QUINAZOLINE SYNTHESIS
Field Of Invention The present invention provides a method for synthesizing a compound or a library of compounds comprising a quinazoline nucleus. Background
Synthesis of quinazoline derivatives has been reported by Manoury et al., J. Med. Chem., 29:19-25 (1996); Myers et al., Bioorganic and Medicinal Chemistry Letters, 7(4):421-424 (1997); and Leonardi, et al, J. Med. Chem. 42:427-437 (1999). In addition, the application of nucleophilic aromatic substitution reactions in the synthesis of combinatorial libraries in solution and on solid support has been described by Nugiel et al., J. Org. Chem.62:201-203 (1997), Feng et al., J. Am. Chem. Soc.120:10768-10769 (1998), MacDonald et al., Tetrahedron Lett. 37:4815-4818 (1996), Smith et al., Tetrahedron Lett. 40:7633-7636 (1999), Stankova et al., Molecular Diversity 2:75-80 (1996) and Johnson et al, Tetrahedron 54:4097-4106 (1998).
Quinazoline based compounds have been known to have useful biological activity. Curd et al., Synthetic Antimalarials, Part XXXI, pp. 1759-1766 (1948) have reported the synthesis of quinazoline based compounds as antimalarial agents. The synthesis was essentially accomplished by (a) reaction of urea with a substituted anthranillic acid, and (b) reaction of sodium cyanate with a substituted anthranillic acid, ester, amide or nitrile, and cyclization of the resulting urea. Quinazoline based compounds have also been reported to have αradrenoceptor antagonist activity. Quinazoline based compounds are thus an important class of compounds with applications in the pharmaceutical industry. In spite of the different synthetic techniques known in the art, the pharmaceutical industry is in search of new processes that will enable synthesis of a large number of compounds at a relatively rapid pace. There is thus a need for a method for rapid parallel synthesis of multiple quinazoline based compounds.
Summary Of The Invention The present invention provides a method for synthesizing a compound or a library of quinazoline based compounds represented by Formula I, II and III.
Detailed Description
Definitions:
The following terms and phrases as used herein have the following meaning, unless indicated otherwise. The term "array of compounds" or "library of compounds" indicates a collection of independent (individual) compounds that are synthesized by the method of the present invention. Generally the term array of compounds indicates a collection of individual compounds distinct from one another. Also included in the array (library) of compounds is a mixture of the mdividual compounds. The term "library of compounds" can be interchangeably used with the term "array of compounds".
The term "alkyl" as used herein represents a straight (unbranched) or branched saturated hydrocarbon radical comprising from 1-14 carbon atoms, unless indicated otherwise and includes as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like. The foregoing alkyl group can be substituted with
1-3 substituents independently selected from the group consisting of -N(C1.4alkyl)2,
-N(C1.4alkyl)(aryl), -OH, -O- -όalkyl and aryl. Accordingly, the term "alkyl" is intended to include both unsubstituted and substituted alkyl groups.
The term "cycloalkyl" as used herein represents a - -ualkyl group as defined above wherein the alkyl group contains a saturated cyclic hydrocarbon radical comprising from 4-10 carbon atoms, unless indicated otherwise. As with alkyl, the term "cycloalkyl" is intended to include both unsubstituted and substituted cycloalkyl groups.
The term "(CH2)n" refers to a straight carbon chain linker having "n" carbons. When n is zero, the linker is a covalent bond.
The term "aryl" is used to represent an aromatic monocyclic or polycyclic hydrocarbon radical comprising from 5-14 carbon atoms, unless indicated otherwise.
Thus, an aryl group includes phenyl, naphthyl, anthracenyl, biphenyl, etc. The aryl group can be substituted with 1-3 substituents independently selected from the group consisting of -OH, -d.6alkyl, - -ealkyl-OH, -CF3, halo, -O-aryl, -S-aryl, -O-Cμ
6alkyl, -C(O)-CMalkyl, -SO2-NH2, -NO2 and -r OO". Accordingly, the term "aryl" is intended to mclude both unsubstituted and substituted aryl groups.
The term "heterocycloalkyl" is intended to represent a stable 3- to 7- membered monocyclic or 7- to 10- membered polycyclic ring which is saturated or
partially unsaturated (e.gi, containing one or more double bonds) and contains 1-4 heteroatoms (N, O or S), while the term "heteroaryl" as used herein represents a stable 5- to 7- membered monocyclic or 7- to 10- membered polycyclic ring which is unsaturated and contains 1-4 heteroatoms within a single ring (e.g., such as pyridyl, imidazolyl, thiazolyl, pyrimidine, oxazolyl, and the like), or within two rings (e.g., indolyl, quinolinyl, benzofuranyl, and the like). The heterocycloalkyl ring and heteroaryl ring may be substituted with 1-3 substituents independently selected from the group consisting of =0, -OH, -Ci-βalkyl, -Cι-6alkyl-OH, -O-Cι.6alkyl, -(CH2)0.2- C(O)-O-C1.4alkyl, -NH-C(O)-C1.4alkyl, -C(O)-NH2, cycloalkyl, heteroaryl, aryl, benzyl, -(CH2)0.2-heterocycloalkyl and -C(O)-N(Cι-4alkyl)2. These substitutions can be on a carbon or a heteroatom if the resulting compound is stable. For example, any amino group contained within the heterocycloalkyl ring can be a primary, secondary or tertiary amine, as long as the structure is stable. Accordingly, the terms "heterocycloalkyl" and "heteroaryl" are intended to include both unsubstituted and substituted groups .
The term "optional" or "optionally" generally means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase "optionally is substituted with one or more substituents", as used herein, means that the group referred to may or may not be substituted in order to fall within the scope of the invention. Thus the term "optionally substituted" is intended to mean that any one or more hydrogens on a designated atom can be replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound. When the substituent is keto (=O) then 2 hydrogens on the atom are replaced.
The term "alkoxy" represents an oxygen atom attached to an alkyl group and comprises from one to six carbon atoms
unless indicated otherwise. The term "halo" is intended to represent the CI, Br, I or F radicals. The term "amido" as used herein represents a group of the formula -
C(O)NRa b wherein Ra and Rb independently at each occurrence are selected from a group consisting of -H, alkyl, cycloalkyl and alkenyl.
As used in the present invention, the illustration:
generally indicates a point of attachment of the group, comprising the illustration, to another group or atom. The term "suitable medium" or "suitable solvent" as used herein is meant to indicate a medium/solvent that is compatible with the respective reaction conditions. Representative examples of a suitable medium/solvent are THF, dioxane, toluene, N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethyl acetamide, dichloromethane, N-methyl pyrrolidinone or mixtures thereof. A list of suitable mediums/solvents can be found in Tetrahedron Letters 39:8451-8454 (1998), which is incorporated herein by reference.
The term "base" as used herein represents a chemical entity that can absorb or abstract a proton. Illustrative examples of a base are N-methylmorpholine, N- ethylmorpholine, N-methylpiperidine, N-ethylpiperidine, triethylamine, pyridine, lutidine, l,8-diazabicyclo[5.4.0]undec-7-one, N,N-diisopropylethylamine, tetrabutylammonium hydroxide, tetramethylammonium hydroxide, lithium hydroxide, and aqueous solutions of alkali metal hydroxides, carbonates and bicarbonates. The term "acid" as used herein represents a chemical entity capable of donating a proton (Bronsted acid) or accepting a pair of electrons (Lewis acid). The term "cation scavenger" represents an agent which captures any cations generated during a given reaction. Illustrative examples of a cation scavenger are triethylsilane, triisopropylsilane, water, ethanedithiol, anisole and thioanisole. As used herein, the term "leaving group" or "LG" represents a functional group that may be displaced by a nucleophile. Illustrative examples of leaving groups are halo groups, -O-COCH3, and -O-tosyl.
As used in the present invention, the term "solid support" or "SS" signifies a polymeric material for supported synthesis. The solid support should be labile under certain conditions to facilitate formation of a compound of Formula I, and should otherwise be chemically stable under the conditions of the present method. Illustrative examples of suitable solid supports are 3,5-dimethoxy-4-formylphenoxy polystyrene; 2-(3,5-dimethoxy-4-formylphenoxy)ethoxymethyl polystyrene; 2-(3,5-
dimethoxy-4-formylphenoxy)ethyl polystyrene; 4-(3,5-dimethoxy-4-formylphenoxy)- butyramidomethyl polystyrene; 4-(3,5-dimethoxy-4-formylphenoxy) propionamidomethyl polystyrene; and 4-(3,5-dimethoxy-4- formylphenoxy)acetamidomethyl. A detailed description of the terms linker molecule and solid support can be found in B. A. Bunin, "The Combinatorial Index", Academic Press (1998), which is incorporated herein by reference.
The term "reaction plate" as used herein represents a plate comprising multiple wells or cavities useful for conducting reactions therein. A Polyfiltronics plate is an illustrative example of a reaction plate. Abbreviations
DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
DCC 1,3-dicyclohexylcarbodiimide
DCM dichloromethane or CH2C12
DIG 1 ,3 -dicyclohexylcarbodiimide DIPEA NN-diisopropylethylamine
DMA NN-dimethylacetamide
DMF NN-dimethylformamide
DMSO dimethylsulfoxide
EDCI 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
ESI electrospray ionization
EtOH ethanol
HBTU O-benzotriazol- 1 -yl-N,N,N,N-tetramethyluronium hexafluorophosphate HOBt 1-hydroxybenzotriazole
MeOH methanol
MS mass spectroscopy
ΝEP N-ethylpyridine
ΝMM N-methylmorpholine PyBOP benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate
TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran
TMOF trimethylorthoformate
The present invention provides a method for synthesizing a compound or an array of compounds of Formula I:
R1 is selected from the group consisting of -H, -(CH )1.6-aryl, -(CH2)ι_6- heteroaryl, -(CH2)0.6-heterocycloalkyl, -(CH2)0.6-cycloalkyl and -Cι-14-alkyl;
R2 and R3 are independently selected from the group consisting of -H, -C\. 4alkyl, -(CH2)1-6-aryl, , -(CH2)0-6-cycloalkyl, -(CH2)M-heteroaryl, -(CH2)0.6- heterocycloalkyl and -C(O)-heterocycloalkyl; or R2 and R3 along with the nitrogen atom to which they are attached are taken together to form a heterocycloalkyl ring; and
R4 and R5 are independently selected from the group consisting of halo, -H, - O-Cι-6alkyl, -d-6alkyl, -CON(C1-4alkyl)2, -NO2 and -N(d-4 alkyl)2.
This method comprises the steps of:
(i) treating, in a suitable medium, a compound or an array of compounds of Formula 1:
SS-CH2-NHR1 (1) with a compound or array of compounds of Formula 2:
in the presence of a base and at a temperature of from about 0-145°C to form a compound or an array of compounds of Formula 3:
where SS represents a solid support, LG represents a leaving group, and R
1, R
4 and R
5 are as defined above; and
(ii) treating a compound or an array of compounds of Formula 3 with a compound or array of compounds of Formula 4: NHR2R3 (4) in a suitable medium and an optional base, at a temperature ranging from about 50- 200°C, to form a compound or an array of compounds of Formula I.
In one embodiment of this method of the invention, the suitable medium in step (i) is selected from the group consisting of THF, DCM, DMA, DMF, toluene, DMSO and mixtures thereof. In another embodiment, the base in step (i) is selected from the group consisting of DIPEA, TEA, DBU, NMM, NEP, pyridine, lutidine, l,5-diazabicyclo[4.3.0]non-5-ene, tetramethylguanidine and l,2-dimethyl-l,4,5,6- tetrahydropyrimidine. In yet another embodiment, step (i) is conducted at a temperature within the range of about 25-75°C, typically about 50-60°C. In one embodiment of the invention, the suitable medium in step (ii) is selected from the group consisting of DMSO, DMA, DMF, toluene, xylenes, ethanol, l-methyl-2-pyrrolidine and mixtures thereof. In yet another embodiment of the invention, step (ii) includes a base selected from the group consisting of DIPEA, TEA, DBU, NMM, NEP, pyridine, lutidine, l,5-diazabicyclo[4.3.0]non-5-ene, tetramethylguanidine and l,2-dimethyl-l,4,5,6-tetrahydropyrimidine. In another embodiment, step (ii) is conducted at a temperature within the range of about 85- 190°C typically about 120°C.
The present invention also provides a method for synthesizing a compound or an array of compounds of Formula II:
wherein:
R1 is selected from the group consisting of -H, -(CH2)ι-6-aryl, -(CH2)ι„6- heteroaryl, -(CH2)0.6-heterocycloalkyl, -(CH2)0.6-cycloalkyl and -d.14-alkyl;
R2 and R3 are independently selected from the group consisting of -H, -Cι_ 4alkyl, -(CH2)ι_6-aryl, , -(CH2)0.6-cycloalkyl, -(CH2)1. -heteroaryl, -(CH2)0.6- heterocycloalkyl and -C(O)-heterocycloalkyl; or R and R along with the nitrogen atom to which they are attached are taken together to form a heterocycloalkyl ring; and
R4 and R5 are independently selected from the group consisting of halo, -H, - O-d.6alkyl, -Cι_6alkyl, -CON(d-4alkyl)2, -NO2 and -N(CM alkyl)2.
This method comprises the step of treating a compound or an array of compounds of Formula I with an acid, to form a compound or an array of compounds of Formula II. The acid acts as a cleaving agent and can be a lewis or protic acid, such as an acid selected from the group consisting of TFA, HF, triflic acid, HCl, HBr, trifluoromethanesulfonic acid, perfluorobutyric acid, sulfuric acid and mixtures thereof. In one embodiment of this method of the invention, this acid is selected from the group consisting of TFA, HF, triflic acid, HCl and mixtures thereof. In another embodiment, a cation scavenger such as triethylsilane is also included in this step.
The present invention also provides a method for synthesizing a compound or an array of compounds of Formula III:
R1 is selected from the group consisting of -H, -(CH2)1.6-aryl, -(CH2)ι.6- heteroaryl, -(CH2)0.6-heterocycloalkyl, -(CH2)0.6-cycloalkyl and -Cι-i4alkyl; '
R is selected from the group consisting of -H and -d_ι4alkyl; R3 is selected from the group consisting of -C1.6alkyl-NH2 and -d-6alkyl-
NH(C1.4alkyl); or R2 and R3 ' along with the nitrogen atom to which they are attached are taken together to form a ring structure selected from the group consisting of - heterocycloalkyl comprising two N atoms, -heterocycloalkyl-d-6alkyl- heterocycloalkyl where each -heterocycloalkyl ring comprises one N atom, and -heterocycloalkyl-C0.4alkyl-NH2 where the heterocycloalkyl ring comprises at least one N atom;
X is selected from the group consisting of -CO-, -CO-NH- and -SO2-; R6 is selected from the group consisting of -(CH2)0.6-aryl, -(CH )1.4-O-aryl, heteroaryl, -(CH2)0-6-cycloalkyl, -(CH2)1.4-S-C(S)-aryl, -CH2-(O-CH2-CH2)0.2-OCH3 and amido; and
R4 and R5 are independently selected from the group consisting of halo, -H, -O-d-6alkyl, -Cι.6alkyl, -CON(d.4alkyl)2, -NO2 and -N(CM alkyl)2. This method comprises the steps of:
(a) treating, in a suitable medium in the presence of a base, and at a temperature of from about 100-150°C, a compound or array of compounds of Formula 3:
where SS represents a solid support, LG represents a leaving group, and R1, R4 and R5 are as defined above, with a diamine compound or array of diamine compounds of Formula 5:
NHR2 R3 ' (5)
9 ' ' wherein R and R are as defined above, to form a compound or array of compounds of Formula 6:
(b) treating the compound or array of compounds of Formula 6 in a suitable medium in the presence of a base, an optional coupling agent and an optional catalyst, with an acylator compound or array of compounds selected from the group consisting of R6COOH, R6COCl, R6SO2Cl and R6-N=C=O, where R6 is as defined above, to form a compound or array of compounds of Formula 8:
where X is as defined above; and (c) treating a compound or array of compounds of Formula 8 with an acid to form a compound or array of compounds of Formula III.
In one embodiment of this method of the invention, the suitable medium in step (a) is selected from the group consisting of DMA, DMF, DCM, and mixtures thereof and the base in step (a) is selected from the group consisting of NMM, DIPEA, TEA and DBU. In another embodiment, step (a) is carried out at temperature of from about 135-140°C *
In another embodiment of this method of the invention, in step (b), the suitable medium is selected from the group consisting of DMA, DMF, DCM, THF, 1,4- dioxane, 1,2-dichloroethane, N-methylpyrrolidone, chloroform and mixtures thereof; the base is selected from the group consisting of ΝMM, DIPEA, TEA, DBU, N- ethylpiperidine, pyridine and lutidine; the coupling agent is selected from the group consisting of PyBOP (described in Coste et al, Tetrahedron Lett. 31:205-208 (1980)),
DIC, DCC, EDCI and HBTU (described in Knorr et al., Tetrahedron Lett. 30:1927- 1930 (1989)); and the optional catalyst is selected from the group consisting of HOBt, N-hydroxysuccinimide, N-hydroxy-7-azabenzotriazole and e«-io-N-hydroxy-5- norbornene-2,3-dicarboximide. Exemplary combinations of reagents include the acylator R6COOH with the base ΝMM, the coupling agent PyBOP and the catalyst HOBt; the acylator R6COCl with the base ΝMM, DIPEA or TEA; and the acylator R6SO2Cl with the base ΝMM, pyridine or lutidine.
In yet another embodiment, the acid in step (c) is a cleaving agent as described above in Scheme II. In one embodiment of this method of the invention, this acid is selected from the group consisting of TFA and HCl.
In one embodiment of the invention, the methods described above are useful for synthesizing a compound or an array of compounds of Formulas I, II and III, where R1 is selected from the group consisting of -H; a -(CH2)!-6-aryl selected from the group consisting of -CH2-(C6H5), -(CH2)2-(C6H5), -(CH2)4-(C6H5), -(CH2)3-C6H5,
a -(CH^-e-heteroaryl selected from the group consisting of:
■-0 ^"G" ~O a -(CH2)0-6-heterocycloalkyl selected from the group consisting of:
a -(CH )0.6-cycloalkyl selected from the group consisting of -C6Hπ and -CH2-C6Hπ; and a -Cι.14alkyl selected from the group consisting of methyl, ethyl, butyl, isobutyl, -CH2-CH(C2H5)-C4H9, -CH2-CH(OH)-CH3, -(CH2)2-C(CH3)3, -(CH2)2-CH(CH3)2, -(CH2)3-O-CH(CH3)2, -(CH2)-CH(CH3)(C6H5), -(CH2)2-CH(C6H5)2, -CH2-
CH(OH)(C6H5), -CH2-CH(OH)(CH3), -(CH2)3-N(C2H5)3, -CH(C2H5)(CH2-O-CH3) and -(CH2)3-N(CH3)-C6H5.
In another embodiment of the invention, the method described above is useful for synthesizing a compound or an array of compounds of Formulas I and II, where R and R
3 are independently selected from the group consisting of -H; a -Cι-
4alkyl selected from the group consisting of methyl, -(CH
2)
4OH, -(CH
2)
5OH, -(CH
2)
2- CH(C
6H
5)
2, -(CH
2)-CH(C
6H
5)
2, -(CH
2)
3-O-CH(CH
3)
2, -CH
2-CH(C
2H
5)-C
4H
9, -CH
2-CH(OH)-(CH
2)
2OH, -CH
2-CH(OH)-(C
6H
5), -(CH
2)
3-N(C
2H
5)
2 and -(CH
2)
3- N(CH
3)(C
6H
5); a -(CH
2)ι-
6-aryl selected from the group consisting of -CH
2-(C
6H
5), -(CH
2)
4-(C
6H
5),
the -(CH2)o-6-cycloalkyl -CH2-C6Hπ; the -(CH2)1.4-heteroaryl
a -(CH2)o-6-heterocycloalkyl selected from the group consisting of:
O
and; the -C(O)-heterocycloalkyl
In another embodiment of the invention, the method described above is useful for synthesizing a compound or an array of compounds of Formulas I and II, where R
2 and R along with the nitrogen atom to which they are attached are taken together to form a heterocycloalkyl ring selected from the group consisting of:
In another embodiment of the invention, the method described above is useful
for synthesizing a compound or an array of compounds of Formula III, where R2 is selected from the group consisting of -H and -CH3.
In another embodiment of the invention, the method of the invention is useful for synthesizing a compound or an array of compounds of Formula III, where R3 is selected from the group consisting of a -C1.6alkyl-NH2 selected from the group consisting of -(CH2)3-NH2,
-(CH2)4-NH2 and -(CH2)-C(CH3)2-CH2-NH2; and the -Cι-6alkyl-NH(CMalkyl) group - (CH2)2-NH(CH3).
In still another embodiment of the invention, the method of the invention is useful for synthesizing a compound or an array of compounds of Formula III, where R2 ' and R3 along with the nitrogen atom to which they are attached are taken together to form a compound selected from the group consisting of a -heterocycloalkyl comprising two N atoms, selected from the group consisting of:
the -heterocycloalkyl-Cι.6alkyl-heterocycloalkyl:
and a -heterocycloalkyl-Co.4alkyl-NH2 where the heterocycloalkyl ring comprises at least one N atom, selected from the group consisting of:
In another embodiment of the invention, the method described above is useful for synthesizing a compound or an array of compounds of Formula III, where X is -CO- and R is selected from the group consisting of: -(CH
2)
0.
6-aryl selected from the group consisting of:
-(CH2)!- -O-aryl selected from the group consisting of:
heteroaryl selected from the group consisting of:
-(CH
2)
0-
6-cycloalkyl selected from the group consisting of:
.CH.
-.- -
fhe -(CH2)ι.4-S-C(S)-aryl group:
-CH2-(O-CH2-CH2)0.2-OCH3 selected from the group consisting of -CH2-O-(CH2)2-O- (CH2)2-OCH3 and -CH2-(O-CH2-CH2)0.2-OCH3; and amido.
In yet another embodiment of the invention, the methods described above are useful for synthesizing a compound or an array of compounds of Formulas I, II and III, where R4 and R5 are -O-d-όalkyl groups, for example -OCH3.
Experimental Details Scheme I below further illustrates the method of the present invention for preparing an individual compound or an array of compounds of Formula I.
Scheme I
where R1, R2, R3, R4 and R5 are as defined above, SS represents a solid support and LG represents a leaving group.
Compounds of Formula 1 and Formula 2 and other reactants used in Scheme I
are available from commercial sources or can be synthesized by using techniques known to one skilled in the art. For example, Compounds of Formula 1 can be synthesized by first attaching 2-methoxy-4-hydroxybenzaldehyde to chloromethylpolystyrene (Merrifϊeld resin; 100-200 mesh; loading 1.0-1.2 mmol/gram) with cesium carbonate in DMA. The resulting aldehyde resin is then converted to the secondary amine using the two-step sequence described by Sarantakis, et al., Tetrahedron Letters 38(42): 7325-7328 (1997). Scheme I, Step (i . Formula 3
A mixture of a compound of Formula 1 (1 eq.) and a suitable medium is combined with a compound of Formula 2 (2-4 eq.) and a base (4-8 eq.) in a reaction vessel. The reaction vessel is topped with a vented top. The vented reaction vessel then is placed from about 2-20 hours in a nitrogen purged oven, optionally preheated to a temperature of up to about 100°C. The reaction mixture, if previously heated, is cooled to ambient temperature. Resin from the cooled reaction mixture is isolated and washed sequentially with DCM (x2), THF (x2), DCM (x2) and MeOH (x2). The washed resin is dried to yield a compound of Formula 3. Similar conditions were reported for a solution phase selective chlorine displacement reaction in Curd et al, J. Chem. Soc. 1559-1566 (1948) and Millen, et al, J. Med. Chem. 28:12-17 (1985). Scheme I, Step (ii . Formula I A mixture of a compound of Formula 3 (1 eq.), an optional base and a suitable medium (1 mL) is combined with a mixture of a compound of Formula 4 (6-20 eq. ) and DMA (1 mL) to form a reaction mixture. The reaction mixture is optionally agitated at a temperature of from about 50-200°C from about 2-24 hours. The reaction mixture then is cooled to ambient temperature and the reaction solids (resin) are separated. The reaction solids then are sequentially washed with MeOH (x2), DCM (x2) and MeOH (x2). The washed resin is dried to yield a compound of Formula I.
Scheme II below further illustrates the method of the present invention for preparing an individual compound or an array of compounds of Formula II.
Scheme II
where R1, R2, R3, R4 and R5 are as defined above and SS represents a solid support.
The reactants used in Scheme II are available from commercial sources or can be synthesized by using techniques known to one skilled in the art. Scheme IL Formula II
A structurally distinct compound of Formula I is placed in each well of a reaction plate and the plate is sealed from the bottom. A cation scavenger (e.g., a 2.5% triethylsilane solution) in an acid, e.g., TFA, then is added to each well. The reaction plate is sealed from the top and the well contents are let stand from about 0.5- 4 hours. The well contents are warmed to ambient temperature and the liquid contents of each well of the reaction plate are drained. The solid contents of each well of the reaction plate are washed with DCM (x2). The DCM washings are combined with the respective filtrates. Each resulting mixture is concentrated to yield an array of compounds of Formula II.
Scheme III below further illustrates the method of the present invention for preparing an individual compound or an array of compounds of Formula III.
Scheme III
where R1, R2 ', R3 ', R4, R5, R6 and X are as defined above, SS represents a solid support, LG represents a leaving group and the acylator is selected from the group consisting of R6COOH, R6COCl, R6SO2Cl and R6-N=C=O.
Compounds of Formula 5 and the other reactants used in Scheme III are available from commercial sources or can be synthesized by using techniques known to one skilled in the art.
Scheme III. Step (a . Formula 6 A solution of a compound of Formula 3 in a suitable medium and a base (3-8 eq.) is combined with a compound of Formula 5 (3-8 eq.). This resulting mixture is heated for several hours then cooled to room temperature. The resulting resin of
Formula 6 is sequentially washed with MeOH, DCM, MeOH and DCM.
Scheme III, Step (fr). Formula 8 A solution of a coupling agent (3-8 eq.) in a suitable medium and optional catalyst (e.g., HOBt; 0.5 to 1.2 eq) is combined with the desired acylator (3-8 eq.).
This resulting mixture is shaken and the resin of Formula 6 in a base is then added.
The reaction mixture is shaken overnight. The resulting resin of Formula 8 is sequentially washed with MeOH, 4:1 DCM:DIPEA, MeOH, DMF, MeOH and DCM (2x3 mL each) to yield a compound of Formula 8.
Scheme III, Step (c . Formula III
A compound of Formula 8, preferably in an inert medium, is combined with an excess of an acid, preferably TFA. The resulting mixture is let stand for up to 2
hours and the reaction liquids are isolated. The reaction solids are washed with TFA (x2) and these washings are combined with the isolated reaction liquids. The combined liquid is concentrated to yield a compound of Formula III. Synthesis of an Array of Compounds of Formula III Synthesis of an Array of Compounds of Formula 6
A compound of Formula I (1 eq.) is placed in each well of a reaction plate. The plate is sealed from the bottom and to each well then is added a solution of a coupling agent, HOBt, a structurally distinct individual compound of Formula 5 (in the form of a solution) and a base (3-8 eq.). The reaction plate is sealed from the top and the well contents are agitated at ambient temperature from about 8 h to about 24 h. Liquid contents of each well of the reaction plate are drained and the solid contents of each well of the reaction plate are sequentially washed with methanol (x2), 80:20 DCM2/DIPEA (x2), methanol (x2), DMF (x2), MeOH (x2) and DCM (x2) to yield an array of compounds of Formula 6. Synthesis of an Array of Compounds of Formula III
The reaction plate from above is sealed from the bottom and an acid (excess) is added to each well containing a compound of Formula 6. The reaction plate is sealed from the top and the well contents are let stand for up to 2 hours. The well contents then are cooled to a temperature of from about 0°C to about -90°C for at least about 30 minutes. The plate then is placed on top of a collection plate and allowed to warm to ambient temperature. The liquid contents of each well of the reaction plate are drained into individual wells of the collection plate. The solid contents of each well of the reaction plate are washed with TFA (x2). The combined filtrate in each well is concentrated to yield a residue. The residue is diluted with an acid (e.g., acetic acid, 1 mL per well) and the resulting well contents are agitated for up to 5 hours.
The preceding residue can also be diluted with dioxane, water, acetonitrile, benzene, j9-xylene or mixtures thereof. The agitated well contents are cooled until frozen and the frozen well contents are lyophilized by techniques known to one skilled in the art to yield an array of compounds of Formula III. Purification
Compounds of Formulas II and III can be purified by techniques known to one skilled in the art. Illustrative purification techniques that can be used to purify compounds of Formula II and III are recrystallization, distillation, flash chromatography or High Pressure Liquid Chromatography (HPLC). In one
embodiment, the compounds can be purified by reverse-phase HPLC using acetonitrile and water as the solvents and TFA as buffer.
Examples The invention is further illustrated by way of the following examples which are intended to enable those skilled in the art to more clearly understand and to practice the present invention. These examples illustrate the synthesis of representative examples of compounds of Formula II and Formula III that were prepared using the method of the present invention. These examples are not intended, nor are they to be construed, as limiting the scope of the invention, but are merely illustrative and representative thereof. It should be understood that all of the parts, percentages, and proportions referred to herein and in the appended claims are by weight unless otherwise indicated.
Example 1 Synthesis of an Array of Compounds of Formula I Synthesis of compounds of Formula 1
Merrifield Resin To a nitrogen-purged, flask was added a mixture of 2-methoxy-4- hydroxybenzaldehyde (71.6 g; 470 mmol) cesium carbonate (296.7 g; 911 mmol) and potassium iodide (25.0 g; 151 mmol) in 2000 mL of anhydrous DMA. Stirring was initiated and the suspension was heated to about 30-35°C, then 255.5 g (307 mmol) of chloromethylpolystyrene (loading 1.2 mmol/gram) was added in one portion. The temperature was raised to 50-60°C and kept at this temperature for about 23 hours. The suspension was filtered hot into a 3000 mL coarse glass fritted funnel, and the resin washed according to the following sequence: DMF (2x), water (2x), DMF (2x), water (2x), DMF (2x), MeOH (2x), DCM (2x), MeOH (2x), 10% acetic acid in DCM (2x), MeOH (2x), DCM (2x) and finally diethyl ether (3x), where lx=1000 mL. The resin was briefly dried in vacuo in the funnel, then under a stream of nitrogen. The resin was transferred and dried for 36 hours in vacuo, then dried to constant weight under high vacuum to yield: 277 g of tan beads of the aldehyde resin [(3-methoxy-4- formylphenoxy)methyl]polystyrene.
To a 500 mL bottle was added 15.0 g of the aldehyde resin, which was suspended in 170 mL of anhydrous THF, followed by the addition of the desired amine (R1NH2, 600 mol%) and 42 mL of TMOF. The bottle was capped and shaken for 15 hours. The resin slurry was filtered and the resin washed according to the
following sequence: anhydrous THF (2x), MeOH (2x), DCM (2x), MeOH (2x) and finally EtOH (2x), where lx=200 mL. The resin was dried in vacuo then suspended in 200 mL of a mixture of anhydrous THF-EtOH (3:1) and treated with 7.2 g (190 mmol; 1270 mole%) of sodium borohydride. The suspension was agitated overnight. The resin was filtered and washed according to the following sequence: THF (2x), EtOH (2x), THF (2x), water (2x), THF (2x) and MeOH (2x), where lx=200 mL. The resulting secondary amine resin of Formula 1 was then dried in vacuo to constant weight then used immediately in the next step.
Rink Resin Rink resin (Advanced Chemtech; 15.0 g; loading 0.56 mmol/gram) was washed with DMF (2x150 mL). The resin was then suspended in 120 mL of 20% piperidine in DMF and agitated for 5 minutes. The solution was drained and the resin exposed to another portion (120 mL) of 20% piperidine in DMF for 10 minutes. The resin was filtered and washed with DMF (2x), MeOH (2x), toluene (2x), MeOH (2x), toluene (2x) and diethyl ether (3x), where lx=150mL. Synthesis of compounds of Formula 3
Using Merrifield Resin-based compound of Formula 1 The secondary amine resin (Merrifield resin-based compound of Formula 1, 15 g; 18 mmol) was suspended in anhydrous, inhibitor-free THF (150 mL). The resin slurry was then treated with 12.5 g (48.2 mmol) of 2,4-dichloro-6,7- dimethoxyquinazoline (a compound of Formula 2), followed by 16.8 mL (12.5 g; 96.7 mmol) of DIPEA. The resin slurry was heated at 60°C for 15 hours. The reaction mixture was cooled to room temperature and the resin washed according to the following sequence: DCM (2x), THF (2x), DCM (2x) and MeOH (lx), where lx=200 mL. The resulting monochloroquinazoline resin of Formula 3 was then dried in vacuo to constant weight and stored under nitrogen.
Using Rink Resin-based compound of Formula 1 12.5 g of the resin (Rink resin-based compound of Formula 1) was suspended in 120 mL of THF and 7.3 mL (5.41 g; 41.9 mmol) of DIPEA. The resulting slurry was treated with 5.42 g (20.9 mmol) of 2,4-dichloro-6,7-dimethoxyquinazoline (a compound of Formula 2). The mixture was shaken for 18 hours, then filtered and the resin washed with THF (2x150 mL), methanol (2x150 mL), CH2C12 (2x150 mL), and finally diethyl ether (3x150 mL). The resulting resin of Formula 3 was then dried in vacuo to constant mass.
Synthesis of compounds of Formula I
The resins of Formula 3 (either Merrifield resin-based or Rink resin based, 100 mg) was suspended in a 0.83 M solution of the desired amine of Formula 4 (NHR2R3) in DMA (1.0 mL) and the resulting suspension heated at 135-140°C for 16 hours. The mixture was cooled to room temperature and the resulting resin of Formula I was washed according to the following sequence: MeOH (2x1 mL), DCM(2xl mL), MeOH (2x1 mL), DCM (2x1 mL) and MeOH (2x1 mL).
Example 2
Synthesis of an Array of Compounds of Formula π
The following compounds of Formula II were prepared using the method of
Scheme II, and in a manner analogous to that described in Examples 1 and 2. l-{3-r2-(4-Benzylpiperidin-l-yl -6,7-dimethoxyquinazolin-4
-ylamino"|-prop yl> -pyrrolidin-2-one (II- 1
1H-NMR (270 MHz, DMSO-J6) δ: 1.22 (br q, 2H), 1.66-1.95 (m, 8H), 2.18 (t, 2H), 2.55 (d, 2H), 3.06 (t, 2H), 3.26 (t, 2H), 3.48-3.58 (m, 2H), 3.84 (s, 3H), 3.88 (s, 3H), 4.48 (br d, 2H), 7.12-7.35 (m, 6H), 7.62 (s, IH), 9.04 (br s, IH), 11.57 (br s, IH), 11.95 (br s, IH); MS (ESI) m/z 504.2 [(M+H)+]. Elemental Analysis: Calc. for C29H37N5O3 »C2HF3O2
Calc: C, 60.28 H, 6.28 N, 11.34
Found: C, 60.43 H, 6.19 N, 11.13
l-{6,7-Dimethoxy-4-|"2-(3-methoxyphenyl -ethylaminolquinazolin-2-yl) -piperidine-3-carboxylic acid amide (II-2
1H-NMR (270 MHz, DMSO--4) δ: 1.42-1.86 (m, 3H), 1.94-2.04 (m, IH), 2.36-2.46 (m, IH), 2.92 (t, 2H), 3.13-3.30 (m, 2H), 3.69-3.79 (m, with s at δ 3.71, 5H), 3.83 (s, 3H), 3.88 (s, 3H), 4.36-4.50 (br s, 2H), 6.80 (br t, 4H), 7.00 (br s, IH), 7.15 (s, IH), 7.21 (t, IH), 7.45 (br s, IH), 7.64 (s, IH), 9.24 (br s, IH), 11.62 (br s, IH); MS (ESI) m/z 466.1 [(M+H)+]. Elemental Analysis: Calc. for C25H31N5O4 »C2HF3O2
Calc: C, 55.95 H, 5.57 N, 12.08 F, 9.83 Found: C, 55.74 H, 5.70 N, 11.88 F, 9.66
N4-Butyl-6,7-dimethoxy-N2-r2-(3-methoxyphenyl -ethyll- quinazoline-2,4-diamine (II-3
1H-ΝMR (270 MHz, DMSO--4) δ: 9.20 (t, 3H), 1.31-1.45 (m, 2H), 1.60-1.70 (m,
2H), 2.87 (br t, 2H), 3.54-3.68 (br s, 3H), 3.72 (s, 3H), 3.84 (s, 3H), 3.88 (s, 3H),
6.76-6.86 (m, 2H), 7.21 (t, IH), 7.67 (s, IH), 7.95 (br s, IH), 9.19 (br s, IH), 12.08 (br s, IH); MS (ESI) m/z 411.0 [( +H)4].
Elemental Analysis: Calc. for C23H30N4O3 »C2HF3O2
Calc: C, 57.24 H, 5.96 N, 10.68 F, 10.87
Found: C, 56.99 H, 5.77 N, 10.49 F, 10.66
N4-Benz yl-6,7-dimethoxy-N2- [2-(3 -metlioxy-phenvD-ethyl] - quinazoline-2,4-diamine fII-4)
(II-4)
1H-ΝMR (270 MHz, CD3OD) δ 2.83 (br t, J= 6.93 Hz, 2H), 3.68 (t, J= 7.18 Hz, 2H), 3.70 (s, 3H), 3.90 (s, 3H), 3.95 (s, 3H), 6.69-6.76 (m, 3H), 6.87 (br s, IH), 7.14 (t, J= 7.43 Hz, IH), 7.23-7.41 (m, 5H), 7.58 (s, IH); MS (ESI) m/z 445.1 [(M+H)+]; Elemental Analysis: Calc. for C26H28N4O3 eC2HF3O2
Calc: C, 60.21 H, 5.23 N, 10.03 F, 10.20
Found: C, 60.08 H, 5.12 N, 9.84 F, 10.31
r6,7-Dimethoxy-2-(4-methylpiperazin- 1 -yl -quinazolin-4-yl] -phenethylamine (II-5
1H-NMR (270 MHz, CD3OD) δ 2.98 (s, 3H), 3.03 (t, J= 7.18 Hz, 2H), 3.46 (br s, 4H), 3.80 (br t, 2H), 3.90-3.99 (m, with two s's at 3.93 and 3.96, 8H), 3.96 (s, 3H),
4.18 (br s, 2H), 7.12 (s, IH) 7.16-7.31 (m, 5H), 7.54 (s, IH); MS (ESI) m/z 408.1
[(M+H)+];
Elemental Analysis: Calc. for C23H29N5O2*2C2HF3O2
Calc: C, 51.02 H, 4.92 N, 11.02 F, 17.94 Found: C, 51.00 H, 4.99 N, 10.91 F, 17.79
6,7-Dimethoxy-N2-["2-(3-methoxy-phenyl -ethyl]-N4-phenethyl- quinazoline-2,4-diamine (II-6
1H-ΝMR (270 MHz, CD3OD) δ 2.93 (br t, 7= 7.18 Hz, 2H), 3.02 (br t, J= 7.92 Hz, 2H), 3.69 (s, 3H), 3.75 (t, J= 7.18 Hz, 2H), 3.85-3.90 (m, with s at 3.89, 5H), 3.94 (s, 3H), 6.73-6.83 (m, 3H), 6.86 (br s, IH), 7.12-7.28 (m, 6H), 7.47 (s, IH), 8.92 (br s, IH); MS (ESI) m/z 459.1 [(M+H)+];
Elemental Analysis: Calc. for C27H30N4O3 »C2HF3O2 (572.5): Calc: C, 60.83 H, 5.46 N, 9.79 F, 9.95
Found: C, 60.60 H, 5.40 N, 9.61 F, 9.83
Example 4 Synthesis of an Array of Compounds of Formula III Synthesis of compounds of Formula 6 A mixture of a monochloroquinazoline resin of Formula 3 (200 mg), the desired diamine of Formula 5 (4.0 mmol), DMA (2 mL) and DBU (600 μL, 4.0 mmol) was heated to 135°C for 14 hours. After cooling to room temperature the resin was washed with MeOH, DCM, MeOH and DCM (2x3 mL each) to yield the resin of Formula 6. Synthesis of compounds of Formula 8
Solutions of PyBOP (0.8 mL x 1.0 M in DMF, 0.80 mmol) and HOBt (0.8 mL x 1.0 M in DMF, 0.80 mmol) were added to a solution of the desired acylator compound (0.96 mmol) in DMF (1.6 mL). The mixture was shaken for 10 minutes. The resin of Formula 6 (200 mg) and NMM (110 μL, 1.0 mmol) were added, and the mixture was shaken overnight. The resulting resin of Formula 8 was washed with MeOH, DCM/DIPEA (4:1), MeOH, DMF, MeOH and DCM (2x3 mL each).
Synthesis of compounds of Formula III
TFA (2 mL) was added to the resin of Formula 8. After one hour the solution was drained and the resin was washed with TFA (2x1 mL). The combined filtrate and washings were concentrated to afford the compound of Formula III.
Example 5 Synthesis of Compounds of Formula III
The following compounds of Formula III were prepared using the method of Scheme III, and in a manner analogous to that described in Example 4. ir4-(3-{l-r4-(3,3-Diphenylpropylamino)-6,7-dimethoxyquinazolin-2-yll- piperidin-4-yl>-propyl)-piperidin-l-yll-(5-fluoro-2-methyl-phenyl')-methanone (πi-l
1H-NMR (270 MHz, CD3OD) δ 7.45 (s, 1 H), 7.27 (m, 10 H), 7.17-6.88 (m, 5 H), 4.66 (d, 12.9 Hz, 1 H), 4.39 (d, 13.4 Hz, 2H), 4.06 (t, 7.7 Hz, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 3.64 (t, 7.4 Hz, 2 H), 3.40 (m, IH), 3.05 (t, 13.0 Hz, 3H), 2.83 (t, 12. Hz, IH), 2.5 (m, 2H), 2.24 (d, 19.1 Hz, 3 H), 1.72 (m, 5 H), 1.21 (m, 10H). Elemental Analysis: Calc. for C46H54FN5O3 «2CF3COOH
Calc: C, 61.98 H, 5.83 N, 7.24
Found: C, 62.35 H, 6.08 N, 7.41
Dithiobenzoic acid (4-{6,7-dimethoxy-4-[3-fmethylphenylamino')- propylaminol-quinazolin-2-ylamino| -butylcarbamoylVmethyl ester (III-2
1H-NMR (270 MHz, CD
3OD) δ 7.85 (s, 2 H), 7.40 (m, 10 H), 6.87 (s, 1 H) 4.16 (s, 2 H), 3.93 (s, 3 H), 3.87 (s, 3 H), 3.66 (m, 4 H), 3.43 (t, 6.1 Hz, 2 H), 3.30 (m, 2 H), 3.20 (s, 3 H), 1.96 (m, 2 H), 1.65 (m, 4 H); MS m/z 633 (MH
+, 100%) Elemental Analysis: Calc. for C
33H
40N
6O
3S
2.2CF
3COOH
Calc: C, 51.62 H, 4.92 N, 9.76
Found: C, 51.75 H, 5.05 N, 9.69
N-{4-[4-(2-Chloro-6-methyl-benzylamino')-6,7-dimethoxyquinazolin-2- ylamino]-butyl> -3-(4-fluorophenoxy)-propionamide (III-3)
1H-ΝMR (270 MHz, CD3OD) δ 7.62 (s, 1 H), 7.22 (m, 4 H), 6.91 (m, 6 H), 5.0 (s, 2 H), 4.16 (m, 3 H), 3.95 (s, 3 H), 3.82 (s, 3 H), 3.55 (s, 2 H), 2.70 (t, 3 H), 2.41 (s, 3 H), 1.69 (m, 4 H); MS m/z 596 (MH+, 100%) Elemental Analysis: Calc. for C3ιH35ClFN5O4.2CF3COOH
Calc: C, 54.44 H, 5.26 N, 9.62
Found: C, 54.11 H, 5.28 N, 9.34
N-(l-{6,7-Dimethoxy-4-[rthiophen-2-ylmethyl -amino1-quinazolin-2-yl|- pyrrolidin-3 - ylV isonicotinamide (III-4
1H-NMR (270 MHz, CD
3OD) δ 8.79 (m, 2 H), 8.04 (m, 2 H), 7.56 (s, 1 H), 7.25 (m, 1
H), 7.11 (m, 2 H), 6.94 (m, 1 H), 5.02 (br s, 2 H), 4.79 (br s, 1 H), 3.99 (br m, 4 H),
3.94 (s, 3 H), 3.90 (s, 3 H), 2.49 (br s, 1 H), 2.33 (br s, 1 H); MS m z 491 (MH1",
100%)
Elemental Analysis: Calc. for C25H26N6O3S.2CF3COOH
Calc: C, 48.43 H, 3.92 N, 11.68
Found: C, 48.04 H, 4.28 N, 11.68
N-{l-r6,7-Dimethoxy-4-(3-phenylpropylamino -quinazolin-2-yl] -pyrrolidin-3-yl>-oxalamide (ffl-5
1H-NMR (270 MHz, CD3OD) δ 7.50 (s, 1 H), 7.14 (m, 6 H), 4.56 (m, 1 H), 3.95 (s, 3 H), 3.91 (s, 3 H), 3.85 (s, 1 H), 3.69 (m, 4 H), 3.55 (m, 1 H), 2.72 (t, 7.2 Hz, 2 H), 2.37 (s, 1 H), 2.20 (s, 1 H), 2.06 (m, 2 H); MS m/z 479 (MH+, 100%) Elemental Analysis: Calc. for C25H30N6O4.CF3COOH.H2O
Calc: C, 53.11 H, 5.45 N, 13.76
Found: C, 53.25 H, 5.26 N, 13.97 l-(3-{2-r4-(3-(l-r(2,5-Dimethoxy-phenyl -acetyl]-piperidin-4-yl|-propyl - piperidin-1 -yll-6,7-dimethoxy-quinazolin-4-ylamino| -propyl)-pyrrolidin-2-one (ffl-6)
1H NMR (270 MHz, CD3OD) δ 7.52 (s, IH), 7.08 (s, IH), 6.78 (m, 3H), 4.54 (m, 3H),
3.98 (m, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.77 (s, 3H), 3.72 (s, 3H), 3.66 (m, 4H), 3.45
(m, 6H), 3.14 (m, 2H), 3.01 (m, IH), 2.62 (m, IH), 2.38 (t, J= 8.1 Hz, 2H), 1.99 (m,
6H), 1.66 (m, 2H), 1.52 (m, IH), 1.27 (m, 10H), 0.96 (m, IH); MS (ESI) m/z 1X1
[M+H]+
Elemental Analysis: Calc. for C40H56N6O6 #2C2HF3O2
Calc: C, 55.93 H, 6.19 N, 8.89
Found: C, 56.15 H, 6.37 N, 9.17
Quinoline-2-carboxylic acid [2-({6,7-dimethoxy-4-[3-f2-oxo-pyrrolidin-l -yl)- propylamino1-quinazolin-2-yl>-methyl-amino -ethyll-methyl-amide (III-7)
1H NMR (CDC13) δ 8.18 (d, J= 8.7 Hz, 0.5H, amide rotamer), 7.97 (m, 1.5H, amide rotamer), 7.82-7.36 (m, 5.5H, amide rotamer), 6.99 (s, 0.5H, amide rotamer), 6.6 (br s, IH), 4.09 (m, IH), 3.98 (s, 6H), 3.87 (m, 2H), 3.79 (m, IH), 3.60 (m, IH), 3.36 (m, 3H), 3.26 (s, 6H), 3.13 (m, 2H), 2.43 (m, 2H), 2.04 (m, 2H), 1.80 (m, IH), 1.62 (m, IH); MS (ESI) m/z 572 [M+H]+ Elemental Analysis: Calc. for C31H37N7O »0.50 H2O
Calc: C, 64.12 H, 6.60 N, 16.88
Found: C, 63.82 H, 6.63 N, 16.70 l-{4-["6,7-Dimethoxy-4-(3-phenyl-propylamino')-quinazolin-2-yl1-
[ 1 ,4]diazepan- 1 -yl| -2-(3 -nitro-phenoxy -ethanone (III-8
1H NMR (CDC13) δ 7.65 (m, 2H), 7.23 (m, 6 H), 6.98 (m, IH), 6.84 (m, IH), 6.62 (m,
IH), 5.28 (br s, IH), 4.81 (s, 0.3 H, amide rotamer), 4.67 (s, 0.7H, amide rotamer), 3.93 (m, 12H), 3.58 (m, 4H), 2.76 (m, 2H), 2.04 (m, 4H); MS (ESI) m/z 601 [M+H]+ Elemental Analysis: Calc. for C32H36N6θ6#0.50 H2O
Calc: C, 63.04 H, 6.12 N, 13.78
Found: C, 63.08 H, 5.86 N, 13.72
2-(3,4-Dimethoxy-phenv -N-(2-{4-r6,7-dimethoxy-4-(3-trifluoromethyl- benzylamino)-quinazolin-2-yl]-piperazin-l-yl|-ethyl -acetamide (III-9
1H ΝMR (CDC13) δ 7.61 (s, IH), 7.52 (m, 2H), 7.40 (m, IH), 6.90 (m, 2H), 6.77 (m, 3H), 6.35 (br s, IH), 6.17 (br s, IH), 4.78 (d, J= 5.2 Hz, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H), 3.76 (s, 3H), 3.66 (m, 4H), 3.47 (s, 2H), 3.27 (m, 2H), 2.36 (m, 6H); MS (ESI) m/z 669 [M+H]+ Elemental Analysis: Calc. for C34H39F3Ν6O5 Calc: C, 61.07 H, 5.88 N, 12.57
Found: C, 60.71 H, 5.76 N, 12.27
N-{3-[6,7-Dimethoxy-4-(2-methoxy-benzylamino -quinazolin-2-ylamino]- 2,2-dimethyl-propyll -3-phenoxy-propionamide (III- 10)
1H NMR (CDCI3) δ 7.23 (m, 4H), 6.88 (m, 7H), 4.77 (d, J- 5.4 Hz, 2H), 4.28 (t, J--
6.6 Hz, 2H), 3.87 (s, 9H), 3.33 (d, J= 6.9 Hz, 2H), 3.11 (d, J= 6.4 Hz, 2H), 2.79 (m,
2 H), 0.93 (s, 6H); MS (ESI) m/z 574 [M+H]+
Elemental Analysis: Calc. for C32H39N5O5-0.50 H2O
Calc: C, 65.96 H, 6.92 N, 12.02
Found: C, 65.73 H, 6.68 N, 11.95
(4-{3-|"l-(4-Benzylamino-6,7-dimethoxy-quinazolin-2-yl -piperidin-4-yll-propyl>- piperidin-l-yl -(4-nitro-2-methoxy-phenyl methanone (III- 11)
1H NMR (CDC13) δ 7.83 (d, J- 8.2 Hz, IH), 7.72 (s, IH), 7.29 (m, 6H), 6.91 (s, 2H),
4.72 (m, 5H), 3.89 (s, 6H), 3.83 (s, 3H), 3.31 (m, IH), 2.99-2.72 (m, 4H), 1.82-1.00
(m, 17H); MS (ESI) m/z 683 [M+H]+
Elemental Analysis: Calc. for C 8H46N6θ6Η2O
Calc: C, 65.12 H, 6.90 N, 11.99
Found: C, 65.34 H, 6.51 N, 11.98
Furan-2-carboxylic acid (2-{[4-(3-imidazol-l-yl-propylamino -6,7-dimethoxy quinazolin-2- yl]methylamino I ethypmethyl-amide (III- 12)
lR NMR (270 MHz, CDC13) δ 7.47 (m, 2H), 7.03-6.91 (m, 5H), 6.42 (m, IH), 6.0, (br s, IH), 4.04 (m, 2H), 3.93 (s, 6H), 3.86 (s, 6H), 3.9-3.6 (m, 4H), 3.53 (m, IH), 3.29-
3.12 (m, 3H), 2.14 (m, IH); MS (ESI) m/z 494 [M+H]+ Elemental Analysis: Calc. for C25H31N7O4*H2O
Calc: C, 58.70 H, 6.50 N, 19.17
Found: C, 58.65 H, 6.20 N, 18.93
Each of the patent applications, patents, publications, and other published documents mentioned or referred to in this specification is herein incorporated by reference in its entirety, to the same extent as if each individual patent application, patent, publication, and other published document was specifically and individually indicated to be incorporated by reference.
While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention and the appended claims. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, method, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.