702; WO 98/05335), among others. One of these compounds has been shown to inhibit neointima formation in an animal model of restenosis (see above).
Other classes of small molecule Cdk inhibitors described in the patent literature include the aminothiazoles independently developed by Agouron (WO 99/21845) and by Bristol-Myerss Squibb (WO 99/24416); indolinones that have been developed by Sugen (WO 98/50356) and by Glaxo (WO 99/24416); benzothiadiazines (WO 98/49146); peptides (WO 97/11174); pyrazolo [3,4-b] pyridines (WO 99/30710) and phenylaminopyrimidines (Novartis, unpublished results). Several of these classes of structures of protein kinase inhibitors have been reviewed by McMahon et al., Curr. Opin. Drug. Discovery & Develop. 1998; 1: 131-146). Very few in vitro and nonclinical data are available for any of these compounds and there is still a need for more potent and selective Cdk inhibitors with good pharmacokinetic properties that can be used not only as in vitro but also in vivo tools.
A class of pyrido [2,3d] pyrimidines which selectively deploy for Cdks against protein kinases has been previously described (WO 98/33798). These compounds are different from 6-aryl-pyrido [2,3d] pyrimidines (WO 96/15128; WO 96/34867) which displays the opposite selectivity, preferring tyrosine kinases over dependent kinases • Det ^ lin. In addition, they represent a new structural class when compared to the pyrimidines and 3,4-dihydropyrimidines of the International Patent application PCTUS9910187, filed on May 10, 1999 or the naphthyridones described in the international patent application WO 99/09030.
Notwithstanding the progress that has been made, the search continues for low molecular weight compounds that are orally bioavailable and useful for treating a wide variety of diseases and proliferative disorders, cancer, infections, autoimmune diseases, gout, kidney disease. and diseases and neurodegenerative disorders.
SUMMARY OF THE INVENTION This invention provides quinazolines which are useful for treating cell proliferative diseases, such as vascular smooth muscle proliferation associated with arteriosclerosis, post-surgical vascular stenosis and restenosis and endometriosis.
This invention also provides quinazolines which are useful for treating infections, which include viral infections such as DNA viruses such as herpes and RNA viruses such as HIV and fungal infections.
This invention also provides quinazolines which are useful for treating autoimmune diseases such as psoriasis, inflammation such as rheumatoid arthritis, lupus, type 1 diabetes, diabetic neuropathy, multiple sclerosis and glomerulonephritis, rejection of organ transplantation, including graft disease. against the guest.
This invention also provides quinazolines which are useful for treating neurodegenerative diseases such as Alzheimer's disease.
This invention also provides quinazolines that are useful for treating cancer.
This invention also provides quinazolines that are useful for treating gout.
This invention also provides quinazolines which are useful for treating kidney disease, such as polycystic kidney disease.
The methods previously identified for the preferred treatment are carried out by the therapeutically effective administration of a compound of Formulas I and / or II (set forth below) to a subject in need of treatment. It has been found that a 2-arylamino-7- (alkyl) oxy-8-alkylquinazolines and 8-alkyl-2-arylamino-quinazoline-2,7-diamines are potent inhibitors of cyclin-dependent kinases (cdks). The compounds are rapidly synthesized and can be administered by a variety of routes, including orally and parenterally and have less or no toxicity.
This invention also provides pharmaceutical formulations comprising a compound of Formulas I or II together with a pharmaceutically acceptable carrier, diluent or excipient thereof.
Compounds within the scope of the present invention are inhibitors of cyclin dependent kinases such as cdkl, cdk2, cdk4 and cdk5.
DETAILED DESCRIPTION OF THE INVENTION A new class of compounds that are potent inhibitors of cyclin-dependent kinases (cdks) have been discovered and are useful agents for treating subjects suffering from diseases caused by abnormal cell proliferation. Compounds within the scope of the present invention are inhibitors of cyclin dependent kinases such as cdkl, cdk2, cdk4 and cdk5. As cyclin-dependent inhibitors, the compounds of the present invention are useful in controlling proliferative diseases and disorders, cancer, infections, autoimmune ages, gout, kidney disease and diseases and neurodegenerative disorders.
The compounds of the invention comprise those of Formula I: wherein, R 1 is hydrogen, alkyl, alkyl substituted with at least one amine, halogen, hydroxy or alkoxy, cycloalkyl or heterocycloalkyl; R2 is OH, alkyloxy, aryloxy or NR3R4; A is N or CW3; R3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, (CH2) nAr, cycloalkyl, heterocycloalkyl or heteroaryl or R3 and R4 together with the nitrogen to which they are optionally added can form a ring having from 3 to 7 carbon atoms. carbon and said ring optionally contains 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen and sulfur including S (O) and S (0) 2. Said ring can also be further substituted with more than 3 three groups selected from alkyl, haloalkyl, NR8C (0) R9, C (0) OR8, C (0) R8, C (0) NR8R9, NR8R9, NR8S02R9, OR8, S02NR3R4 or SR8; Wf and W2 are independently selected from NR3R4, N (0) R3R4, NR3R4R8X, OR3, SR3, hydrogen, halogen, haloalkyl, COR3, C02R3, CONR3R4, S (0) R3, S02R3, S02NR3R4, S02R3, S02NR3R4, S03R3, P (0) (OR3) 2, aldehyde, nitrile, nitro, alkyl, T (CH2) mQR8, C (0) T (CH2) mQR8 or T (CH2) mC02R8 where m is 1-6. T is O, S, NR3, N (0) R3, NR3R4X or CR3R4 and Q is O, S, NR9, NXOJ 9 or NR9R10X or NR9C (0) T (CH2) mQR9; R5 is hydrogen or alkyl, R1 is hydrogen, alkyl, halogen, haloalkyl, alkynyl, alkenyl, COR3, C02R3, CONR3R4, S02NR3R4, S02R3, S03R3, P (0) (OR3) 2, aldehyde, nitro, nitro, OR3 or NR3R4 W3 is NR3R4, NR3R4R8X, OH, OR3, SH, SR3, halogen, COR3, C02R3, CONR3R4, S (0) R3, S02R3, S02NR3R4, SO3R3, (CH2) nP (0) (OR3) 2, NR3S02R4, aldehyde, nitrile, nitro, alkyl, T (CH2) mQR8, C (0) T (CH2) mQR8, NR8C (0) T (CH2) mQR11 or T (CH2) mC02R3 where m and n are independently 1-6, T is O, S, NR3, N (0) R3, NR3R4W or CR3R4 and Q is O, S, NR9, N (0) R9 or NR9R10X; R8, R9, R10 and R11 are hydrogen, alkyl or aplo; X is halogen; or a pharmaceutically acceptable salt, ester, amide or pro-drug thereof.
The compounds of the invention further comprise those of Formula II: where, the dotted line represents a link at position C5-C6, C6-C7 or C7-C8.
R1 is hydrogen, alkyl, alkyl substituted with at least one amino, halogen, hydroxy or alkoxy, cycloalkyl or heterocyclic; R2 is OH, alkyloxy, aryloxy or NR3R4; A is N or CW3; R3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, (CH2) nAr, cycloalkyl, heterocycloalkyl or heteroaryl or R3 and R4 together with the nitrogen to which they are optionally attached can form a ring having 3 to 7 carbon atoms and said ring optionally contains 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen and sulfur including S (O) and S (0) 2. Said ring can also be further substituted with more than 3 groups selected from alkyl, haloalkyl, NR8C (0) R9, C (0) OR8, C (0) R8, C (0) NR8R9, NR8R9, NR8R9, NR8S02R9, OR8, S02NR3R4 or SR8; W1 and W2 are independently selected from NR3R4, N (0) R3R4, NR3R4R8X, OR3, SR3, hydrogen, halogen, haloalkyl, COR3, C02R3, CONR3R4, S (0) R3, S02R3, S02NR3R4, S03R3, P (0) ( OR3) 2, aldehyde, nitrile, nitro, alkyl, T (CH2) mQR8, C (0) T (CH2) mQR8 or T (CH2) mC02R8 where m is 1-6, T is O, S, NR3, N (0) R3, NR3R4X or CR3R4 and Q is O, S, NR9, N (0) R9 or NR9R10X or NR9C (0) T (CH2) mQR9; R5 is hydrogen or alkyl; R6 is hydrogen, alkyl, halogen, haloalkyl, alkynyl, alkenyl, COR3, C02R3, CONR3R4, S02NR3R4, S02R3, S03R3, P (0) (OR3) 2, aldehyde, nitrile, nitro, OR3 or NR3R4 W3 is NR3R4, N ( 0) R3R4, NR3R4R8X, OH, OR3, SH, SR3, halo, COR3, C02R3, CONR3R4, S (0) R3, S02R3, S02NR3R4, SO3R3, (CH2) nP (0) (0R3) 2, NR3S02R4, aldehyde, nitrile, nitro, alkyl, T (CH2) mQR8, C (0) T (CH2) mQR8, NR8C (0) T (CH2) mQR11 or T (CH2) mC02R3 where n and m are independently 1-6; T is O, S, NR3, N (0) R3, NR3R "WO CR3R4 and Q is O, S, NR9, N (0) R9 or NR9R10X; R8, R9, R10 and R11 are hydrogen, alkyl or aryl; X is a halogen, or a pharmaceutically acceptable salt, ester, amide or a prodrug thereof.
"^ T" A further particularly preferred group of compounds of Formulas I and II have the above formulas wherein W3 is piperazine or substituted piperazine, R2 is alkyloxy and R1 is • alkyl or cycloalkyl.
The following compounds illustrate the specific embodiments provided by the present invention and the compounds listed below are within the preferred embodiments: (8-lsopropyl-7-methoxy-quinazolin-2-yl) -phenylamine; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) -phenyl-amine; (8-isopropyl-7-methoxy-quinazolin-2-yl) -4- (piperidin-1-yl-phenyl) -amine; (8-Cyclopentyl-7-methox? -quinazolin-2-yl) - (4-piperidin-1-yl-phenyl) -amine; (8-Cyclopentyl-7-methoxy-quinazole? N-2-yl) - (4-pyrrolidin-1-yl-phenyl) -amine; 8-lsopropyl-2-phenylamino-quinazolin-7-ol; 4- [4- (8-lsopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester. 4- [4- (8-Cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - (4-piperazin-1-yl-phenyl) -amine; 8-Cyclopentyl-2- (4-piperazin-n-1-yl-phenylamino) -quinazolin-7-ol; 2-amino-'Í-. { 4- [4- (8-cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; 8-lsopropyl-2- (4-piperaxyin-1-yl-phenamino) -quinazole? N-7-ol; (8-lsopropyl-7-methoxy-quinazolin-2-yl) - (4-p-perazin-1-yl-phenyl) -amine; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-hydroxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; 2-Amino-1-. { 4- [4- (8-isopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; 2-Amino-1-. { 4- [4- (7-hydroxy-8-isopropyl-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; 2-Amino-1-. { 4- [4- (8-Cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -4-methyl-pentan-1-one; íá.? É? É * hÁ¿? i * n..t .. ». -f? Ü i... ..,. -.,. ,,.: .-,,? iíi i¡ ^ AMé¿ & * sÍgÍm¡ ^^ á £ £ i "* 2 Amino-1 - { 4- [4- (8-cyclopentyl-7-hydroxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -4-methyl-pentan-1-one; -Amino-1- {4-f4- (8-isopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -4-methyl-pentan-1-one; 2-Amino-1- { 4- [4- (7-hydroxy-8-? -propyl-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -4-methyl-pentan-1 -one; N- (4- { 4- [4- (8-cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl.} -4-oxo-butyl) -acetamide: N- (4- { 4- [4- (8-isopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl.} -4-oxo-butyl) -acetamide: N- (4- { 4- [4- (7-Hydroxy-8-isopropyl-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl.} -4-oxo-butyl) -acetamide: 8-lsopropyl-2- (pyridin-4-ylamino) -quinazolin-7-ol; (8-lsopropyl-7-methoxy-quinazolin-2-yl) -pyridin-4-l-amine; -cyclopentyl-7-methoxy-quinazoin-2-yl) -pyridin-4-yl-amine; 8-cyclopentyl-2- (pyridin-4-ylamino) -quinazolin-7-ol; (8-Ci) clopentyl-7-methoxy-qu? nazole? n-2-yl) - [4- (5-meth? l-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenyl] -amine; 8-Cyclopentyl-2- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -quinazolin-7-ol; (8-lsopropyl-7-methoxy-quinazolin-2-? L) - [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenyl] -amine; 8-lsopropyl-2- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -quinazolin-7-ol; [4- (3-Amino-pyrrolidin-1-yl) phenyl] - (8-cyclopentyl-7-methoxy-quinazolin-2-yl) -amine; 2- [4- (3-Amino-pyrrolidin-1-yl) -phenamine] -8-cyclopentyl-quinazolin-7-ol; [4- (3-Amino-pyrrolidin-1-yl) -phenyl] - (8-isopropyl-7-methoxy-quinazolin-2-yl) -amine; 2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -8-isopropyl-quinazolin-7-ol; (4-Fluoro-3-trifluoromethyl-phenyl) - (8-isopropyl-l-7-methoxy-quinazolin-2-yl) -amine; 2- (4-Fluoro-3-trifluoromethyl-phenylamino) -8-? -propyl-quinazolin-7-ol; tlteÍ fc ** - --- *. -i. ~? ... tM ^ "" A «t JÍ-,. s. "I -. you.fc. * M itm? ^ * - *** J ^ rjJt? At? ^ .abtá? »I» A4 l (4-Fluoro-3-trifluoromethyl-phenyl) - (8-cyclopentyl-7-methoxy-quinazolin-2) -yl) -amine; 2- (4-Fluoro-3-trifluoromethyl-phenylamino) -8-cyclopentyl-quinazolin-7-ol; N-. { 1- [4- (8-Cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -pyrrolidin-3-yl} -acetamide; N-. { 1- [4- (8-Cyclopentyl-7-hydroxy-quinazolin-2-ylamino) -phenyl] -pyrrolidin-3-yl} -acetamide; N-. { 1- [4- (8-lsopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -pyrrolidin-3-yl} -acetamide; N-. { 1- [4- (8-lsopropyl-7-hydroxy-quinazolin-2-ylamino) -phenyl] -pyrrolidin-3-yl} -acetamide; 1-. { 4- [4- (8-lsopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; 1-. { 4- [4-Hydroxy-8-isopropyl-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; . { 4- [4- (8-Cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -pyrrolidin-2-yl-methanone; . { 4- [4- (8-Cyclopentyl-7-hydroxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -pyrrolidin-2-yl-ethanone; 1-. { 4- [4- (8-Cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; 1-. { 4- [4- (8-Cyclopentyl-7-hydroxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; . { 4- [4- (8-lsopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -pyrrolidin-2-yl-methanone; . { 4- [4- (7-Hydroxy-8-isopropyl-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -pyrrolidin-2-yl-methanone; 2-Amino-1-. { 4- [4- (8-isopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 2-Amino-1-. { 4- [4- (7-hydroxy-8-isopropyl-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-hydroxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 1-. { 4- [4- (8-Cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 1 -. { 4- [4- (8-lsopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1 -one; 1-. { 4- [4- (7-Hydroxy-8-isopropyl-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 8-lsopropyl-2-phenylamino-5,6-dihydro-quinazolin-7-ol; (8-lsopropyl-7-methoxy-5,6, -dihydro-quinazolin-2-yl) -phenylamine; 8-lsopropyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) -phenyl-amine; 8-Cyclopentyl-2-phenylamino-5,6-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) -phenyl-amine; 8-Cyclopentyl-2-phenylamino-5,8-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) -phenyl-amine; 8-lsopropyl-2- (4-pyrrolidin-1-yl-phenylamino) -5,6-dihydro-quinazolin-7-ol; (8-lsopropyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) - (4-pyrrolidin-1-yl-phenyl) -amine; 8-lsopropyl-2- (4-pyrrolidin-1-yl-phenylamino) -5,8-dihydro-quinazolin-7-ol; (8-lsopropyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) - (4-pyrrolidin-1-yl-phenyl) -amine; 8-Cyclopentyl-2- (4-pyrrolidin-1-yl-phenylamino) -5,6-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) - (4-pyrrolidin-1-yl-phenyl) -amine; 8-Cyclopentyl-2- (4-pyrrolidin-1-yl-phenylamino) -5,8-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) - (4-pyrrolidin-1-yl-phenyl) -amine; 8-lsopropyl-2- (4-piperazin-1-yl-phenylamino) -5,6-dihydro-quinazolin-7-ol; (8-lsopropyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) - (4-piperazin-1-yl-phenyl) -amine; 8-lsopropyl-2- (4-piperazin-1-yl-phenylamino) -5,8-dihydro-quinazolin-7-ol; (8-lsopropyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) - (4-piperazin-1-yl-phenyl) -amine; 8-Cyclopentyl-2- (4-piperazin-1-yl-phenylamino) -5,6-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) - (4-piperazin-1-yl-phenyl) -amine; 8-Cyclopentyl-2- (4-piperazin-1-yl-phenylamino) -5,8-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) - (4-piperazin-1-yl-phenyl) -amine; 2- (4-Fluoro-3-methyl-phenylamino) -8-isopropyl-5,6-dihydro-quinazolin-7-ol; (4-Fluoro-3-methyl-phenyl) - (8-isopropyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) -amine; 2- (4-Fluoro-3-methyl-phenylamino) -8-isopropyl-5,8-dihydro-quinazolin-7-ol; (4-Fluoro-3-methyl-phenyl) -8-isopropyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) -amine; 8-Cyclopentyl-2- (4-fluoro-3-methyl-phenylamino) -5,6-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) - (4-fluoro-3-methyl-phenyl) -amine; i ii "11 i1i? l? n? i? tl? íMMr ^^ s - ^ 'aA ^ i * ^ ri L ^ 8-Cyclopentyl-2- (4-fluoro-3-methyl-phenylamino) -5, 8-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) - (4-fluoro-3-methyl-phenyl) -amine; 8-lsopropyl- 2- (pyridin-4-ylamino) -5,6-dihydro-quinazolin-7-ol; (8-lsopropyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) -pyridin-4-yl- amine; 8-lsopropyl-2- (pyridin-4-ylamino) -5,8-dihydro-quinazolin-7-ol; (8-lsopropyl-7-methoxy-5,8-dihydro-quinazole? n-2-yl; ) -pyridin-4-yl-amine; 8-Cyclopentyl-2- (pyridin-4-ylamino) -5,6-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,6-dihydro) -quinazolin-2-yl) -pyridin-4-yl-amine; 8-Cyclopentyl-2- (pyridin-4-ylamino) -5,8-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7) -methoxy-5,8-dihydro-quinazolin-2-yl) -pyrridin-4-ylamine; 2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -8-isopropyl-5, 6-dihydro-quinazolin-7-ol; [4- (3-Amino-pyrrolidin-1-yl) -phenyl] - (8-isopropyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) - amine; 2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -8 -isopropyl-5,8-dihydro-quinazolin-7-ol; [4- (3-Amino-pyrrolidin-1-yl) -phenyl] - (8-isopropyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) -amine; 2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-5,6-dihydro-quinazolin-7-ol; [4- (3-Amino-pyrrolidin-1-yl) -phenyl] - (8-cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) -amine; 2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-5,8-dihydro-quinazolin-7-ol; [4- (3-Amino-pyrrolidin-1-yl) -phenyl] - (8-Cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) -amine; 8-lsopropyl-2- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -5,6-dihydro-quinazolin-7-ol; (8-lsopropyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) - [4- (5-methyl-hexahydro-pyrrolo [3,4-c.] Pyrrol-2-yl) - phenyl [-amine; 8-lsopropyl-2- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -5,8-dihydro-quinazolin-7-pl; (8-lsopropyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) - [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenyl] - amine; 8-Cyclopentyl-2- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -5,6-dihydro-quinazolin-7-ol; '- "I; (|« Cyclopentyl-7-methoxy-5,6-d? -hydro-quinazolin-2-yl) - [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrole - 2-yl) -phenyl] amine; 8-Cyclopentyl-2- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -5 , 8-dihydro-quinazolin-7-ol; 5 (8-Cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) - [4- (5-methyl-hexahydro-pyrrolo [3,4-] c] pyrrol-2-yl) -phenyl] amine; 1-. {4- [4- (7-Hydroxy-8-isopropyl-l, 6,6-dihydro-quinazolin-2-ylamino) -phenyl] - piperazin-1-yl.}.-ethanone; 1- { 4- [4- (8-lsopropyl-7-methoxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1- Figure imgf000014_0001 Figure imgf000018_0001 Figure imgf000018_0001 Figure imgf000032_0001 Figure imgf000018_0001 Figure imgf000032_0002 -etanone; 0 1-. {4- [4- (8-lsopropyl-7-methoxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -ethanone; 1- { 4- [4- (8-Cyclopentyl-7-hydroxy-5,6-d? -hydro-qu? Nazolin-2-ylamino) -phenyl] -piperazin-1-yl}. ethanone; 1- {4- [4- (8-Cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - ethanone; -. { 4- [4- (8-Cyclopentyl-7-hydroxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - ethanone; 1-. { 4- [4- (8-Cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - ethanone; 1-. { 4- [4- (7-Hydroxy-8-isopropyl-l, 6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-0 1-one; 1-. { 4- [4- (8-lsopropyl-7-methoxy-5,6-d? Hydro-quinazolin-2-ylamide) -phenyl] -piperazin-1-yl} -propan-1-one; 1-. { 4- [4- (7-Hydroxy-8-isopropyl-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 5 1-. { 4- [4- (8-lsopropyl-7-methoxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 1-. { 4- [4- (8-Cyclopentyl-7-hydroxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 1-. { 4- [4- (8-Cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 1-. { 4- [4- (8-Cyclopentyl-7-hydroxy? -5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 1-. { 4- [4- (8-Cyclopentyl-7-methoxy-5,8-dihydro-qu? Nazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 2-Amino-1-. { 4- [4- (7-hydroxy-8-isopropyl-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - 3-methyl-butan-1-one; 2-Amino-1-. { 4- [4- (8-? -propyl-7-methoxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -1-yl} -3-methyl-butan-1-one; 2-Amino-1-. { 4- [4- (7-hydroxy-8-isopropyl-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - 3-methyl-butan-1-one; 2-Amino-1-. { 4- [4- (8-isopropyl-7-methoxy-5,8-d? Hydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - 3-methyl-butan-1-one; 2-Amino-1. { 4- [4- (8-Cyclopentyl-7-hydroxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -3-methyl-butan-1 -one; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-methoxy? -5,6-d? Hydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -3-methyl-butan-1-one, 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-hydroxy-5,8-d-hydroquinoline-2-ylamino) -phenyl] -piperazin-1-yl} -3-methyl-butan-1-one; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -3-methyl-butan-1 -one; 2-Amino-1-. { 4- [4- (7-hydroxy-8-isopropyl-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - 4-methyl-pentan-1 -one; 2-Amino-1-. { 4- [4- (8-isopropyl-7-methoxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - 4-methyl-pentan-1-one; 2-Amino-1-. { 4- [4- (7-hydroxy? -8-isoprop? L-5,8-d? Hydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - 4-methyl-pentan-1 -one; % '2-Amino-1-. { 4- [4- (8-isopropyl-7-methoxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - 4-methyl-pentan-1 -one; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-hydroxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -4-methyl-pentan-1 -one; 5 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -4-methyl-pentan-1 -one; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-hydroxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -4-methyl-pentan-1 -one; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} il} -4-methyl-pentan-1-one; 2-Amino-1-. { 4- [4- (7-hydroxy-8-isopropyl-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - Etanone; 2-Amino-1-. { 4- [4- (8-isopropyl-7-methoxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - ethanone; 5 2-Amino-1-. { 4- [4- (7-hydroxy-8-isopropyl-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - ethanone; 2-Amino-1-. { 4- [4- (8-isopropyl-7-methoxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - ethanone; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-hydroxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} il} -etanone; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-hydroxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; 5 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; (4-Fluoro-3-methyl-phenyl) - (8-isopropyl-7-methoxy-quinazolin-2-yl) -amine; 2- (4-Fluoro-3-methyl-phenylamino) -8-isopropyl-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - (4-fluoro-3-methyl-phenyl) -amine; 8-Cyldpentyl-2- (4-fluoro-3-methyl-phenylamino) -quinazolin-7-ol; (3-Chloro-4-fluoro-phenyl) - (8-isopropyl-7-methoxy-quinazolin-2-yl) -amine; 2- (3-Chloro-4-fluoro-phenylamino) -8-isopropyl-quinazolin-7-ol; (3-Chloro-4-fluoro-phenyl) - (8-cyclopentyl-7-methoxy-quinazolin-2-yl) -amine; 2- (3-Chloro-4-fluoro-phenylamino) -8-cyclopentyl-quinazolin-7-ol; (3,4-Difluoro-phenyl) - (8-isopropyl-7-methoxy-quinazolin-2-yl) -amine; 2- (3,4-Difluoro-phenylamino) -8-isopropyl-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) -3,4-difluoro-phenyl) -amine; 8-Cyclopentyl-2- (3,4-difluoro-phenylamino) -quinazolin-7-ol; (3-Fluoro-4-piperazin-1-yl-phenyl) - (8-isopropyl-7-methoxy-quinazolin-2-yl) -amine; 2- (3-Fluoro-4-piperazin-1-yl-phenylamino) -8-isopropyl-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - (3-fluoro-4-piperazin-1-yl-phenyl) -amine; 8-Cyclopentyl-2- (3-fluoro-4-piperazin-1-yl-phenylamino) -quinazolin-7-ol; [4- (3-Amino-pyrrolidin-1-yl) -3-fluoro-phenyl] - (8-isopropyl-7-methoxy-quinazolin-2-yl) -amine; 2- [4- (3-Amino-pyrrolidin-1-yl) -3-fluoro-phenylamino] -8-isopropyl-quinazolin-7-ol; [4- (3-Amino-pyrrolidin-1-yl) -3-fluoro-phenyl] - (8-cyclopentyl-7-methoxy-quinazolin-2-yl) -amino; 2- [4- (3-Amino-pyrrolidin-1-yl) -3-fluoro-phenylamino] -8-cyclopentyl-quinazolin-7-ol; . { 3-Fluoro-4- [4- (3-morpholin-4-yl-propyl) -piperidin-1-yl] -phenyl} - (8-isopropyl-7-methoxy-quinazolin-2-ylamine; 2- {3-fluoro-4- [4- (3-morpholin-4-yl-propyl) -piperidin-1-yl]] -phenylamino.} - 8-isopropyl-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) -. {3-fluoro-4- [4- (3-morpholin-4 -yl-propyl) -piperidin-1-yl] -phenyl} -amine; 8-Cyclopentyl-2-. {3-fluoro-4- [4- (3-morpholin-4-yl-propyl) ) -piperidin-1-yl] -phenylamino.}. -quinazolin-7-ol; (8-lsopropyl-7-methoxy-quinazolin-2-yl) - { 4- [4- (3-morpholin-4 -yl-propyl) -piperidin-1-yl] -phenyl.} -amine; 8-lsopropyl-2- { 4- [4- (3-morpholin-4-yl-propyl) -piperidin-1- il] -phenylamino.}. -quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - { 4- [4- (3-morpholin-4-yl-propyl) - piperidin-1-yl] -phenyl.} - amine; «8 CiGlopentil-2-. { 4- [4- (3-morpholin-4-yl-propyl) -piperidin-1-yl] -phenylamino} -quinazolin-7-ol; (8-lsopropyl-7-methoxy-quinazolin-2-yl) -. { 4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl} -amine; 8-lsopropyl-2-. { 4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenylamino} -quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) -. { 4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenyl} - amine; 8-Cyclopentyl-2-. { 4- [4- (3-piperazin-1-yl-propyl-1) -piperidin-1-yl] -phenylamino} -quinazolin-7-ol; . { 3-Chloro-4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenyl} - (8-isopropyl-7-methoxy-quinazolin-2-yl) -amine; 2-. { 3-Chloro-4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenylamino} -8-isopropyl-quinazolin-7-ol; . { 3-Chloro-4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenyl} - (8-cyclopentyl-7-methoxy-quinazolin-2-yl) -amine; 2-. { 3-Chloro-4- [4- (3-piperazin-1-yl-propyl) -pipoeridin-1-yl] -phenylamino} -8-cyclopentyl-quinazolin-7- ol; (3-Fluoro-4- { 4- [3- (1 H-tetrazol-5-yl) -propyl] -piperidin-1-yl.} - phenyl) - (8-isopropyl-7-methoxy) quinazolin-2-yl) -amine; 2- (3-Fluoro-4- { 4- [3- (1 H -tetrazol-5-yl) -propyl] -piperidin-1-yl.} - phenylamino) -8-isopropyl-quinazolin-7 - ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - (3-fluoro-4-. {4- [3- (1 H-tetrazol-5-yl) -propyl] -piperidin-1-yl} .}. -phenyl) -amine; 8-Cyclopentyl-2- (3-fluoro-4-. {4- [3- (1 H -tetrazol-5-yl) -petroyl] -piperidin-1-yl] -phenylamino) -quinazolin-7 -ol; (4- { 4- [3- (3-Amino-pyrrolidin-1-yl) -propyl] -piperidin-1-yl}. -3-chloro-phenyl) - (8-isopropyl-7-methoxy) - quinazolin-2-yl) -amine; 2- (4- { 4- [3- (3-Amino-pyrrolidin-1-yl) -propyl] -piperidin-1-yl.} - 3-chloro-phenylamino) -8-isopropyl-quinazolin- 7-ol; (4- { 4- [3- (3-Amino-pyrrolidin-1-yl) -propyl] -piperidin-1-yl}. -3-chloro-phenyl) - (8-cyclopentyl-7-methoxy - quinazolin-2-yl) -amino; "" a- 4-. { 4- [3- (3-Amino-pyrrolidin-1-yl) -propyl] -piperidin-1-yl} 3-chloro-phenylamino) -8-cyclopentyl-quinazolin-7-ol; (4- {4- [3- (3-Amino-pyrrolidin-1-yl) -propyl] -piperidin-1-yl} - phenyl) - (8-isopropyl-7-methoxy-quinazolin-2) -yl) -amine; 2- (4- { 4- [3- (3-Amino-pyrrolidin-1-yl) -propyl] -piperidin-1-yl}. Phenylamino) -8-isopropyl-quinazolin-7- ol; (4- { 4- [3- (3-Amino-pyrrolidin-1-yl) -propyl] -piperidin-1-yl}. Phenyl) - (8-cyclopentyl-7-methoxy-quinazolin-2) -yl) -amine; 2- (4- { 4- [3- (3-Amino-pyrrolidin-1-yl) -propyl] -piperidin-1-yl} -phenylamino) -8-cyclopentyl-quinazoli? - 7-ol; (8-lsopropyl-7-methoxy-quinazolin-2-yl) -. { 4- [4- (4-methoxy-phenyl) -piperazin-1-yl] -phenyl} -amine; 8-lsopropyl-2-. { 4- [4- (4-methoxy-phenyl) -piperazin-1-yl] -phenylamino} -quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) -. { 4- [4- (4-methoxy-phenyl) -piperazin-1-yl] -phenyl} -amine; 8-Cyclopentyl-2-. { 4- [4- (4-methoxy-phenyl) -piperazin-1-yl] -phenylamino} -quinazolin-7-ol; (8-lsopropyl-7-methoxy-quinazolin-2-yl) - [4- (3,3,4-trimethyl-piperazin-1-yl) -phenyl] -amine; 8-lsopropyl-2- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenyl] -amine; 8-Cyclopentyl-2- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -quinazolin-7-ol; 8-lsopropyl-2- [4- (3,3,4-trimethyl-piperazin-n-1-yl) -phenylamino] -quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - [4- (3,3,4-trimethyl-piperazin-1-yl) -phenyl] -amine; 8-Cyclopentyl-2- [4- (3,3,4-trimethyl-piperazin-1-yl) -phenylamino] -quinazolin-7-ol; (8-lsopropyl-7-methoxy-quinazolin-2-yl) - [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenyl] -amine; (8-Cyclopentyl-7-methoxy-quinazolin-2-? L) - (4-perhydro-1,4-diazepin-1-yl-phenyl) -amine; 8-Cyclopentyl-2- (4-perhydro-1,4-diazepin-1-yl-phenylamino) -quinazolin-7-ol; 2-. { 4- [4- (8-Cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -2,6-dimethyl-piperazin-1-yl} -ethanol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - [4- (2-methylamino-ethoxy) -phenyl] -amine; 1-. { 4- [4- (8-Cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -perhydro-1,4-diazepin-1-yl} - ethylene: 1 8-Cyclopentyl-2- [4- (3,3-dimethyl-piperazin-1-yl) -phenylamino] -quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - [4- (3,3-dimethyl-piperazin-1-yl) -phenyl] -amine; 1-. { 4- [4- (8-Cyclopentyl-7-hydroxy-quinazolin-2-ylamino) -phenyl] -perhydro-1,4-diazepin-1-yl} - ethanone; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - (4-. {4- [3- (1 H -tetrazol-5-yl) -propyl] -piperidin-1-yl}. phenyl) -amine; 8-Cyclopentyl-2- (4-. {4- [3- (1 H -tetrazol-5-yl) -propyl] -piperidin-1-yl} -phenylamino) -quinazolin-7-ol; 8-Cyclopentyl-N2- (4-piperazin-1-yl-phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-N2- [4- (4-methyl-piperazin-1-yl) -phenyl] -quinazoline-2,7-diamine; 1-. { 4- [4- (7-Amino-8-cyclopentyl-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; 8-Cyclopentyl-N2- (4-perhydro-1,4-diazepin-1-yl-phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-N2- [4- (3,3-dimethyl-p-perazin-1-yl) -phenyl] -quinazoline-2,7-diamine; 8-Cyclopentyl-N7-methyl-N2- (4-piperazin-1-yl-phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-N7-methyl-N2- [4- (4-methyl-piperazin-1-yl) -phenyl] -quinazoline-2,7-diamine; 1-. { 4- [4- (8-Cyclopentyl-7-methylamino-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; 8-Cyclopentyl-N7-methyl-N2- (4-perhydro-1,4-diazepin-1-yl-phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-N2- [4- (3,3-dimethyl-piperazin-1-yl) -phenyl] -N7-methyl-quinazoline-2,7-diamine; 8-Cyclopentyl-N7, N7-dimethyl-N2- (4-piperazin-1-yl-phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-N7, N7-dimethyl-N2- [4- (4-methyl-p-perazin-1-yl) -phenyl] -quinazoline-2,7-diamine; 1-. { 4- [4- (8-Cyclopentyl-7-dimethylamino-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl] -ethanone; 8-Cyclopentyl-N7, N7-dimethyl-N2- (4-perh-dro-1,4-diazepin-1-yl-phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-N2- [4- (3,3-dimethyl-piperazin-1-yl) -phenyl [-N7, N7-dimethyl-quinazoline-2,7-diamine; 8-Cyclopentyl-N2- (4-. {4- [3- (1 H -tetrazol-5-yl) -propyl] -piperidin-1-yl} -phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-N7-methyl-N2- (4-. {4- [3- (1 H -tetrazol-5-yl) -propyl] -piperidin-1-yl.} - phenyl) -quinazoline- 2,7-diamine; 8-Cyclopentyl-N -. { 4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenyl} -quinazoline-2,7-diamine *, 8-Cyclopentyl-N7-methyl-N2-. { 4- [4- (3-p-piperazin-1-yl-propyl) -piperidin-1-yl] -phenyl} -quinazoline-2,7-diamine; 8-Cyclopentyl-N7, N7-dimethyl-N2-. { 4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenyl} -quinazoline-2,7-diamine; (8-Cyclopentyl-7-methoxy-5-methyl-1-quinazolin-2-yl) - (4-perhydro-1,4-diazepin-1-yl-phenyl) -amine; 8-Cyclopentyl-5-methyl-2- (4-perh-dro-1,4-diazepin-1-yl-phenylamino) -quinazolin-7-ol; 2-. { 4- [4- (8-Cyclopentyl-7-methoxy? -5-methyl-quinazolin-2-ylamino) -phenyl] -2,6-dimethyl-piperazin-1-yl} - ethanol; (8-Cyclopentyl-7-methoxy-5-methyl-quinazolin-2-yl) - [4- (2-methylamino-ethoxy) -phenyl] -amine; 1-. { 4- [4- (8-Cyclopentyl-7-methoxy-5-methyl-quinazolin-2-ylamino) -phenyl] -perhydro-1,4-diazepin-1-yl} -etanone; 8-Cyclopentyl-2- [4- (3,3-dimethyl-piperazin-1-yl) -phenylamino] -5-methyl-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5-methyl-quinazolin-2-yl) - [4- (3,3-dimethyl-piperazin-1-yl) -phenyl] -amine; 1-. { 4- [4- (8-Cyclopentyl-7-hydroxy-5-hydroxy-5-methyl-quinazolin-2-ylamino) -phenyl] -perhydro-1,4-diazepin-1-yl} -etanone; (8-Cyclopentyl-7-methoxy-5-methyl-quinazolin-2-yl) - (4-. {4- [3- (1 H-tetrazol-5-yl) -propyl] -piperidin-1-yl} .}. -phenyl) -amine; 8-Cyclopentyl-5-methyl-2- (4-. {4- [3- (1 H -tetrazol-5-yl) -propyl] -piperidin-1-yl.} - phenylamino) -quinazolin- 7 -ol; 1-. { 4- [4- (8-Cyclopentyl-7-hydroxy-5-methyl-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; 1-. { 4- [4- (8-Cyclopentyl-7-methoxy-5-methyl-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; 8-Cyclopentyl-5-methyl-2- (4-piperazin-1-yl-phenylamino) -quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5-methyl-quinazole? N-2-yl) - (4-piperazin-1-yl-phenyl) -amine; (8-Cyclopentyl-7-methoxy-5-methyl-quinazolin-2-yl) -. { 4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenyl} -amine; 8-Cyclopentyl-5-methyl-N2- (4-piperazin-1-l-phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-5-methyl-N2- [4- (4-methyl-piperazin-1-yl) -phenyl] -quinazoline-2,7-diamine; 1-. { 4- [4- (7-Amino-8-cyclopentyl-5-methyl-l-qu? Nazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; 8-Cyclopentyl-5-methyl-N2- (4-perhydro-1,4-diazepin-1-yl-phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-N2- [4- (3,3-dimethyl-piperazin-1-yl) -phenyl] -5-methyl-quinazoline-2,7-diamine; 8-Cyclopentyl-5, N7-dimethyl-N2- (4-piperazin-1-yl-methyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-5, N7-dimethyl-N2- [4- (4-methyl-piperazin-1-yl) -phenyl] -quinazoline-2,7-diamine; 1-. { 4- [4- (8-Cyclopentyl-5-methyl-7-methylamino-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - ethanone; 8-Cyclopentyl-5, N7-dimethyl-N2- (4-perhydro-1,4-diazepin-1-yl-phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-N - [4- (3,3-dimethyl-piperazin-1-yl) -phenyl] -5, N7-dimethyl-quinazoline-2,7-diamine; 10 8-Cyclopentyl-5, N7, N7-trimethyl-N2- (4-piperazin-1-yl-phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-5, N7, N7-trimethyl-N2- [4- (4-meth? L-piperazin-1-yl) -phenyl] -quinazoline-2,7-diamine; 1-. { 4- [4- (8-Cyclopentyl-7-dimethylamino-5-methyl-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - ethanone; 8-Cyclopentyl-5, N7, N7-trimethyl-N2- (4-perhydro-1,4-diazepin-1-yl-phenyl) -quinazoline-2,7-diamine; 15 8-Cyclopentyl-N2- [4- (3,3-dimethyl-piperazin-1-yl) -phenyl] -5, N7, N7-trimethyl-qulnazoline-2,7-diamine; 8-Cyclopentyl-5-methyl-N2- (4- {4- [3- (1 H-tetrazol-5-yl) -propyl] -piperidin-1-yl} -phenyl] -quinazoline-2 7- diamine: 8-Cyclopentyl-5, N7-dimethyl-N2- (4-. {4- [3- (1 H -tetrazol-5-yl) -propyl] -piperidin-1-yl}. phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-5-methyl-N2-. {4- [4- (3-piperazn-1-yl-propyl) -piperidin-1-yl} ] -phenyl.}. -quinazoline-2J-diamine; 8-Cyclopentyl-5, N7-dimethyl-N2- { 4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl} ] phenyl.}. -quinazoline-2,7-diamine and 8-Cyclopentyl-5, N7, N7-trimethyl-N2- { 4- [4- (3-piperazin-1-yl-propyl) -piperidine- 1-yl] -phenyl.} - 25-quinazoline-2,7-diamine.
Additional preferred embodiments of the present invention include those of Examples 1-10, 85, 54 and 57 infra.
The compounds of Formula I wherein R 2 is alkyl, R 5 and R 6 are hydrogen are especially useful as intermediates that lead to compounds that display good inhibitory activity against cyclin-dependent kinases. Other especially useful intermediates that lead to compounds that display good inhibitory activity against cyclin-dependent kinases are compounds of Formula III wherein R1, R2, R5 and R6 are as defined above and X is oxygen or halogen, Particularly useful intermediates are those wherein R2 is alkyloxy, R5 is hydrogen or alkyl, R6 is hydrogen and R8 is oxygen or chlorine or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
The present invention also describes processes for preparing the compounds of Formula I, II and III. These methods are described by the non-limiting examples described below.
Unless otherwise specified, the following definitions are used throughout the description.
"Alkyl" means a branched or linear hydrocarbon radical having 1 to 10 carbon atoms (unless stated otherwise) and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec. -butyl, isobutyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl and the like. "Halo" includes fluorine, chlorine, bromine and iodine. , *? > .- * • * < • ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• il, 2-ethenyl butyl, 3-hexen-1-yl and the like.
"Alkynyl" means branched and linear hydrocarbon radicals having from 2 to 6 carbon atoms and a triple bond and includes ethinyl, 3-butin-1-yl, propinyl, 2-butin-1-yl, 3-pentyin-1 -il and the like.
"Cycloalkyl" means a monocyclic or polycyclic hydrocarbyl group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbomyl, cyclohexyl and cyclopentyl. Said groups can be substituted with groups such as hydroxy, keto and the like. Also included are rings in which 1 to 3 heteroatoms replace the carbons. Such groups are called "heterocyclic" which means a cycloalkyl group which also supports at least one heteroatom selected from O, S or NR2, examples being unsubstituted or substituted by oxirane, pyrrolidinyl, piperidyl, tetrahydropyran, piperazinyl, acylpiperazinyl, pyrrolidinyl and morpholine.
"Alkoxy" refers to the aforementioned alkyl groups that are bonded through oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy and the like. In addition, alkoxy refers to polyethers such as -0- (CH2) 2-0-CH3 and the like.
"Alkanoyl" groups are alkyls bonded through a carbonyl, ie C ^ Cs-CÍO).
"Acyl" means an aryl or alkyl (Ar) group bonded through a carbonyl group, ie R-C (O) -. For example, acyl includes a C6-C6 alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by NR4R5 or a carboxyl or heterocyclic group. Typical acyl groups include acetyl, benzoyl and the like. _.M »J¡. - **? . - *. ^ * ^ * .. ^. The alkyl, alkenyl, alkoxy and alkynyl groups described above are optionally substituted, preferably by 1 to 3 groups selected from NR4R5, phenyl, substituted phenyl, thio alkyl, C6 alkoxy, hydroxy, carboxy, C-C 1 alkoxycarbonyl, halo, nitrile, cycloalkyl and a 5- or 6-membered carbocyclic ring or a heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen and sulfur. "Substituted nitrogen" means nitrogen that supports C6 alkyl or (CH2) nPh where n is 1, 2 or 3. Polyhalo or perhalo substitution may also occur.
Examples of substituted alkyl groups include 2-aminomethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl. , pentafluoroethyl, 3-morpholinopropyl, piperazinylmethyl and 2- (4-methylpiperazinyl) ethyl.
Examples of the substituted alkynyl groups include 2-methoxyethynyl, 2-ethylsulfanylethynyl, 4- (1-piperazinyl) -3- (butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro- 3-butynyl, 4-cyclobutyl-4-hexenyl and the like.
Typical substituted alkoxy groups include aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxyproproxy, 6-carboxyhexyloxy and the like.
In addition, examples of the substituted alkyl, alkenyl and alkynyl groups include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl, 4-morpholinobutyl, 4-tetrahydropyridinylbutyl, 3-imidazolid? N-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl and the like.
The terms "Ar" and "aryl" refer to substituted and unsubstituted aromatic groups. Heteroaryl groups having from 4 to 9 ring atoms, from 1 to 4 of which are independently selected from the group consisting of O, S and N. Preferred heteroaryl groups have 1 or 2 heteroatoms in the 5 or 6 membered aromatic ring. The mono or bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl. The heteroaryl groups and, * ' Typical aryl include phenyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl. , pyrrole, pyrazole, imidazole, thiazole and the like.
Preferred Ar groups are phenyl and phenyl substituted by 1, 2 or 3 groups independently selected from the group consisting of alkyl, alkoxy, thio, thiolalkyl, hydroxy, -COOR7, amino of the formula -NR4R5 and T (CH2) mQR4 or T (CH2) mC02R4 where m is 1 to 6, T is O, S, NR4, N (0) R4, NR4R6Y or CR4R5, Q is O, S, NR5, N (0) R5 or NR5R6Y where R4 and R5 as described above and R7 is alkyl or substituted alkyl, for example, methyl, triclproethyl, diphenylmethyl and the like. The alkyl or alkoxy groups can be substituted as described above. For example, typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy and alkoxyalkyl.
The symbol 2"-" means a link. The term "patient" means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep and pigs.
The compounds of the present invention can exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, solvated forms, including hydrated forms, are equivalent to solvated forms and are within the scope of the present invention.
The compounds of formulas I, II and III are capable of further forming both pharmaceutically acceptable formulations comprising salts, esters, amides and prodrugs. As used herein, the term "pharmaceutically acceptable salts, esters, amides, and prodrugs" refers to those carboxylated salts, amino acid addition salts, esters, , * *% Anegas and prodrugs of the compounds of the present invention that are within the scope of medical judgment, suitable for use in contact with the tissues of patients without being under toxicity, irritation, allergic response and the like, commensurable with a proportion of risk / reasonable and effective benefit for the intended use, as well as the amphoteric forms, where possible, of the compounds of the invention. The term "salts" refers to the organic and inorganic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the purification and final isolation of the compounds or by separately reacting the purified compound in its free form with an appropriate organic and inorganic acid and isolating the salt in this manner by forming and including but not limited to basic salts and / or addition acids, solvents and N-oxides of a compound of Formulas I, II and III. This invention also provides pharmaceutical formulations comprising a compound of Formulas I, II or III in conjunction with a pharmaceutically acceptable carrier, diluent or excipient thereof. All forms are within the present invention.
The pharmaceutically acceptable acid addition salts of the compounds of Formulas I, II and III include salts which form the inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroonic, phosphorus and the like, as well as the salts derived therefrom. of organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aromatic and aliphatic sulfonic acids, etc. Said salts further include sulfate, pyrosulfate, sulfite, bisulfite, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dthydrogen phosphate, metaphosphate, pyrophosphate, chlorine, bromine, iodine, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelato, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate and the like. Also contemplated are salts or amino acids such as arginate, gluconate, galacturonate and I? Sj? Mimilares, see, for example, Berge et al., "Pharmaceutical Salts," J. of Pharmaceutical Science, 1977; 66: 1-19.
The acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in a conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base forms differ from their respective salt forms in some way in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for the purposes of the present invention.
The pharmaceutically acceptable base addition salts are formed with metals or amines, such as the alkali and alkaline metal hydroxides or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of the appropriate amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine, see for example, Berge et al., Supra.
The basic addition salts of the acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
Examples of non-toxic pharmaceutically acceptable esters of the compounds of this invention include CrC6 alkyl esters wherein the alkyl group is a branched or straight chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as esters arylalkyl such as, but not limited to, benzyl. The d-C4 alkyl esters are preferred. The esters of compounds of the present invention can be prepared in accordance with conventional methods.
Examples of pharmaceutically acceptable non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C 1 -C alkyl amines and secondary dialkyl amines, wherein the alkyl groups are straight or branched chain. In the case of the secondary amines, the amine may also be in the form of a 5- or 6-membered heterocyclic containing a nitrogen atom. Amines derived from ammonia, primary C 3 alkyl amines and C C 2 dialkyl secondary amines are preferred. The amides of the compounds of the invention can be prepared in accordance with conventional methods.
The term "prodrug" refers to compounds that are rapidly transformed in vivo to produce the parent compound of the above formulas, for example, by hydrolysis in the blood. A detailed description of the prodrugs is provided in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of A.C.S. of the Symposium Series and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
A therapeutically effective amount is an amount of a compound of Formulas I, II or III which, when administered to a patient, decreases a symptom of the disease. The term "cardiovascular diseases and disorders" includes, but is not limited to arteriosclerosis, psoriasis and restenosis. Those skilled in the art have the ability to identify patients who have arteriosclerosis, psoriasis, restenosis or at risk of having arteriosclerosis or restenosis. For example, patients who are at risk of having restenosis include, but are not limited to patients who have undergone pressure angioplasty or other surgical vascular procedures.
The term "cancer" includes, but is not limited to, the following cancers: breast, ovarian, cervical, prostate, testicular, esophagus, gioblastoma, neuroblastoma, stomach, skin, ceratoacanthoma, lung, squamous cell carcinoma, adenoma of the pancreas, adenocarcinoma, thyroid, follicular carcinoma, non-differential carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, carcinoma of the liver and biliary passages, carcinoma of the kidney, myeloid diseases , lymphoid diseases, Hodgkins disease, capillary cells, oral cavity and pharynx (oral), lips, tongue, mouth, pharynx, small intestine, rectum-colon , of the large intestine, rectum, brain and central nervous system and leukemia.
The term autoimmune diseases includes, but is not limited to, inflammation, such as rheumatoid arthritis and rejections to organ transplantation.
The term kidney disease includes, but is not limited to, kidney disease, such as polycystic kidney disease.
Compounds within the scope of the present invention effectively inhibit vascular proliferation and migration of vascular smooth muscle. The method involves the inhibition of proliferation and / or migration of vascular smooth muscle by administering an effective amount of a compound of Formulas I, II or III to a subject in need of treatment.
The compounds of the present invention are useful for treating cancer (e.g., leukemia and lung, breast, prostate and skin cancers such as melanoma), cardiovascular diseases and disorders, infections, autoimmune diseases, gout , kidney disease and diseases and neurodegenerative disorders. To use a compound of the present invention to treat these indications, a patient having the indication is administered a therapeutically effective amount of a pharmaceutically acceptable composition comprising a compound of the invention.
The term "diseases and neurological disorders" includes, but is not limited to, Alzheimer's disease. The compounds within the scope of the present invention effectively inhibit the degradation of neurons. The method involves the inhibition of neural degeneration by administering an effective amount of a compound of Formulas I, II or III to a subject in need of treatment.
The compounds of the present invention can be formulated and administered in a wide variety of parenteral and oral dosage forms including rectal and transdermal administration. It will be recognized by those skilled in the art that the following dosage forms can be understood as the active component, either a compound of Formulas I, II or III or a corresponding pharmaceutically acceptable salt or solvate of a compound of Formulas I, II or lll.
A further embodiment of this invention is a pharmaceutical formulation comprising a compound of Formulas I, II or III in conjunction with a pharmaceutically acceptable carrier, diluent or excipient thereof. To prepare the pharmaceutical compositions with the compounds of the present invention, the pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, suppositories and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents or an encapsulating material.
In powders, the carrier is a finely divided solid such as talc or starch which is a mixture with the finely divided component. In tablets, the active component is mixed with the carrier having the necessary binding properties in the appropriate proportions and compacted in the desired shape and size.
* - The formulations of this invention preferably contain from about 5% to about 70% or more of the effective compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, frost, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting point wax, cocoa butter and the like . A preferred form for oral use are capsules, which includes the formulation of the active compound with the encapsulating material as a carrier that provides a capsule in which the active compound with or without other carriers, is surrounded by a carrier, which is also in association with him. Similarly, tablets and pills are included. The tablets, capsules, pills and pills can be used as solid dosage forms useful for oral administration.
For the preparation of suppositories, a wax with a low melting point, such as a mixture of fatty acid glycerides or cocoa butter, is first mixed and the active component dispersed homogeneously therein, as by agitation. The homogeneous mixture subsequently mixed is poured into molds of suitable size, allowed to cool and subsequently solidified.
Liquid form preparations include solutions, suspensions and emulsions such as water or polyethylene glycol / water solutions. For parenteral injection, the liquid preparations can be formulated in solution in aqueous polyethylene glycol solution, isotonic saline, 5% aqueous glucose and the like. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding the appropriate colorants, flavors, thickening and stabilizing agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water and mixing it with a viscous material, such as synthetic or natural gums, resins, methylcellulose, sodium carboxymethylcellulose or other well-known suspending agents.
Also included are the solid form preparations that are intended to be converted, rapidly before use to the liquid form preparations for oral administration. Said liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, binders, natural and artificial sweeteners, dispersants, thickeners, solubilizing agents and the like. Waxes, polymers, microparticles and the like can be used to prepare sustained release dosage forms. Also, osmotic pumps can be used to release the active compound uniformly over a prolonged period of time.
The pharmaceutical preparations of the invention are preferably in the unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the active compound. The unit dosage form may be a packaged preparation, the package containing discrete quantities of the preparation, such as packed tablets, capsules and powders in ampoules or injections. Also, the unit dosage form may be a capsule, tablet, lozenge or troche on its own or may be the appropriate number of any of these in the packaged form.
The therapeutically effective dose of a compound of Formulas I, II or III will generally be from about 1 mg to about 100 mg / kg per body weight per day. Typical doses for adults will be from about 50 mg to about 800 mg per day. The amount of the active component in a unit dose preparation can be varied or adjusted from about 0.1 mg to about 500 mg, preferably about 0.5 mg to 100 mg in accordance with the particular application and potency of the active compound. The composition may also, if desired, contain other compatible therapeutic agents. A subject in need of treatment with a compound of Formulas I, II or III is administered in a dose of about 1 to about 500 mg per day, either alone or in multiple doses over a period of 24 hours.
", The components of the present invention are capable of binding to and inhibiting the activity of protein kinases that have the ability to phosphorylate other proteins such as cdks. Cdks form complexes with cyclins and these complexes phosphorylate the key proteins that regulate the progression of cells through the cell cycle (Meijer L., Progress in Cell Cycle Research, 1995; 1: 351-363). The compounds of this invention inhibit this phosphorylation and therefore can be used as anti-proliferative agents for the treatment of cancer and / or restenosis and other proliferative diseases and as anti-neural degenerative agents for the treatment of neural degenerative diseases such as Alzheimer disease.
Due to their inhibitory activity against cdks and other kinases, the components of the present invention are also useful as search tools to study the mechanism of action of those kinases, both in vivo and in vitro.
While the forms of the invention in this document constitute the currently preferred embodiments, many others are possible. No attempt is made to mention all possible equivalent forms or ramifications of the invention. It is understood that the terms used are only descriptive and not limiting and those skilled in the art will understand that various changes can be made without departing from the spirit and scope of the invention.
The components of Formulas I, II and III can be prepared in accordance with the syntheses set forth in Scheme 1, inflates. Although this scheme sometimes indicates the exact structures, those skilled in the art will appreciate that the methods broadly applied to the analogous compounds of Formulas I, II and III give appropriate consideration to protection and deprotection or reactive functional groups by the methods standards of the technique of organic chemistry. For example, hydroxy groups to prevent unwanted side reactions, generally necessary to convert to ethers or esters during chemical reactions at other sites in the molecule. The hydroxy protecting group is rapidly removed to provide the free hydroxy group. Amino groups and groups of carboxylic acid are similarly derived to protect them against unwanted side reactions. Typical protection groups and methods for joining and penetrating them are described extensively in Greene and Wuts in Protective Groups in Organic Synthesis, John Wiley and Sons, New Cork, (2nd Ed. 1991) and McOmie, Protective Groups in Organic Chemistry, Plenum Press, New York, 1973.
Scheme 1 describes a typical method for the preparation of the quinazoline compounds of the invention. ufa im ^ ?? i, ** - ... -.-! .- * Mi --- t. * i: a. **? ...?, ¿OÉÍJttí -ill? * '. i &*. SSl4t¡ ±.
Scheme 1 Schemes 2 and 3 Scheme 2 (16) Scheme 3 (ref Bernato? v7 el al Telrahedron Le 1993, J-, 3389) (2) TFA (17) EXAMPLES The following examples are for illustrative purposes and are not intended to be limiting of the invention in any way. Those skilled in the art will appreciate that various variations and modifications may be made without departing from the scope and spirit of the invention.
EXAMPLE 1 1.5-Dimethoxy-cyclohexa-1,4-diene To a solution containing 1,3-methoxybenzene (10 g), dry THF (15 ml) and tBuOH (15 ml) was added to distilled ammonia (ca 250 ml) ). To the reaction mixture, lithium wire (1.5 g) was added in small portions and the deep blue solution was stirred for 3 hours. The reaction mixture was decolorized by dropwise addition of methanol. The ammonia was evaporated at room temperature. To the residue, a solution of ammonium chloride was added, subsequently the product was extracted with hexane (3 x 120 ml). The extracts were washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave the title compound as a clear liquid (9.5 g). 1 H NMR (CDCl 3): d 2.7-2.9 (m, 4 H, 2 x CH 2), 3.58 (s, 6 H, 2 X OCH 3), 4.66 (t, 2 H, olefinic).
EXAMPLE 2 6-lsopropyl-1,5-djmethoxy-cyclohexa-1,4-dione To a solution of 1,5-dimethoxy-cyclohexa-1,4-diene (7 g, 50 mmol) in dry THF (140 ml) was added drip into a nBuli solution (2.5 M, 30 ml) in hexane at -20 ° C. The orange colored reaction mixture was stirred for 0.5 h at -20 ° C, then drip isopropyl iodide (17 g, 100 mmol). The reaction mixture was stirred for 1 hour, while the temperature was raised to 0 ° O The excess of nBuLi was carefully destroyed with methanol. (140 ml) of cold water was added to the reaction mixture, then the product was extracted with ethyl acetate (3 x 70 ml). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the title compound as a light yellow liquid (8.5 g, 93.4%). H NMR (CDCl 3): d 0.90 (d, 6H, 2X CH 3), 2.1 (m, 1 H, CH), 2.76 (m, 3H, CH 2 and CH), 3.53 (s, 6H, 2 x OCH 3), 4.73 (t, 2H, olefinic).
EXAMPLE 3 2-lsopropyl-3-methoxy-cyclohex-3-enone To a solution of 6-isopropyl-1,5-dimethoxy-cyclohexa-1,4-dione (7 g) in methanol (50 ml) was added 2.5% of hydrochloric acid dropwise (10 ml) at 0 ° C. The reaction mixture was stirred for 45 minutes, then diluted with water on ice (30 ml). The product was extracted with ether (3 x 70 ml). The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded the title compound as a pale yellow oil (6 g, 93%).
EXAMPLE 4 2-lsopropyl-3-methoxy-cyclohex-2-enone To a solution of 2-isopropyl-3-methoxy-cyclohex-3-enone (6 g) in dry THF (120 ml), sodium methoxide was added ( 1.5 g) in portions at room temperature. After stirring at room temperature for 1.5 hours, the reaction mixture was cooled in an ice bath and neutralized with a 10% sodium hydrogen phosphate solution. The organic layer was separated, then the aqueous layer was extracted with ethyl acetate (2 x 50 ml). The combined organic extracts were washed with brine, then dried over sodium sulfate. The solvent was removed under reduced pressure and the resulting product was purified on a column of silica gel (Hex: EtOAc) to give the title compound as a yellow liquid (5.4 g, 90%). 1 H NMR (CDCl 3): d 1.09 (d, 6 H, 2 X CH 3), 1.95 (m, 2 H, CH 2), 2.31 (t, 2 H, CH 2), 2.54 (t, 2 H, CH 2), 3.2 (m, 1 H , CH), 3.78 (s, 3H, OCH3).
EXAMPLE 5 6-Hydroxymethylene-2-isopropyl-3-methoxy-cyclohex-2-enone To a suspension of sodium hydride (3.6 g, 60% suspension, 90 mmol) in benzene (100 ml), a mixture of ethyl (12.5 g) and 2-isopropyl-3-methoxy-cyclohex-2-enone (5 g, 29.7 mrnol) in benzene was added dropwise at 5 ° C. The reaction mixture was stirred at ice temperature for 1 hour and at room temperature for 18 hours. The reaction mixture was cooled in an ice bath and 10% sodium phosphate solution (200 ml) was added dropwise. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 50 ml). The organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the resulting product was purified on a column of silica gel (Hex: EtOAc) to give the title compound as a thick viscous liquid (3.5 g, 60%). 1 H NMR (CDCl 3): d 1.15 (d, 2 x CH 3), 2.35-2.6 (m, 4 H, 2 x CH 2), 3.15 (m, 1 H, CH), 3.8 (s, 3 H, OCH 3), 7.17 (d, 1H, = CHOH).
EXAMPLE 6 8-lsopropyl-7-methoxy-quinazolin-2-ylamine A mixture of 6-hydroxymethylene-2-isopropyl-3-methoxy-cyclohex-2-enone (3.5 g) and guanidine carbonate (7 g) in DMF ( 40 ml) was heated at 150 ° C for 4 hours. The solvent was removed under reduced pressure, then ice water was added to the residue. The product was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with water, then brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a crude mixture of dihydroquinazolines (4 g). The dihydroquinazolines were aromatized for the title compound by heating them in nitrobenzene (70 ml) at 150 ° C in the presence of 10% Pd-C (400 mg) for 3 days. The catalyst was removed by filtration, then concentrated and the resulting product was purified on a column of silica gel (Hex: EtOAc) to give the title compound as a grayish solid (2.1 g, 54.2%), mp 112-113 ° C; 1 H NMR (CDCl 3): d 1.38 (d, 6 H, 2 x CH 3), 3.95 (s, 3 H, OCH 3), 4.24 (m, 1 H, CH), 5.0 (br s, 2 H, NH 2), 7.02 (d, 1 H, Ar-H, J = 9 Hz), 7.55 (d, 1 H, Ar-H, J = 9 Hz), 8.87 (s, 1H, Ar-H); MS m / z 218.05; C12H15N30 (M ++ 1).
EXAMPLE 7 8-lsopropyl-7-methoxy-1H-quinazolin-2-one H solution of 2-amino-7-methoxy-8- (2-propyl) quinazole (1.3 g) in acid (50 ml), sodium nitrite solution (2.6 g in 10 ml of water) was added dropwise at 0o C. The reaction mixture was stirred at 0 ° C for 1 hour and at room temperature for 18 hours. The reaction mixture was cooled in an ice bath and neutralized with a 30% ammonia solution. The product was extracted with ethyl acetate (3 x 50 ml), the combined organic extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound as a grayish solid (1.2 g, 92.3%), mp 188-190 ° C (decom); 1 H NMR (CDCl 3): d 1.32 (d, 6 H, 2 x CH 3), 3.44 (m, 1 H, CH), 3.97 (s, 3 H, OCH 3), 6.88 (d, 1 H, Ar H, J = 8.8 Hz) , 7.59 (d, 1 H, Ar-H, 8.8 Hz), 9.0 (s, 1 H, Ar-H), 9.1 (brs, 1 H, NH). EXAMPLE 8 2-Chloro-8-isopropyl-7-methoxy-auinazoline 7-Methoxy-8- (2-propyl) quinazole-2 (1 H) -one (1.2 g) was dissolved in 25 ml of phosphorus oxychloride and The resulting reaction mixture was heated at 110 ° C for 2 hours. The excess of POCI3 was removed under reduced pressure. To the ethyl acetate residue was added cold water and the product was extracted with ethyl acetate (3 x 50 ml). The combined organic extract was washed with brine, dried over anhydrous sodium sulfate and concentrated to give the title compound. This was purified on a column of silica gel (Hexane.ethyl acetate), a grayish solid (780 mg, 60%), mp 135-137 ° C; 1 H NMR (CDCl 3): d 1.41 (d, 6H, 2X CH 3), 4.02 (s, 3 H, OCH 3), 4.33 (m, 1 H, CH), 7.8 (d, 1 H, Ar-H, J = 9 20 Hz), 9.1 (s, 1 H, Ar-H).
EXAMPLE 9 (8-lsopropyl-7-methoxy-qu? Nazolin-2-yl) -phenyl-amine A mixture of 2-chloro-7-methoxy-8- (2-propyl) quinazoline (100 mg, 0.42 mmol) and Aniline (120 mg, 1.29 mmol) in acetonitrile (3 ml) was heated at 80 ° C for 18 hours in a sealed tube. The solvent was removed under reduced pressure, 5% of the sodium carbonate solution was added to the residue. The product was extracted with ethyl acetate (3 x 25 ml). The combined organic extract was washed with brine, dried (Na2SO4) and concentrated. The product was purified on a silica column § to give the title compound as a grayish solid. (95 mg, 76.3%), mp 172-173 ° C; 1H NHR (ODCI3): d 1.46 (d, 6H, 2 x CH3), 3.97 (s, 3H, OCH3), 4.33 (m, 1 H, CH), 7.0-7.1 (m, 2H, Ar-H), 7.58 (d, 1H, Ar-H), 7.85 fti, 2H, Ar-H), 8.93 (s, 1 H, Ar-H); MS m / zx C18H19N30 294.21 (M ++ 1); Analysis Cale. C, 73.7; H, 6.53; N, 14.32. Found: C, 73.8; H, 6.83; N, 14.59.
EXAMPLE 10 6-Cyclopentyl-1, 5-dimethoxy-cyclohexa-1,4-dione To a solution of 2,5-dihydro-1,3-dimethoxybenzene (9.88 g, 70 mmol) in dry THF (150 ml) was added drip in nBuli solution (2.5 M, 42.4 ml) in hexane at -20 ° C. The orange colored reaction mixture was stirred for 0.5 hours at -20 ° C, then cyclopentyl bromide (20.9 g, 140 mmol). The reaction mixture was stirred at 1 hour at -20 ° C for 0 ° C. The excess of nBuli was cautiously destroyed with methanol. 140 ml of cold water was added to the reaction mixture. The product was extracted with ethyl acetate (3 x 80 ml). The combined organic extract was washed with brine, dried over anhydrous sodium sulfate and concentrated to give the title compound as a light yellow liquid (14.12 g, 96.8%). 1 H NMR: d 1.0-2.4 (Complex, 9H), 2.7-2.94 (m, 3H), 3.52 (s, 6H, 2 x OCH3), 4.70 (t, 2H).
EXAMPLE 11 2-Cyclopentyl-3-methoxy-cyclohex-3-enone To a solution of 2-cyclopentyl-2,5-dihydro-1,3-dimethoxybenzene (5 g, 27 mmol) in methanol (50 ml) was added 2.5 % hydrochloric acid (10 ml) per drop at 0 ° O The reaction mixture was stirred for 45 minutes and diluted with 30 ml of ice water. The product was extracted with ether (3 x 100 ml). The combined organic extract was washed with brine and dried (Na 2 SO). Removal of the solvent in vacuo afforded the title compound as light yellow oil (4.3 g, 94.7%).
EXAMPLE 12 2-Cyclopentyl-3-methox-cyclohex-2-enone To a solution of 2-cyclopentyl-3-methoxycyclohex-3-en-1-one 84.3 g) in dry THF (120 ml), sodium ectoxide (1.1 g) was added in portions at room temperature. After stirring the reaction mixture at room temperature for 1.5 hours, it was cooled in an ice bath and neutralized with sodium hydrogen phosphate solution. The organic layer was separated, the aqueous layer was extracted with ethyl acetate (2 x 50 ml). The combined organic extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the resulting product was purified on a column of silica gel (Hex: EtOAc) to give the title compound as a yellow liquid (2.82 g, 65.5%). 1 H NMR (CDCl 3): d 1.25-1.8 (m, 8 H, 4 x CH 2), 1.96 (m, 2 H, CH 2), 2.36 (t, 2 H, CH 2), 2.56 (t, 2 H, CH 2), 3.22 (m , 1 H, CH), 3.79 (s, 3 H, OCH 3).
EXAMPLE 13 2-Cyclopentyl-6-hydroxymethylene-3-methoxy-cyclohex-2-enone To a suspension of sodium hydride (2.04 g, 60% suspension, 51 mmol) in benzene (100 ml), a mixture of ethyl (6.7 ml) and 2-cyclopentyl-3-methoxycyclohex-3-en-1-one (2.82 g, 17 mmol) in benzene was added dropwise at 5 ° C. The reaction mixture was stirred at ice-cold temperature for 1 hr. hour and 18 hours at room temperature. The reaction mixture was cooled on ice ice and 200 ml of 10% sodium hydrogen phosphate solution which was added dropwise. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 50 ml). The combined organic extract was washed with brine and dried over aqueous sodium sulfate. The solvent was removed in vacuo and the resulting product was purified on a column of silica gel (Hex: EtOAc) to give the title compound as a viscous liquid (2 g, 60%).
EXAMPLE 14 8-Cyclopentyl-7-methoxy-quinazolin-2-ylamine A mixture of 6-formyl-2-cyclopentyl-3-methoxycyclohex-2-en-1-one (2.0 g, 10.2 mmol) and guanidine carbonate ( 4.6 g) in DMF (30 ml) was heated at 150 ° C for 4 hours. The solvent was removed under pressure and ice water was added to the residue. The product was extracted with ethyl acetate (3 x 50 ml). The combined organic extract was washed with water and brine and dried over of sodium anhydrous. The solvent was removed under reduced pressure to give 2.0 g of crude dihydrofoquinazoline. The dihydroquinazoline was flavored for the title compound by heating in nitrobenzene at 150 ° C in the presence of 10% Pd-C. To a solution of dihydroquinazoline (2.0 g, 8.2 mmol) in nitrobenzene (20 ml), 200 mg of 10% Pd-C were added and the reaction mixture was heated at 150 ° C for 3 days. The Pd-C was removed by filtration. The filtrate was concentrated and the resulting product was purified on a silica gel column (Hex.EtOAc) to give the title compound as a grayish solid (1 g, 50% produced), mp 181- 183 ° C; 1 H NMR (CDCl 3): d 1.6-2.2 (complex, 8 H, 4 x CH 2), 3.9 (s, 3 H, OCH 3), 4.27 (t, 1 H, CH), 5.02 (brs, 2 H, NH 2), 7.02 (d , 1H, Ar-H, J = 9 Hz), 7.54 (d, 1H, Ar-H, J = 9Hz), 8.87 (s, 1H, Ar-H); MS: m / z 244.07, C14H17N30 (M ++ 1).
EXAMPLE 15 8-Cyclopentyl-7-methoxy-1 H-quinazolin-2-one To a solution of 2-amino-8-cyclopentyl-7-methoxyquinazoline (1.38 g) in tetrahydrofluorophic acid (30 ml) was added dropwise a sodium nitro solution (1.16 g in 10 ml of water at 0 ° C.). The reaction mixture was stirred at 0 ° C for 1 hour at room temperature for 18 hours, the reaction mixture was cooled in an ice bath and neutralized with 30% ammonia solution, extracted with ethyl acetate (3 x 50 ml), combined with organic extract, washed with brine and dried over anhydrous sodium sulfate. give the title compound as an orange solid (1.0 g, 73%), mp 201-204 ° C; 1 H NMR (CDCl 3): d 1.7-2.0 (complex, 8 H, 4 x CH 2), 3.43 (m, 1 H, CH ), 3.96 (s, 3H, OCH3), 6.89 (d, 1H, Ar-H, J = 8.8 Hz), 7.59 (d, 1H, Ar-H, J = 8.8 Hz), 8.92 (brs, 1H, NH ), 9.03 (s, 1 H, Ar-H).
EXAMPLE 16 2-Chloro-8-cyclopentyl-7-methoxy-quinazoline 7-Methoxy-8- (2-propyl) quinazole-2 (1 H) -one (0.95 g) was dissolved in 40 ml of phosphorus oxychloride and the The resulting reaction mixture was heated at 110 ° C for 4 hours. The excess of POCI3 was removed under reduced pressure. To the residue, ice water was added and the product was extracted with - * ethyl acetate (3 x 50 ml). The combined organic extract was washed with brine, dried over anhydrous ## STR3 ## and concentrated to give the chlorine compound. This was purified on a column of ethyl gel (Hexane: ethyl acetate), beige solid. (710 mg, 69% produced), mp 250 ° C (decomp); 1 H NMR (CDCl 3): d 1.7-2.0 (complex, 8 H, 4 x 5 CH 2), 4.17 (s, 3 H, OCH 3), 4.27 (m, 1 H, CH), 7.65 (d, 1 H, Ar-H , J = 9 Hz), 8.30 (d, 1H, Ar-H), 8.30 (d, 1H, Ar-H); 9.71 (s, 1 H, Ar-H).
EXAMPLE 17 (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) -phenyl-amine O To a mixture of 2-chloro-7-methoxy-8- (2-propyl) quinazoline (200 mg, 0.76 mmol) and Aniline (212 mg, 2.28 mmol) in acetonitrile (3 ml) was heated at 90 ° C for 60 hours in a sealed tube. The solvent was removed under pressure, 5% sodium carbonate solution was added to the residue. The product was extracted with ethyl acetate (3 x 40 ml). The combined organic extract was washed with brine, dried (Na2SO) and concentrated. The product was purified on a column of silica gel 5 to give the title compound as a yellow solid (90 mg, 37%), mp 187-188 ° C; 1 H NMR (CDCl 3): d 1.72-2.30 (complex, 8 H, 4 x CH 2), 3.96 (s, 3 H, OCH 3), 4.33 (m, 1 H, CH), 7.23-7.41 (m, 2 H, Ar-H ), 7.58 (d, 1 H, Ar-H), 7.83 (d, 2 H, Ar), 8.93 (s, 1 H, Ar-H); MS: m / z 319.81, C20H21N3O Analysis Cale. C, 75.21; H 6.63; N 13.16. Found: C, 75.03; H, 6.73; N, 13.05. 0 EXAMPLE 18 General procedure for aniline binding A mixture of 2-chloroquinazoline (0.03 mmol) and the appropriate aniline (0.09 mmol) in acetonitrile (5 ml) heated in a sealed tube for 24 to 72 hours at 110 ° C. The solvent it removed under reduced pressure and the residue suspended in ethyl acetate and treated with 5% Na2CO3 solution. The organic layer separated and the aqueous layer extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were ed with brine and dried over Na2SO4. The product purified by silica gel chromatography.
EXAMPLE 19 (8-Solpropih7-methox? -Kinazolin-2-yl) -phenyl-amine pf. 172-173 ° C; ? NMR (CDCl3): d 1.46 (d, 6H, 2xCH3), 3.97 (s, 3H, OCH3), 4.33 (m, 1H, CH), 7.0-7.1 (m, 2H, Ar-H), 7.38 (t, 2H, Ar-H), 7.58 (d, 1 H, Ar-H), 7.85 m, 2H, Ar-H), 8.93 (s, 1H, Ar-H); MS: m / z C18H19N30 294.21 (M ++ 1); Analysis Cale. C 73.7, H 6.53, N 14.32; Found: C 73.8, H 6.83, N 14.59.
EXAMPLE 20 1- (4-f4- (8-Cyclopentyl-7-methoxy-quinazolin-2-ylamino) -fenin-piperazin-1-yl) -ethanone Yellow solid, 83% produced, mp 247-249 ° C; 1 H NMR (CDCl 3): d 1.6-2.3 (complex, 8 H, 4 x CH 2), 2.18 (s, 3 H, COCH 3), 3.13 (m, 4 H), 3.63 (m, 2 H), 3.78 (m, 2 H), 3.96 (s, 3H, OCH3), 4.30 (m, 1H, CH), 6.96 (d, 2H, Ar-H, J = 9 Hz), 7.05 (d, 1 H, Ar-H, J = 8.8 Hz) , 7.11 (s, 1 H, NH), 7.56 (d, 1H, Ar-H, J = 8.8 Hz), 7.72 (d, 2H, Ar-H, J = 9Hz), 8.90 (s, 1 H, Ar -H); MS (EN): miz 446.29 C26H31N502. Analysis calculated for C, 70.09; H, 701; N, 15.72. Found: C, 69.38; H, 7.43; N, 15.06.
EXAMPLE 21 (8-lsopropyl-7-methoxy-quinazolin-2-yl) - (4-piperidin-1-yl-phenyl) -amine Yellow solid, 54.5% produced, mp 166-167 ° C; 1 H NMR (CDCl 3): d 1.44 (d, 6 H, 2 x CH 3), 1.6 (m, 2 H, CH 2), 1.74 (m, 4 H, 2 x CH 2), 3.13 (t, 4 H, 2 x CH 2), 3.96 ( s, 3H, COCH3), 4.30 (m, 1H, CH), 6.9-7.1 (2nd, ys combined, 3 Ar-H, NH), 7.54 (d, 1 H, Ar-H), 7.7 (d, 2H, Ar-H), 8.88 (s, 1 H, Ar- H); MS (ES): m / z 376.97 C23H28N40. Analysis calculated for C, 73.37; H, 7.5; N, 14.88. Found: C, 73.18; H, 7.69; N, 14.89.
EXAMPLE 22 { 8-ls? Propyl-7-methoxy-quinazolin-2-yl) - (4-pyrrolidin-1-yl-phenyl) -am? Na Orange solid, 83%, mp 188-190 ° C; 1 H NMR (CDCl 3): d 1.43 (d, 6 H, 2 x CH 3), 2.01 (m, 4 H, 2 x CH 2), 3.95 (s, 3 H, OCH 3), 4 29 (m, 1 H, CH), 6.61 (d, 2H, Ar-H, J = 8.9 Hz), 6.9-7.1 (dys Ido, 2H, 1 Ar-H, NH), 7.52 (d, 1H, Ar-H, J = 8.9 Hz), 7.63 (d, 2H, Ar-H, J = 8.9 Hz), 8.85 (s, «Ar -H); MS (ES): m / z 363.02 C22H26N40. Analysis calculated for C, 72.90; H, 7.23; N, 15.46. Found: C, 73.35; H, 7.67; N, 14.74.
EXAMPLE 23 (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - (4-piperidin-1-yl-phenyl) -am? Na Yellow solid, 28%, mp 212-214 ° C; 1 H NMR (CDCl 3): d 1.55-2.28 (complex, 14H, 7 x CH2), 3.08-3.14 (m, 4H, 2 x CH2), 3.95 (s, 3H, OCH3), 4.29 (m, 1 H, CH), 6.94-7.08 (complex, 4H, 3 Ar-H, NH), 7.52-7.57 (m, 1 H, Ar-H), 7 65-7.72 (m, 2H, Ar-H), 8.88 (s, 1 H, Ar-H); MS (ES): m / z 403.17 C25H3oN40. (M ++ 1); Analysis calculated for C, 74.60; H, 7.51; N, 13.92. Found: C, 74. 83; H, 7.57; N, 13.83.
EXAMPLE 24 (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - (4-pyrrolidin-1-yl-phenyl) -amine Yellow solid, 28% produced, mp 240-242 ° C; 1 H NMR (CDCl 3): d 1.68-2.29 (complex, 12H, 6 x CH2), 3.30 (m, 4H, 2 x CH2), 3.94 (s, 3H, OCH3), 4.28 (m, 1 H, CH), 6.59 (d, 2H, Ar-H, J = 8.9 Hz), 6.95 (s, 1 H, NH), 7.0 (d, 1 H, Ar-H), J = 8.9 Hz), 7.52 (d, 1 H, Ar-H, J = 8 9 Hz), 7.60 (d, 2H, Ar-H, J = 8.9 Hz), 8.86 (s, 1H, Ar-H); MS (ES): m / z 388.98 C24H28N40. (M ++ 1); Analysis calculated for C, 74.20; H, 7.26; N, 14.42. Found: C, 73 94; H, 7.34; N, 14.36.
EXAMPLE 25 4-l4- (8-lsopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl-piperazine-1-earboxylic acid tert-butyl ester Yellow solid, 64.4%, mp 173-175 ° C; 1 H NMR (CDCl 3): d 1.44 (d, 6 H, 2 x CH 3), 1.49 (s, 9 H, 3 x CH 3), 3.1 (t, 4 H, 2 x CH 2), 3.6 (t, 4 H, 2 x CH 2), 3.96 (s, 3H, OCH3), 4.3 (m, 1 H, CH), 6.98 (d, 2H, Ar-H), 7.04 (d, 1 H, Ar-H), 7.13 (s, 1 H, NH ), 7.56 (d, 1 H, Ar-H), 7.74 (d, 2H, Ar-H), 8.89 (s, 1 H, Ar-H); MS (ES): m / z 478.1 1 C27H35N503. (M ++ 1); Analysis calculated for C, 67.9; H, 7.39; N, 14.66. Found: C, 68.06; H, 7.61; N, 14.16.
EXAMPLE 26 Ester tert-buty? O of 4-f4- (8-Cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl-piperazine-1-carboxylic acid Yellow solid, 54% produced, mp 183-184 ° C; 1 H NMR (CDCl 3): d 1.49 (s, 9 H, 3 x CH 3), 1.68-2.29 (complex, 8 H, 4 x CH 2), 3.10 (t, 4 H, 2 x CH 2), 3.61 (t, 4 H, 2 x CH2), 3.96 (s, 3H, OCH3), 4. 29 (m, 1 H, CH), 6.96 (d, 2H, Ar-H, J = 8.9 Hz), 7.09 (s, 1 H, NH), 7.56 (d, 1 H, Ar-H, J = 8.9 Hz), 7 71 (d, 2H, Ar-H, J = 8.9 Hz), 8.89 (s, 1 H, Ar-H); MS (ES): m / z 504.35 C29H37N503. (M ++ 1); Analysis calculated for C, 69.19; H, 7.4; N, 13.91. Found: C, 68.84; H, 7.73; N, 13.58.
EXAMPLE 27 (8-Cyclopentyl-7-methoxy-quinazolin-2-ylM4-piperazin-1-yl-phenyl) -amine Yellow solid, 77% produced, mp 218-219 ° C; 1 H NMR (CDCl 3): d 1.68-2.29 (complex, 8H, 4 x CH 2), 3.11 (m, 8H, 2 x CH 2), 3.96 (s, 3 H, OCH 3), 4.30 (m, 1 H, CH), 6.97 (d, 2H, Ar-H, J = 8.9 Hz), 7.04 (d, 1 H, Ar-H, J = 8.8 Hz), 7.06 (s, 1 H, NH), 7.55 (d, 1 H, Ar-04.12, C 24 H 29 N 50 (M + 1 +), Analysis calculated for C, 71.44; H, 7.24; N, 17.36, Found: C, 70.33; H, 7.86; N, 16.73.
EXAMPLE 28 1-. { 4-f4- (8-isopropyl-7-methoxy-quinazolin-2-ylamino) -fenip-piperazin-1-yl) -ethanone Light yellow solid, 79% produced, mp 197-198 ° C; 1 H NMR (CDCl 3): d 1.44 (d, 6H, 2 x CH 3), 2.16 (s, 3 H, COCH 3), 3.15 (m, 4 H), 3.65 (m, 2 H), 3.80 (m, 2 H), 3.97 ( s, 3H, OCH3), 4.30 (m, 1H, CH), 6.98 (d, 2H, Ar-H), 7.04 (d, 1 H, Ar-H), 7.13 (s, 1 H, NH), 7.56 (d, 1 H, Ar-H), 7.75 (d, 2H, Ar-H), 8.89 (s, 1 H, Ar-H); MS (ES): m / z 420.0 C24H29N502. (M ++ 1); Analysis calculated for C, 68.71; H, 6.97; N, 16.69 Found: C, 69.07; H, 7.42; N, 16.24.
EXAMPLE 29 8-lsoBrop? L-2-phenylamino-quinazolin-7-ol A mixture of 1 (150 mg, 0.51 mmol9 and sodium thioethoxide (214 mg, 2.55 mmol) in dimethylformamide (5 ml) was heated to 150 C for 5 hours The solvent was removed under pressure reduced. To the residue, ice water (30 ml) was added and the mixture was acidified with acetic acid (0.5 ml). The product was extracted with ethyl acetate (3 x 30 ml). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. The product was purified on a column of silica gel (EtOAc.MeOH) to give a yellow solid cairo, 70% produced, mp 103-104 | O Yellow solid, 54% produced, mp 183-184 ° C; 1 H NMR (CDCl 3): d 1.52 (d, 6 H, 2 x CH 3), 4.30 (m, 1 H, CH), 5.7 brs 1 H, OH), 6.83 (d, 1 H, Ar-H, J = 8.7 Hz ), 7.06 (m, 1 H, Ar-H), 7.3-7.5 (combined sym, 3H, 2 Ar-H, NH), 7.49 (d, 1 H, Ar-H, 8.7 Hz), 7.83 (m, 2H, Ar-H), 8.89 (s, 1H, Ar-H); MS (ES): m / z 279.37 C17H17N30. (M +); Analysis calculated for C, 73.10; H, 6.13; N, 15.04. Found: C, 73.34; H, 6.37; N, 14.72.
EXAMPLE 30 General procedure for the deprotection of a N-Boc group To a solution of the protected compound N-Boc (0.2 mmol) in dichloromethane (3 ml) was added trichloroacetic acid. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and ice water (30 ml) was added to the residue. This mixture was basified with a 5% solution of Na 2 CO 3, subsequently, the product was extracted with chloroform (3 x 30 ml). The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was purified on a florisil column (EtOAc: MeOH).
EXAMPLE 31 f8-lsopropyl-7-mtoxy-ouinazolin-2-yl) - (4-piperazin-1-yl-phenyl) -amine Amorphous solid, 84% produced. 1 H NMR (CDCl 3): d 1.44 (d, 6H, 2 x CH 3), 3.0-3.2 (m, 8H, 4 x CH2), 3.96 (s, 3H, OCH3), 4.3 (m, 1 H, CH), 6.9-7.1 (2d combined, 3H, Ar-H), 7.2 (s, 1H, NH ), 7.55 (d, 1 H, Ar-H), 7.73 (d, 2 H, Ar-H), 8.88 (s, 1 H, Ar-H); MS (ES): m / z 378.15 C22H27N50. (M ++).
EXAMPLE 32 2-Amin? -1-f4-f4- (8-isopropyl-7-mtoxy-quinazolin-2-ylamino) -phenyl-1-piperazin-1-yl) -ethanone Yellow solid, 85% produced, mp 183-185 ° C; 1 H NMR (CDCl 3): d 1.44 (s, 6 H, 2 x CH 3), 3.15 (m, 4 H), 3.52 (s, 2 H), 3.55 (m, 2 H, CH 2), 3.83 (m, 2 H), 3.97 ( s, 3H, OCH3), 4.30 (m, 1H, CH), 6.98 (d, 2H, Ar-H, J = 8.9 Hz), 7.05 (d, 1 H, Ar-H, 8.9 Hz), 7.14 (s , 1 H, NH), 7.56 (d, 1 H, Ar-H, J = 8.9 Hz), 7.76 (d, 2 H, Ar-H, J = 8.9 Hz), 8.89 (s, 1 H, Ar-H ); MS (IS): m / z 434.66 C24H30N6O2 EXAMPLE 33 1-. { 4-f4- (8-lsopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl-piperazin-1-yl) -ethanone Light yellow solid, 79% produced, mp 197-198 ° C; 1 H NMR (CDCl 3): d 1.44 (d, 6H, 2x CH 3), 2.16 (s, 3 H, OCH 3), 3.15 (m, 4 H), 3.65 (m, 2 H), 3.80 (m, 2 H), 3.97 (s) , 3H, OCH3), 4.30 (m, 1H, CH), 6.98 (d, 2H, Ar-H), 7.04 (d, 1 H, Ar-H), 7.13 (s, 1 H, NH), 7.56 ( d, 1 H, Ar-H), 7.75 (d, 2H, Ar-H), 8.89 (s, 1 H, Ar-H), MS (ES): m / z 420.0 C24H29N502. (M ++ 1); Analysis calculated for C, 68 71; H, 6.97; N, 16.69. Found: C, 69.07; H, 7.42; N, 16.24.
EXAMPLE 34 (8-lsopropyl-7-methoxy-quinazolin-2-yl) - (4-piperazin-1-yl-phenyl) -amine Amorphous solid, 84.4% produced. 1 H NMR (CDCl 3): d 1.44 (d, 6 H, 2 x CH 3), 3.0-3.2 (m, 8 H, 4 x CH 2), 3.96 (s, 3 H, OCH 3), 4.3 (m, 1 H, CH), 6.9-7.1 (2d combined, 3H, Ar-H), 7.2 (s, 1 H, NH), 7.55 (d, 1H, Ar-H), 7.73 (d, 2H, Ar-H), 8.88 (s, 1H, Ar-H); MS (ES): m / z 378.15 C22H2rN50. (M ++).
EXAMPLE 35 2-Amino-1-. { 4-R4- (8-isopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl-1-piperazin-1-yl) -ethanone Yellow solid, 85% produced, mp 183-185 ° C; 1 H NMR (CDCl 3): d 1.44 (d, 6 H, 2 x CH 3), 3.15 (m, 4 H), 3.52 (s, 2 H), 3.55 (m, 2 H, CH 2), 3.83 (m, 2 H), 3.97 (s , 3H, OCH3), 4.30 (m, 1 H, CH), 6.98 (d, 2H, Ar-H), 7.05 (d, 1H, Ar-H, 8.9 Hz), 7.14 (s, 1 H, NH) , 7.56 (d, 1 H, Ar-H, J = 8.9 Hz), 7.76 (d, 2H, Ar-H, J = 8.9 Hz), 8.89 (s, 1 H, Ar-H), MS (ES) : m / z 434.66 C24H3oN602. (M +).
EXAMPLE 36 > , - ropil-7-methoxy-quinazolin-2-yl) - (4'-methoxy-biphenyl-4-yl) -amine Solid, 69% produced, mp 198-199 ° C; 1 H NMR (CDCl 3): d 1.45 (d, 6H, 2x CH 3), 3.2-3.4 (m, 8H, xCH 2), 3.78 (s, 3 H, OCH 3), 3.96 (s, 3 H, OCH 3), 4.31 (m, 1 H, CH), 6.8-7.2 (complex, 8H, 7 Ar-H, NH), 7.56 (d, 1H, Ar-H), 7.75 (d, 2H, Ar-H), 8.89 (s, 1 H , Ar-H), MS (ES): m / z 484.22 * C29H33N502. (M ++ 1); Analysis calculated for C, 72.02; H, 6.88; N, 14.48. Found: C, 71.58; H, 7.30; N, 14.29 EXAMPLE 37 10 f4- (3-Amino-pyrrolidin-1-yl) -phenyl-1- (8-isopropyl-7-methoxy-guinazolin-2-yl) -amine Yellow solid, 82.3% produced, mp 125- 127 ° C; 1 H NMR (CDCl 3): d 1.43 (d, 6 H, 2 x CH 3), 1.84 (m, 1 H), 2.3 (m, 1 H), 3.08 (m, 1 H), 3.3-3.6 (complex, 3 H), 3.76 (m , 1 H), 3.95 (s, 3H, OCH3), 4.30 (s, 1H), 6.59 (d, 2H, Ar-H, J = 8.7 Hz), 6.99 (d, 1H, Ar-HJ, J = 8.8 Hz), 7.02 (s, 1H, NH), 7.52 (d, 1H, Ar-H, J = 8.8 Hz), 7.64 (d, 2H, ar-H, J = 8.7 Hz), 8.86 (s, 1 H , Ar-H), MS (ES): m / z 378.15 15 C22H27N50.
EXAMPLE 38 (3-Fluoro-4-morpholin-4-yl-phenyl) - (8-isopropyl-7-methoxy-guinazolin-2-yl) -amine Yellow solid, 65.7% produced, mp 202-203 ° C; ? NMR (DMSO-d6): d 1.41 (d, 6H, 2x CH3), 2.96 (t, 4H, 2xCH2), 3.74 (t, 4H, 2XCH2), 3.95 (s, 3H, OCH3), 4.25 (m, 1 H, CH), 7.01 (m, 1 H, Ar-H), 7.24 (d, 1H, Ar-H, J = 8.9 Hz), 7.55 (m, 1 H, Ar-H), 7.78 (d, 1 H, Ar-H, J = 8.9 Hz), 8.04 (m, 1H, Ar-H), 9.12 (s, 1 H, Ar-H), 9.79 (s, 1 H, NH). MS (ES): m / z 397.35 C22H29FN4? 2. Analysis calculated for C, 66.65; H, 6.36; N, 14.13. Found: C, 66.76; H, 6.34; N, 13.96.
EXAMPLE 39"8-lsopropyl-7-methoxy-guinazolin-2-yl) - (4-morpholin-4-yl-phenyl) -amine Yellow solid, 81.8% produced, mp 187-189 ° C; 1 H NMR (CDCl 3): d 1.44 (d, 6 H, 2 x CH 3), 3.15 (t, 4 H, 2 x CH 2), 3.89 (t, 4 H, 2 X CH 2), 3.96 (s, 3 H, OCH 3), 4.31 (m, 1 H , CH), 6.97 (d, 2H, Ar-H, J «8.9 Hz), 7.04 (d, 1 H, Ar-H, J = 8.9 Hz), 7.12 (s, 1 H, NH), 7.56 (d, 1 H, Ar-H, J = 8.9 Hz), 7.75 (d, 2H, Ar-H, J = 8.9 Hz), 8.89 (s, 1 H, Ar-H), MS (ES): m / z 379.18 (MH +), C22H26N402. Analysis calculated for C, 69.82; H, 6.92; N, 14.80. Found: C, 69.95; H, 7.06; N, 14.59.
EXAMPLE 40 2-Amino-1-. { 4-f4- (8-Cyclopentyl-7-methoxy-guinazolin-2-ylamino) -phenyl-piperazin-1-yl) -ethanone Yellow solid, 60% produced, mp 202 ° C; 1 H NMR (CDCl 3): d 1.6-2.3 (complex, 8 H, 4 x CH 2), 3.1 (t, 4 H, 2 x CH 2), 3.52 (s, 2 H, CH 2), 3.56 (m, 2 H), 3.83 (m, 2 H), 3.96 (s, 3H, OCH3), 4.3 (m, 1H, CH), 6.96 (d, 2H, Ar-H, J = 9 Hz), 7.05 (d, 1 H, Ar-H, J = 8.9 Hz) , 7.1 (s, 1H, NH), 7.57 (d, 1H, Ar-H, J = 8.9 Hz), 7.72 (d, 2H, Ar-H, J = 8.9 Hz), 8.9 (s, 1 H, Ar -H) MS (ES): m / z 461.19 (MH +), C 26 H 32 N 602.
EXAMPLE 41 T4- (3 'Amino-pyrrolidin-1-yl) -fenin- (8-cyclopentyl-7-methoxy-guinazolin-2-yl) -amine Yellow solid, 83% produced, mp 220-221 ° C; 1 H NMR (CDCl 3): d 1.6-2.4 (complex, 10 H), 3.04 (m, 1 H), 3.3-3.6 (m, 3 H), 3.7 (m, 1 H), 3.95 (s, 3 H, OCH 3), 4.30 (m, 1 H, CH), 6.58 (d, 2H, Ar-H, J = 8.9 Hz), 6.98 (s, 1 H, NH), 7.0 (d, 1 H, Ar-H, J = 8.8 Hz ), 7.53 (d, 1 H, Ar-H, J = 8.8 Hz), 7.61 (d, 2H, Ar-H, J = 8.9 Hz), 8.86 (s, 1 H, Ar-H), m / z 404.22 (MH +), C24H29N50. Analysis calculated for C, 71.44; H, 7.24; N, 17.36. Found: C, 70.75; H, 7.44; N, 17.1.
EXAMPLE 42 2-Amino-1-l4-f4- (8-cyclopethyl-7-methoxy-quinazolin-2-ylamino) -fenin-P-piperazin-1-yl) -4-methyl-pentan-1-one Yellow solid 77% produced, mp 130-132 ° C; ? NMR (CDCl 3): d 0.97 (m, 6H, 2x CH 3), 1.39 (m, 2H), 1.6-2.1 (m, 7H), 2.2 (m, 2H), 3.16 (m, 4H), 3.64 (m, 2H), 3.8 (m, 3H), 3.81 (s, 3H, OCH3), 4.3 (m, 1 H, CH), 6.96 (d, 2H, Ar-H, J = 8.9 Hz), 7.05 (d, 1 H, Ar-H, J = 8.8 Hz), 7.1 (s, 1 HOUR, NH), 7.57 (d, 1 H, Ar-H, J = 8.8 Hz), 7.72 (d, 2H, Ar-H, J = 8.9 Hz), 8.9 (s, 1 H, Ar-H). MS (ES), m / z 517. 28 (MH +), C30H40N6O2. Analysis calculated for C, 69.14; H, 7.8; N, 16.27. Found: C, 69.08; H, 8.22; N, 15.96. .TO EXAMPLE 43 f8-Cyclopentyl-7-methoxy-qu? Nazolin-2-yl) - (3-fluoro-4-morpholin-4-yl-phenyl) -amine Yellow solid, 50% produced, mp 252-253 ° C; 1H NMR (DMSO-d6): d 1.6-2.2 (complex, 8H, 4xCH2), 2.95 (t, 4H, 2XCH2), 3.74 (t, 4H, 2xCH2), 3.95 (s, 3H, OCH3), 4.24 (m , 1H, CH), 7.05 (m, 1H, Ar-H), 7.2 (d, 1 H, Ar-H, J = 8.9 Hz), 7.78 (d, 1 H, Ar-H, J = 8.9 Hz) , 8.07 (m, 1 H, Ar-H), 9.12 (S, 1H, Ar-H), 9.78 (s, 1 H, NH). MS (ES): m / z 423.19 C24H27FN402.
EXAMPLE 44 (8 »Cyclopentyl-7-methoxy-quinazolin-2-yl) - (4-morpholin-4-yl-phenyl) -amine Yellow solid, 85% produced, mp 243-244 ° C; ? NMR (DMSO-d6): d 1.6-2.3 (m, 8H, 4xCH2), 3.05 (t, 4H, 2XCH2), 3.75 (t, 4H, 2xCH2), 3.93 (s, 3H, OCH3), 4.24 (m, 1 H, CH), 6.91 (d, 2 H, Ar-H, J = 9 Hz), 7.19 (d, 1 H, Ar-H, J = 8.9 Hz), 7.7-7.9 (2d, combined, 3H "Ar -H), 9.06 (s, 1 H, Ar-H), 9.47 (s, 1 H, NH). MS (ES): m / z 405.2 C24H28N4? 2.
EXAMPLE 45 (1-f4- (8-Cyclopentyl-7-methoxy-quinazolin-2-ylamino) -fenin-pyrrolidin-3-yl) -carbamic acid tert-butyl ester Yellow solid, 65%, mp 157 ° C (decomp); ? NMR (CDCI3): d 1.57 (s, 9H, 3 x CH3), 1.6-2.4 (complex, 10H), 3.1-3.65 (m, 4H), 3.96 (s, 3H, OCH3), 4.2-4.4 (m, 2H), 4.75 (s, 1 H, CONH), 6.6 (d, 2H, Ar-H, J = 8.9 Hz), 7.06 (s, 1 H, NH), 7.08 (d, 1 H, Ar-H, J = 8.9 Hz), 7.54 (d, 1 H, Ar-H, J = 8.9 Hz), 7.63 (d, 2 H, Ar-H, J = 8.9 Hz), 8.88 (s, 1 H, Ar-H) . MS (ES): m / z 504.24 (MH +) C29H37N503.
EXAMPLE 46 (4-Fluoro-3-methyl-phenyl) - (8-isopropyl-7-methoxy-quinazolin-2-yl) -amine Grayish solid, 80%, mp 169-171 ° C; ? NMR (CDCl 3): d 1.46 (d, 6H, 2 x CH 3), 2.33 (d, 3H, Ar-CH3, J = 1.7 Hz), 3.97 (s, 3H, OCH3), 4.3 (m, 1 H, CH), 6.99 (m, 1 H, Ar-H), 7.06 (d, 1 H, Ar- H, J = 8. 9 Hz), 7.18 s, 1H, NH), 7.4 (m, 1 H, Ar-H), 7.58 (d, 1H, Ar-H, J = 8.9 Hz), 7.90 (m, 1H, Ar-H, J = 8. 9 Hz), 7.90 (m, 1 H, Ar-H), 8.91 (s, 1 H, Ar-H). MS (ES): m / z 326.24 (MH +) Analysis calculated for C19H20FN3O.1 / 3H2O; C, 68.86; H, 6.29; N, 12.68. Found: C, 69.21; H, 6.26; N, 12.59.
EXAMPLE 47 (8-lsspropyl-7-methoxy-quinazolin-2-yl) - (4-piperidin-1-yl-phenyl) -amine Yellow solid, 72%, mp 160-161 ° C; ? NMR (CDCl 3): d 1.46 (d, 6H, 2 x CH3), 1.6 (m, 2H, CH2), 1.77 (m, 4H, 2xCH2), 3.0 (t, 4H, 2xCH2), 3.97 (s, 3H, OCH3), 4.31 (m, 1 H, CH), 6.96 (m, 1H, Ar-H), 7.06 (d, 1H, Ar-H, J = 8.8 Hz), 7.17 (s, 1 H, NH), 7.25 (m, 1 H, Ar-H), 7.58 (d, 1 H, Ar-H, J = 8.8 Hz), 7.93 (m, 1H, Ar-H), 8.9 (s, 1 H, Ar-H). MS (ES): m / z 395.48 (MH +) C23H27FN40. Analysis calculated for; C, 70.03; H, 6.9; N, 14.2. Found: C, 69.44; H, 7.01; N, 14.06.
EXAMPLE 48 (8-Skypentyl-7-methoxy-quinazolin-2-yl) - (4-fluoro-3-methyl-phenyl) -amine Greyish solid, 56%, mp 208-209 ° C; ? NMR (CDCI3): d 1.6-2.2 (8H complex, 4XCH2), 2. 32 (d, 3 H, CH 3, J = 1.8 Hz), 3.97 (s, 3 H, OCH 3), 4.36 (m, 1 H, CH), 6.98 (m, 1 H, Ar-H), 7.07 (d, 1H, Ar-H, J = 8.9 Hz), 7.132 (s, 1 H, NH), 7.44 (m, 1 H, Ar-H, J = 8.9 Hz), 7.82 (m, 1 H, Ar-H) 8.91 (s, 1H, Ar-H). MS (ES): m / z 352.29 (MH +) Analysis calculated for C 21 H 22 FN 30; Analysis calculated for C2? H22FN30.1 / 2 H20: C, 69.98; H, 6.43; N, 11.66. Found: C, 69.62; H, 6.09; N, 11.51.
EXAMPLE 49 8-cyf-pentyl-7-methoxy-quinazolin-2-yl) - (3-Fluoro-4-piperidin-1-yl-phenyl) -amine Yellow solid, 56% produced, mp 200-201 ° C; 1 H NMR (CDCl 3): d 1.4-2.3 (complex, 14 H, 7 x CH 2), 3.0 (t, 4 H, 2 x CH 2), 3.96 (s, 3 H, OCH 3), 4.32 (m, 1 H, CH), 6.95 (m , 1H, Ar-H), 7.06 (d, 1H, Ar-H, J = 8.8 Hz), 7.16 (m, 1 H, Ar-H), 7.19 (s, 1 H, NH), 7.57 (d, 1 H, Ar-H, J = 8.8 Hz), 7.96 (m, 1 H, Ar-H), 8.9 (s, 1 H, Ar-H). MS (ES): m / z 421.20 (MH +). C25H29FN40. Analysis calculated for C2sH29FN40.1 / 2 H20; C, 69.91; H, 7.04; N, 13.04. Found: C, 69.67; H, 6.84; N, 12.79.
EXAMPLE 50 (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - (3-Fluoro-4-p-perazin-1-yl-phenyl) -amine Yellow solid, 82% produced, mp 228-229 ° C; ? NMR (CDCI3): d 1.7-2.3 (complex, 8H, 4 x CH2), 3.6 (s, 8H, 4xCH2), 3.97 (s, 3H, OCH3), 4.3 (m, 1 H, CH), 6.94 (m , 1 H, Ar-H), 7.08 (d, 1H, Ar-H, J = 9 Hz), 7.1-7.2 (sym combined, 2H, NH, Ar-H), 7.58 (d, 1 H, Ar- H, J = 9 Hz), 7.99 (m, 1 H, Ar-H), 8.91 (s, 1H, Ar-H). MS (ES): m / z 422.24 (MH +). C24H28FNsO. Analysis calculated for C24H28FN50. H20; C, 65.58; H, 6.88; N, 15.93. Found: C, 65.44; H, 6.2; N, 15.57.
Table 1. IC50 values in μM < As can be seen from the above, the components of this invention are potent inhibitors of cyclin-dependent kinases and therefore, are useful in the treatment and prevention of neurodegenerative diseases, arteposclerosis and other cell proliferative diseases such as cancer. The compounds have exhibited excellent inhibitory activity against a wide variety of cylin-dependent kinases, all in systems routinely used to measure such activity. A typical test, for example, measures the inhibitory activity against the enzyme 4 cmasa dependent on cyclin D (cdk4 / D). The compounds of the invention of Formula I exhibited IC 50 values ranging generally from 0.011 μM to 1.75 μM. The cd test 4 was carried out as follows.
Test of Kinase 4 Dependent of Ciclin (cdk4) Enzyme tests for IC50 determinations (Table 1 above) and kinetic evaluation were performed on 96 well filter plates (Millipore MADVN6550). The total volume was 0.1 ml containing a final concentration of 20 mM TRIS (tris [hydroxymethyl] aminomethane), at a pH of 7.4, 50 mM NaCl, 1 mM dithiothreitol 10 mM MgCl, 25 μM ATP containing 0.25 μCi of [32 P] ATP, 20 ng of cdk4 complex, 1 μg of retinoblastoma and the appropriate dilutions of a compound of the present invention. All components except ATP were added to the wells and the plate was placed in a plate mixer for 2 minutes. The reaction was started by adding [32PJATP and the plate was incubated at 25 ° C for 15 minutes. The reaction was terminated by the addition of 0.1 ml of 20% trichloroacetic acid (TCA). The plate was kept at 4 ° C for at least 1 hour to allow the substrate to precipitate. The wells were subsequently washed five times with 0.2 ml of 1% TCA and the 32 P incorporation was determined with a beta plate counter (Wallac Inc., Gaithersburg, Mapland).
The IC50 determinations and the kinetic evaluation were performed in a 96-well filter plate (Millipore MADVN6550) in a total volume of 0.1 ml of 20 mM TRIS (tris [hydroxymethyl] aminomethane), at a pH of 7.4, 50 mM NaCl , 1 mM dithiothreitol 10 mM MgCl 2, 25 μM ATP containing 0.25 μCi of [32 P] ATP, 20 ng of enzyme (either cdk2 / ciclinE, - • * '• - * Cdk2 / A or cdc2 / ciclinB), 1 μg of retinoblastoma and the appropriate dilutions of a paticular compound of the invention. All components except ATP were added to the wells and the plate was placed in a plate mixer for 2 minutes. The reaction was started by adding '. 2PJATP and the plate was incubated at 25 ° C for 15 minutes. The reaction was terminated by the addition & 0.1 ml of 20% trichloroacetic acid (TCA). The plate was stored at 4 ° C for at least 1 hour • to allow the substrate to precipitate.The wells were subsequently washed five times with 0.2 ml of 1% TCA and the 32P incorporation was determined with a beta plate counter (Wallac Inc., Gaithersburg, Mariland). 10 The IC 50 values were determined using enzyme tests performed in a total volume of 0.1 ml of a solution comprising 25 mM Hepes, pH 7.4, 5 mM MgCl 2, 2 mM MnCl 2, 50 μM sodium vanadate, 5 a 10 ng of cdk4 and 200 μM of a peptide substrate Ala-Glu-Gly-Ser-Ala-Tyr472-Glu-Glu-Val-NH2, derived from the amino acid [Try472 has been shown to be 1 of the 4 tyrosines in PLC-? which were phosphorylated by the tyrosine kinase of the EGF receptor (Wahl M.I., et al., J. Biol. Chem., 1990; 265: 3944-3948) and the peptides derived from the enzyme sequence around this site are excellent substrates for the enzyme], 10 μM of ATP containing 1 μCi of 2] ATP and incubated for 10 minutes at room temperature. The reaction was terminated by 2 ml of 75 mM phosphoric acid and the contents of the reaction passed through a 2.5 cm phosphocellulose filter disk to bind the peptide. The filter was washed five times with 75 mM of 0"phosphoric acid, placed in an ampoule with 5 ml of flash fluid (Ready gel, Beckman) and counted in a flash counter.
Compounds of Formula I have also exhibited good inhibitory activity against other cylin-dependent kinase enzymes such as cdk2 / ciclinE, cdk2 / ciclinA and 5 cdkl / ciclinB.
When measured against cdk2 / E, the compounds of the invention exhibited IC50 values generally ranging from about 0.004 to more than 5 μM. Against the cdk2 / A, the compounds exhibited IC50 values ranging from about 0.028 to more than 5 μM and against cdk2 / B, generally from about 0.214 to more than 5 μM. The tests were carried out as described above and the specific data are provided in Table 1 above.
Kinease Test Protocol Proline-directed protein cdk5 / p25 Enzyme source: insect sf9 cell infected with recombinant baculovirus - recombinant Cdk5-p25 complex expressed.
Purpose: To assess the ability of test agents to inhibit Cdk5 / p25 phosphorylation of Histone H1. # " Method: His-tagged baculovirus insect enzyme complex Cdk5 / Glu labeled p25 (0 GST-p25) was diluted to a concentration of 50 ng / 20 μl in Enzyme Dilution Stabilizer (EDB - 50 mM Tris-HCl [pH 8.0], 10 mM NaCl, 10 mM MgCl 2 and 1 mM DTT). A 20 μl sample of the final Cdk5 / p25 enzyme preparation and remained for 5 minutes at room temperature. Twenty-five microliters of the substrate solution containing 115 μl / ml of Histone H1, 30 μM of ATP (vanadate-free) and 30 μCi / ml? -33 ATP (Amersham) in EDB was subsequently added to the preparation of the enzyme / agent test and stirred at 30 ° C for 45 minutes. A 50 μl sample of the final preparation was added to 100 ml of 150 mM phosphoric acid on ice for 30 minutes to facilitate precipitation. The precipitate was then filtered through a 96-well phosphocellulose filter plate and subsequently rinsed 3 times with 75 mM phosphoric acid. Each well subsequently received 20 μl of the flash cocktail and the plates were counted for beta emissions using a Trilux Counter (33P filter protocol). The samples were compared to the Control (without the test agent present, as 0% inhibition) and the Baseline level (without enzyme, without test agent, as 100% inhibition) of the beta emissions to determine the Percentage inhibition of histone H1 phosphorylation.
The compounds of the invention can be formulated in conventional manners to provide convenient dosage forms for delivery in mammals by various routes, including oral, parenteral (i.e., subcutaneous, intravenous and intramuscular), transdermal, i.e., skin patches slow release or cream, as well as slow release devices such as osmotic pumps, suppositories and mouth seals. The following examples further illustrate how the compounds are rapidly formulated.
EXAMPLE 51 Formulation of 50 mg Tablets By Tab, e, a and 0.050 g Example 20 500 g 0.080 g Lactose 800 g 0.010 g Corn starch (per mixture) 100 g 0.008 g Corn starch (per paste) 80 g 0.148 g 1480 g 0.002 g Magnesium stearate (1 %) 20 g 0.150 g 1500 g Quinazoline, lactose and corn starch (for mixing) are mixed uniformly. The corn starch (for pasta) is suspended in 600 ml of water and heated with agitation to form a paste. This paste is used to granulate the mixed powders. The wet granules are passed through a No. 8 hand sieve and dried at 80 ° C. The dried granules are passed through a No. 16 sieve. The mixture is lubricated with 1% magnesium stearate and Compresses inside tablets in a conventional sheeting machine. The tablets are useful for treating cancers such as breast, prostate, lung, ovarian, colon, pancreatic, melanoma, esophageal, brain, Kaposi's sarcoma, and lymphomas or neurodegenerative diseases such as Alzheimer's. .
EXAMPLE 52 Preparation of the oral suspension Ingredient Quantity Example 20 500 g Sorbitol solution (70% N.F.) 40 ml Sodium benzoate 150 mg Saccharin 10 mg Cherry flavor 50 mg Distilled water qa 100 ml The sorbitol solution was added to 40 ml of distilled water and the quinazoline was suspended therein. Saccharin, sodium benzoate and flavoring were added and dissolved. The volume was adjusted to 100 ml with distilled water. Each millimeter of syrup contains 5 mg of the compound of the invention.
EXAMPLE 53 Preparation of Parenteral Solution In a solution of 700 ml of propylene glycol and 200 ml of water for injection, 20.0 g of Example 20 were suspended with stirring. After the suspension was complete, the pH was adjusted to 5.5 with hydrochloric acid and the volume was raised to 1000 ml with water for injection. The formulation was sterilized, filled into 5.0 ml ampoules, each containing 2.0 ml (representing 40 mg of the compound of the invention) and sealed under nitrogen.
EXAMPLE 54 Suppositories A mixture of 400 mg of Example 20 and 600 mg of theobromine oil was stirred at 60 ° C for uniformity. The mixture was cooled and hardened in a conical mold to provide a 1 g suppository.
EXAMPLE 55 Slow Release Form Five hundred milligrams of Example 20 were converted to a hydrochloric salt and placed in an osmotic pump for the controlled release for the treatment of arteriosclerosis.
EXAMPLE 56 Formulation of Skin Patches Fifty milligrams of Example 20 were mixed with 50 mg of propylene glycol monolaurate in a polydimethylsiloxane adhesive. The mixture was separated into layers in an elastic film made with an adhesive formulation of polybutene, polyisobutylene and propylene glycol monolaurate. The layers were placed between two layers of a polyurethane film. A release cover was added to the adhesive surface and removed before application to the surface of the skin. Propylene glycol monolaurate serves as an agent to improve penetration.

Claims (80)

* CLAIMS
1. A compound of Formula I: wherein, Rf is hydrogen, alkyl, alkyl substituted with at least one amine, halogen, hydroxy or alkoxy, cycloalkyl or heterocycloalkyl; 1 & R2 is OH, alkyloxy, aryloxy or NR3R4; A is N or CW3; R3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, (CH2) nAr, cycloalkyl, heterocycloalkyl or heteroaryl or R3 and R4 together with the nitrogen to which they are optionally added can form a ring having from 3 to 7 carbon atoms. carbon and said ring 20 optionally contains 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen and sulfur including S (O) and S (0) 2. Said ring can also be further substituted with more than 3 three groups selected from alkyl, haloalkyl, R ^ CfOR9, C (0) OR8, C (0) R8, C (0) NR8R9, NR8R9, NRdS02R9, OR8, S02NR3R4 or SR8; - w1 and W2 are independently selected from NR3R4, N (0) R3R4, NR3R R8X, OR3, SR3, 25 hydrogen, halogen, haloalkyl, COR3, C02R3, CONR3R4, S (0) R3, S02R3, S02NR3R4, S02R3, 602NR3R4, S03R3, P (0) (OR3) 2, aldehyde, nitrile, nitro, alkyl, T (CH2) mQRd, C (0) T (CH2) mQR8 or 3? -. 4? 3r- > 4 T (CH2) mC02R ° where m is 1-6. T is O, S, NRJ, N (0) Rβ, NRJR * X or CRJR * and Q is O, S, NRa, N (0) R9 or NR9R10X or NR9C (0) T (CH2) mQR9; - '' i * R is hydrogen or alkyl,% S hydrogen, alkyl, halogen, S02NR3R4, S02R3, S03R3, P (0) (OR3) 2 W3 is NR3R4, NR3R4R8X, OH, OR3, SH, SR3, halogen, COR3, C02R3, CONR3R4, S (0) R3, S02R3, S02NR3R4, S03R3, (CH2) nP (0) (OR3) 2, NR3S02R4, aldehyde, nitrile, nitro, alkyl, T (CH2) mQR8, C (0) T (CH2) mQR8, NR8C (0) T (CH2) mQR11 or T (CH2) mC02R3 where m and n are independently 1-6, T is O, S, NR3, N (0) R3, NR3R4W or CR ^ R4 and Q is O, S, NR9, N (0) R9 or NR9R 0X; R8, R9, R10 and R11 are hydrogen, alkyl or aryl; X is a halogen; or a pharmaceutically acceptable salt, ester, amide or pro-drug thereof.
2. A compound according to claim 1, wherein R 1 is alkyl.
3. A compound according to claim 1, wherein R 1 is isopropyl.
4. A compound according to claim 1, wherein R 1 is cycloalkyl.
5. A compound according to claim 1, wherein R 1 is cyclopentyl.
A compound according to claim 1, wherein R is hydroxy.
A compound according to claim 1, wherein R is alkyloxy.
8. A compound according to claim 1, wherein R is methoxy.
9. A compound according to claim 1, wherein R 2 ü 3? - > 4 is NR R
10. A compound according to claim 1, wherein A is CW3.
11. A compound according to claim 1, wherein W3 is piperidine.
12. A compound according to claim 1, wherein W3 is substituted piperidine.
13. A compound according to claim 1, wherein W3 is pyrrolidine.
14. A compound according to claim 1, wherein W3 is substituted pyrrolidine.
15. A compound according to claim 1, wherein W3 is piperazine.
16. A compound according to claim 1, wherein W3 is substituted piperazine.
17. A compound according to claim 1, wherein W3 is hydrogen.
18. A compound according to claim 1, wherein W2 and W3 are hydrogen.
19. A compound according to claim 1, wherein R is hydrogen
20. A compound according to claim 1, wherein R5 is alkyl.
21. A compound according to claim 1, wherein R6 is hydrogen.
22. A compound according to claim 1, wherein R is alkyl.
23. A compound according to claim 1, wherein W1, W2 and W3 are hydrogen.
24. A compound according to claim 1, wherein R5 and R6 are hydrogen.
25. A compound according to claim 1, wherein W1, W2 and W3 are hydrogen and R1 is alkyl.
26. A compound according to claim 1, wherein W1, W2 and W3 are hydrogen and R1 is cycloalkyl.
27. A compound according to claim 1, wherein W3 is piperidine or substituted piperidine and R1 is alkyl or cycloalkyl.
28. A compound according to claim 1, wherein W3 is pyrrolidine or substituted pyrrolidine and R1 is alkyl or cycloalkyl.
29. A compound according to claim 1, wherein W3 is piperazine or substituted piperazine and R1 is alkyl or cycloalkyl.
30. A compound according to claim 1, wherein W3 is piperidine or substituted piperidine, R2 is alkyloxy and R1 is alkyl or cycloalkyl.
* 31. A compound according to claim 1, wherein W3 is pyrrolidine or substituted pyrrolidine, R2 is alkyloxy and R1 is alkyl or cycloalkyl.
32. A compound according to claim 1, wherein W is piperazine or IF substituted piperazine, R2 is alkyloxy and R1 is alkyl or cycloalkyl. 8 *
33. A compound selected from: (8-lsopropyl-7-methoxy-quinazolin-2-yl) -phenyl-amine; (8-Cyclopentyl-7-methoxy-quinazole? N-2-yl) -phenyl-amine; (8-isopropyl-7-methoxy-quinazolin-2-? L) -4- (piperidin-1-yl-phenyl) -amine; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - (4-piperidin-1-yl-phenyl) -amine; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - (4-pyrrolidin-1-yl-phenyl) -amine; 8-lsopropyl-2-phenylamino-quinazolin-7-ol; 4- [4- (8-lsopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester. 4- [4- (8-Cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazine-1-carboxylic acid tert-butyl ester; h '"(8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - (4-piperazin-1-yl-phenyl) -amine; 8-Cyclopentyl-2- (4-piperazin-1-yl-phenylamino) -quinazolin-7-ol; 2-amino-1- {4- [4- (8-cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl} -piperazin-1-yl} -ethanone; 8-lsopropyl-2- (4-piperaxin-1-yl-phenylamino) -quinazolin-7-ol; (8-lsopropyl-7-methoxy-quinazolin-2-yl) - (4-piperazin-1-yl- phenyl) -amine; 2-Amino-1- {4- {4- (8-cyclopentyl-7-hydroxy-quinazolin-2-ylamino) -phenyl} -piperazin-1-yl} -ethanone; -Amino-1- { 4- [4- (8-isopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -p? Peraz? N-1-yl.}.-Ethanone; 2-Amino -1-. {4- [4- (7-hydroxy-8-isopropyl-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -ethanone; 2-Amino-1- {. 4- [4- (8-cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazn-1-yl} -4-methyl-pentan-1-one; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-hydroxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -4-methyl-pentt-1-one; f * * 2-Amino-1-. { 4- [4- (8-isopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -4-methyl-pentan-1-one; 2-Amino-1-. { 4- [4- (7-hydroxy-8-isopropyl-quinazole? N-2-ylamino) -phenyl] -piperazin-1-yl} -4-methyl- 'pentan-1-one; N- (4- { 4- [4- (8-cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -4-oxo-butyl) -acetamide; N- (4- { 4- [4- (8-cyclopentyl-7-hydroxy-quinazole? N-2-? Lamino) -phenyl] -piperazin-1-yl.} -4-oxo-butyl) - »> i i. acetamide; N- (4- { 4- [4- (8-isopropyl-7-methoxy-quinazolin-2-alamino) -phenyl] -piperazin-1-yl.} -4-oxo-butyl) -acetamide; N- (4- { 4- [4- (7-Hydroxy-8-isopropyl-qu? Nazolin-2-ylamino) -phenyl] -piperazin-1-yl.} -4-oxo-butyl) - Aeetamide; 8-lsopropyl-2- (pyridin-4-ylamino) -quinazolin-7-ol; (8-lsopropyl-7-methoxy-quinazolin-2-yl) -pyridin-4-yl-amine; (8-cyclopentyl-7-methoxy-quinazolin-2-yl) -pyridin-4-yl-amine; 8-Cyclopentyl-2- (pyridin-4-alamino) -quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - [4- (5-methy- hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenyl] -amine; 8-Cyclopentyl-2- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -quinazolin-7-ol; (8-lsopropyl-7-methoxy-quinazolin-2-yl) - [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenyl] -amine; 8-lsoprTpil-2-t4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -quinazolin-7-ol; [4- (3-Amino-pyrrolidin-1-yl) phenyl] - (8-cyclopentyl-7-methoxy-quinazolin-2-yl) -amine; 2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-quinazolin-7-ol; [4- (3-Amino-pyrrolidin-1-yl) -phenyl] - (8-isopropyl-7-methoxy-quinazolin-2-yl) -amine; 2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -8-isopropyl-quinazolin-7-ol; s? (4-Fluoro-3-trifluoromethyl-phenyl) - (8-isopropyl-7-methoxy-quinazolin-2-yl) -amine; 2- (4-Fluoro-3-trifluoromethyl-phenylamino) -8-isopropyl-quinazole? N-7-ol; (4-Fluoro-3-trifluoromethyl-phenyl) - (8-cyclopentyl-7-methoxy-quinazolin-2-yl) -amine; 2- (4-Fluoro-3-trifluoromethyl-phenylamino) -8-cyclopentyl-quinazolin-7-ol; N-. { 1- [4- (8-Cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -pyrrolidin-3-yl} -acetamide; N-. { 1- [4- (8-Cyclopentyl-7-hydroxy-quinazolin-2-ylamino) -phenyl] -pyrrolidin-3-yl} -acetamide; N-. { 1- [4- (8-lsopropyl-7-methoxy-quinazolin-2-alamino) -phenyl] -pyrrolidin-3-yl} -acetam? da; N-. { 1- [4- (8-lsopropyl-7-hydroxy-quinazolin-2-ylamino) -phenyl] -pyrrolidin-3-yl} -acetamide; 1-. { 4- [4- (8-lsopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; 1-. { 4- [4- (7-Hydroxy-8-isopropyl-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; . { 4- [4- (8-Cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -pyrrolidin-2-yl-methanone; . { 4- [4- (8-C? Clopentyl-7-Hydroxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -pyrrolidin-2-yl-methanone; 1 -. { 4- [4- (8-Cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; 1-. { 4- [4- (8-Cyclopentyl-7-hydroxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; . { 4- [4- (8-lsopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -pyrrolidin-2-yl-methanone; . { 4- [4- (7-Hydroxy-8-isopropyl-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -pyrrolidin-2-yl-methanone; 2-Amino-1-. { 4- [4- (8-isopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 2-Amino-1-. { 4- [4- (7-hydroxy-8-isopropyl-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-hydroxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 1-. { 4- [4- (8-C? Clopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 1-. { 4- [4- (8-C? Clopentyl-7-hydroxy-quinazolin-2-ylamino) -phenyl? -piperazin-1-yl} -propan-1-one; 1 - . 1 -. { 4- [4- (8-lsopropyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1 -one; 1 -. { 4- (7-Hydroxy-8-isopropyl-quinazolirh-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1 -one; 8-lsopropyl-2-phenylamino-5,6-dihydro-quinazolin-7-ol; (8-lsopropyl-7-methoxy-5,6, -dihydro-quinazolin-2-yl) -phenylamine; 8-lsopropyl-7-methoxy-5,8-dihydro-quinazolin-2-yl-phenyl-amine; (8-lsopropyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) -phenyl-amine; 8-Cyclopentyl-2-phenylamino-5,6-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) -phenyl-amine; 8-Cyclopentyl-2-phenylamino-5,8-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) -phenyl-amine; 8-lsopropyl-2- (4-pyrrolidin-1-yl-phenylamino) -5,6-dihydro-quinazolin-7-ol; (8-lsopropyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) - (4-pyrrolidin-1-yl-phenyl) -amine; 8-lsopropyl-2- (4-pyrrolidin-1-yl-phenylamino) -5,8-dihydro-quinazolin-7-ol; (8-lsopropyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) - (4-pyrrolidin-1-yl-phenyl) -amine; 8-Cyclopentyl-2- (4-pyrrolidin-1-yl-phenylamino) -5,6-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) - (4-pyrrolidin-1-yl-phenyl) -amine; 8-Cyclopentyl-2- (4-pyrrolidin-1-yl-phenylamino) -5,8-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) - (4-pyrrolidin-1-yl-phenyl) -amine; 8-lsopropyl-2- (4-piperazin-1-yl-phenylamino) -5,6-dihydro-quinazolin-7-ol; (8-lsopropyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) - (4-piperazin-1-yl-phenyl) -amine; 8-lsopropyl-2- (4-piperazin-1-yl-phenylamino) -5,8-dihydro-quinazolin-7-ol; (8-lsopropyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) - (4-piperazin-1-yl-phenyl) -amine; 8-Cyclopentyl-2- (4-piperazin-1-yl-phenylamino) -5,6-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) - (4-piperazin-1-yl-phenyl) -amine; 8-Cyclopentyl-2- (4-piperazin-1-yl-phenylamino) -5,8-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) - (4-piperazin-1-yl-phenyl) -amine; 2- (4-Fluoro-3-methyl-phenylamino) -8-isopropyl-5,6-dihydro-quinazolin-7-ol; (4-Fluoro-3-methyl-phenyl) - (8-isopropyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) -amine; 2- (4-Fluoro-3-methyl-phenylamino) -8-isopropyl-5,8-dihydro-quinazolin-7-ol; (4-Fluoro-3-methyl-phenyl) -8-isopropH-7-methoxy-5,8-dihydro-quinazolin-2-yl) -amine; 8-Cyclopentyl-2- (4-fluoro-3-methyl-phenylamino) -5,6-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) - (4-fluoro-3-methyl-phenyl) -amine; 8-Cyclopentyl-2- (4-fluoro-3-methyl-phenylamino) -5,8-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) - (4-fluoro-3-methyl-phenyl) -amine; 8-lsopropyl-2- (pyridin-4-ylamino) -5,6-dihydro-quinazolin-7-ol; (8-lsopropyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) -pyridin-4-yl-amine; 8-lsopropyl-2- (pyridin-4-ylamino) -5,8-dihydro-quinazolin-7-ol; (8-lsopropyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) -pyridin-4-yl-amine; 8-Cyclopentyl-2- (pyridin-4-ylamino) -5,6-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) -pyridin-4-yl-amine; 8-Cyclopentyl-2- (pyridin-4-ylamino) -5,8-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,8-dihydro-quinazol? N-2-yl) -pyrridin-4-yl-amine; 2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -8-isopropyl-5,6-dihydro-quinazolin-7-ol; [4- (3-Amino-pyrrolidin-1-yl) -phenyl] - (8-isopropyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) -amine; 2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -8-isopropyl-5,8-dihydro-quinazolin-7-ol; t4- (3-Amino-pyrrolidin-1-yl) -phenyl] - (8-isopropyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) -amine; 2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-5,6-dihydro-quinazolin-7-ol; [4- (3-Amino-pyrrolidin-1-yl) -phenyl] - (8-cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) -amine; 2- [4- (3-Amino-pyrrolidin-1-yl) -phenylamino] -8-cyclopentyl-5,8-dihydro-quinazolin-7-ol; [4- (3-Amino-pyrrolidin-1-yl) -phenyl] - (8-Cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) -amine; 8-lsopropyl-2- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -5,6-dihydro-quinazolin-7-ol; (8-lsopropyl-7-methoxy-5,6-dihydro-quinazolin-2-yl) - [4- (5-methyl-hexahydro-pyrrolo [3,4-c.] Pyrrol-2-yl) -phenyl [-amine; 8-lsopropyl-2- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -5,8-dihydro-quinazolin-7-pl; (8-lsopropyl-7-methoxy-5,8-dihydro-quinazolin-2-yl) - [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrole-2-- "'Sl)" feWI] -amine; 8-Cyclopentyl-2- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -5,6-dihydroquinazoline? n-7 -ol; 5 '(8-Cyclopentyl-7-methoxy-5,6-dihydro-quinazole? n-2-? l) - [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenyl] amine; * - **.? - 8-Cyclopentyl-2- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino ] -5,8-dihydro-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5,8-dihydro-qu? Nazolin-2-? L) - [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-0 2-yl) -phenyl] amine; 1-. {4- [4- (7-Hydroxy-8-isopropyl-5,6-dihydro-quinazolin-2-ylamino) phenyl] -piperazin-1-yl.}.-ethanone; 1-. {4- [4- (8-lsopropyl-7-methoxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] - piperazin-1-yl.}. -etanone; 1- { 4- [4- (7-Hydroxy-8-isopropyl-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazine- 1-yl.) -etanone; 1- { 4- [4- (8-lsopropyl-7-methoxy-5,8-d? Hydro-quinazolin-2-ylamino) -phen?] -piperazine- 1-il.}.-Etanon to; 5 1-. { 4- [4- (8-C? Clopentyl-7-hydroxy-5,6-d? Hydro-quinazolin-2-ylamino) -phenyl? -piperazin-1-yl} - ethanone; 1-. { 4- [4- (8-Cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - ethanone; 1-. { 4- [4- (8-Cyclopentyl-7-hydroxy-5,8-d? Hydro-quinazolin-2-ylamino) -phenyl] -piperaz? N-1-yl} -0 ethanone; 1-. { 4- [4- (8-Cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - ethanone; 1-. { 4- [4- (7-Hydroxy-8-isopropyl-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; S 1-. { 4- [4- (8-lsopropyl-7-methoxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1- ojia; 1-. { 4- [4- (7-Hydroxy-8-isopropyl-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 1-. { 4-I4- (8-lsopropyl-7-methoxy-5,8-dihydro-quinazoline "2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 1-. { 4- [4- (8-Cyclopentyl-7-hydroxy-5,6-a1hydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-fl} -propan-1-one; 1-. { 4-. { 4- (8-Cyclopentyl-7-methoxy? -5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 1-. { 4- [4- (8-Cyclopentyl-7-hydroxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 1-. { 4- [4- (8-Cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -propan-1-one; 2-Amino-1-. { 4- [4- (7-hydroxy-8-isopropyl-5,6-d? Hydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - 3-methyl-butan-1-one; 2-Amino-1-. { 4- [4- (8-isopropyl-7-methoxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -1-yl} -3-methyl-butan-1-one; 2-Am? No-1 -. { 4- [4- (7-hydroxy-8-isopropyl-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - 3-methyl-butan-1-one; 2-Amino-1-. { 4- [4- (8-isopropyl-7-methoxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - 3-methyI-butan-1 -one; 2-Amino-1. { 4- [4- (8-Cyclopentyl-7-hydroxy-5,6-d? Hydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -3-methyl-butan-1-one; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -3-methyl-butan-1 -one, 2-Amino-1-. { 4- [4- (8-C-Clopentyl-7-hydroxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -3-met? L-butan-1 -one; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-fl-3-methyl-1-butan-1-one; 2-Amino-1-. { 4- [4- (7-hydroxy-8-? -propyl-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazine-1-? L} - 4-metB-pentan-1 -one; 4- < -Ni »* ris * - • *« * 2-Amino-1-. { 4- [4- (8-isoprop? L-7-methoxy-5,6-dihydro-qujr? Azolin-2-ylamino) -phenyl] -piperazin-1-yl} - 4-methyl-pentan-1 -one; 2-Amino-1-. { 4- [4- (7-hydroxy-8-isopropyl-5,8-dihydro-quinazolin-2-8amino) -phenyl] -piperazin-1-yl} - 4-methyl-pentan-1-one; 5 2-Amino-1-. { 4- [4- (8-isopropyl-7-methoxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - 4-methyl-pentan-1-one; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-hydroxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -4-methyl-pentan-1 -one; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -4-methyl-pentan-1-one; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-hydroxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -p-perazin-1-yl} -4-methyl-pentan-1 -one; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -4-methyl-pentan-1 -one; 15 2-Amino-1-. { 4- [4- (7-hydroxy-8-isopropyl-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - ethanone; 2-Amino-1-. { 4- [4- (8-isopropyl-7-methoxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - ethanone; 2-Amino-1-. { 4- [4- (7-hydroxy-8-isopropyl-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - 20 ethanone; 2-Amino-1-. { 4- [4- (8-isopropyl-7-methoxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - ethanone; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-hydroxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazine-1-yl} -etanone; 25 2-Amino-1-. { 4- [4- (8-Cyclopentyl-7-methoxy-5,6-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-hydroxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -p-perazin-1-yl} -etanone; 2-Amino-1-. { 4- [4- (8-cyclopentyl-7-methoxy-5,8-dihydro-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl-ene; (4-Fluoro-3-methyl-phenyl) - (8-isopropyl-7-methoxy-quinazolin-2-yl) -amine; 2- (4-Fluoro-3-methyl-phenylamino) -8-isopropyl-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - (4-fluoro-3-methyl-phenyl) -amine; 8-Cyclopentyl-2- (4-fluoro-3-methyl-phenylamino) -quinazolin-7-ol; (3-Chloro-4-fluoro-phenyl) - (8-isopropyl-7-methoxy-quinazolin-2-yl) -amine; 2- (3-Chloro-4-fluoro-phenylamino) -8-isopropyl-quinazolin-7-ol; (3-Chloro-4-fluoro-phenyl) - (8-cyclopentyl-7-methoxy-quinazolin-2-yl) -amine; 2- (3-Chloro-4-fluoro-phenylamino) -8-cyclopentyl-quinazolin-7-ol; (3,4-Difluoro-phenyl) - (8-isopropyl-7-methoxy-quinazolin-2-yl) -amine; 2- (3,4-Difluoro-phenylamino) -8-isopropyl-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) -3,4-difluoro-phenyl) -amine; 8-Cyclopentyl-2- (3,4-difluoro-phenylamino) -quinazolin-7-ol; (3-Fluoro-4-piperazin-1-yl-phenyl) - (8-isopropyl-7-methoxy-quinazolin-2-yl) -amine; 2- (3-Fluoro-4-piperazin-1-yl-phenylamino) -8-isopropyl-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - (3-fluoro-4-piperazin-1-yl-phenyl) -amine; 8-Cyclopentyl-2- (3-fluoro-4-piperazin-1-yl-phenylamino) -quinazolin-7-ol; [4- (3-Amino-pyrrolidin-1-yl) -3-fluoro-phenyl] - (8-isopropyl-7-methoxy-quinazolin-2-yl) -amine; 2- [4- (3-Amino-pyrrolidin-1-yl) -3-fluoro-phenylamino] -8-isopropyl-quinazolin-7-ol; [4- (3-Amino-pyrrolidin-1-yl) -3-fluoro-phenyl] - (8-cyclopentyl-7-methoxy-quinazolin-2-yl) -amino; 2- [4- (3-Amino-pyrrolidin-1-yl) -3-fluoro-phenylamino] -8-cyclopentyl-quinazolin-7-ol; . { 3-Fluoro-4- [4- (3-morpholin-4-yl-propyl) -piperidin-1-yl] -phenyl} - (8-isopropyl-7-methoxy-quinazolin-2-ylamine; 2- {3-fluoro-4- [4- (3-morpholin-4-yl-propyl) -piperidin-1-yl]] -phenylamino.} - 8-isopropyl-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) -. {3-fluoro-4- [4- (3-morpholin-4 -yl-propyl) -piperidin-1-yl] -phenyl} -amine; 8-Cyclopentyl-2-. {3-fluoro-4- [4- (3-morpholin-4-yl-propyl) - piperidin-1-yl] -phenylamino.} --quinazolin-7-ol; (8-lsopropyl-7-methoxy-quinazolin-2-yl) -. { 4- [4- (3-morpholin-4-yl-propyl) -piperidin-1-yl] -phenyl} -amine; 8-lsopropyl-2-. { 4- [4- (3-morpholin-4-yl-propyl) -piperidin-1-yl] -phenylamino} -quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) -. { 4- [4- (3-morpholin-4-yl-propyl) -piperidin-1-yl] -phenyl} - amine; 8-Cyclopentyl-2-. { 4- [4- (3-morpholin-4-yl-propyl) -piperidin-1-yl] -phenylamino} -quinazolin-7-ol; (8-lsopropyl-7-methoxy-quinazolin-2-yl) -. { 4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl} -amine; 8-lsopropyl-2-. { 4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenylamino} -quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) -. { 4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenyl} - amine; 8-Cyclopentyl-2-. { 4- [4- (3-piperazin-1-yl-propyl-1) -piperidin-1-yl] -phenylamino} -quinazolin-7-ol; . { 3-Chloro-4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenyl} - (8-isopropyl-7-methoxy-quinazolin-2-yl) -amine; 2-. { 3-Chloro-4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenylamino} -8-isopropyl-quinazolin-7-ol; . { 3-Chloro-4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenyl} - (8-cyclopentyl-7-methoxy-quinazolin-2-yl) -amine; 2-. { 3-Chloro-4- [4- (3-piperazin-1-yl-propyl) -pipoeridin-1-yl] -phenylamino} -8-cyclopentyl-quinazolin-7- ol; (3-Fluoro-4- { 4- [3- (1 H-tetrazol-5-yl) -propyl] -piperidin-1-yl.} - phenyl) - (8-isopropyl-7-methoxy) quinazolin-2-yl) -amine; 2- (3-Fluoro-4- { 4- [3- (1 H -tetrazol-5-yl) -propyl] -piperidin-1-yl.} - phenylamino) -8-isopropyl-quinazolin-7 - ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - (3-fluoro-4- { 4- [3- (1 H -tetrazol-5-yl) -propyl] -piperidin-1-yl} phenyl) -amine; 8-Cyclopentyl-2- (3-fluoro-4-. {4- [3- (1 H -tetrazol-5-yl) -petroyl] -piperidin-1-yl} - phenylamino) -quinazolin-7 -ol; (4- { 4- [3- (3-Amino-pyrrolidin-1-yl) -propyl] -piperidin-1-yl}. -3-chloro-phenyl) - (8-isopropyl-7-methoxyl) - quinazolin-2-yl) -amine; qttinazolin-7-ol; (4- { 4- [3- (3-Amino-pyrrolidin-1-yl) -propyl-J-piperidin-1-yl.} - 3-chloro-phenyl) - (8-cyclopentyl-7-methoxy) quinazole? n-2-yl) -amino; 2- (4- { 4- [3- (3-Amino-pyrrolid? N-1-yl) -propyl] -piperidin-1-yl.} - 3-chloro-phenylamino) -8-cyclopentyl- quinazolin-7-ol; (4- {4-t3- (3-Amino-pyrrolidin-1-yl) -propyl] -piperidin-1-yl.} - phenyl) - (8-isopropyl-7-methoxy-quinazolin-2) -yl) -amine; 2- (4- { 4- [3- (3-Amino-pyrrolidin-1-yl) -prop] -1] -piperid? N-1-yl.}.-Phenylamino) -8-isopropyl-quinazolin- 7- ol, (4- { 4- [3- (3-Am? No-pyrrolidin-1-yl) -propyl] -piper? Din-1-yl.}. -phenyl) - (8-cyclopentyl) -7-methoxy-quinazolin-2-yl) -amine; 2- (4- { 4- [3- (3-Amino-pyrrolidin-1-yl) -propyl] -piperidin-1-yl} -phenylamino) -8-cyclopentyl-quinazolin-7-ol; (8-lsopropyl-7-methoxy-quinazolin-2-yl) -. { 4- [4- (4-methoxy-phenyl) -piperazin-1-yl] -phenyl} -amine; 8-lsopropyl-2-. { 4- [4- (4-methoxy-phenyl) -piperazin-1-yl] -phenylamino} -quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) -. { 4- [4- (4-methoxy-phenyl) -piperazin-1-yl] -phenyl} -amine; 8-Cyclopentyl-2-. { 4- [4- (4-methoxy-phenyl) -piperazn-1-yl] -phenylamino} -quinazolin-7-ol; (8-lsopropyl-7-methoxy-quinazolin-2-yl) - [4- (3,3,4-trimethyl-piperazin-1-yl) -phenyl] -amine; 8-lsopropyl-2- [4- (5-meth? L-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenyl] -amine; 8-Cyclopentyl-2- [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenylamino] -quinazolin-7-ol; 8-lsopropyl-2- [4- (3,3,4-tr? Methyl-piperazin-1-yl) -phenylamino] -quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - [4- (3,3,4-trimethyl-piperazin-1-yl) -phenyl] -amine; 8-Cyclopentyl-2- [4- (3,3,4-trimethyl-piperazin-1-yl) -phenylamino] -quinazole? N-7-ol; (8-lsopropyl-7-methoxy-quinazolin-2-yl) - [4- (5-methyl-hexahydro-pyrrolo [3,4-c] pyrrol-2-yl) -phenyl] -amine; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - [4- (2-methylamino-ethoxy) -phenyl] -amine; ., 0? »1-. { 4- [4- (8-Cyclopentyl-7-methoxy-quinazolin-2-ylamino) -phenyl] -perhydro-1,4-diazepin-1-yl} - • ethanone; 8-Cyclopentyl-2- [4- (3,3-dimethyl-piperazin-1-yl) -phenylamino] -quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - [4- (3,3-dimethyl-piperazin-1-yl) -phenyl] -amine; 1-. { 4- [4- (8-Cyclopentyl-7-hydroxy-quinazolin-2-ylamino) -phenyl] -perhydro-1,4-diazepin-1-yl} - "10, R ethanone; (8-Cyclopentyl-7-methoxy-quinazolin-2-yl) - (4- { 4- [3- (1H-tetrazol-5-yl) -propyl] -piperidin-1 -yl.}.-phenyl) -amine; 8-Cyclopentyl-2- (4-. {4- [3- (1 H -tetrazol-5-yl) -propyl] -piperidin-1-yl}. phenylamino) -quinazolin-7-ol; 8-Cyclopentyl-N- (4-piperazin-1-yl-phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-N2- [4- (4-methyl -piperazin-1-yl) -phenyl] -quinazoline-2,7-diamine; 1-. {4- [4- (7-Amino-8-cyclopentyl-quinazolin-2-ylamino) -phenyl] -piperazine- 1-yl.} -etanone; 8-Cyclopentyl-N2- (4-perhydro-1,4-diazepin-1-yl-phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-N2- [4- (3,3-dimethyl-piperazin-1-yl) -phenyl] -quinazoline-2,7-diamine; 8-Cyclopentyl-N7-methyl-N2- (4-piperazin-1-yl-phenyl) -quinazoline-2 7-diamine; 8-Cyclopentyl-N7-methyl-N2- [4- (4-methyl-piperazin-1-yl) -phenyl] -quinazoline-2,7-diamine; 1- { 4- [ 4- (8-Cyclopentyl-7-methylamino-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -ethanone; 8-Cyclopentyl-N7-methyl-N2- (4-perhydro-1,4) -diazepin-1-yl-phenyl) -quinazoline-2,7-diam ina; 8-Cyclopentyl-N2- [4- (3,3-dimethyl-piperazin-1-yl) -phenyl] -N7-methyl-quinazoline-2,7-diamine; 8-Cyclopentyl-N7, N7-dimethyl-N2- (4-piperazin-1-yl-phenyl) -quinazoline-2,7-diamine; 25-Cyclopentyl-N7, N7-dimethyl-N2- [4- (4-methyl-piperazin-1-yl) -phenyl] -quinazoline-2,7-diamine; 1-. { 4- [4- (8-Cyclopentyl-7-dimethylamino-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl] -ethanone; 8-Cyclopentyl-N7, N7-dimethyl-N2- (4-perhydro-1,4-diazepin-1-yl-phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-N2- [4- (3,3-dimethyl-piperazin-1-yl) -phenyl [-N7, N7-dimethyl-quinazoline-2J-diamine; 8-Cyclopentyl-N - (4- {4- [3- (1 H-tetrazol-5-yl) -propyl] -piperidin-1-yl} -phenyl) -quinazoline-2,7-dia ina; 8-C? Clopentyl-N7-methyl-N2- (4-. {4- [3- (1R-J-tetrazol-5-yl) -propyl] -piperidin-1-yl} -phenyl) - quinazoline-2,7-diamine; 8-Cyclopentyl-N2-. { 4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenyl} -quinazoline-2,7-diamine 8-Cyclopentyl-N7-methyl-N2-. { 4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenyl} -quinazoline-2,7- diamine; 8-Cyclopentyl-N7, N7-dimethyl-N2-. { 4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenyl} -quinazol? na-2-diamine; , (8-Cyclopentyl-7-methoxy-5-methyl-quinazolin-2-yl) - (4-perhydro-1,4-diazepin-1-yl-phenyl) -amine; 8-Cyclopentyl-5-methyl-2- (4-perhydro-1,4-diazepin-1-l-phenylamino) -quinazolin-7-ol; 2-. { 4- [4- (8-Cyclopentyl-7-methoxy-5-methyl-quinazolin-2-ylamino) -phenyl] -2,6-dimethyl-p-perazin-1-yl} - ethanol; (8-Cyclopentyl-7-methoxy-5-methyl-quinazolin-2-yl) - [4- (2-methylamino-ethoxy) -phenyl] -amine; 1-. { 4- [4- (8-Cyclopentyl-7-methoxy-5-methyl-quinazolin-2-ylamino) -phenyl] -perhydro-1,4-diazep? N-1-yl} -etanone; 8-Cyclopentyl-2- [4- (3,3-dimethyl-piperazin-1-yl) -phenylamino] -5-methyl-quinazolin-7-ol; (8-Cyclopentyl-7-methoxy-5-methyl-quinazolin-2-yl) - [4- (3,3-dimethyl-piperazin-1-yl) -phenyl] -amine; 1-. { 4- [4- (8-Cyclopentyl-7-hydroxy-5-hydroxy-5-methyl-quinazolin-2-ylamino) -phenyl] -perhydro-1, 4- "; -; diazepin-1-yl}. -etanone; (8-C? clopentyl-7-methoxy-5-methyl-quinazolin-2-? l) - (4- { 4- [3- (1 H-tetrazol-5?) -propyl ] -piperidin-1-yl.} -phenyl) -amine; 8-Cyclopentyl-5-methyl-2- (4-. {4- [3- (1 H -tetrazol-5-yl) -propyl] -piperidin-1-yl.}.-phenylamino) -quinazolin-7-ol; 1- {4- [4- (8-Cyclopentyl-7-hydroxy-5-methyl-quinazolin-2-ylamino) - phenyl] -piperazin-1-yl.}.-ethanone; 1- {4- [4- (8-Cyclopentyl-7-methoxy-5-methyl-quinazolin-2-ylamino) -phenyl] -piperazin-1} -yl.}.-ethanone; 8-Cyclopentyl-5-methyl-2- (4-piperazn-n-1-yl-phenamino) -quinazole? n-7-ol; (8-Cyclopentyl-7-methoxy-5-methyl-quinazolin-2-yl) -. { 4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenyl} -amine; 8-Cyclopentyl-5-methyl-N2- (4-piperazin «. 1 -yl-phenyl) -quinazoline-2,7-d-amine; 8-Cyclopentyl-5-methyl-N2- [4- (4-meth? L-piperazin-1-yl) -phenyl] -quinazoline-2,7-diamine; 1-. { 4- [4- (7-Amino-8-cyclopentyl-5-methyl-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} -etanone; 8-Cyclopentyl-5-methyl-N2- (4-perhydro-1,4-d? Azepin-1-yl-phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-N2- [4- (3,3-dimethyl-piperazin-1-yl) -phenyl] -5-methyl-quinazoline-2,7-diamine; 8-Cyclopentyl-5, N7-dimethyl-N2- (4-piperazin-1-yl-methyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-5, N7-dimethyl-N2- [4- (4-methyl-piperazin-1-yl) -phenyl] -quinazoline-2,7-diamine; 1-. { 4- [4- (8-Cyclopentyl-5-methyl-7-methylamino-quinazolin-2-ylamino) -phenyl] -piperazin-1-yl} - ethanone; 8-Cyclopentyl-5, N7-dimethyl-N2- (4-perhydro-1,4-diazepin-1-yl-phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-N2- [4- (3,3-dimethyl-piperazin-1-yl) -phenyl] -5, N7-dimethyl-quinazoline-2J-diamine; 8-C? Clopentyl-5, N7, N7-trimethyl-N2- (4-piperaz? N-1-yl-phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-5, N7, N7-trimethyl-N2- [4- (4-methyl-piperazin-1-yl) -phenyl] -quinazoline-2,7-diamine; 1-. { 4- [4- (8-Cyclopentyl-7-dimethylamino-5-methyl-quinazol? N-2-ylamino) -phenyl] -piperazin-1-yl} - ethanone; 8-Cyclopentyl-5, N7, N7-trimethyl-N2- (4-perhydro-1,4-diazepin-1-yl-phenyl) -quinazoline-2,7-diamine; 8-Cyclopentyl-N - [4- (3,3-dimethyl-piperazin-1-yl) -phenyl] -5, N7, N7-trimethyl-quinazoline-2,7-diamine; 8-Cyclopentyl-5-methyl-N2- (4- {4- [3- (1 H-tetrazol-5-yl) -propyl] -piperidin-1-yl} -phenol] -quinazoline -2,7-diamine; 8-Cyclopentyl-5, N7-dimethyl-N2- (4-. {4- [3- (1 H-tetrazol-5-yl) -propyl] -piperidin-1- il.} - phenyl) - quinazoline-2J-diamine; 8-Cyclopentyl-5-methyl-N2-. {4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-yl] -phenyl.}. -quinazoline-2,7-diamine; 8-Cyclopentyl-5, N7-dimethyl-N2- { 4- [4- (3-piperazin-1-yl-propyl) -piperidin-1- il] phenyl.}. -quinazoline-2,7-diamine and 8-Cyclopentyl-5, N7, N7-trimethyl-N2-. { 4- [4- (3-piperazin-1-yl-propyl) -piperidin-1-ill-phenyl} - chenazoline-2,7-diamine.
34. A compound of Formula II: where, the dotted line represents a link at position C5-C6, C6-C7 or C7-C8. R1 is hydrogen, alkyl, alkyl substituted with at least one amino, halogen, hydroxy or alkoxy, cycloalkyl or heterocyclic; R2 is OH, alkyloxy, aryloxy or NR3R4; A is N or CW3; R3 and R4 are independently hydrogen, alkyl, alkenyl, alkynyl, (CH2) nAr, cycloalkyl, heterocycloalkyl or heteroaryl or R3 and R4 together with the nitrogen to which they are optionally attached can form a ring having 3 to 7 carbon atoms and said ring optionally contains 1, 2 or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen and sulfur including S (O) and S (0) 2. Said ring can also be further substituted with more than 3 groups selected from alkyl, haloalkyl, NR8C (0) R9, C (0) OR8, C (0) R8, C (0) NR8R9, NR8R9, NR8R9, NR8S02R9, OR8, S02NR3R4 or SR8; W1 and W2 are independently selected from NR3R4, N (0) R3R4, NR3R4R8X, OR3, SR3, hydrogen, halogen, haloalkyl, COR3, C02R3, CONR3R4, S (0) R3, S02R3, S02NR3R4, S03R3, P (0) (OR3) 2, aldehyde, nitrile, nitro, alkyl, T (CH2) mQR8, C (0) T (CH2) mQR8 or T (CH2) mC02R8 where m is 1-6, T is O, S, NRJ, N (0) RJ, NRJR4X or CR ^ R * and Q is O, S, NRa, N (0) Ra or NR? 9aRn1? 0? X or NR9C (0) T (CH2) mQR9; R5 is hydrogen or alkyl; R6 is hydrogen, alkyl, halogen, haloalkyl, alkynyl, alkenyl, COR3, C02R3, C ^ RdR, S02NRJR4, S02Rd, S03RJ, P (0) (ORJ) 2, aldehyde, nitrile, nitro, ORJ or NR 3J0R W3 is NR3R4, N (0) R3R4, NR3R4R8X, OH, OR3, SH, SR3, halo , COR3, C02R3, CONR3R4, S (0) R3, S02R3, S02NR3R4, S03R3, (CH2) nP (0) (OR3) 2, NR3S02R4, aldehyde, nitrile, nitro, alkyl, T (CH2) mQR8, C (0) T (CH2) mQR8, NR8C (0) T (CH2) mQR11 or T (CH2) mC02R3 where n and m are independently 1-6, T is O, S, NR3, N (0) R3, NR3R4W or CR3R4 and Q is O, S, NR9, N (0) R9 or NR9R10X; R8, R9, R10 and R11 are hydrogen, alkyl or aryl; X is a halogen; or a pharmaceutically acceptable salt, ester, amide or a pro-drug thereof.
35. A compound according to claim 1, wherein R 1 is alkyl.
36. A compound according to claim 1, wherein R 1 is isopropyl.
37. A compound according to claim 1, wherein R is cycloalkyl.
38. A compound according to claim 1, wherein R 1 is cyclopentyl.
39. A compound according to claim 1, wherein R is hydroxy
40. A compound according to claim 1, wherein R is alkyloxy.
41. A compound according to claim 1, wherein R is methoxy.
42. A compound according to claim 1, wherein R2 is NR3R4.
43. A compound according to claim 1, wherein A is CW.
44. A compound according to claim 1, wherein W is piperidine.
45. A compound according to claim 1, wherein W is substituted piperidine.
46. A compound according to claim 1, wherein W3 is pyrrolidine. t.
47. A compound according to claim 1, wherein W3 is substituted pyrrolidine.
48. A compound according to claim 1, wherein W3 is piperazine. f *
49. A compound according to claim 1, wherein W3 is substituted piperazine. < 2
50. A compound according to claim 1, wherein W3 is hydrogen.
51. A compound according to claim 1, wherein W2 and W3 are hydrogen.
- 52. A compound according to claim 1, wherein R5 is hydrogen.
53. A compound according to claim 1, wherein R5 is alkyl.
54. A compound according to claim 1, wherein R6 is hydrogen.
55. A compound according to claim 1, wherein R is alkyl.
56. A compound according to claim 1, wherein W1, W2 and W3 are hydrogen.
57. A compound according to claim 1, wherein R5 and R6 are hydrogen.
58. A compound according to claim 1, wherein W1, W2 and W3 are hydrogen and R1 is alkyl.
59. A compound according to claim 1, wherein W1, W2 and W3 are hydrogen and R1 is cycloalkyl.
60. A compound according to claim 1, wherein W is piperidine or substituted piperidine and R 1 is alkyl or cycloalkyl.
61. A compound according to claim 1, wherein W3 is substituted pyrrolidine or pyrrolidine and R1 is alkyl or cycloalkyl.
62. A compound according to claim 1, wherein W3 is piperazine or substituted piperazine and R1 is alkyl or cycloalkyl.
63. A compound according to claim 1, wherein W is piperidine or substituted piperidine, R 2 is alkyloxy and R 1 is alkyl or cycloalkyl.
64. A compound according to claim 1, wherein W3 is pyrrolidine or substituted pyridine, R2 is alkyloxy and R1 is alkyl or cycloalkyl.
65. A compound according to claim 1, wherein W is piperazine or "* < t. substituted piperazine, R2 is alkyloxy and R1 is alkyl or cycloalkyl. ^ w »
66. A pharmaceutical formulation comprising a compound selected from the, * < - * "*,; * claims 1-66 in combination with a pharmaceutically acceptable carrier, diluent or excipient.
67. A method for controlling proliferative diseases in mammals comprising administering to said mammal a therapeutically effective pharmaceutical formulation according to one of claims 1-66.
68. A method for controlling the proliferative disease according to claim 67, wherein the disease is selected from the group consisting of arteriosclerosis, post-surgical vascular stenosis and restenosis.
69. A method for controlling neurodegenerative diseases in mammals comprising administering to said mammal a therapeutically effective pharmaceutical formulation according to one of claims 1-66.
70. A method for inhibiting a cylin dependent kinase comprising contacting the cylinase dependent cyclin with a compound selected from one of claims 1-66.
71. A method according to claim 70 wherein said cyclin-dependent kinase is cdkl.
72. A method according to claim 70 wherein said cylin dependent kinase is cdk2.
73. A method according to claim 70 wherein said cylin dependent kinase is cdk4.
74. A method for controlling infections in mammals comprising administering to said mammal a therapeutically effective pharmaceutical formulation of * compliance with one of claims 1-66.
75. A method for controlling cancer in mammals comprising administering to said mammal a therapeutically effective pharmaceutical formulation according to one of claims 1-66.
76. A method for controlling autoimmune diseases in mammals comprising the administration to said mammal of a therapeutically effective pharmaceutical formulation according to one of claims 1-66.
77. A method for controlling gout in mammals comprising administering to said mammal a therapeutically effective pharmaceutical formulation according to one of claims 1-66.
78. A method for controlling kidney disease in mammals comprising administering to said mammal a therapeutically effective pharmaceutical formulation according to one of claims 1-66.
79. A compound of Formula III wherein R1 is hydrogen, alkyl, alkyl substituted with at least one amine, halogen, hydroxy or alkoxy, cycloalkyl or heterocycloalkyl; R is OH, alkyloxy, aryloxy or NR 3DR4 *; R5 is hydrogen or alkyl; R6 is hydrogen, alkyl, halogen, haloalkyl, alkynyl, alkenyl, COR3, C02R3, CONR3R4, S02NR3R4, S02R3, S03R3, P03R3, aldehyde, nitrile, nitro, OR3 or NR3R4 and X is oxygen or halogen or a salt, ester, pharmaceutically amide acceptable or prodigal thereof.
80. A compound according to claim 79, wherein R2 is alkyloxy, R5 is hydrogen or alkyl, R6 is hydrogen and R8 is oxygen or chlorine.
MXPA02003140A 1999-11-22 2000-11-03 Quinazolines and their use for inhibiting cyclin dependent kinase enzymes. MXPA02003140A (en)

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