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):
-CH
2[CH(OH)CH
2]
nC(0)R
2
(Formula I) In 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
5R
6; n is 1 or 2; R
3 is a radical selected from the group consisting of hydrogen and nitrile; R
4 is a radical selected from the group consisting of hydrogen and (C1-C6) alkyl; R
5 and R
6 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 R
5 and R
6 together with N forms a (C5-C8) heterocyclic ring either unsubstituted or substituted with one or more hydroxyls, ketones, ethers, and carboxylic acids; or NR
5R
6 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, 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:
In a second preferred subgenus of the first aspect of the invention represented by Formula I, R
2 is -NR
5R
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:
Further embodiments of the second subgenus of the first aspect of the invention include compounds represented by the following structures:
In each of the CORE structures (l-Vlll), R
2 is selected from the group consisting of radical represented by the following structures:
A second aspect of the invention is directed to a compound of formula (II):
ln 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
3R
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, (C3-C8) cycloalkyl, (C5-C8) heterocycloalkyl, (C6-C10) aryl, (C5-C9) heteroaryl, (C3-C8) cycloalkyl carboxylic acid; or R
3 and R
4 together with N forms a (C5-C8) heterocyclic ring either unsubstituted or substituted with one or more hydroxyls, ketones, ethers, and carboxylic acids; or NR
3R
4 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:
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:
Further embodiments of the second subgenus of the second aspect of the invention include compounds represented by the following structures:
Further embodiments of the second subgenus of the second aspect of the invention include compounds represented by the following structures:
wherein: R 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. 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:
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 (3R,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
The procedure for the synthesis of the title compound is depicted in Figure 1.
1-2: 6-Hydroxy-7-methoxy-3,4-dihy roquinazolin-4-one was obtained according to WO96/33980 in 93% yield. 1H NMR (DMSO-d6, ppm): δ 7.92 (s, 1 H), 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. o HNJ 0A'i
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.
1-4: 4-Chloro-6-acetoxy-7-methoxyquinazoline hydrochloride was obtained according to WO96/33980 and used for the next step without purification.
C FI S MH Λ .^ .OAc V ^0^ 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 , 2.1 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 (ά, J = 18.0 Hz), 116.3 (d, J = 21.6 Hz), 109.5, 107.1 , 105.2, 55.9.
1b: (4R,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 (CDCI
3, 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), 1.38 (s, 3H), 1.32 (m, 1 H), 1.26 (t, 3H, J = 6.9Hz).
3C NMR (DMSO-d
6, 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.
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 MgSO , 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, 2.1 Hz), 7.58 (m, 1 H), 7.20 (s, 1 H), 7.14 (t, J = 9.0 Hz, 1 H), 6.77 (s, 1 H), 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, 1H, 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.
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 mL) was stirred at 20 °C for 24 h. Saturated aqueous Na
2CO
3 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 MgSO
4, concentrated to give the product (0.12 g, 46%) as a yellow solid.
1H NMR (300 MHz, CDCl
3, 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, CDCI
3, 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.
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: (3R,5S)-6-[{4-(4-Bromo-2-fluorophenylamino)-6- methoxyquinazolin-7-yl}oxy]-3,5-dihydroxyhexanoic acid, sodium salt.
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, C; Stokes, E.S.E.; Pie, PA; 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-methoxyquinazoIin-4-yI)-(4-bromo-2-fluorophenyl)- amine
A mixture of 2-2 (7-benzyloxy-4-chloro-6-methoxyquinazoline, 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, 1 H), 5.26 (s, 2H), 3.94 (s, 3H). 13C NMR (75 MHz, DMSO-de): 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
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. 1H 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: ((4R,6S)-6-Methanesulfonyloxymethyl-2,2-dimethyl-[1,3]dioxan-4- yl)-acetic acid ethyl ester
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, 1 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, CDCl3): δ 170.64, 99.41 , 72.37, 67.37, 65.61 , 60.84, 41 .52, 32.04, 30.04, 14.51.
2-5: (4R,6S)-{6-[4-(4-Bromo-2-fluorophenylamino)-6-methoxyquinazolin-7- yloxymethyl]-2,2-dimethyl-[1 ,3]dioxan-4-yl}-acetic acid ethyl ester
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, 118.48 (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: (3R,5S)-6-[(4-(4-Bromo-2-fluorophenylamino)-6-methoxyquinazolin-7- yl)oxy]-3,5-dihydroxyhexanoic acid ethyl ester
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, 118.78 (d, J - 22.6 Hz), 115.95 (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: (3R,5S)-6-{[4-(4-Bromo-2-fluorophenylamino)-6-methoxyquinazolin- 7-yl]oxy}-3,5-dihydroxyhexanoic acid, sodium salt
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 (10 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 mL). 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. H NMR (300 MHz, CDCI
3): 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, 1 H, J = 8.4 Hz), 7.27 (br s, 1 H), 7.14 (s, 1 H), 5.16 (br s, 1 H), 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-d
6): 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: (3R,5S)-6-{[4-(3-Chloro-4-fluorophenylamino)-7- methoxyquinazolin-6-yl]oxy}-3,5-dihydroxy-1 -(pyrrolidin-1 -yl)-hexan-1 -one.
The synthesis of the amide derivatives of Example 1 is shown in Scheme 3 below:
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 NaHCO
3 (3x) and brine (3x), and dried over Na
2SO
4. 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, 1 H), 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-fluorophenyIamino)-7- methoxyquinazolin-6-yl]oxy}-3,5-dihydroxy-1-(morpholin-4-yl)-hexan-1-one.
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, 1H), 7.20 (s, 1H), 5.06 (s, 1 H), 4.82 (s, 1H), 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-chIoro-4-(3-fluorobenzyloxy) phenylamino]-quinazolin-6-yl)oxy}-3,5-dihydroxy hexanoate
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 te/ -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 mL) was added ((4R,6S)-2,2-dimethyl-6-trifluoromethanesulfonyloxymethyl- [1 ,3]dioxan-4-yl)-acetic acid terf-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
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 terf-butyl ester
To a solution of the product from Example 5, Step A in THF was added 1 M 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.
Example 9: Amide derivatives of Example 2
The synthesis of the amide derivatives of Example 2 is described in Scheme 4 below:
An amine (3 equiv) was added to a solution of Compound 4-1 (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 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.
Example 10. Following the above procedures and known procedures in the literature, the following examples 10a-j can be made.
10i 10j
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.
Examples 16 - 565: Still further amide examples are shown in the following table:
CORE IX CORE X CORE XI
-I-- 4-- to O o o U\
4-- to to o Uλ o o
Ex# Core R2 Ex# Core R2 Ex# Core R 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 R
2 Ex# Core R
2 Ex# Core R
2
317 VII b 367 viπ b 417 IX b 318 VII c 368 viπ c 418 IX c 319 VII d 369 VIΠ d 419 IX d 320 VII e 370 VIΠ e 420 IX e 321 VII f 371 VIΠ f 421 IX f 322 VII g 372 VIΠ g 422 IX g 323 VII h 373 vm h 423 IX h 324 VII i 374 vm 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
331 VII P 381 vm P 431 IX P
334 VII s 384 vm s 434 IX s 335 VII t 385 vm t 435 IX t 336 VII u 386 vm u 436 IX u 337 VII V 387 vm V 437 IX V 338 VII w 388 viπ w 438 IX w 339 VII X 389 vm X 439 IX X
Ex# Core R
2 Ex# Core R
2 Ex# Core R
z 341 VII z 391 vm z 441 IX z 342 VII aa 392 viπ aa 442 IX aa 343 vπ ab 393 vm ab 443 IX ab 344 VII ac 394 viπ ac 444 IX ac 345 VII ad 395 viπ ad 445 IX ad 346 VII ae 396 vm ae 446 IX ae 347 VII af 397 vm af 447 IX af 348 VII ag 398 VIII ag 448 IX ag 349 VII ah 399 vm ah 449 IX ah 350 VII ai 400 vm ai 450 IX ai 351 vπ aj 401 VIII aj 451 IX aj 352 VII ak 402 VIII ak 452 IX ak 353 VII al 403 vm al 453 IX al 354 VII am 404 viπ am 454 IX am 355 VII an 405 VIII an 455 IX an 356 VII ao 406 viπ ao 456 IX ao 357 VII ap 407 VIΠ ap 457 IX ap 358 VII aq 408 VIΠ aq 458 IX aq 359 VII ar 409 VIΠ ar 459 IX ar 360 VII as 410 vm as 460 IX as 361 VII at 411 vm at 461 IX at 362 VII au 412 VIII au 462 IX au 363 VII av 413 VIII av 463 IX av 364 VII aw 414 viπ aw 464 IX aw 365 VII ax 415 VIΠ ax 465 IX ax
E3x# 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 Ii 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
i-o to to o o <~n i
b c d
e f
. g i j k !
m n o p q
r
HO HOOC> H VOOC H
*OOCX*?HOOC
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 S Ar-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.