WO2005097137A2 - Advanced quinazoline based protein kinase inhibitors - Google Patents

Advanced quinazoline based protein kinase inhibitors Download PDF

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WO2005097137A2
WO2005097137A2 PCT/US2005/010974 US2005010974W WO2005097137A2 WO 2005097137 A2 WO2005097137 A2 WO 2005097137A2 US 2005010974 W US2005010974 W US 2005010974W WO 2005097137 A2 WO2005097137 A2 WO 2005097137A2
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salt
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prodrug
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Congxin Liang
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The Scripps Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • 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
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • 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
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to protein kinase inhibitors and to their use in treating disorders related to abnormal protein kinase activities such as cancer and inflammation. More particularly, the invention relates to quinazoline based protein kinase compounds and their pharmaceutically acceptable salts employable as protein kinase inhibitors.
  • Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups of tyrosine, serine, and threonine residues of proteins. Many aspects of cell life (for example, cell growth, differentiation, proliferation, cell cycle and survival) depend on protein kinase activities. Furthermore, abnormal protein kinase activity has been related to a host of disorders such as cancer and inflammation. Therefore, there is a great deal of effort directed to identifying ways to modulate protein kinase activities. In particular, many attempts have been made to identify small molecules which act as protein kinase inhibitors.
  • the invention is directed to hydroxy containing quinazoline derivatives and to their use as inhibitors of protein kinases. It is disclosed herein that hydroxy containing quinazoline derivatives have enhanced and unexpected drug properties that advantageously distinguish this class of compounds over known quinazoline derivatives having protein kinase inhibition activity. It is also disclosed herein that hydroxy containing quinazoline derivatives are useful in treating disorders related to abnormal protein kinase activities such as cancer.
  • One aspect of the invention is directed to a compound represented by Formula (I):
  • X is a triradical selected from the group consisting of N and C(R 3 ); Y is a diradical selected from the group consisting of N(R 4 ) and O; Z is a radical selected from the group consisting of optionally substituted phenyl, pyridine, indole, indazole, naphthalene, benzofuran, and benzothiophene; R 1 is a radical selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkoxy, and (C5-C8) heterocycloalkoxy; R 2 is a radical selected from the group consisting of hydroxyl, (C1-C6) alkoxy, (C5-C8) cycloalkoxy, and -NR 5 R 6 ; n is 1 or 2; R 3 is a radical
  • R 2 is a radical selected from the group consisting of hydroxyl, (C1-C6) alkoxy, and (C5- C8) cycloalkoxy.
  • Preferred embodiments of this first subgenus compounds represented by the following structures:
  • Further embodiments of the first subgenus of the first aspect of the invention include compounds represented by the following structures: Further embodiments of the first subgenus of the first aspect of the invention include compounds represented by the following structures:
  • R 2 is -NR 5 R 6 .
  • Embodiments of the second subgenus of the first aspect of the invention include compounds represented by the following structures:
  • Further embodiments of the second subgenus of the first aspect of the invention include compounds represented by the following structures: Further embodiments of the second subgenus of the first aspect of the invention include compounds represented by the following structures:
  • R 2 is selected from the group consisting of radical represented by the following structures: N / ⁇ )-OH ⁇ ⁇ > ⁇ - 1 ⁇ 0 ⁇ K ⁇
  • a second aspect of the invention is directed to a compound of formula (II):
  • W is a diradical selected from the group consisting of O and S;
  • R 1 is a radical selected from the group consisting of optionally substituted phenyl, benzyl, heteroaryl, and heteroarylalkyl;
  • R 2 is a radical selected from the group consisting of hydroxyl, (C1-C6) alkoxy, (C3-C8) cycloalkoxy, and NR 3 R 4 ;
  • n is 1 or 2;
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) dihydroxyalkyl, (C1-C6) alkoxy , (C1-C6) alkyl carboxylic acid, (C1-C6) alkyl phosphoric acid, (C1-C6) alkyl sulfonic acid, (C1-C6) hydroxyalkyl carboxylic acid, (C1-C6) alkyl amide, (
  • R 2 is a radical selected from the group consisting of hydroxyl, (C1-C6) alkoxy, and (C5-C8) cycloalkoxy.
  • Embodiments of the first subgenus of the second aspect of the invention include compounds represented by the following structures:
  • R 2 is -NR 5 R 6 .
  • Preferred embodiments of the second subgenus of the second aspect of the invention include compounds represented by the following structures:
  • R 2 is selected from the group consisting of radical represented by the following structures:
  • Provisos may apply to any of the above inventive aspects, subgenera, or embodiments wherein any one or more of the other above described embodiments or species may be excluded from its corresponding inventive aspect, subgenus, or embodiments.
  • a third aspect of the invention is directed to a method for the modulation of the catalytic activity of a protein kinase with a compound or salt of any one of Formula I or Formula II.
  • the protein kinase is a VEGF receptor, FGF receptor, EGF receptor, or PDGF receptor.
  • hydroxy compounds may have interesting and unexpected properties that advantageously distinguish them from known compounds. They are therefore useful in treating disorders related to abnormal protein kinase activities such as cancer.
  • all compounds of Formula (I) or (II) have at least one asymmetric center and the stereochemistry at the asymmetric center(s) is (are) either RS, R, or S.
  • Figure 1 illustrates a scheme showing the synthesis of the 6-(omega alkanoic acid) quinazolines from 6,7-dimethoxy-3,4-dihydroquinazolin-4-one.
  • Figure 2 illustrates is a scheme showing the synthesis of 2-Na, which is the 7-(omega alkanoic acid) quinazoline derivative, from 7-benzyloxy-4-chloro-6- methoxyquinazoline.
  • Figure 3A illustrates a table of preferred compounds of the invention. All of the compounds shown have at least one asymmetric center and the stereochemistry at any given asymmetric center is RS, R, or S.
  • Figure 3B illustrates a table of preferred compounds of the invention. All of the compounds shown have at least one asymmetric center and the stereochemistry at any given asymmetric center is RS, R, or S.
  • Figure 3C illustrates a table of preferred compounds of the invention. All of the compounds shown have at least one asymmetric center and the stereochemistry at any given asymmetric center is RS, R, or S.
  • Figure 4 illustrates a table of preferred compounds of the invention. All of the compounds shown have at least one asymmetric center and the stereochemistry at any given asymmetric center is RS, R, or S.
  • the compounds of this invention can be synthesized by following the published general procedures. But the following intermediates are specific to compounds of this invention and may be used in place of their respective counterparts in the published general procedures: ethyl (3f?,5S)-6-hydroxy-3,5- O-isopropylidene-3,5-dihydroxyhexanoate, ethyl (R)-4-chloro-3-hydroxybutyrate, and ethyl (S)-4-chloro-3-hydroxybutyrate. These intermediates may be purchased from commercial sources (e.g. Takasago International Corp., Rockleigh, New Jersey). This change from the published general procedures can be understood and carried out by those skilled in the art.
  • Example 1 (3R,5S)-6-[4-(3-Chloro-4-fluorophenylamino)-7- methoxyquinazolin-6-yl]oxy-3,5-dihydroxy-hexanoic acid sodium salt.
  • EHA-Ms ((4/?,6S)-6-Methanesulfonyloxymethyl-2,2-dimethyl-[1,3]dioxan-4- yl)-acetic acid ethyl ester
  • [1 ,3]dioxan-4-yl)-acetic acid ethyl ester 0.5 g, 2.15 mmol, provided by Takasago was dissolved in anhydrous dichloromethane (3.0 mL) with pyridine (1.0 mL). The flask was cooled in an ice-water bath and methanesulfonyl chloride (0.5 g, 4.36 mmol) in dichloromethane (1.0 mL) was added dropwise over 5 minutes. The solution was stirred for 1 hour at 5 °C. Toluene (20 mL) was added and the solution was concentrated under reduced pressure.
  • Phenol 2-4 (0.78 g, 2.14 mmol), the mesylate of EHA (0.63 g, 2.02 mmol), and anhydrous potassium carbonate (0.60 g, 4.34 mmol) were added to N,N- dimethylacetamide (DMA, 5.0 mL) that contained a catalytic amount of 18- crown-6 (2 mg).
  • DMA N,N- dimethylacetamide
  • the mixture was heated to 85-90 °C under an argon atmosphere for 22 hours. After 22 hours, the heating was stopped and the DMA was removed under high vacuum while still warm. The remaining brown solid was purified by flash column chromatography on silica gel (40 g), eluting with 1- 10% methanol in dichloromethane. The product containing fractions were combined and concentrated.
  • Acetonide 2-5 (0.20 g, 0.345 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (1 mL) that contained dilute hydrochloric acid (400 ⁇ L, 6% HCI). The solution was stirred for 20 hours at room temperature. After 20 hours, saturated sodium bicarbonate solution (5 mL) was added and the product was extracted into diethyl ether (2 x 20 mL). The ether extracts were combined, dried over sodium sulfate (5 g), filtered, and concentrated under reduced pressure. The experiment produced 2-7 (0.17 g, 91.3% yield) as a light yellow solid that was used without further purification for the next step.
  • Ester 2-7 (0.17 g, 0.32 mmol) was dissolved in methanol (4 mL) at room temperature. DIUF water (1 mL) containing sodium hydroxide (13.0 mg, 0.33 mmol) was added and the solution was stirred for 3 hours at room temperature. After 3 hours, the methanol/water solution was concentrated. An additional portion of methanol ( 0 mL) was added and the solution was concentrated. The process was repeated with toluene (10 mL) in order to remove traces of water and methanol. The remaining salt was washed with small volumes of isopropanol (5 mL) and diethyl ether (10 L).
  • Step A ((4R,6S)-6- ⁇ (4-[3-Chloro-4-(3-fluorobenzyloxy)phenylamino]- quinazolin-6-yl)oxymethyl ⁇ -2,2-dimethyl-[1 ,3]dioxan-4-yl)-acetic acid terf-butyl ester
  • Step B (4R,6S)-6- ⁇ (4-[3-Chloro-4-(3-fluorobenzyloxy)phenylamino]- quinazolin-6-yl)oxymethyl ⁇ -4-hydroxy-tetrahydropyran-2-one
  • Step C Sodium; (3R,5S)-6- ⁇ (4-[3-chloro-4-(3- fluorobenzyloxy)phenylamino]-quinazolin-6-yl)oxy ⁇ -3,5-dihydroxyhexanoate
  • 3R,5S 3- ⁇ (4-[3-chloro-4-(3- fluorobenzyloxy)phenylamino]-quinazolin-6-yl)oxy ⁇ -3,5-dihydroxyhexanoate
  • Step B To a solution of the product from Example 5, Step B was added Me 2 NH (2M in MeOH, 10 mL). After 18 h, the solution was concentrated in vacuo and the crude residue was purified by reverse-phase preparative HPLC to give the title compound as a pale yellow solid. HPLC:MS 569.3 (M+H).
  • Example 8 Further amide derivatives of Example 1
  • Example 10 Following the above procedures and known procedures in the literature, the following examples 10a-j can be made.
  • Example 11 Amide derivatives of Example 10 are illustrated using derivatives of 10a below: 11e 11f
  • Example 12 Following the above procedures and known procedures in the 3literature, the following examples 12a-f can be made.
  • R 2 is selected from the following radicals:
  • the present invention provides compounds capable of regulating and/or modulating protein kinase activities of, but not limited to, VEGFR (Vascular Endothelial Growth Factor Receptor), EGFR (Epidermal Growth Factor Receptor), FGFR (Fibroblast Growth Factor Receptor) or PDGFR (Platelate Derived Growth Factor Receptor).
  • VEGFR Vascular Endothelial Growth Factor Receptor
  • EGFR Epidermal growth Factor Receptor
  • FGFR Fibroblast Growth Factor Receptor
  • PDGFR Platinum Derived Growth Factor Receptor
  • the present invention provides a therapeutic approach to the treatment of disorders related to the abnormal functioning of these kinases.
  • disorders include, but not limited to, solid tumors such as glioblastoma, melanoma, and Kaposi's sarcoma, and ovarian, lung, prostate, pancreatic, colon and epidermoid carcinoma.
  • VEGFR/FGFR inhibitors
  • this invention relates to the inhibition of vasculogenesis and angiogenesis by receptor-mediated pathways, including the pathways comprising VEGF receptors, and/or FGF receptors.
  • receptor-mediated pathways including the pathways comprising VEGF receptors, and/or FGF receptors.
  • VEGFR Biochemical Assay The compounds were assayed for biochemical activity by Upstate Ltd at Dundee, United Kingdom, according to the following procedure.
  • KDR (h) (5-10 mU) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.33 mg/ml myelin basic protein, 10 mM MgAcetate and [y- 33 P-ATP] (specific activity approx. 500 cpm/pmol, concentration as required).
  • the reaction is initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 5 ⁇ l of a 3% phosphoric acid solution. 10 ⁇ l of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.
  • HUVEC VEGF induced proliferation
  • EGM vascular endothelial growth factor
  • CC-3124 EGM induced proliferation of HUVEC cells.
  • HUVEC cells were maintained in EGM (Cambrex, CC-3124) at 37°C and 5% CO 2 .
  • HUVEC cells were plated at a density 5000 cells/well (96 well plate) in EGM. Following cell attachment (1 hour) the EGM-medium was replaced by EBM (Cambrex, CC- 3129) + 0.1 % FBS (ATTC , 30-2020) and the cells were incubated for 20 hours at 37°C.
  • the medium was replaced by EBM +1% FBS, the compounds were serial diluted in DMSO and added to the cells to a final concentration of 0 - 5,000 nM and 1% DMSO.
  • VEGF 10ng/ml VEGF (Sigma, V7259) and incubated for 45 hours at 37°C.
  • Cell proliferation was measured by BrdU DNA incorporation for 4 hours and BrdU label was quantitated by ELISA (Roche kit, 16472229) using 1 M H 2 SO 4 to stop the reaction. Absorbance was measured at 450nm using a reference wavelength at 690nm.
  • Figure 1 is a scheme showing the synthesis of the 6-(omega alkanoic acid) quinazolines from 6,7-dimethoxy-3,4-dihydroquinazolin-4-one.
  • the acid- promoted deprotection of the 6-hydroxy group of the quinazoline went according to the procedure in WO96/33980. Routine acetylation of the revealed hydroxyl was carried out in refluxing acetic anhydride/pyridine to give compound 1-3.
  • the amide group of the quinazolin-4-one was converted to the chloroimine to give 6- acetoxy-4-chloro-7-methoxyquinazoline as the hydrochloride salt. Overall yield for the two steps was 82%.
  • the 4-chloro-quinazoline 1-4 was converted to the aniline derivative by displacement of the chloride to give 1-5 in good yield by reaction with 3-chloro-4-fluoroaniline.
  • the acetyl group is removed by reaction with ammonium hydroxide in refluxing methanol to provide 1-6 in 90% yield.
  • the hydroxyl group of 1-6 was deprotonated with potassium carbonate in dimethyl acetamide and a catalytic amount of 18-crown-6 ether and alkylated with primary mesylate 1b to give 1-7 in adequate yield according to the procedure of Jendrella, H.; et al. J. Med. Chem. 1991, 34, 2962-2983.
  • Figure 3A is a table of preferred compounds of the invention. All of the compounds shown have at least one asymmetric center and the stereochemistry at any given asymmetric center is RS, R, or S.
  • Figure 3B is a table of preferred compounds of the invention. All of the compounds shown have at least one asymmetric center and the stereochemistry at any given asymmetric center is RS, R, or S.
  • Figure 3C is a table of preferred compounds of the invention. All of the compounds shown have at least one asymmetric center and the stereochemistry at any given asymmetric center is RS, R, or S.
  • Figure 4 is a table of preferred compounds of the invention. All of the compounds shown have at least one asymmetric center and the stereochemistry at any given asymmetric center is RS, R, or S. These compounds differ from those in Figures 3 in that they have a piperazine ring directly bonded to the quinazoline ring.

Abstract

Hydroxy containing quinazoline based derivatives have enhanced and unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as cancer.

Description

ADVANCED QUINAZOLINE BASED PROTEIN KINASE INHIBITORS
Description
Field of Invention This invention relates to protein kinase inhibitors and to their use in treating disorders related to abnormal protein kinase activities such as cancer and inflammation. More particularly, the invention relates to quinazoline based protein kinase compounds and their pharmaceutically acceptable salts employable as protein kinase inhibitors.
Background Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups of tyrosine, serine, and threonine residues of proteins. Many aspects of cell life (for example, cell growth, differentiation, proliferation, cell cycle and survival) depend on protein kinase activities. Furthermore, abnormal protein kinase activity has been related to a host of disorders such as cancer and inflammation. Therefore, there is a great deal of effort directed to identifying ways to modulate protein kinase activities. In particular, many attempts have been made to identify small molecules which act as protein kinase inhibitors.
Quinazoline and quinoline based derivatives having activity as protein kinase inhibitors have been disclosed in International Patent Applications WO 0132651 , WO 0174360, WO 0212226, WO 0340108, WO 0340109, WO 0216361 , WO 0216351 , and WO 0236587. What is needed is a class of modified quinazoline based derivatives having both activity as protein kinase inhibitors and enhanced drug properties.
Summary: The invention is directed to hydroxy containing quinazoline derivatives and to their use as inhibitors of protein kinases. It is disclosed herein that hydroxy containing quinazoline derivatives have enhanced and unexpected drug properties that advantageously distinguish this class of compounds over known quinazoline derivatives having protein kinase inhibition activity. It is also disclosed herein that hydroxy containing quinazoline derivatives are useful in treating disorders related to abnormal protein kinase activities such as cancer.
One aspect of the invention is directed to a compound represented by Formula (I):
- CH2[CH(OH)CH2]nC(0)R2
Figure imgf000003_0001
(Formula I) In Formula I, X is a triradical selected from the group consisting of N and C(R3); Y is a diradical selected from the group consisting of N(R4) and O; Z is a radical selected from the group consisting of optionally substituted phenyl, pyridine, indole, indazole, naphthalene, benzofuran, and benzothiophene; R1 is a radical selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkoxy, and (C5-C8) heterocycloalkoxy; R2 is a radical selected from the group consisting of hydroxyl, (C1-C6) alkoxy, (C5-C8) cycloalkoxy, and -NR5R6; n is 1 or 2; R3 is a radical selected from the group consisting of hydrogen and nitrile; R4 is a radical selected from the group consisting of hydrogen and (C1-C6) alkyl; R5 and R6 are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) dihydroxyalkyl, (C1-C6) alkoxy , (C1-C6) alkyl carboxylic acid, (C1-C6) alkyl phosphoric acid, (C1-C6) alkyl sulfuric acid, (C1-C6) hydroxyalkyl carboxylic acid, (C1-C6) alkyl amide, (C3-C8) cycloalkyl, (C5-C8) heterocycloalkyl, (C6- C10) aryl, (C5-C9) heteroaryl, (C3-C8) cycloalkyl carboxylic acid; or R5 and R6 together with N forms a (C5-C8) heterocyclic ring either unsubstituted or substituted with one or more hydroxyls, ketones, ethers, and carboxylic acids; or NR5R6 may form a cyclic ring containing 0-3 additional heteroatoms selected from N, O, or S; or, a pharmaceutically acceptable salt, its tautomer, a pharmaceutically acceptable salt of its tautomer, or a prodrug thereof. In a first preferred subgenus of this first aspect of the invention, R2 is a radical selected from the group consisting of hydroxyl, (C1-C6) alkoxy, and (C5- C8) cycloalkoxy. Preferred embodiments of this first subgenus compounds represented by the following structures:
Figure imgf000004_0001
Further embodiments of the first subgenus of the first aspect of the invention include compounds represented by the following structures:
Figure imgf000005_0001
Further embodiments of the first subgenus of the first aspect of the invention include compounds represented by the following structures:
Figure imgf000005_0002
In a second preferred subgenus of the first aspect of the invention represented by Formula I, R2 is -NR5R6. Embodiments of the second subgenus of the first aspect of the invention include compounds represented by the following structures:
Figure imgf000006_0001
Further embodiments of the second subgenus of the first aspect of the invention include compounds represented by the following structures:
Figure imgf000006_0002
Further embodiments of the second subgenus of the first aspect of the invention include compounds represented by the following structures:
Figure imgf000007_0001
Further embodiments of the second subgenus of the first aspect of the invention include compounds represented by the following structures:
Figure imgf000007_0002
In each of the CORE structures (l-VIII), R2 is selected from the group consisting of radical represented by the following structures: N/~)-OH < ~ > ^ -1^0^ KΓΛ
Figure imgf000008_0001
A second aspect of the invention is directed to a compound of formula (II):
Figure imgf000008_0002
In Formula II, W is a diradical selected from the group consisting of O and S; R1 is a radical selected from the group consisting of optionally substituted phenyl, benzyl, heteroaryl, and heteroarylalkyl; R2 is a radical selected from the group consisting of hydroxyl, (C1-C6) alkoxy, (C3-C8) cycloalkoxy, and NR3R4; n is 1 or 2; R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) dihydroxyalkyl, (C1-C6) alkoxy , (C1-C6) alkyl carboxylic acid, (C1-C6) alkyl phosphoric acid, (C1-C6) alkyl sulfonic acid, (C1-C6) hydroxyalkyl carboxylic acid, (C1-C6) alkyl amide, (C3-C8) cycloalkyl, (C5-C8) heterocycloalkyl, (C6-C10) aryl, (C5-C9) heteroaryl, (C3-C8) cycloalkyl carboxylic acid; or R3 and R4 together with N forms a (C5-C8) heterocyclic ring either unsubstituted or substituted with one or more hydroxyls, ketones, ethers, and carboxylic acids; or NR3R4 may form a cyclic ring containing 0-3 additional heteroatoms selected from N, O, or S; or, a pharmaceutically acceptable salt, its tautomer, a pharmaceutically acceptable salt of its tautomer, or a prodrug thereof.
In a first preferred subgenus of this second aspect of the invention represented by Formula II, R2 is a radical selected from the group consisting of hydroxyl, (C1-C6) alkoxy, and (C5-C8) cycloalkoxy. Embodiments of the first subgenus of the second aspect of the invention include compounds represented by the following structures:
Figure imgf000009_0001
In a second preferred subgenus of this second aspect of the invention represented by Formula II, R2 is -NR5R6. Preferred embodiments of the second subgenus of the second aspect of the invention include compounds represented by the following structures:
Figure imgf000010_0001
Further embodiments of the second subgenus of the second aspect of the invention include compounds represented by the following structures:
Figure imgf000010_0002
Further embodiments of the second subgenus of the second aspect of the invention include compounds represented by the following structures:
Figure imgf000011_0001
CORE I CORE II CORE III
wherein: R2 is selected from the group consisting of radical represented by the following structures:
Figure imgf000011_0002
Provisos may apply to any of the above inventive aspects, subgenera, or embodiments wherein any one or more of the other above described embodiments or species may be excluded from its corresponding inventive aspect, subgenus, or embodiments.
A third aspect of the invention is directed to a method for the modulation of the catalytic activity of a protein kinase with a compound or salt of any one of Formula I or Formula II. In a preferred embodiment of the third aspect of the invention, the protein kinase is a VEGF receptor, FGF receptor, EGF receptor, or PDGF receptor.
This invention discloses that certain hydroxy compounds may have interesting and unexpected properties that advantageously distinguish them from known compounds. They are therefore useful in treating disorders related to abnormal protein kinase activities such as cancer.
It should be understood that a compound of Formula (I) or (II) where R2 is OH may exist in its open-acid form or its cyclic-lactone form or the two forms may co-exist in solution or in vivo as illustrated below:
Figure imgf000012_0001
Open-acid form Cyclic-lactone form
Furthermore, all compounds of Formula (I) or (II) have at least one asymmetric center and the stereochemistry at the asymmetric center(s) is (are) either RS, R, or S.
Brief Description of Drawings: Figure 1 illustrates a scheme showing the synthesis of the 6-(omega alkanoic acid) quinazolines from 6,7-dimethoxy-3,4-dihydroquinazolin-4-one. Figure 2 illustrates is a scheme showing the synthesis of 2-Na, which is the 7-(omega alkanoic acid) quinazoline derivative, from 7-benzyloxy-4-chloro-6- methoxyquinazoline. Figure 3A illustrates a table of preferred compounds of the invention. All of the compounds shown have at least one asymmetric center and the stereochemistry at any given asymmetric center is RS, R, or S.
Figure 3B illustrates a table of preferred compounds of the invention. All of the compounds shown have at least one asymmetric center and the stereochemistry at any given asymmetric center is RS, R, or S.
Figure 3C illustrates a table of preferred compounds of the invention. All of the compounds shown have at least one asymmetric center and the stereochemistry at any given asymmetric center is RS, R, or S.
Figure 4 illustrates a table of preferred compounds of the invention. All of the compounds shown have at least one asymmetric center and the stereochemistry at any given asymmetric center is RS, R, or S.
Detailed Description:
The compounds of this invention can be synthesized by following the published general procedures. But the following intermediates are specific to compounds of this invention and may be used in place of their respective counterparts in the published general procedures: ethyl (3f?,5S)-6-hydroxy-3,5- O-isopropylidene-3,5-dihydroxyhexanoate, ethyl (R)-4-chloro-3-hydroxybutyrate, and ethyl (S)-4-chloro-3-hydroxybutyrate. These intermediates may be purchased from commercial sources (e.g. Takasago International Corp., Rockleigh, New Jersey). This change from the published general procedures can be understood and carried out by those skilled in the art. The amides of Tables 1 -2 can be readily synthesized from their corresponding acids. Thus, the compounds of the present invention can be synthesized by those skilled in the art. Example 1: (3R,5S)-6-[4-(3-Chloro-4-fluorophenylamino)-7- methoxyquinazolin-6-yl]oxy-3,5-dihydroxy-hexanoic acid sodium salt.
Figure imgf000014_0001
The procedure for the synthesis of the title compound is depicted in Figure 1.
Figure imgf000014_0002
1-2: 6-Hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one was obtained according to WO96/33980 in 93% yield. 1H NMR (DMSO-d6, ppm): δ 7.92 (s, 1H), 7.39 (s, 1 H), 7.09 (s, 1 H), 3.89 (s, 3H). 13C NMR (DMSO-d6, ppm): δ 160.0, 153.8, 152.3,
146.4, 143.7, 115.9, 108.6, 108.1 , 55.9.
Figure imgf000014_0003
1-3: 6-Acetoxy-7-methoxy-3,4-dihydroquinazolin-4-one was obtained according to WO96/33980 in 82% yield. The crude product was used for the next step without purification.
Figure imgf000014_0004
1-4: 4-Chloro-6-acetoxy-7-methoxyquinazoline hydrochloride was obtained according to WO96/33980 and used for the next step without purification.
Figure imgf000014_0005
1-5: 4-(3'-Chloro-4'-fluoroanilino)-6-acetoxy-7-methoxyquinazoline hydrochloride was obtained according to WO96/33980 in 82% yield from 1-4. The crude material was used for the next step without purification. 1-6: 4-(3'-Chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline was obtained according to WO96/33980 in 90% isolated yield. 1H NMR (DMSO-d6, ppm): δ 9.64 (br s, 1 H), 9.38 (br s, 1 H), 8.37 (s, 1 H), 8.10 (dd, 1 H, J = 8.1 , 2.7 Hz), 7.72 (m, 1 H), 7.66 (s, 1 H), 7.30 (t, J = 9.0 Hz, 1 H), 7.11 (s, 1 H), 3.87 (s, 3H). 13C NMR (DMSO-d6, ppm): δ 155.7, 153.8, 152.7 (d, J = 241.6 Hz), 151.8, 146.6, 146.0, 137.0, 122.6, 121.6 (d, J = 6.7 Hz), 118.6 (d, J = 18.0 Hz), 116.3 (d, J = 21.6 Hz), 109.5, 107.1, 105.2, 55.9.
Figure imgf000015_0001
1b: (4ft,6S)-(6-Methanesulfonyloxymethyl-2,2-dimethyl-[1 ,3]dioxan-4-yl)-acetic acid ethyl ester was obtained according to a known method (H. Jendralla, E. Granzer, B. Von Kerekjarto, R. Krause, U. Schacht, E. Baader, W. Bartmann, G. Beck, A. Bergmann, et al.; Synthesis and biological activity of new HMG-CoA reductase inhibitors. 3. Lactones of 6-phenoxy-3,5-dihydroxyhexanoic acids. J. Med. Chem. 1991, 34, 2962 - 2983) in 91% isolated yield. 1H NMR (CDCI3, ppm): δ 4.38-4.34 (m, 1 H), 4.23-4.12 (m, 1 H), 3.06 (s, 3H), 2.60-2.36 (m, 2H), 1.62 (d, 1 H, J = 12.6 Hz), 1.47 (s, 3H), .38 (s, 3H), 1.32 (m, 1 H), 1.26 (t, 3H, J = 6.9Hz). 13C NMR (DMSO-d6, ppm): δ 170.6, 99.3, 72.3, 67.3, 65.6, 60.8, 41.4, 37.9, 31.9, 30.0, 19.9, 14.5.
Figure imgf000015_0002
1-7: (4R,6S)-{6-([4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6- yl]oxymethyl)-2,2-dimethyl-[1 ,3]dioxan-4-yl}-acetic acid ethyl ester was obtained in analogy to the publication (Jendralla, H.; et al. J. Med. Chem. 1991, 34, 2926- 2983). A mixture of 1-6 (0.32 g, 1.0 mmol), 1b (0.33 g, 1.0 mmol), K2CO3 (0.38 g, 2.75 mmol), 18-crown-6 (1 mg), and DMAc (5 mL) was heated at 91 °C for 7 h. Another 0.2 g (0.6 mmol) of 1b was added. Heating at 91 °C was continued for 17 h and the mixture was cooled to room temperature. Water (20 mL) and saturated sodium bicarbonate solution (20 mL) were added. The obtained solution was extracted with MTBE (60 mL * 3), the combined organic layers were washed with saturated sodium bicarbonate solution (50 mL) and saturated sodium chloride solution (50 mL), dried over MgSO4, and concentrated to give the crude product (0.50 g) as a viscous syrup. The crude material was subjected to chromatography on silica eluting with heptane/ethyl acetate (3:1 , 2:1 and 1:1) to give pure 1-7 (0.28 g, 50%) as a pale yellow solid. Mp 135-136 °C. 1H NMR (300 MHZ, CD3OD, ppm): δ 8.27 (s, 1 H), 7.95 (dd, 1 H, J = 6.9, 2.7 Hz), 7.58 (m, 1H), 7.20 (s, 1H), 7.14 (t, J = 9.0 Hz, 1H), 6.77 (s, 1H), 4.40 (m, 2H), 4.20-3.81 (m, 4H), 3.78 (s, 3H), 2.49 (d, 2H, J = 6.3 Hz), 1.73 (d, 1 H, J = 12.9 Hz), 1.52 (s, 3H), 1.36 (s, 3H), 1.26 (t, 3H, J - 6.9 Hz), 1.25 (m, 1 H). 13C NMR (75 MHz, CD3OD, ppm): δ 172.2, 157.4, 155.9, 155.3 (d, J = 244.0 Hz), 153.3, 149.5, 147.0, 137.2, 125.0, 123.0 (d, J = 6.7 Hz), 120.9 (d, J = 18.0 Hz), 117.0 (d, J = 21.6 Hz), 109.7, 106.8, 102.7, 100.3, 73.2, 69.0, 67.0, 61.6, 56.4, 42.3, 30.3, 20.1 , 14.6.
Figure imgf000016_0001
1-8: (3R,5S)-6-{[4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6- yl]oxy}-3,5-dihydroxyhexanoic acid ethyl ester was obtained in analogy to previous publication (Jendralla, JMC, 1991). The material was used for next step without purification. A suspension of 1-7 (0.28 g, 0.51 mmol) and aqueous HCI solution (2 N, 0.56 mL) in ethanol (6 mL) and THF (3 L) was stirred at 20 °C for 24 h. Saturated aqueous Na2CO3 solution (ca. 4 mL) was added to adjust to pH 9. The solvent was evaporated to give a solid residue to which water (10 mL) was added. The solution was lightly extracted with EtOAc (40 mL * 2). The combined organic layers were dried over MgSO4, concentrated to give the product (0.12 g, 46%) as a yellow solid. 1H NMR (300 MHz, CDCI3, ppm): δ 8.40 (s, 1 H), 7.75 (dd, 1 H, J = 6.6, 2.4 Hz), 7.44 (m, 1 H), 7.18 (s, 1 H), 6.95 (t, J - 9.0 Hz, 1 H), 6.84 (s, 1 H), 4.30 (br s, 2H), 4.08-3.81 (m, 4H), 3.63 (s, 3H), 2.49 (d, 2H, J = 5.7 Hz), 1.69 (br s, 2H), 1.20-1.11 (m, 4H). 13C NMR (75 MHz, CDCI3, ppm): δ 172.3, 156.4, 154.8, 154.5 (d, J = 246.4 Hz), 152.9, 148.2, 146.1, 135.5, 124.2, 122.0 (d, J = 6.5 Hz), 120.6 (d, J = 18.6 Hz), 116.3 (d, J = 21.6 Hz), 108.7, 106.5, 102.2, 73.1 , 69.3, 67.9, 61.1 , 56.1 , 42.1 , 39.2, 14.4.
Figure imgf000017_0001
1-Na: 6-{[4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl]oxy}- 3,5-dihydroxyhexanoic acid. A solution of 1-8 (0.20 g, 0.39 mmol) and aqueous NaOH solution (0.51 N, 0.77 mL, 0.39 mmol) in methanol (6 mL) was stirred at 20 °C for 24 h. The solvents were evaporated. The residue was dissolved in water (20 mL), extracted with MTBE (30 mL), and lyophilized to give 1-8 as a pale orange solid (210 mg, 99% yield). Mp 225 °C (decomposition). 1H NMR (300 MHz, CD3OD, ppm): δ 8.39 (s, 1 H), 8.01 (dd, 1 H, J = 6.6, 2.1 Hz), 7.62 (m, 2H), 7.19 (t, J = 9.0 Hz, 1 H), 7.05 (s, 1 H), 4.32-4.07 (m, 4H), 3.96 (s, 3H), 2.42 (m, 2H), 1.86 (m, 2H). 13C NMR (CDCI3, ppm): δ 180.1, 157.9, 156.2, 155.6 (d, J = 267.3 Hz), 153.6, 150.0, 147.3, 137.4, 125.3, 123.4, 121.0 (d, J = 18.0 Hz), 117.1 (d, J = 21.6 Hz), 110.3, 107.0, 103.4, 74.4, 69.0, 68.5, 56.6, 45.7, 41.4.
Example 2: (3/?,5S)-6-[{4-(4-Bromo-2-fluorophenylamino)-6- methoxyquinazolin-7-yl}oxy]-3,5-dihydroxyhexanoic acid, sodium salt.
Figure imgf000017_0002
The synthesis of the title compound, outlined in Figure 2, was accomplished in six steps from compound 2-2 (purchased from J.W. Pharmlab). Intermediates 2- 3 and 2-4 were prepared by the method of Hennequin et al. (Hennequin, L.F.; Thomas, A.P.; Johnstone, O; Stokes, E.S.E.; Pie, P.A.; Lohmann, J.M.; Ogilvie, D.J.; Dukes, M.; Wedge, S.R.; Curwen, J.O.; Kendrew, J.; Brempt, L. J. Med. Chem. 1999, 42, 5369-5389). Intermediate 2-4 was then coupled with the mesylate of EHA, which was prepared from EHA (provided by Takasago). Both the coupling and the preparation of the mesylate were conducted by the methods of Jendralla et al. Once the coupling was complete, 2-5 was treated with dilute hydrochloric acid to remove the acetonide protective group. The ester 2-7 was then converted to the salt 2-Na by treatment with one equivalent of sodium hydroxide.
2-3: (7-Benzyloxy-6-methoxyquinazolin-4-yl)-(4-bromo-2-fluorophenyl)- amine
Figure imgf000018_0001
A mixture of 2-2 (7-benzyloxy- -c obtained from J. W. Pharmlab, 2.05 g, 6.81 mmol) and 4-bromo-2-fluoroaniline (3.04 g, 15.9 mmol) was heated to reflux in isopropyl alcohol (80 mL) for 24 hours. After cooling to room temperature, the mixture was made basic with sodium bicarbonate (1.0 g) in DIUF water (10 mL). The mixture was concentrated under reduced pressure and dried under high vacuum before purification by flash column chromatography on silica gel (80 g), eluting with 1-10% methanol in dichloromethane. The procedure produced 2-3 as a light yellow solid (1.37 g, 45% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.48 (s, 1 H), 8.33 (s, 1 H), 7.80 (s, 1 H), 7.56-7.33 (m, 8H), 7.26 (s, 1H), 5.26 (s, 2H), 3.94 (s, 3H). 13C NMR (75 MHz, DMSO-d6): δ 156.69, 156.46 (d, J = 249.6 Hz), 153.10, 152.77, 148.92, 146.64, 136.14, 129.42, 128.37, 127.89, 127.39, 126.23 (d, J = 12.0 Hz), 119.21 (d, J = 23.2 Hz), 117.45 (d, J = 9.0 Hz), 108.65, 108.22, 101.91, 69.92, 56.12.
2-4: 4-(4-Bromo-2-fluorophenylamino)-6-methoxyquinazolin-7-ol
Figure imgf000018_0002
Intermediate 2-3 (1.30 g, 2.86 mmol) was dissolved in trifluoroacetic acid (15 mL) and the solution was heated to reflux for 1.5 hours. The solution was cooled to room temperature and concentrated under reduced pressure. Methanol (20 mL) was added to the remaining brown solid and the pH was adjusted to 11 with concentrated ammonium hydroxide. The mixture was concentrated under reduced pressure and dried under high vacuum before purification by flash column chromatography on silica gel (20 g), eluting with 5-20% methanol in dichloromethane. The experiment generated 2-4 (1.03 g, 99% yield) as a light yellow solid. H NMR (300 MHz, DMSO-d6): δ 10.5 (br s, 1 H), 9.53 (br s, 1 H), 8.34 (s, 1 H), 7.81 (s, 1 H), 7.63 (d, 1 H, J = 9.6 Hz), 7.54 (dd, 1 H, J = 8.4, 7.8 Hz), 7.44(d, 1 H, J = 8.4 Hz), 7.12 (s, 1 H), 3.95 (s, 3H). 13C NMR (75 MHz, DMSO-d6): δ 156.77, 156.49, 152.92, 152.62, 148.62, 146.74, 129.40, 127.39, 126.46 (d, J = 12 Hz), 119.23 (d, J = 23.2 Hz), 117.4 (d, J = 8.3 Hz), 109.96, 108.08, 102.23, 56.09.
EHA-Ms: ((4/?,6S)-6-Methanesulfonyloxymethyl-2,2-dimethyl-[1,3]dioxan-4- yl)-acetic acid ethyl ester
Figure imgf000019_0001
Under argon atmosphere, EHA ((4R,6S)-6-hydroxymethyl-2,2-dimethyl-
[1 ,3]dioxan-4-yl)-acetic acid ethyl ester 0.5 g, 2.15 mmol, provided by Takasago) was dissolved in anhydrous dichloromethane (3.0 mL) with pyridine (1.0 mL). The flask was cooled in an ice-water bath and methanesulfonyl chloride (0.5 g, 4.36 mmol) in dichloromethane (1.0 mL) was added dropwise over 5 minutes. The solution was stirred for 1 hour at 5 °C. Toluene (20 mL) was added and the solution was concentrated under reduced pressure. An additional portion of toluene (20 mL) was added and the solution was extracted with saturated sodium bicarbonate solution (20 mL) and DIUF water (20 mL). The toluene layer was dried over sodium sulfate (5 g), filtered and concentrated. The remaining oil was stirred with heptane (5 mL) for ten minutes. The stirring was stopped and the heptane was decanted away from the underlying oil. The remaining clear oil was dried under high vacuum for 4 hours. The procedure afforded the mesylate of EHA (0.64 g, 95.8% yield) as colorless oil that solidified after an extended period of time. 1H NMR (300 MHz, CDCI3): δ 4.38-4.30 (m, H), 4.21 (m, 5H), 3.05 (s, 3H), 2.55 (dd, 1 H, J = 15.6, 6.9 Hz), 2.40 (dd, J = 15.6, 6.0 Hz), 1.63- 1.58 (m, 2H), 1.46 (s, 3H), 1.37 (s, 3H), 1.25 (t, 3H, J = 7.2 Hz). 13C NMR (75 MHz, CDCI3): δ 170.64, 99.41 , 72.37, 67.37, 65.61 , 60.84, 41.52, 32.04, 30.04, 14.51.
2-5: (4f?,6S)-{6-[4-(4-Bromo-2-fluorophenylamino)-6-methoxyquinazolin-7- yloxymethyl]-2,2-dimethyl-[1,3]dioxan-4-yl}-acetic acid ethyl ester
Figure imgf000020_0001
Phenol 2-4 (0.78 g, 2.14 mmol), the mesylate of EHA (0.63 g, 2.02 mmol), and anhydrous potassium carbonate (0.60 g, 4.34 mmol) were added to N,N- dimethylacetamide (DMA, 5.0 mL) that contained a catalytic amount of 18- crown-6 (2 mg). The mixture was heated to 85-90 °C under an argon atmosphere for 22 hours. After 22 hours, the heating was stopped and the DMA was removed under high vacuum while still warm. The remaining brown solid was purified by flash column chromatography on silica gel (40 g), eluting with 1- 10% methanol in dichloromethane. The product containing fractions were combined and concentrated. The remaining orange solid was crystallized from methanol (10 mL). After filtration and drying, the experiment produced 2-5 (0.48 g, 38.7 % yield) as a light yellow solid. 1H NMR (300 MHz, CDCI3): δ 8.66 (s, 1 H), 8.36 (t, 1 H, J = 8.4 Hz), 7.52 (br s, 1 H), 7.34-7.24 (m, 3H), 7.08 (s, 1 H), 4.45-4.37 (m, 2H), 4.21-3.99 (m, 4H), 3.97 (s, 3H), 2.58 (dd, 1 H, J = 15.3, 7.2 Hz), 2.43 (dd, J = 15.3, 5.7 Hz), 1.87-1.79 (m, 2H), 1.51 (s, 3H), 1.37 (s, 3H), 1.27 (t, 3H, J = 7.2 Hz). 13C NMR (75 MHz, CDCI3): δ 170.54, 155.42, 154.02, 153.29 (d, J = 245.4 Hz), 152.97, 149.80, 147.19, 127.47, 126.34 (d, J = 12.0 Hz), 124.40, 18.48 (d, J = 23.2 Hz), 115.45 (d, J = 9.0 Hz), 109.25, 108.84, 99.24, 99.10, 71.95, 67.25, 65.35, 60.48, 56.24, 41.38, 33.24, 29.86, 14.21. 2-7: (3/?,5S)-6-[(4-(4-Bromo-2-fluorophenylamino)-6-methoxyquinazolin-7- yl)oxy]-3,5-dihydroxyhexanoic acid ethyl ester
Figure imgf000021_0001
Acetonide 2-5 (0.20 g, 0.345 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (1 mL) that contained dilute hydrochloric acid (400 μL, 6% HCI). The solution was stirred for 20 hours at room temperature. After 20 hours, saturated sodium bicarbonate solution (5 mL) was added and the product was extracted into diethyl ether (2 x 20 mL). The ether extracts were combined, dried over sodium sulfate (5 g), filtered, and concentrated under reduced pressure. The experiment produced 2-7 (0.17 g, 91.3% yield) as a light yellow solid that was used without further purification for the next step. 1H NMR (300 MHz, CDCI3): δ 8.58 (s, 1 H), 8.26 (t, 1 H, J = 8.1 Hz), 7.56 (br s, 1 H), 7.30-7.24 (m, 2H), 7.12 (s, 1 H), 6.97 (s, 1 H), 4.70 (br s, 1 H), 4.37 (m, 3H), 4.14 (q, 2H, J = 7.0 Hz), 4.03 (m, 2H), 3.88 (s, 3H), 2.52 (m, 2H), 1.80 (m, 2H), 1.24 (t, 3H, J = 7.0 Hz). 13C NMR (75 MHz, CDCI3): δ 172.30, 155.76, 154.05, 153.68 (d, J = 245.7), 152.04,
149.82, 146.97, 127.67, 126.34 (d, J = 12.0 Hz), 124.86, 1 18.78 (d, J = 22.6 Hz), 1 15.95 (d, J = 9.0 Hz), 109.34, 108.47, 99.33, 73.04, 69.47, 68.07, 60.99, 56.31 , 42.12, 39.01 , 14.44.
2-Na: (3/?,5S)-6-{[4-(4-Bromo-2-fluorophenylamino)-6-methoxyquinazolin- 7-yl]oxy}-3,5-dihydroxyhexanoic acid, sodium salt
Figure imgf000021_0002
Ester 2-7 (0.17 g, 0.32 mmol) was dissolved in methanol (4 mL) at room temperature. DIUF water (1 mL) containing sodium hydroxide (13.0 mg, 0.33 mmol) was added and the solution was stirred for 3 hours at room temperature. After 3 hours, the methanol/water solution was concentrated. An additional portion of methanol ( 0 mL) was added and the solution was concentrated. The process was repeated with toluene (10 mL) in order to remove traces of water and methanol. The remaining salt was washed with small volumes of isopropanol (5 mL) and diethyl ether (10 L). The remaining light yellow salt was dried under high vacuum at room temperature (1 hour) and at 50 °C (3 hours) to remove the bulk of the remaining solvent. The procedure generated 2-Na (0.16 g, 95.4% yield) as a light yellow solid. 1H NMR (300 MHz, CDCI3): δ 9.70 (br s, 1 H), 8.29 (s, 1 H), 7.80 (s, 1 H), 7.60 (d, 1 H, J = 9.6 Hz), 7.52 (t, 1 H, J = 8.4 Hz), 7.42 (d, 1H, J = 8.4 Hz), 7.27 (br s, 1H), 7.14 (s, 1 H), 5.16 (br s, 1H), 4.10-3.80 (m, 7H), 2.10 (dd, 1 H, J = 15.3, 3.9 Hz), 1.91 (dd, 1 H, J = 15.3, 8.7 Hz), 1.58 (m, 2H). 13C NMR (75 MHz, DMSO-d6): δ 17.31, 156.86, 156.40 (d, J = 249.6 Hz), 153.48, 152.80, 148.62, 146.59, 129.12, 127.78 (d, J = 12.0 Hz), 127.15 (d, J = 3 Hz), 118.96 (d, J = 23.8 Hz), 116.34 (d, J = 9.0 Hz), 109.10, 107.49, 102.36, 73.03, 66.51 , 65.88, 55.97, 43.69, 41.15.
Example 3: (3f?,5S)-6-{[4-(3-Chloro-4-fluorophenylamino)-7- methoxyquinazolin-6-yl]oxy}-3,5-dihydroxy-1-(pyrrolidin-1-yl)-hexan-1-one.
Figure imgf000022_0001
The synthesis of the amide derivatives of Example 1 is shown in Scheme 3 below:
Figure imgf000022_0002
Scheme 3 An amine (3 equiv) was added to a solution of Compound 1-Na (1 equiv), EDC (5 equiv), HOBt (5 equiv), and DIEA (5 equiv) in DMF. After the solution was stirred at 25 °C overnight (stirred at 55 °C for a couple of hours if necessary), DMF was removed via evaporation under reduced pressure. The resulting residue was suspended in ethyl acetate, washed by saturated NaHCO3 (3x) and brine (3x), and dried over Na2SO4. The ethyl acetate was removed under vacuum to give the crude product. This crude material was subjected to preparative HPLC to give the final product amide, which was subsequently characterized by LC-MS and NMR spectroscopy.
Synthesis of (3R,5S)-6-{[4-(3-Chloro-4-fluorophenylamino)-7- methoxyquinazolin-6-yl]oxy}-3,5-dihydroxy-1-(pyrrolidin-1-yl)-hexan-1-one. An amount of 55 mg (92%) product was obtained after preparative HPLC from 70 mg (0.143 mmol) of Compound 1-Na. LC-MS: single peak at 254 nm, MH+ calcd for C25H28CIFN4O5: 519, obtained: 519. H-NMR (DMSO-d6, 400 MHz), δ 8.49 (s, 1 H), 8.12 (dd, J = 3.2 Hz, J - 7.2 Hz, 1H), 7.82 (s, 1 H), 7.78 (m, 1 H), 7.44 (t, J = 9.2 Hz, 1 H), 7.20 (s, 1 H), 5.09 (s, 2H), 4.86 (s, 1 H), 4.20-4.00 (m, 4H), 3.93 (s, 3H), 3.43 (m, 2H), 3.28-3.15 (m, 4H), 2.40 (m, 2H), 1.88-1.62 (m, 4H).
Example 4: (3R,5S)-6-{[4-(3-Chloro-4-fluorophenylamino)-7« methoxyquinazolin-6-yl]oxy}-3,5-dihydroxy-1-(morpholin-4-yl)-hexan-1-one.
Figure imgf000023_0001
An amount of 23 mg (60%) product was obtained after preparative HPLC from 35 mg (0.072 mmol) of Compound 1-Na. LC-MS: single peak at 254 nm, MH+ calcd for C25H28CIFN4O6: 535, obtained: 535. 1H-NMR (DMSO-d6, 400 MHz), δ 8.48 (s, 1 H), 8.11 (dd, J = 2.8 Hz, J = 6.8 Hz, 1 H), 7.80 (s, 1 H), 7.77 (m, 1 H), 7.43 (t, J = 9.2 Hz, 1 H), 7.20 (s, 1 H), 5.06 (s, H), 4.82 (s, 1 H), 4.12 (m, 2H), 4.05 (m, 2H), 3.93 (s, 3H), 3.60-3.40 (m, 8H), 2.58-2.40 (m, 2H, buried in the DMSO signals), 1.82-1.64 (m, 2H). Example 5: Sodium; (3R,5S)-6-{(4-[3-chloro-4-(3-fluorobenzyloxy) phenylamino]-quinazo!in-6-yl)oxy}-3,5-dihydroxy hexanoate
Figure imgf000024_0001
Step A: ((4R,6S)-6-{(4-[3-Chloro-4-(3-fluorobenzyloxy)phenylamino]- quinazolin-6-yl)oxymethyl}-2,2-dimethyl-[1 ,3]dioxan-4-yl)-acetic acid terf-butyl ester
To a mixture of 4-[3-Chloro-4-(3-fluorobenzyloxy)phenylamino]-quinazolin- 6-ol (300 mg, 0.76 mmol) and cesium carbonate (491 mg, 1.5 mmol) in DMAC (4 L) was added ((4R,6S)-2,2-dimethyl-6-trifluoromethanesulfonyloxymethyl- [1 ,3]dioxan-4-yl)-acetic acid fe/f-butyl ester (243 mg, 0.84 mol). The mixture was stirred at rt for 18 h, and then diluted with EtOAc. The mixture was filtered through a plug of SiO2 and concentrated. The crude residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford 200 mg of the title compound as a pale yellow oil which was used without further purification. HPLC:MS 638.2 (M+H).
Step B: (4R,6S)-6-{(4-[3-Chloro-4-(3-fluorobenzyloxy)phenylamino]- quinazolin-6-yl)oxymethyl}-4-hydroxy-tetrahydropyran-2-one
To a solution of the product from Step A (275 mg, 0.43 mmol) in CH2CI2 (1 mL) was added 5 mL of TFA. The reaction was aged at rt until the starting material was consumed as judged by HPLC analysis. The reaction was concentrated and then azeotroped with toluene to give a yellow oil which was used without further purification. HPLC:MS 542.2 (M+H).
Step C: Sodium; (3R,5S)-6-{(4-[3-chloro-4-(3- fluorobenzyloxy)phenylamino]-quinazolin-6-yl)oxy}-3,5-dihydroxyhexanoate To a solution of the product from Step B in THF (3 mL) at rt was added 3 mL of 1 M NaOH. When the reaction was judged complete by HPLC analysis, the reaction was acidified with 2M HCI until a pH ~4 was reached. The crude reaction mixture was concentrated to remove the organics, diluted with DMSO, and purified by reverse-phase preparative HPLC to give the TFA salt of the dihydroxyacid contaminated with the corresponding δ-lactone. To this residue in THF was added 1 M NaOH (2 eq). The resulting solution was stirred for 30 min, purged with CO2, concentrated to remove the THF and then frozen and lyophilized to give the title compound as a yellow solid homogeneous by HPLC analysis. HPLC:MS 542.2 (M+H).
Example 6: (3R,5S)-6-{(4-[3-Chloro-4-(3-fluorobenzyloxy)phenylamino]- quinazolin-6-yl)oxy}-3,5-dihydroxy-hexanoic acid dimethylamide
Figure imgf000025_0001
To a solution of the product from Example 5, Step B was added Me2NH (2M in MeOH, 10 mL). After 18 h, the solution was concentrated in vacuo and the crude residue was purified by reverse-phase preparative HPLC to give the title compound as a pale yellow solid. HPLC:MS 569.3 (M+H).
Example 7: (3R,5S)-6-{(4-[3-Chloro-4-(3-fluorobenzyloxy)phenylamino]- quinazolin-6-yl)oxy}-3,5-dihydroxyhexanoic acid tert-butyl ester
Figure imgf000025_0002
To a solution of the product from Example 5, Step A in THF was added 1M HCI. After 3 h, the solution was purified by reverse-phase preparative HPLC to give the title compound as a bright yellow solid. HPLC:MS 598.2 (M+H).
Example 8: Further amide derivatives of Example 1
The following derivatives can be made utilizing the above procedures.
Figure imgf000026_0001
8a 8b
Example 9: Amide derivatives of Example 2
The synthesis of the amide derivatives of Example 2 is described in Scheme 4 below:
Figure imgf000026_0002
Scheme 4
An amine (3 equiv) was added to a solution of Compound 4-1 (1 equiv), EDC (5 equiv), HOBt (5 equiv), and D1EA (5 equiv) in DMF. After the solution was stirred at 25 °C overnight (stirred at 55 °C for a couple of hours if necessary), DMF was removed via evaporation under reduced pressure. The resulting residue was suspended in ethyl acetate, washed by saturated NaHCO3 (3x) and brine (3x), and dried over Na2SO . The ethyl acetate was removed under vacuum to give the amide crude product. This crude material was treated with HCI (1 M) in MeOH for 1 h at 25 °C to remove the acetonide, and the reaction mixture was directly subjected to preparative HPLC to give the final product dihydroxy amide, which was subsequently characterized by LC-MS and NMR spectroscopy. Following the procedure above, amides 9a-f can be made by those skilled in the art.
Figure imgf000027_0001
9c 9cl
Figure imgf000027_0002
9e 9f
Example 10. Following the above procedures and known procedures in the literature, the following examples 10a-j can be made.
Figure imgf000028_0001
Figure imgf000028_0002
10i 10j
Example 11. Amide derivatives of Example 10 are illustrated using derivatives of 10a below:
Figure imgf000029_0001
11e 11f
Example 12. Following the above procedures and known procedures in the 3literature, the following examples 12a-f can be made.
Figure imgf000029_0002
Further Examples:
Examples 16 - 565: Still further amide examples are shown in the following table:
Figure imgf000030_0001
CORE IX CORE X CORE XI Ex# Core Rz Ex# Core R2 Ex# Core Rz 16 1 [ a 66 II a 116 in a
Figure imgf000031_0001
18 1 [ c 68 II c 118 in c
Figure imgf000031_0002
20 1 e 70 II e 120 in e
Figure imgf000031_0003
22 1 £ g 72 II g 122 in g 23 1 [ h 73 II h 123 m h 24 1 i 74 II i 124 in i 25 1 [ J 75 II j 125 m j 26 1 [ k 76 π k 126 in k 27 1 [ 1 77 II 1 127 in 1 28 1 m 78 II m 128 in m
Figure imgf000031_0004
30 1 0 80 II 0 130 in 0
Figure imgf000031_0005
35 1 [ t 85 II t 135 in t
Figure imgf000031_0006
42 1 [ aa 92 II aa 142 m aa 43 1 ab 93 II ab 143 in ab 44 1 ac 94 II ac 144 in ac 45 1 [ ad 95 II ad 145 in ad 46 1 [ ae 96 II ae 146 in ae
Figure imgf000031_0007
50 1 [ ai 100 II ai 150 in ai
Figure imgf000031_0008
54 1 [ am 104 II am 154 III am 55 1 [ an 105 II an 155 m an 56 1 ao 106 II ao 156 m ao 57 1 [ ap 107 II ap 157 in ap
Figure imgf000031_0009
Ex# Core R2 Ex# Core R2 Ex# Core R2 60 1 [ as 110 II as 160 m as
Figure imgf000032_0001
62 1 [ au 112 π au 162 in au 63 1 [ av 113 II av 163 m av 64 1 aw 114 II aw 164 in aw 65 1 [ ax 115 II ax 165 in ax
Ex# Core W Ex# Core R2 Ex# Core Rz 166 IV a 216 V a 266 VI a 167 IV b 217 V b 267 VI b 168 IV c 218 V c 268 VI c 169 IV d 219 V d 269 VI d 170 IV e 220 V e 270 VI e 171 IV f 221 V f 271 VI f 172 IV g 222 V g 272 VI g 173 IV h 223 V h 273 VI h 174 IV i 224 V i 274 VI i 175 IV j 225 V i 275 VI i 176 IV k 226 V k 276 VI k 177 IV 1 227 V 1 277 VI 1 178 IV m 228 V m 278 VI m 179 IV n 229 V n 279 VI n 180 IV 0 230 V 0 280 VI 0 181 IV P 231 V P 281 VI P 182 IV q 232 V q 282 VI q 183 IV r 233 V r 283 VI r 184 IV s 234 V s 284 VI s 185 IV t 235 V t 285 VI t 186 IV u 236 V u 286 VI u 187 IV V 237 V V 287 VI V 188 IV w 238 V w 288 VI w 189 IV X 239 V X 289 VI X 190 IV y 240 V y 290 VI y 191 IV z 241 V z 291 VI z 192 IV aa 242 V aa 292 VI aa 193 IV ab 243 V ab 293 VI ab 194 IV ac 244 V ac 294 VI ac 195 IV ad 245 V ad 295 VI ad 196 IV ae 246 V ae 296 VI ae 197 IV af 247 V af 297 VI af 198 IV ag 248 V ag 298 VI ag 199 IV ah 249 V ah 299 VI ah Ex# Core R2 Ex# Core R2 Ex# Core R2
200 IV ai 250 V ai 300 VI ai
201 IV aj 251 V aj 301 VI aj
202 IV ak 252 V ak 302 VI ak
203 IV al 253 V al 303 VI al
204 IV am 254 V am 304 VI am
205 IV an 255 V an 305 VI an
206 IV ao 256 V ao 306 VI ao
207 IV ap 257 V ap 307 VI ap
208 IV aq 258 V aq 308 VI aq
209 IV ar 259 V ar 309 VI ar
210 IV as 260 V as 310 VI as
211 IV at 261 V at 311 VI at
212 IV au 262 V au 312 VI au
213 IV av 263 V av 313 VI av
214 IV aw 264 V aw 314 VI aw
215 IV ax 265 V ax 315 VI ax
Ex# Core R2 Ex# Core R2 Ex# Core R2
316 VII a 366 viπ a 416 IX a
317 VII b 367 vin b 417 IX b
318 VII c 368 VIII c 418 IX c
319 VII d 369 vra d 419 IX d
320 VII e 370 VIΠ e 420 IX e
321 VII f 371 VIΠ f 421 IX f
322 vπ g 372 VIΠ g 422 IX g
323 VII h 373 VIΠ h 423 IX h
324 VII i 374 VIΠ i 424 IX i
325 VII j 375 VIΠ j 425 IX j
326 VII k 376 VIΠ k 426 IX k
327 VII 1 377 VIΠ 1 427 IX 1
328 VII m 378 VIΠ m 428 IX m
329 VII n 379 VIII n 429 IX n
330 VII 0 380 vra 0 430 IX o
331 VII P 381 viπ P 431 IX p
332 VII q 382 VIII q 432 IX q
333 VII r 383 vra r 433 IX r
334 VII s 384 VIΠ s 434 IX s
335 VII t 385 vra t 435 IX t
336 VII u 386 viπ u 436 IX u
337 " VII V 387 VIII V 437 IX v
338 VII w 388 viπ w 438 IX w
339 VII X 389 vra X 439 IX x
340 VII y 390 vra y 440 IX y Ex# Core R2 Ex# Core R2 Ex# Core R2
341 VII z 391 vra z 441 IX z
342 VII aa 392 vra aa 442 IX aa
343 VII ab 393 vra ab 443 IX ab
344 vπ ac 394 vra ac 444 IX ac
345 VII ad 395 vra ad 445 IX ad
346 VII ae 396 viπ ae 446 IX ae
347 VII af 397 vra af 447 IX af
348 VII ag 398 vra ag 448 IX ag
349 VII ah 399 vra ah 449 IX ah
350 vπ ai 400 viπ ai 450 IX ai
351 VII aj 401 vra aj 451 IX aj
352 VII ak 402 VIII ak 452 IX ak
353 VII al 403 vra al 453 IX al
354 VII am 404 viπ am 454 IX am
355 VII an 405 vra an 455 IX an
356 VII ao 406 viπ ao 456 IX ao
357 VII ap 407 VIII ap 457 IX ap
358 VII aq 408 vra aq 458 IX aq
359 VII ar 409 vra ar 459 IX ar
360 VII as 410 VIII as 460 IX as
361 VII at 411 VIII at 461 IX at
362 VII au 412 viπ au 462 IX au
363 VII av 413 vra av 463 IX av
364 VII aw 414 viπ aw 464 IX aw
365 VII ax 415 VIII ax 465 IX ax
Ex# Core R2 Ex# Core R2
466 X a 516 XI a
467 X b 517 XI b
468 X c 518 XI c
469 X d 519 XI d
470 X e 520 XI e
471 X f 521 XI f
472 X g 522 XI g
473 X h 523 XI h
474 X i 524 XI i
475 X j 525 XI j
476 X k 526 XI k
477 X 1 527 XI 1
478 X m 528 XI m
479 X n 529 XI n
480 X 0 530 XI 0
481 X P 531 XI P Ex# Core R2 Ex# Core R2 482 X q 532 XI q 483 X r 533 XI r 484 X s 534 XI s 485 X t 535 XI t 486 X u 536 XI u 488 X w 538 XI w 489 X x 539 XI x 490 X y 540 XI y 491 X z 541 XI z 492 X aa 542 XI aa 493 X ab 543 XI ab 494 X ac 544 XI ac 495 X ad 545 XI ad 496 X ae 546 XI ae 497 X af 547 XI af 498 X ag 548 XI ag 499 X ah 549 XI ah 500 X ai 550 XI ai 501 X aj 551 XI aj 502 X ak 552 XI ak 553 X al 553 XI al 504 X am 554 XI am 505 X an 555 XI an 506 X ao 556 XI ao 507 X ap 557 XI ap 508 X aq 558 XI aq 509 X ar 559 XI ar 510 X as 560 XI as 511 X at 561 XI at 512 X au 562 XI au 513 X av 563 XI av 514 X aw 564 XI aw 515 ax 565 XI ax
In the above table, R2 is selected from the following radicals:
< •o.ΓΛ O ~.H.
Figure imgf000036_0001
Figure imgf000036_0002
m n o p q r
Figure imgf000036_0003
s t u w X
Figure imgf000036_0004
H00(/ A H00£/ j y z aa ab ac ad
Figure imgf000036_0005
ae af ag ah ai
Figure imgf000036_0006
aj ak al am an
NhPOOOH
Figure imgf000036_0007
ao ap aq ar as
NXCOOH
Figure imgf000036_0008
at au av aw ax
These amide examples 16 - 565 can be made by those skilled in the art following the above procedure and/or known procedures. The compounds described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention.
Utility: The present invention provides compounds capable of regulating and/or modulating protein kinase activities of, but not limited to, VEGFR (Vascular Endothelial Growth Factor Receptor), EGFR (Epidermal Growth Factor Receptor), FGFR (Fibroblast Growth Factor Receptor) or PDGFR (Platelate Derived Growth Factor Receptor). Thus, the present invention provides a therapeutic approach to the treatment of disorders related to the abnormal functioning of these kinases. Such disorders include, but not limited to, solid tumors such as glioblastoma, melanoma, and Kaposi's sarcoma, and ovarian, lung, prostate, pancreatic, colon and epidermoid carcinoma. In addition, VEGFR/FGFR inhibitors may also be used in the treatment of restenosis and diabetic retinopathy.
Furthermore, this invention relates to the inhibition of vasculogenesis and angiogenesis by receptor-mediated pathways, including the pathways comprising VEGF receptors, and/or FGF receptors. Thus the present invention provides therapeutic approaches to the treatment of cancer and other diseases that involve the uncontrolled formation of blood vessels.
VEGFR Biochemical Assay The compounds were assayed for biochemical activity by Upstate Ltd at Dundee, United Kingdom, according to the following procedure. In a final reaction volume of 25 μl, KDR (h) (5-10 mU) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.33 mg/ml myelin basic protein, 10 mM MgAcetate and [y- 33P-ATP] (specific activity approx. 500 cpm/pmol, concentration as required). The reaction is initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 5 μl of a 3% phosphoric acid solution. 10 μl of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.
EGFR biochemical assay
The compounds were assayed for biochemical activity by Upstate Ltd at Dundee, United Kingdom, according to the following procedure. In a final reaction volume of 25 μl, EGFR (h) (5-10 mU) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 10 mM MnCI2, 0.1 mg/ml poly(Glu, Tyr) 4:1, 10 mM MgAcetate and [γ-33P-ATP] (specific activity approx. 500 cpm/pmol, concentration as required). The reaction is initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 5 μl of a 3% phosphoric acid solution. 10 μl of the reaction is then spotted onto a filtermat A and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.
Cellular Assay: HUVEC: VEGF induced proliferation The compounds were assayed for cellular activity in the VEGF induced proliferation of HUVEC cells. HUVEC cells (Cambrex, CC-2517) were maintained in EGM (Cambrex, CC-3124) at 37°C and 5% CO2. HUVEC cells were plated at a density 5000 cells/well (96 well plate) in EGM. Following cell attachment (1 hour) the EGM-medium was replaced by EBM (Cambrex, CC- 3129) + 0.1 % FBS (ATTC , 30-2020) and the cells were incubated for 20 hours at 37°C. The medium was replaced by EBM +1% FBS, the compounds were serial diluted in DMSO and added to the cells to a final concentration of 0 - 5,000 nM and 1% DMSO. Following a 1 hour pre-incubation at 37°C cells were stimulated with 10ng/ml VEGF (Sigma, V7259) and incubated for 45 hours at 37°C. Cell proliferation was measured by BrdU DNA incorporation for 4 hours and BrdU label was quantitated by ELISA (Roche kit, 16472229) using 1 M H2SO4 to stop the reaction. Absorbance was measured at 450nm using a reference wavelength at 690nm.
Detailed Description of Figures:
Figure 1 is a scheme showing the synthesis of the 6-(omega alkanoic acid) quinazolines from 6,7-dimethoxy-3,4-dihydroquinazolin-4-one. The acid- promoted deprotection of the 6-hydroxy group of the quinazoline went according to the procedure in WO96/33980. Routine acetylation of the revealed hydroxyl was carried out in refluxing acetic anhydride/pyridine to give compound 1-3. The amide group of the quinazolin-4-one was converted to the chloroimine to give 6- acetoxy-4-chloro-7-methoxyquinazoline as the hydrochloride salt. Overall yield for the two steps was 82%. The 4-chloro-quinazoline 1-4 was converted to the aniline derivative by displacement of the chloride to give 1-5 in good yield by reaction with 3-chloro-4-fluoroaniline. The acetyl group is removed by reaction with ammonium hydroxide in refluxing methanol to provide 1-6 in 90% yield. The hydroxyl group of 1-6 was deprotonated with potassium carbonate in dimethyl acetamide and a catalytic amount of 18-crown-6 ether and alkylated with primary mesylate 1b to give 1-7 in adequate yield according to the procedure of Jendrella, H.; et al. J. Med. Chem. 1991, 34, 2962-2983. The acetonide protecting group was removed in acidic ethanol/THF to provide 1-8 in 46% yield. Saponification of the ester to the sodium salt 1-Na was done with sodium hydroxide in aqueous methanol at room temperature. Figure 2 is a scheme showing the synthesis of 2-Na, which is the 7-
(omega alkanoic acid) quinazoline derivative, from 7-benzyloxy-4-chloro-6- methoxyquinzoline. This starting material was purchased from J.W. Pharmlab. The first reaction is an SNAr-type displacement of chloride from 2-2 with an excess of 4-bromo-2-fluoroaniline in refluxing isopropanol to give the aniline derivative 2-3 in 45% yield. This was dissolved in trifluoroacetic acid and refluxed for 1.5 hours to provide the debenzylated 2-4 in 99% yield. The 7- hydroxyquinazoline 2-4 was treated with an excess of potassium carbonate in dimethylacetamide in the presence of a catalytic amount of 18-crown-6 ether at 85-90 °C for 22 hours. There was obtained approximately 39% of a light yellow solid, 2-5. Standard acetonide deprotection conditions have the dihydroxy ethyl ester 2-7 in 91% yield. A stoichiometric amount of sodium hydroxide in aqueous methanol hydrolyzed the ester to provide the sodium salt, 2-Na in 95% yield. Legend of scheme: A) isopropanol, 90 °C; B) TFA, reflux; C) K2CO3, 90 °C; D) THF, 5% HCI; E) methanol, water, NaOH (1 equivalent).
Figure 3A is a table of preferred compounds of the invention. All of the compounds shown have at least one asymmetric center and the stereochemistry at any given asymmetric center is RS, R, or S.
Figure 3B is a table of preferred compounds of the invention. All of the compounds shown have at least one asymmetric center and the stereochemistry at any given asymmetric center is RS, R, or S. Figure 3C is a table of preferred compounds of the invention. All of the compounds shown have at least one asymmetric center and the stereochemistry at any given asymmetric center is RS, R, or S.
Figure 4 is a table of preferred compounds of the invention. All of the compounds shown have at least one asymmetric center and the stereochemistry at any given asymmetric center is RS, R, or S. These compounds differ from those in Figures 3 in that they have a piperazine ring directly bonded to the quinazoline ring.

Claims

What is claimed is: 1. A compound of Formula (I):
Figure imgf000041_0001
(Formula I)
wherein: X is a triradical selected from the group consisting of N and C(R3); Y is a diradical selected from the group consisting of N(R4) and O; Z is a radical selected from the group consisting of optionally substituted phenyl, pyridine, indole, indazole, naphthalene, benzofuran, and benzothiophene; R is a radical selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkoxy, and (C5-C8) heterocycloalkoxy; R2 is a radical selected from the group consisting of hydroxyl, (C1-C6) alkoxy, (C5-C8) cycloalkoxy, and -NR5R6; n is 1 or 2; R3 is a radical selected from the group consisting of hydrogen and nitrile; R4 is a radical selected from the group consisting of hydrogen and (C1- C6) alkyl; R5 and R6 are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) dihydroxyalkyl, (C1-C6) alkoxy , (C1-C6) alkyl carboxylic acid, (C1-C6) alkyl phosphoric acid, (C1-C6) alkyl sulfuric acid, (C1-C6) hydroxyalkyl carboxylic acid, (C1-C6) alkyl amide, (C3-C8) cycloalkyl, (C5-C8) heterocycloalkyl, (C6-C10) aryl, (C5-C9) heteroaryl, (C3-C8) cycloalkyl carboxylic acid; or R5 and R6 together with N forms a (C5-C8) heterocyclic ring either unsubstituted or substituted with one or more hydroxyls, ketones, ethers, and carboxylic acids; or NR5R6 may form a cyclic ring containing 0-3 additional heteroatoms selected from N, O, or S; or, a pharmaceutically acceptable salt, its tautomer, a pharmaceutically acceptable salt of its tautomer, or a prodrug thereof.
2. The compound, salt, tautomer, or prodrug according to claim 1 wherein R2 is a radical selected from the group consisting of hydroxyl, (C1-C6) alkoxy, and (C5-C8) cycloalkoxy.
3. The compound or salt of claim 2, wherein the compound is selected from the group represented by the following structures:
Figure imgf000042_0001
4. The compound or salt of claim 2, wherein the compound is selected from the group represented by the following structures:
Figure imgf000043_0001
5. The compound or salt of claim 2, wherein the comp ound is selected from the group represented by the following structures:
Figure imgf000043_0002
6. The compound, salt, tautomer, or prodrug according to claim 1 wherein R2 is -NR5R6.
7. The compound or salt of claim 6, wherein the compound is selected from the group represented by the following structures:
Figure imgf000044_0001
8. The compound or salt of claim 6, wherein the compound is selected from the group represented by the following structures:
Figure imgf000044_0002
9. The compound or salt of claim 6, wherein the compound is selected from the group represented by the following structures:
Figure imgf000045_0001
10. The compound or salt of claim 6, wherein the compound is selected from the group represented by the following structures:
Figure imgf000045_0002
wherein: R2 is selected from the group consisting of radical represented by the following structures:
Figure imgf000046_0001
.OH <* Y OAccOOH J^ ^ ∞* N ^H * -JsH \ N S03H
11. A compound of formula (II):
Figure imgf000046_0002
wherein: W is a diradical selected from the group consisting of O and S; R1 is a radical selected from the group consisting of optionally substituted phenyl, benzyl, heteroaryl, and heteroarylalkyl; R2 is a radical selected from the group consisting of hydroxyl, (C1-C6) alkoxy, (C3-C8) cycloalkoxy, and NR3R4; n is 1 or 2; R3 and R4 are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) dihydroxyalkyl, (C1-C6) alkoxy , (C1-C6) alkyl carboxylic acid, (C1-C6) alkyl phosphoric acid, (C1-C6) alkyl sulfonic acid, (C1-C6) hydroxyalkyl carboxylic acid, (C1-C6) alkyl amide, (C3-C8) cycloalkyl, (C5-C8) heterocycloalkyl, (C6-C10) aryl, (C5-C9) heteroaryl, (C3-C8) cycloalkyl carboxylic acid; or R3 and R4 together with N forms a (C5-C8) heterocyclic ring either unsubstituted or substituted with one or more hydroxyls, ketones, ethers, and carboxylic acids; or NR3R4 may form a cyclic ring containing 0-3 additional heteroatoms selected from N, O, or S; or, a pharmaceutically acceptable salt, its tautomer, a pharmaceutically acceptable salt of its tautomer, or a prodrug thereof.
12. The compound, salt, tautomer, or prodrug according to claim 11 wherein R2 is a radical selected from the group consisting of hydroxyl, (C1-C6) alkoxy, and (C5-C8) cycloalkoxy.
13. The compound or salt of claim 12, wherein the compound is selected from the group represented by the following structures:
Figure imgf000047_0001
14. The compound, salt, tautomer, or prodrug according to claim 12 wherein R2 is -NR5R6.
15. The compound or salt of claim 14, wherein the compound is selected from the group represented by the following structures: 16. from the
Figure imgf000048_0001
17. The compound or salt of claim 11 , wherein the compound is selected from the group represented by the following structures:
Figure imgf000049_0001
CORE I CORE II CORE III wherein: R2 is selected from the group consisting of radical represented by the following structures:
Figure imgf000049_0002
18. The compound, salt, tautomer, or prodrug according to any of claims 1-10 with the following provisos: the compound, salt, tautomer, or prodrug of claim 2 is excluded or the compound, salt, tautomer, or prodrug of claim 3 is excluded or the compound, salt, tautomer, or prodrug of claim 4 is excluded or the compound, salt, tautomer, or prodrug of claim 5 is excluded or the compound, salt, tautomer, or prodrug of claim 6 is excluded or the compound, salt, tautomer, or prodrug of claim 7 is excluded or the compound, salt, tautomer, or prodrug of claim 8 is excluded or the compound, salt, tautomer, or prodrug of claim 9 is excluded or the compound, salt, tautomer, or prodrug of claim 10 is excluded.
19. The compound, salt, tautomer, or prodrug according to any of claims 11-17 with the following provisos: the compound, salt, tautomer, or prodrug of claim 2 is excluded or the compound, salt, tautomer, or prodrug of claim 13 is excluded or the compound, salt, tautomer, or prodrug of claim 14 is excluded or the compound, salt, tautomer, or prodrug of claim 15 is excluded or the compound, salt, tautomer, or prodrug of claim 16 is excluded or the compound, salt, tautomer, or prodrug of claim 17 is excluded.
20. A method for the modulation of the catalytic activity of a protein kinase with a compound or salt of any one of claims 1-19.
21. The method of claim 20, wherein said protein kinase is selected from the group consisting of VEGF receptors, FGF receptors, EGF receptors, PDGF receptors.
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