AP715A

AP715A - Quinoline and quinazoline compounds useful in therapy.

Info

Publication number: AP715A
Application number: APAP/P/1996/000900A
Authority: AP
Inventors: Allan John Collis; David Nathan Abraham Fox; Julie Newman
Original assignee: Pfizer Res & Dev; Pfizer Central Res
Priority date: 1995-12-23
Filing date: 1996-12-19
Publication date: 1998-12-30
Also published as: CA2236814A1; PT877734E; PL327610A1; YU68896A; ZA9610784B; EP0877734A1; US6103738A; DE69609353D1; AU708979B2; HN1996000082A; US20030220332A1; GB9526546D0; AP9600900A0; ES2151192T3; TNSN96161A1; GR3034225T3; OA10703A; DK0877734T3; HUP9903560A2; HUP9903560A3

Abstract

The invention provides compounds of formula I. fluorine atoms; icier.. C1-6aikoxy and R1 represents C1-. alkoxy optionally substituted by one or —ore fluor R: represent H or C-6 alkax.y optionally substituted by one or more R3 represents one or more groups independently selected from H. h Cf; in addition. R: and one RJ srcup may together represent -OCH;-.the methylene group being attached to the ortho-position of the pendant phenyl ring; R4 represents a 4-, 5- or 6-membered heterocyciic ring containing selected from N, 0 and S, the ring being optionally fused to a benzene membered heterocyciic ring containing 1 or 2 hereroatoms selected ring system as a whole being optionally substituted; X represents CH or N; and L is absent or represents a cyclic group or an open chain group; and pharmaceuticaily acceptable salts thereof The compounds of formula I are useful in the treatment of inter alia prostatic hyperplasia

Description

Quinoline and quinazoline compounds useful in therapy

This invention relates to novel compounds useful in therapy, particularly in the treatment of benign prostatic hyperplasia.

International Patent Application WO 89/05297 discloses a number of substituted quinazoline compounds which are indicated as inhibitors of gastric acid secretion.

According to the present invention, there is provided a compound of formula I,

wherein

R¹ represents C_M alkoxy optionally substituted by one or more fluorine atoms;

R represents H or C].₆ alkoxy optionally substituted by one or more fluorine atoms;

R^J represents one or more groups independently selected from H, halogen, C_M alkoxy and CF₃;

in addition, R and one R group may together represent -OCH₂-, the methylene group being attached to the ortho-position of the pendant phenyl ring;

R⁴ represents a 4-, 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms 20 selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, 0 and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, CM alkyl, CM alkoxy, halogen, SO2NR⁸R⁹ and NHSO2(C_M alkyl), and when S is a member of the ring system, it may be substituted by one or two oxygen atoms;

R and R independently represent H or C_M alkyl;

X represents CH or N; and

L is absent, or represents a cyclic group of formula la,

00600/96 /d/dV

ΖλΡ v V» ί /^N\ /^Zx / (CH_:)_m ^Λ in which N is attached to the 2-position of the quinoline or quinazoline ring;

A is absent or represents CO or SO<

Z represents CH or N;

m represents 1 or 2, and in addition, when Z represents CH, it may represent 0; and n represents 1, 2 or 3, provided that the sum of m and n is 2, 3, 4 or 5; or represents a chain of formula lb, /^N\ /^Z’x,/ (CHU A lb in which N is attached to the 2-position of the quinoline or quinazoline ring;

A’ and Z’ have the same significance as A and Z above, respectively;

R⁶ and R⁷ independently represent H or C_M alkyl; and p represents 1, 2 or 3, and in addition, when Z’ represents CH, it may represent 0;

AP/P/ Q 6 / 0 0 Q 0 0

or a pharmaceutically acceptable salt thereof (referred to together herein as “the compounds of the invention”).

Pharmaceutically acceptable salts include acid addition salts, such as hydrochloride and hydrobromide salts, and phosphate salts.

Alkyl and alkoxy groups that R may represent or include can be straight chain, branched chain, cyclic, or a combination thereof.

Heterocyclic groups that R⁴ represents may be saturated or unsaturated.

The compounds of the invention may be optically active. In particular, they may exhibit atropisomerism about the bond joining the pendant phenyl ring to the rest of the molecule when an R substituent is in the 2- or 3- position of the phenyl ring. The invention includes all optical isomers of the compounds of formula I, and all diastereoisomers thereof.

AP.00/(5

Preferred groups of compounds that may be mentioned include those in which:

(a) R¹ represents methoxy;

(b) R represents methoxy;

(c) R and an R group together represent -OCH₂-;

(d) R'¹ represents H or 4-fluoro;

(e) R¹ represents a group having the formula II, III. IV, V or VI,

OH

IV wherein

Y represents O, CH₂, SO₂, NR³ or CHF; and R⁵ represents H or C_M alkyl;

the group of formula II being of particular interest, especially when Y represents O; and (f) L represents a group of formula VII,

AP/F/ 96/00900

VII or is absent, this latter preference being of particular interest when R⁴ represents a group of formula V or VI.

According to the invention, there is also provided a process for the production of a 20 compound of the invention, which comprises:

(a) when X represents CH, cyclizing a compound of formula X,

L IR

N

R^J in which R¹ ⁴ and L are as defined above;

(b) when A or A’ is present, and Z or Z’ represents N, reacting a compound of formula XHIa or XHIb, as appropriate,

XHIa

6 7 in which R , R , R , X, m, n and p are as defined above, with a compound of formula

XIV,

A¹

R Lg xrv

ΛΡίΡΙ 96/00900 in which R⁴ is as defined above, A’ represents CO or SO₂ and Lg represents a leaving 10 group;

(c) reacting a compound of formula XVIII,

XVIII in which R¹, R², R⁴, X and L are as defined above, with a compound of formula XIX, B(OH)₂

R

XLX β

in which R is as defined above: or (d) when X represents N, reacting a compound of formula XXII.

XXII in which R^1_J are as defined above, with a compound of formula XXIIIa or XXIIIb, as appropriate, (CHJ /

R⁴

XXIIIa

HNI Z'^ N- / ^A (CHA ,R⁴

XXIIIb in which R⁴, R⁶, R⁷, A, A’, Z, Z’, m, n and p are as defined above;

(e) when A or A’ represents CO, reacting a compound of formula XXVIIIa or XXVIIIb, as appropriate,

Z'

R⁷

Lg

XXVIIIb

AP/P/ 9 6 / 0 0 9 0 0

6 7 in which R ’, R , R , X, Z, Z’, m, n and p are as defined above, and Lg is a leaving group, 10 with a compound of formula XXIX,

HR'

4a

XXIX in which R^4a represents the groups defined by R⁴ above which contain a nucleophilic 15 nitrogen atom in the ring, this nucleophilic nitrogen atom being attached to H;

(f) conversion of a compound of formula I in which L represents a cyclic group of formula la, to a corresponding compound of formula I in which L represents a chain of formula lb in which R⁶ and R⁷ each represent H, by the action of a strong base;

AP. 0 0/ ί 5 6 (g) when A or A' is absent and Z or Z' represents N, reacting a compound of formula XHIa or XHIb. as defined above, with a compound of formula XXX,

R⁴-Hal XXX in which R⁴ is as defined above and Hal represents a halogen atom attached to the ring; or 2 3 (h) when R and one R group together represent -OCH₂-, cyclization of a compound of formula XXXI,

in which R¹, R⁴, X and L are as defined above, and R^3a has the same meaning as R³ above except that R² and an R^3a group do not together represent -OCH₂-;

and where desired or necessary converting the resulting compound of the invention into a pharmaceutically acceptable salt or vice versa.

In process (a), the cyclization may be carried out in the presence of a strong base (for example lithium diisopropylamide) in a solvent which does not adversely affect the reaction (for example tetrahydrofuran) around room temperature and quenched with water.

In process (b), suitable leaving groups are OH and Cl. When the compound of formula

XIV is a carboxylic acid, the reaction may be carried out in the presence of conventional coupling agents [for example 1-hydroxybenzotriazole monohydrate, 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-methylmorpholine] in a solvent which does not adversely affect the reaction (for example CH₂C1₂) at or around room temperature. When the leaving group is Cl, the reaction may be carried out in a solvent which does not adversely affect the reaction (for example CH₂C1₂) around 0°C.

In process (c), the reaction may be carried out in the presence of a palladium catalyst [for example tetrakis(triphenylphosphine)palladium] in a solvent which does not adversely &P/PV 96/00900 fi . Cl 7 affect the reaction (for example a mixture of toluene, ethanol and IN aqueous sodium carbonate) at an elevated temperature (for example the reflux temperature of the solvent).

In process (d), the reaction may be carried out in a solvent which does not adversely affect 5 the reaction (for example n-butanol) in the presence of a base (for example triethylamine) at an elevated temperature (for example 100°C).

In process (e), suitable leaving groups include Cl. The reaction may be carried out in a solvent which does not adversely affect the reaction (for example THF) in the presence of a base (for example triethylamine) at room temperature.

The reaction may also be carried out without isolating the compound of formula XXVIIIa or XXVIIIb, by reacting a compound of formula XUIa or XHIb with triphosgene and a compound of formula XXIX. In this case the leaving group is -Cl. The reaction may be carried out in a solvent which does not adversely affect the reaction (for example CH₂C1₂) in the presence of a base (for example triethylamine) at or around room temperature.

In process (f), suitable strong bases include lithium diisopropylamide. The reaction may be carried out in a solvent which does not adversely affect the reaction (for example THP).

20

In process (g), the reaction may be carried out in a solvent which does not adversely affect t-.;—ϋ» vs·» the reaction (for example a mixture or n-BuOH and dimethylacetamide) in the presence of a base (for example triethylamine) at an elevated temperature (for example 80°C).

In process (h), suitable reagents are sodium carbonate with palladium acetate. The reaction may be carried out in a solvent which does not adversely affect the reaction (for example dimethylacetamide) at an elevated temperature (for example 130°C).

It will be apparent to those skilled in the art that in the processes described above [for example process (c)], and in the methods given below for preparation of the starting materials used in the above processes, when R² and R³ are present in different molecules, they cannot together represent -OCH₂-.

AP/P/ 96/00900

Compounds of formula X [see process (a)] may be prepared by reaction of a compound of formula XI,

ΑΡ . 0 0 7 15

XI in which R¹’³ are as defined above, with a combination of a compound of formula XII,

Ο - ι

Y ^R< ch₃ in which R⁴ and L are as defined above, and phosphorous oxychloride in dichloromethane at the reflux temperature of the solvent.

Compounds of formula XHIa or XHIb [see process (b)] in which X represents CH may be prepared from compounds of formula XVa or XVb, as appropriate, o

AP/P/ 96/00900 solution of the compound in dichloromethane.

Compounds of formula XVa or XVb may be prepared from compounds of formula XVIa or XVIb, as appropriate, (CH,)

2'n

Ay

AP

CH.

CN

XVIa

X O'Bu

O'Bu

XVIb hydroxide or lithium diisopropylamide at an elevated temperature (such as 90°C) in DMSO, quenching with water.

Compounds of formula XVIa or XVIb may be prepared by reacting a compound of formula XI, as defined above, with a compound of formula XVIIa or XVIIb, as appropriate, o

R°

I

O . NN O Bu xviia

Y (CHA CH, »6 t>7

R⁷ . ... /V v ^,c,y' L

CH,

XVIIb in which R , R , m, n and p are as defined above, by the method described above for producing compounds of formula X.

Compounds of formula XHIa or XHIb in which X represents N may be prepared by reacting a compound of formula XXII, ci

XXII

AP/P/ 9 6 / 0 0 9 0 0

in which R’’^J are as defined above, with a compound of formula XXIIa or XXIIb, as appropriate.

AP.ο ο / 1 (CH.)

NH

XXIIa

ΗΝ ' (CHJ

R

I

HN

R

I

NH

XXIlb in which R⁶, R⁷, m, n and p are as defined above, using the conditions mentioned for process (d) above.

Compounds of formula XVIII [see process (c)] in which X represents CH may be prepared by cyclization of a compound of formula XX,

xx in which R¹, R², R⁴ and L are as defined above, using the reaction conditions mentioned in process (a) above.

Compounds of formula XX may be prepared by reacting a compound of formula XXI, R< .NH₂

XXI

2 in which R and R are as defined above, with a compound of formula XII as defined above, using the method described above for the preparation of compounds of formula X.

Compounds of formula XVIII in which X represents N may be prepared by reacting a compound of formula XXVII,

Cl

XXVII

AP/P/ 9 6 / 0 0 9 0 0 in which R¹ and R² are as defined above, with a compound of formula XXIIIa or XXIIIb, 20 as appropriate, as defined above, using the reaction conditions mentioned above for process (d).

ΑΡ .00715

Compounds of formula XXII [see process (d)] may be prepared from a compound formula XXIV.

i\ ci

XXIV

in which R are as defined above, by reacrion with a saturated solution of ammonia in 5 methanol.

Compounds of formula XXIV may be prepared from a compound of formula XXV,

XXV

V

I OH

2 m which R and R are as defined above, by reaction with a compound of formula XIX as 10 defined above using the reaction conditions described above for process (c), followed by reaction with POC1₃ and N.N-dimethylaniline.

Compounds of formula XXV may be prepared from a compound of formula XXVI, xxvi

AP/P/ 9 6 / 0 0 9 0 0

2 in which R andR are as defined above, using conventional techniques.

Compounds of formula XXVIIIa and XXVIIIb [see process (e)] in which Lg represents Cl may be prepared from compounds of formula XHIa or XHIb, as appropriate, by reaction with triphosgene. The reaction may be carried out in a solvent which does not adversely affect the reaction (for example CH₂C1₂) in the presence of a base (for example triethylamine) at around -10°C.

Compounds of formula XXXI [see process (h)] may be prepared from compounds of formula XXXII.

HO

NH,

XXXII in which R¹, R⁴, L and X are as defined above, by reaction with a compound of formula 5 XXXIII,

Br

XXXIII wherein R^3a is as defined above, in the presence of sodium hydride in DMF at room temperature.

Compounds of formula XXXII are analogous to compounds of formula I, and may be prepared using analogous methods. For example, when X represents CH, the compounds may be prepared by cyclizing a compound analogous to those of formula X using process (a). When X represents N, the compounds may be prepared from a compound analogous to those of formula XXII and a compound of formula XXIIIa or XXIIIb, as appropriate, using process (d).

Compounds of formulae XI, XII, XIV, XVIIa, XVIIb, XIX, XXI, XXIIa, XXIIb, XXIII, XXVI, XXIX, XXX and XXXIII are either known or are available using known techniques.

The intermediate compounds of formulae X, XHIa, XHIb, XVIII, XXII, XXVIIIa, XXVIIIb and XXXI form a further aspect of the invention.

It wall be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be

AP.00716 achieved by conventional techniques, for example as described in 'Protective Groups in Organic Synthesis' by T W Greene and PGM Wuts. John Wiley and Sons Inc, 1991.

Tire compounds of tlie invention are useful because they possess pharmacological activity in animals. In particular, the compounds are useful in tlie treatment of a number of conditions including hypertension, myocardial infarction, male erectile dysfunction, hvperlipidaemia. cardiac arrhythmia and benign prostatic hyperplasia. The latter condition is of greatest interest. Thus, according to another aspect of the invention, there is provided a method of treatment of benign prostatic hyperplasia which comprises administering a therapeutically

10- effective amount of a compound of the invention to a patient suffering from such a disorder. The use of the compounds of the invention as pharmaceuticals, and the use of the compounds of the invention in the manufacture of a medicament for the treatment of benign prostatic hyperplasia, are also provided.

The compounds of the invention may be administered by any convenient route, for example orally, parenterally (e.g. intravenously, transdermally) or rectally. The daily dose required will of course vary with the particular compound used, the particular condition being treated and with the severity of that condition. However, in general a total daily dose of from about 0.01 to lOmg/kg of body weight, and preferably about 0.05 to lmg/kg, is suitable, administered from 1 to 4 times a day.

AP/P/ 9 6 / 0 0 9 0 0

The compounds of the invention will generally be administered in the form of a suitable pharmaceutical formulation. Thus, according to another aspect of the invention, there is provided a pharmaceutical formulation including preferably less than 50% by weight of a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. The pharmaceutical formulation is preferably in unit dose form. Such forms include solid dosage forms, for example tablets, pills, capsules, powders, granules, and suppositories for oral, parenteral or rectal administration; and liquid dosage forms, for example sterile parenteral solutions or suspensions, suitably flavoured syrups, flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil and peanut oil, and elixirs and similar pharmaceutical vehicles.

AP .00715

	Solid formulations may be prepared by mixing the active ingredient with pharmaceutical carriers, for example conventional tabletting ingredients such as com starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums and other diluents, for example water, to form a homogeneous preformulation formulation in which the active
5	ingredient is uniformly dispersed so that it may be readily subdivided into equally effective unit dosage forms containing typically from 0.1 to about 500mg of the active ingredient. The solid dosage forms may be coated or otherwise compounded to prolong the action of the formulation.
¹⁰	The formulations of the invention may also contain a human 5-a reductase inhibitory
\g>»*	compound [see International Patent Application WO 95/28397], or a compound of the invention could be presented in a pharmaceutical pack also containing a human 5-a reductase inhibitory compound as a combined preparation for simultaneous, separate or
15	sequential use. The compounds of the invention may be tested in the screens set out below. Contractile responses of human prostate
20	Prostatic tissue was cut into longitudinal strips (approximately 3x2x10 mm) and
	suspended in organ baths under a resting tension of 1 g in Krebs Ringer bicarbonate of the following composition (mM): NaCl (119), KC1 (4.7), CaCl₂ (2.5), KH₂PO₄ (1.2), MgSO₄ (1.2), NaHCO₃ (25), glucose (11), and gassed with 95% O₂/5% CO₂. The solution also contained 10 mM cocaine and 10 mM corticosterone. Tissues were
25	exposed to a sensitising dose of (-)-noradrenaline (100 mM) and washed over a 45 minute period. Isometric contractions were obtained in response to cumulative additions of (-)-noradrenaline to obtain control curves in all tissues. A further curve was then generated in the presence or absence of antagonist (incubated for 2 hours). Antagonist affinity estimates (pA₂) were determined using a single concentration of
30	competing antagonist, pA₂ = -log [A]/(DR-1) where the dose ratio (DR), relative to corresponding controls, was produced by a single concentration of antagonist [A], assuming competitive antagonism and Schild regression close to unity.

ΛΡ/ΡΖ 9 6 / Ο Ο 9 Ο Ο

• 7 1 c

Anaesthetised dog model ofprostatic pressure and blood pressure

Mature male beagles (12-15 kg body weight) were anaesthetised with sodium pentobarbitone (30-50 mg,deg i.v.) and a tracheal cannula w^ras inserted. Subsequent anaesthesia w^?as maintained using pentobarbitone infusion. The animals w’ere respirated with air using a Bird Mk8 respirator (Bird Corp.. Palm Springs. CA. U.S.A.) adjusted to maintain blood gasses in the range pO₂ 90-110 mm Hg. pCO·, 3545 mm Hg, pH 7.35-7.45. Body temperature was maintained at 36-37.5°C using a heated operating table. Catheters were placed into the left femoral artery for recording blood pressure and into the left femoral vein for compound administration. Heart rate was recorded via the lead II E.C.G. A laparotomy was performed to cannulate both ureters to prevent change of fluid volume within the bladder. A 7F cardiac catheter (with a 1.5 ml capacity balloon tip) was inserted into the bladder via the urethra. The balloon w'as filled with air and the catheter withdrawn until the balloon became lodged in the prostate, which was confirmed by digital pressure. Balloon pressure was recorded via a Druck transducer. Prostatic pressure and haemodynamic parameters were made on a Grass Polygraph (Grass Instruments, Quincy, Mass, U.S.A.) and the data measured on line using a Motorola 68000-based microcomputer system (Motorola Inc., Temple, AZ, U.S.A.). Compounds were made up in PEG 500 and administered i.v. through a catheter in the femoral vein. Responses to phenylephrine (1-16 pg/kg i.v. in saline) were obtained to generate control dose-response curves (two control curves for each experiment). Compounds w^;ere administered (in terms of compound base) at 10-300 pg/kg i.v. 5 min before construction of phenylephrine curves (constructed up to a maximum dose of 128 pg/kg in the presence of test compound).

AP/P/ 96/00900

Due to ctj-related dysrhythymic properties of phenylephrine, absolute maximal responses were not obtained but w'ere taken as 10 % greater than the control response obtained with 16 pg/kg phenylephrine. Drug concentrations were calculated on the basis of molar weight of compound/kg body weight thus allowing a pseudo pAg

A.P . V Ο 7)5 calculation by Schild analysis using dose ratios derived from shifts in the phenylephrine dose-response curves.

The compounds of the invention may have the advantage that they are more potent, have a 5 longer duration of action, have a broader range of activity, are more stable, have fewer side effects or are more selective (in particular they may have beneficial effects in benign prostatic hyperplasia without causing undesirable cardiovascular effects, for example because they are able to selectively antagonise prostatic subreceptors of the oq-adrenoceptor), or have other more useful properties than the compounds of the prior art.

1°

The invention is illustrated by the following examples, in which the following abbreviations are used:

DMA = dimethylacetamide DMF = dimethylformamide

DMPU = l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidone EtOAc = ethyl acetate EtOH = ethanol h = hour

MeOH = methanol min = minute

AP/P/ 0 6 /00900 n-BuOH = n-butanol

THF = tetrahydrofuran tic = thin layer chromatography

Intermediate 1 l-(t-ButyIoxycarbonvl)-1.4-diazepane

To a solution of homopiperazine (lOOg, 1.0 mol) and triethylamine (210ml, 152g, 1.5mol) in CH₂C1₂ (500ml) at 0°C was added a solution of di-(t-butyl) dicarbonate (195g, 0.89mol) in CH₂C1₂ (300ml). The mixture was allowed to warm to room temperature and stirred for

18h after which time the CH₂C1₂ was evaporated under reduced pressure. The resulting residue was partitioned between ether and 2N citric acid and the aqueous layer was extracted with ether (4x200ml). The aqueous layer was basified with 2N aqueous NaOH

ΛΡ ,00715 and then extracted with CH₂C1₂ (4x400ml). The combined CH₂C1₂ extracts were washed with H₂O (2x), saturated brine (lx) and dried over MgSO₄. Evaporation under reduced pressure followed by azeotroping with CH_;C1₂ (4x) gave the title compound as a yellow waxy solid (94.3g, 53%). R_f 0.25 (CH₂Ck'MeOH/O.SSNH₃ 90/10/1, v/v). MS m/z 201 (MH*). Found: C,5S.S6; H,10.03; N,13.58; C₁₀H₂₀N₂O₂ 0.05.CH₂Cl, requires C, 59.02: H,

9.91: N,13.70%.

Intermediate 2

-(t-Butyloxycarbonyl)-4-(4-morpholinecarbonyl)-l.4-diazepane

A solution of Intermediate 1 (92.0g, 0.46mol) and triethylamine (96.0ml, 69.7g, 0.69mol) in CH₂C1₂ (500ml) at 0°C was treated dropwise with a solution of 4-morpholinecarbonyl chloride (64.0ml, 82.0g, 0.55mol) in CH₂C1₂ (100ml) and the reaction was stirred at room temperature under N₂ for 18h. The reaction mixture was then diluted with CH₂C1₂ (400ml) and washed with 2N citric acid (3x400ml), saturated brine (1x500ml), dried over MgSO₄and evaporated to give the title compound as an off-white solid (141.7g, 98%). R_f 0.80 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 314 (MH*). Found: C,57.50; H,8.69; N,13.41; Ci₅H₂₇N₃O₄ requires C, 57.50; H, 8.69; N,13.41%.

Intermediate 3

-f4-Morpholinecarbonyi)-l .4-diazepane hydrochloride

A solution of Intermediate 2 (140.Og, 0.44mol) in CH₂Cl₂/MeOH (1/1, v/v, 600ml) at 0°C was saturated with HCl gas and the reaction mixture was stirred at room temperature under

N₂ for 18h after which time the reaction mixture was evaporated under reduced pressure and slurried in EtOAc to give, after filtration, a white hygroscopic solid. This was further purified by slurrying in acetone, filtering, washing with ether and drying in vacuo at 60°C to give the title compound as a colourless solid (99.Og, 90%). R_f 0.41 (CH₂Cl₂/MeOH/0.88NH₃ 84/14/2, v/v). MS m/z 214 (MH*). Found: C,47.50; H,8.10;

N,16.55; C₁₀H₁₉N₃O₂ HCl 0.2.H₂O requires C, 47.41; H, 8.12; N,16.59%.

AP/P/ 96/00900

Intermediate 4

-Acety1-4-(4-morpholinecarbonyl)-1.4-diazepane

AP . 00715

IS

To a solution of Intermediate 3 (50g, 0.2mol) and triethylamine (42ml, 30.5g, 0.3mol) in CH₂C1₂ (400ml) at 5°C was added acetic anhydride (23ml, 24.9g, 0.24mol) dropwise over

15min and the reaction was then stirred for a further 2h at room temperature under N₂. Dilution with CH₂C1₂ (600ml) was followed by washing with saturated aqueous sodium bicarbonate (2x200ml) and the combined aqueous layers extracted with CH₂C1₂ (1x100ml). The CH₂C1₂ layers were combined and washed with saturated brine, dried over MgSO₄ and evaporated to give a light brown oil. This was dissolved in CH₂C1₂ (300ml) and treated with triethylamine (8ml, 5.8g, 0.06mol) and EtOH (5ml), stirred for lh at room temperature then washed with saturated sodium bicarbonate and the aqueous layer extracted with CH₂C1₂ (5x). The combined CH₂C1₂ layers were dried over MgSO₄ and evaporated under reduced pressure to give a yellow oil which was then azeotroped with CH₂C1₂ (4x) to give the title compound as a yellow oil (47.lg, 92%). R_f 0.45 (CH₂Cl₂/MeOH/0.88NH₃ 50/10/1, v/v). MS m/z 256 (MH⁺). Found: C,52.62; H,8.18; N,15.02; C₁₂H₂₁N₃O₃ O.3.CH₂C1₂ requires C, 52.61; H, 7.75; N,14.96%.

Example 1

4- Amino-5-(2-chlorophenyl)-7-methoxy-2-[4-(4-morpholinecarbonyl)-1.4-diazepan-l20 yljquinoline (a) 5-(2-ChloropbenyP-4-cyano-3-nitroanisole

5- Bromo-4-cyano-3-nitroanisole [prepared by the method of Harrison et al, J.Chem.Soc.C, 1769 (1966)] (250mg, 0.86mmol) and 2-chlorophenylboronic acid (150mg, 0.96mmol) were dissolved in a mixture of toluene (10ml), EtOH (5.6ml), and IN aqueous sodium carbonate (1.7ml). The solution was placed under a nitrogen atmosphere and tetrakis(triphenylphosphine)palladium (30mg, 0.03mmol) added. After refluxing for 3h, the solvent was removed from the reaction mixture under reduced pressure. The residue was partitioned between H₂O (50ml) and EtOAc (50ml) and the EtOAc layer washed with

H₂O (2x50ml), and dried over MgSO₄. Following removal of the solvent, the crude material was purified on silica gel, eluting with hexane/ether (1/1, v/v). This gave the

AP/P/ 9 6 / 0 0 9 0 0

AP. 0 Ο ? ί $ subtitle compound as a colourless gum (252mg. 100%). R_r 0.38 (hexane/ether 1:1, v/v). MS m/z 306 and 308 (MNH₄ ⁺).

(b) 3-Amino-5-(2-chlorophenyl)-4-cyanoanisoIe 5 The product of step (a) (300mg, l.Ommol) was dissolved in DMF (3ml) and a solution of sodium dithionite hydrate added (500mg, 2.9mmol in 6ml of H_;O). The solution became warm and some solid precipitated out of solution. After stirring for 30 min at room temperature, 15ml of H₂O and 2N HCI were added. This mixture was extracted with EtOAc (2x30ml), neutralised using 2N NaOH and re-extracted with EtOAc (2x30ml). The combined EtOAc extracts were dried over MgSO₄ and the solvent removed to give the Y- crude product. This was purified on silica gel, eluting with CH₂Cl₂/MeOH (98/2, v/v) to give the subtitle compound as colourless gum (190mg, 74%). R_f 0.29 (hexane/ether 1/1, v/v). MS m/e 276 and 278 (MNH₄ ⁺).

(c) 6-(2-Chlorophenyl)-4-methoxy-2-{l-[4-(4-morpholinecarbonyl)-1.4-diazepan-lyl]ethylideneamino}benzonitrile

The product of step (b) (190mg, 0.74mmol) was dissolved in CH₂C1₂ (5ml) and phosphorous oxychloride (0.082ml, 0.86mmol) added in one portion to the stirred solution, at room temperature. After 20 min, a solution of Intermediate 4 (380mg, l.Smmol) in

CH₂C1₂ (5ml) was added to the reaction mixture, and the mixture heated to reflux for 14h. After cooling to room temperature, a further 30ml of CH₂CI₂ was added, and this solution washed with 2N aqueous NaOH (2x20ml), dried over MgSO₄, and the solvent removed to give the subtitle compound as a colourless gum (155mg, 43%). R_f 0.26 (CH₂Cl₂/MeOH 95/5, v/v). MS m/z 496 (MH⁺).

(d) 4-Amino-5-(2-chlorophenyl)-7-methoxy-2-[4-(4-morpholinecarbonyl)-1.4diazepan-1 -yljquinoline

The product of step (c) (155mg, 0.31 mmol) was dissolved in dry THF (5ml), under a dry nitrogen atmosphere, and the solution cooled to -78°C. A 1.5M solution of lithium diisopropylamide in THF (0.25ml, 0.38mmol) was added to the reaction which was allowed to warm to room temperature. Analysis by tic indicated that starting material remained, hence the solution was re-cooled to -78°C and a further 0.25ml of the lithium

AP/P/ 9 6 / 0 0 9 0 0

Λ P . Ο Ο 7 1 5 diisopropylamide solution added. After wanning to room temperature, the mixture was again analysed by tic and then quenched with H₂O (0.5ml). EtOAc was added (30ml) and the solution washed with H₂O (2x20ml), dried over MgSO₄, and the solvent removed under reduced pressure. The crude material was purified on silica gel, eluting with

CH₂Cl₂/MeOH/0.88NH₃ (92/7/1, v/v) to give the title compound as a white foam (50mg, 31%). R_f 0.25 (CH₂Cl₂/MeOH 9/1, v/v). MS m/z 496 (M⁺). ^!H NMR (CDC1₃) 8: 2.05 (2H, m), 3.14 (2H, m), 3.45 (2H, t), 3.60 (6H, m), 3.70 (2H, t), 3.82 (2H bs), 3.86-3.99 (5H, m), 5.75 (1H, s), 6.47 (1H, s), 7.0 (1H, s), 7.28-7.45 (3H, m), 7.45-7.51 (1H, m). Found C, 60.75; H, 6.02; N, 13.13; C₂₆H₃₀ClN₅O₃.0.25CH₂Cl₂ requires G,60.96; H, 5.94; N, 13.54%.

¹⁰

Example 2

4-Amino-7-methoxy-2-[4-(4-morpholinecarbony 1)-1.4-diazepan-1 -vl] -5-phenvl quinoline (a) 4-Cyano-3-nitro-5-phenylanisole

The subtitle compound was prepared by the method of Example 1(a), but using phenylboronic acid. The crude material was triturated with 20ml of ether, and recrystallised from EtOAc to give a white crystalline solid (83%). m.p. 175-176°C. R_f 0.44 (hexane/ether 1:1, v/v). MS m/z 169 (no M⁺ observed).

(b) 3 - Amino-4-cyano-5 -phenvlanisole

Reduction of the product of step (a) using the procedure of Example 1 (b) gave the subtitle compound (41%) yellow gum. R_f 0.30 (hexane/ether 1:1, v/v). MS m/z 242 (no M⁺observed).

(c) 4-Methoxy-2-{l-[4-(morpholine-4-carbonyl)-l.4-diazepan-l-yllethylideneammo}6-phenylbenzonitrile

The subtitle compound was obtained as a white foam from the product of step (b) in 87% yield using the procedure described in Example 1(c). R_f 0.66 (CH₂Cl-,/MeOH 9/1, v/v). MS m/z 462 (MH⁺).

AP/P/ 9 6 / 0 0 9 0 0 (d) 4-Amino-7-methoxy-2-r4-(4-morpholinecarbonyl')-1.4-diazepan-l-vl1-5phenylquinoline

The title compound (87%) was obtained as an off-white powder from the product of step (c) using the procedure described in Example 1(d). R_f 0.16 (CH₂Cl₂/MeOH 9/1. v/v). MS m/z 462 (MH⁺)· 'h NMR (CDCL) δ: 2.05 (2H, m), 3.16 (4H, m), 3.48 (2H, t), 3.56-3.68 (6H, m), 3.71 (2H, t), 3.87-3.99 (7H, m), 5.73 (1H, s), 6.54 (1H, s), 7.01 (1H, bs), 7.41 (5H, s). Found C, 66.89: H, 6.78: N, 14.42; C₂₆H₃₁N₅O₃ O.1.CH₂C1₂ requires C, 66.69; H, 6.69; N, 14.90%

Example 3

4-Amino-6.7-dimethoxy-2-[4-(4-morpholinecarbonyl)-1.4-diazepan-l-yl]-5phenvl quinoline (a) 2-(3.4-Dimethoxyphenyl)-4.4-dimethyl-A²-oxazoline

The subtitle compound was prepared from 3,4-dimethoxybenzoic acid according to the method of Meyers et al., J.Org.Chem., 39, 2787, (1974).

(b) 2-(3.4-Dimethoxy-2-iodophenyl)-4.4-dimethyl-A -oxazoline nButyllithium (2.5M in hexane, 8.9ml, 22.3mmol) was added dropwise to a solution of the 20 product of step (a) (4.2g, 17.8mmol) in dry ether (200ml) at 0°C and the reaction was stirred under N₂ for 2h. This was followed by the dropwise addition of iodine (5.46g,

21.5mmol) in ether (100ml) and the reaction was allowed to warm to room temperature over Ih. The reaction mixture was poured onto H₂O, the ether layer was separated, washed with saturated aqueous sodium thiosulphate solution (lx) followed by saturated brine (lx) then dried over MgSO₄ and evaporated under reduced pressure to give the subtitle compound as a yellow oil (5.2g, 80%). R_f 0.60 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v); MS m/z 362 (MH⁺).

(c) 3-4-Dimethoxy-2-iodobenzonitrile

To a solution of the product of step (b) (5.2g, 14.4mmol) in pyridine (30ml) was added

POC1₃ (2.7ml, 4.4g, 28.8mmol) and the reaction was heated to 85^CC for 18h. The reaction mixture was cooled, partitioned between saturated aqueous sodium carbonate solution

0600/96 /d/dV )0715

(300ml) and then extracted with ether (2x100ml). The ether layer was washed with 2N HCI (2x75ml) followed by H_?O (lx) and then dried over MgSO₄ and evaporated under reduced pressure to afford a yellow oil. This was purified by slurrying with hexane and filtering to give the subtitle compound as an off-white solid (2.82g, 68%). R,· 0.80 (CHiCf/MeOH

95/5, v/v). MS m/z 307 (MH^T). Found: C,3S.O3; H,2.88; N.4.64; C₉H₈NO₂I 0.05.hexane requires C,38.05; H,2.97; N,4.77%.

(d) 3-4-Dimethoxy-2-iodo-6-nitrobenzonitrile

Nitronium tetrafluoroborate (1.73g, 13.0mmol) was added portionwise to a solution of the 10 product of step (c) (2.67g, 9.2mmol) in acetonitrile (40ml) at 0°C. The reaction was stirred for 0.5h under N₂ and then poured into saturated aqueous sodium bicarbonate solution and extracted with EtOAc (lx). The organic layer was washed with saturated brine (lx), dried over MgSO₄ and evaporated under reduced pressure to give a residue which was slurried in hexane and filtered to give the subtitle compound as an off-white solid (2.5lg, 82%). R_f

0.46 (EtOAc/hexane 1/1, v/v). MS m/z 352 (MNH₄ ⁺). .

(e) 3.4-Dimethoxy-6-nitro-2-phenylbenzonitrile

The subtitle compound was prepared from the product of step (d) by the method of Example 1(a) using phenylboronic acid. The subtitle compound (81%) was obtained as a light yellow solid. R_f 0.46 (EtOAc/hexane 1/1, v/v). MS m/z 302 (MNH₄ ⁺). Found: C,63.23; H,4.23; N,9.86; C₁₅H₁₂N₂O₄ requires C,63.38; H,4.23; N,9.86%.

(f) 6-Amino-3.4-dimethoxy-2-phenylbenzonitrile

The subtitle compound was prepared from the product of step (e) by the method of 25 Example 1(b). The crude product was purified on silica gel, eluting with EtOAc/hexane (1/1, v/v) to give the subtitle compound (60%) as a light yellow solid. R_f 0.40 (EtOAc/hexane 1/1, v/v). MS m/z 272 (MNH₄ ⁺). Found: C,70.30; H,5.50; N,10.80; C₁₅H₁₄N₂O₂ 0.1.H₂O requires C,70.37; H,5.55; N, 10.95%.

(g) 3.4-Dimethoxy-6-( 1 -[4-(morpholine-4-carbonyl)-1.4-diazepan-lyl]ethylideneamino}-2-phenylbenzonitrile

AP/P/ 9 6 / 0 0 9 0 0

The subtitle compound was prepared from the product of step (fi and Intermediate 4 by the method of Example 1(c). The crude product was purified on silica gel, eluting with CH₂Cl₂/MeOH (95/5, v/v) to give the subtitle compound (87%) as a colourless foam. MS m/z 492 (MH^-). Found: C.64.75; H.6.74; N.13.67; C₂₇H₃₃N₅O₄ 0.15.CH₂Ch requires

C,60.64; H,6.61; N,13.89%.

(h) 4-Amino-6-7-dirnethoxy-2-[4-f4-rnorpholinecarbonyl)-l .4-diazepan-l-yll-5phenvl quinoline

The title compound was prepared from the product of step (g) using the method of 10 Example 1(d). The crude product was purified on silica gel. eluting with

W CH₂Cl₂/MeOH/0.88NH3 (90/10/1, v/v) to give the subtitle compound (46%) as a colourless foam. R_f 0.30 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 492 (MET). ^]H NMR (CDC1₃) δ: 2.05 (2H, m), 3.16 (4H, m), 3.35 (2H, m), 3.48 (3H, s), 3.63 (6H, m), 3.74 (2H, m), 3.87 (2H, bs), 3.97 (2H, m), 4.00 (3H, s), 5.68 (IH, s), 7.13 (IH, bs), 7.39 (2H, m), 7.45 (3H, m). Found: C,63.02; H,6.62; N,13.35; C₂₇H₃₃N₅O₄ 0.35.CH₂Cl₂requires C,63.02; H,6.47; N,13.44%.

Example 4

4-Amino-6.7-dimethoxy-5-(4-fluorophenyl)-2-[4-(4-morpholinecarbonyl)-1.4-diazepan-l20 yl]quinoline

VA?

(a) 3.4-Dimethoxy-2-(4-fluorophenyl)-6-nitrobenzonitrile

The subtitle compound was prepared by the method of Example 1 (a) from the compound of Example 3(d) and 4-fluorophenylboronic acid. The subtitle compound (83%) was obtained as a light yellow solid. R_f 0.17 (toluene). MS m/z 303 (MH). Found: C.59.19; H.3.63; N.8.84; C_I5H₁₂N₂O₄ 0.15.H₂O requires C,59.04; H,3.71; N,9.18%.

(b) 6-Amino-3.4-dimethoxy-2-f4-fluorophenyl)benzonitriIe

The subtitle compound was prepared by the method of Example 1 (b) from the product of 30 step (a). The subtitle compound (85%) was obtained as a white solid. R_f 0.73 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 273 (MH⁺). Found: C.66.09; H,4.79; N,10.28; C₁₅H₁₃N₂O₂F requires C_:66.16; H,4.81; N,10.28%.

AP/P/ 9 6 / 0 0 9 0 0

ΛΡ, Ο Ο 7 1 5 (c) 3.4-Dimethoxy-2-(4-fluoropheny1)-6-{ 1 -[4-fmorpholine-4-carbonyl)-l,4-diazepanl-vllethylideneamino) benzonitrile

The subtitle compound was prepared by the method of Example 1(c) from the product of 5 step (b) and Intermediate 4. The subtitle compound (83%) was obtained as a colourless solid, mp 174-176°C. R_f 0.12 (EtOAc). MS m/z 510 (MH⁺). Found: C,63.61; H,6.35;

N,13.68; C₂₇H₃₂N₅O₄F requires C,63.67; H,6.33; N,13.74%.

(d) 4-Amino-6,7-dimethoxy-5-(4-fluorophenyl)-2-[4-(4-morphoIinecarbonyl)-l.410 diazepan-1 -yljquinoline

The title compound was prepared by the method of Example 1(d) from the product of step (c). The crude product was purified on silica gel, eluting with CH₂Cl₂/MeOH/0.88NH₃(95/5/0.5, v/v) and then triturated with EtOAc and filtered to give the subtitle compound (41%) as a colourless solid, mp 189-192°C. R_f 0.15 (CH₂Cl₂/MeOH/Q.88NH₃ 95/5/0.5, . v/v). MS m/z 510 (MH⁺). *11 NMR (CDC1₃) 5: 2.05 (2H, m), 3.13 (4H, m), 3.32 (2H, m), 3.48 (3H, s), 3.63 (6H, m), 3.74 (2H, m), 3.77-4.23 (4H, bm), 4.00 (3H, s), 5.71 (1H, s), 7.15 (2H, m), 7.23 (1H, bs), 7.32 (2H, m). Found: C,63.07; H,6.41; N,13.17; C₂₇H₃₂N₅O₄F 0.25.H₂O 0.15EtOAc requires C,62.82; H,6.39; N,13.28%.

Example 5 (¾) (R/S)-4-Amino-2-[4-(1.4-benzodioxan-2-carbonyl)-1.4-piperazin-l-yl1-6.7-dimethoxy-5phenvlguinoline

AP/P/ 9 6 / 0 0 9 0 0 (a) l-Acetyl-4-(t-butyloxycarbonvl)piperazine 25 The subtitle compound was prepared by the methods of Intermediates 1 and 2 but using piperazine in place of homopiperazine and acetyl chloride in place of 4morpholinecarbonyl chloride.

(b) 6-{l-[4-(t-Butyloxycarbonyl)-1.4-piperazin-l-yl]ethylideneamino)-3.4-dimethoxy30 2-phenvlbenzonitrile

The subtitle compound was prepared by the method of Example 1 (c) from the compound of Example 3(f) and the product of step (a). The crude product was purified on silica gel,

AP .00715 eluting with CH₂Cl₂/MeOH (97/3. v/v). The subtitle compound (96%) was obtained as a foam. R_f 0.35 (CH₂Cl₂/MeOH 95/5, v/v). MS m/z 465 (MH).

(c) 4-Amino-2-[4-ft-buty1oxycarbony1)-1.4-piperazin-l-yl]-6.7-dimethoxy-55 phenylauinoline

To a solution of the product of step (b) (270mg, O.SSmmol) in DMSO (3ml) was added KOH flake (33mg,0.58mmol) and the reaction mixture heated to 90°C for 4h after which time the reaction was cooled, poured onto H₂O and extracted with EtOAc (3x). The combined organic layers were dried over MgSO₄ and evaporated under reduced pressure to give the subtitle compound as a foam (65mg, 24%). R_f 0.15 (CH₂Cl₂/MeOH 95/5, v/v). MS m/z 465 (MH⁺).

(d) 4-Amino-6.7-dimethoxy -5-phenvl-2-(l .4-piperazin-l -yl)quinoline

HCl was bubbled through a solution of the product of step (c) (580mg, 1.25mmol) in

CH₂C1₂ at 0°C. After 15 min the reaction mixture was evaporated under reduced pressure and the residue was purified on silica gel, eluting initially with CH₂Cl₂/MeOH/0.88NH₃(92/7/1, v/v) followed by CH₂Cl₂/MeOH/0.88NH₃ (90/10/1) to give the subtitle compound as a light brown foam (380mg, 84%). R_f 0.16 (CH₂Cl₂/MeOH/0.88NH₃ 92/7/1, v/v). MS m/z 365 (MH⁺).

(e) (R/S)-4-Amino-2-[4-( 1,4-benzodioxan-2-carbonyl)-l .4-piperazin-l -vll-6.7dimethoxy-5-phenylquinoline (R/S)-l,4-Benzodioxan-2-carboxylic acid (50mg, 0.28mmol) was added to a solution of 1hydroxybenzotriazole monohydrate (40mg, 0.30mmol) and l-(3-dimethylaminopropyl)-325 ethylcarbodiimide hydrochloride (70mg, 0.38mmol) in CH₂C1₂. This was followed by the sequential addition of 4-methylmorpholine (0.6ml, 0.55mmol) and the product of step (d) (lOOmg, 0.28mmol) and the reaction mixture was stirred at room temperature under N₂ for 20h after which time it was washed with H₂O, saturated aqueous sodium bicarbonate and then saturated brine. The organic layer was separated, dried over MgSO₄ and evaporated under reduced pressure. The crude product was purified on silica gel, eluting initially with

EtOAc/hexane (1/1, v/v) followed by EtOAc to give the title compound as a foam (120mg,

79%). R_f 0.30 (EtOAc/hexane 1/1, v/v). MS m/z 527 (MH). 'HNMR (CDC1₃) δ: 3.41AP/P/ 96/00900 /_ΛΡ . o O71b

4.05 (2H, b) 3.52 (3H. s), 3.73 (4H. m) 3.90 (4H, m), 4.00 (3H. s), 4.35 (1H, dd), 4.50 (1H, dd), 4.S7 (1H. dd), 5.80 (1H, s), 6.89 (4H. m), 7.16 (1H, m), 7.42 (5H, m). Found: C,66.08;

H.5.94; N.9.64; C₃₀H₃₀N₄O₅ 0.5.EtOAc 0.5.H₂O requires C,66.25; H,6.04; N,9.66%.

Example 6

4-Amino-2-[4-(furan-2-carbonyl)-1.4-piperazin-l-yl]-6.7-dimethoxy-5-phenylquinoline

The title compound was prepared by the method of Example 5(e) from the compound of Example 5(d) and 2-furancarboxylic acid. The title compound (74%) was obtained as a foam. R_f 0.30 (EtOAc/hexane 1/1, v/v). MS m/z 459 (MH⁺). ‘HNMR (CDC1₃) δ: 3.41-4.05 (2H, b), 3.52 (3H, s), 3.73 (4H, m), 3.90 (4H, m), 4.00 (3H, s), 4.35 (1H, dd), 4.50 (1H, dd), 4.87 (1H, dd), 5.80 (1H, s), 6.89 (4H, m), 7.16 (1H, m), 7.42 (5H, m). Found: C,65.03; H,5.92;N,11.03; C₃₀H₃₀N₄O₅ 0.4.EtOAc H₂O requires C,64.73; H,6.10; N, 10.94%.

Example 7 (R/S)-4-Amino-6.7-dimethoxy-5-phenyi-2-[4-(tetrahydrofuran-2-carbonyl)-1.4-piperazinl-yl]quinoline

The title compound was prepared by the method of Example 5(e) from the compound of Example 5(d) and (R/S)-tetrahydrofuran-2-carboxylic acid. The crude product was purified on silica gel eluting with CH₂Cl₂/MeOH/0.88NH₃ (95/4.5/0.5, v/v) to give the title compound (53%) as a white foam. R_f 0.45 (CH₂Cl₂/MeOH/0.88NH₃ 92/7/1, v/v). MS m/z @ 463 (MH⁺). 'HNMR (CDC1₃) δ: 1.82-2.05 (3H, m), 2.35 (1H, m), 3.20-4.00 (12H, m),

3.48 (3H, s), 4.00 (3H, s), 4.63 (1H, m), 5.78 (1H, s), 7.10 (1H, s), 7.35-7.48 (5H, m). Found: C,65.57; H,6.51; N,11.60; C₂₆H₃₀N₄O₄ 0.2.CH₂Cl₂ requires C,65.62; El,6.39;

N, 11.68%.

Example 8

4-Amino-6.7-dimethoxy-2-[4-(furan-2-carbonyl)-1.4-diazepan-l-yl1-5-phenyIquinoline (a) l-Acetyl-4-(t-butyloxycarbonyl)-l,4-diazepane

The subtitle compound was prepared by the methods of Intermediates 1 and 2 but using acetyl chloride in place of 4-morpholinecarbonyl chloride. The subtitle compound (82%) was obtained as a yellow oil. R_f 0.28 (CH₂Cl₂/MeOH 95/5, v/v). MS m/z 243 (MH^T).

AP/P/ 9 6 / 0 0 9 0 0

AP .00/15

	(b) 6-1 l-14-(t-Butvioxvcarbonv])-1.4-diazet)an-l-vllethv]idenearnino)-3.4-dimetho\v- 2-phenvIbenzonitrile
5	The subtitle compound was prepared by the method of Example 1 (c) from the compound of Example 3(f) and rhe product of step (a). The subtitle compound (41%) was obtained as a pale yellow foam. R_f 0.21 (CH₂Cl₂/MeOH 97.5/2.5. v/v). MS m/z 479 (MET).
¹⁰	(c) 4-Amino-2-r4-ft-butvloxvcarbonvl)-1.4-diazeDan-l-vll-6.7-dimethoxv-5- phenvlquinoline The subtitle compound was prepared by the method of Example 1 (d) from the product of
	step (b). The subtitle compound (63%) was obtained as a pale orange foam. R_f 0.51 (CH₂Cl₂/MeOH/0.88NH₃ 92/7/1, v/v). MS m/z 479 (MH⁺).
15	(d) 4-Amino-6.7-dimethoxv-2-(1.4-diazepan-l-vl)-5-phenvlquinoline The subtitle compound was prepared by the method of Example 5(d) from the product of step (c). The subtitle compound was obtained in quantitative yield as a pale orange solid. R_f 0.07 (CH2Cl₂/MeOH/0.88NH₃ 92/7/1, v/v). MS m/z 379 (MET).
20 /¾	fe) 4-Amino-6.7-dimethoxv-2-[4-(furan-2-carbonvl)-1,4-diazepan-l -vl]-5- phenvlquinoline The title compound was prepared by the method of Example 5(e) from the product of step (d) and 2-furancarboxylic acid. The product was purified by slurrying in EtOAc to give the title compound (72%) as a white solid. R_f 0.58 (CH₂Cl₂/MeOH/0.88NH₃ 92/7/1, v/v). MS
25	m/z 473 (MH⁺). 'HNMR (CDC1₃) δ: 2.10 (2H, m), 3.50 (3H, s), 3.74 (4H, m), 3.81 (2H, m), 4.00 (8H, m), 5.71 (IH, s), 6.45 (IH, s), 7.01 (IH, bs), 7.65 (IH, bs), 7.44 (5H, m). Found: C,67.57; H.5.90: N,11.63; C₂₇H₂₈N₄O₄ 0.5 H₂O requires C.67.34: H,6.07; N, 11.63%.
30	Example 9 4-Amino-6.7-dimethoxv-5-phenvl-2-r4-(tetrahvdroDvran-4“Carbonvl)-1.4-diazenan-l- vljquinoline

AP/P/ 9 6 / 0 0 9 0 0 kp.00715

The title compound was prepared by the method of Example 5(e) from the compound of Example 5(d) and tetrahydropyran-4-carboxylic acid. The crude product was purified on silica gel, eluting with CH₂Cl₂/MeOH (90/10, v/v) to give the title compound (44%) as a white solid. R_f0.41 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 491 (MH⁺). ’HNMR (CDC1₃) δ: 1.74 (1H, m) 1.84-2.15 (3H, m), 2.6S (1H, m), 3.21 (1H, m), 3.50 (8H, m), 3.80 (7H, m), 4.01 (5H, m), 5.68 (1H, s), 7.65 (1H, bs), 7.21-7.55 (6H, m). Found: C,66.97; H.7.09; N, 10.77; C_2SH₃₄N₄O₄ 0.75 H₂O requires (3,66.71; H,7.10; N,11.11%.

Example 10

4-Amino-5-(4-chlorophenyl)-6.7-dimethoxy-2-[4-(4-morpholinecarbonyl)-1.4-diazepan-lvl]quinoline (a) 6-Amino-3.4-dimethoxy-2-iodobenzonitrile

The subtitle compound was prepared by the method of Example 2(b) from the compound of Example 3(d). The subtitle compound (81%) was obtained as a colqurless solid. R_f 0.55 (EtOAc/hexane 1/1, v/v). MS m/z 322 (MNH₄ ⁺).

(b) 3.4-Dimethoxy-2-iodo-6- {1 - [4-(4-morpholinecarbonvl)-1.4-diazepan-1 vljethy lideneamino} benzonitrile

The subtitle compound was prepared by the method of Example 1(c) from the product of step (a) and Intermediate 4. The crude product was purified on silica gel, eluting with CH₂Cl₂/MeOH (97/3, v/v) to give the subtitle compound (87%) as a colourless solid. R_f0.15 (CH₂C1₂). MS m/z 542 (MH⁺). Found: C,46.00; H,5.17; N,12.44; C₂₁H₂₈N₅O₄I

O o

co o

o to

O.1.CH₂C1₂ requires C,46.08; H,5.17; N,12.74%.

(c) 4-Amino-6.7-dimethoxy-5-iodo-2-[4-(4-morpholinecarbonyl)-1.4-diazepan-lvl]quinoline

The subtitle compound was prepared by the method of Example 1(d) from the product of step (b) except that the reaction was carried out in THF/DMPU (5/1, v/v). The crude product was purified on silica gel, eluting with CH₂Cl₂/MeOH (98/2, v/v). The subtitle compound (65%) was obtained as a light brown solid. R_f 0.50 (CH₂Cl₂/MeOH/0.88NH₃

AP. ύΟ 1 ί 5

9

90/10/1, v/v). MS mz 542 (ΜΗ ). Found; C.45.71: H.5.26: N,12.44; ΟηΗ-^ΝςΟ,Τ O.25.CH₂C1₂ requires C,45.37; H.5.07; N,12.46%.

(d) 4-Amino-5-/4-chlorophenyl)-6.7-dimethoxy-2-[4-(4-morpholinecarbonyl)-I.45 diazepan-1 -yl]quinoline

The title compound was prepared by the method of Example 1(a) from the product of step (c) and 4-chlorophenylboronic acid. The crude product was purified on silica gel. eluting with CH₂Cl₂/MeOH/0.88NH₃ (90/10/1, v/v). The title compound (40%) was obtained as a pale yellow foam. R_f 0.45 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 526, 528 (MH⁺). ^!H NMR (CDC1₃) δ; 2.06 (2H, m), 3.15 (4H, m), 3.35 (2H, m), 3.50 (3H, s), 3.53-3.68 (6H, m), 3.74 (2H, m), 3.97 (5H, m), 4.32 (2H, bs), 5.71 (1H, s), 7.29 (2H, d), 7.45 (2H, d), 7.69 (1H, bs). Found: C,57.34; H,5.71; N,10.97; C₂₇H₃₂N₅O₄C1 0.67.CH₂Cl₂ requires C,57.02; H,5.76; N,12.02%.

Example 1,1.

4-Ammo-5-(3.5-dichlorophenyll-6.7-dimethoxy-2-[4-(4-morpholinecarbonyl)-1.4diazepan-1 -vl]quinoline

The title compound was prepared by the method of Example 1 (a) from the compound of

Example 10(c) and 3,5-dichlorophenylboronic acid. The crude product was purified on silica gel, eluting with CH₂Cl₂/MeOH/0.88NH₃ (90/10/1, v/v). The title compound (24%) was obtained as a pale yellow foam. R_f 0.50 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 560, 562, 564 (MH⁺). ^!HNMR (CDC1₃) δ: 2.06 (2H, m), 3.15 (4H, m), 3.35 (2H, m), 3.55 (3H, s), 3.65 (6H, m), 3.74 (2H, m), 3.99 (7H, m), 5.76 (1H, s), 7.10-7.55 (3H, m),

7.45 (1H, s). Found: C,54.04; H,5.31; N,10.70; C₂₇H₃₂N₅O₄C1₂ O.6.CH₂C1₂ 0.6.MeOH requires C.53.64; H.5.49; N.l 1.10%.

Example 12

4-Amino-6-7-dimethoxy-5-(4-methoxyphenyl)-2-[4-f4-morpholinecarbony])-l .4-diazepan30 l-yl]quinoline

Example 10(c) and 4-methoxyphenylboronic acid. The crude product was purified on silica

00600/96 Zd/dV

ΑΡ , Ο ύ / ι 5 gel. eluting with CH₂Cl₂/MeOH (95/5, v/v). The title compound (30%) was obtained as a pale yellow foam. R_f 0.20 (CH₂Cl₂/MeOH 9/1, v/v). MS m/z 522 (MH⁺). ’HNMR (CDC1₃)

6: 2.06 (2H, m), 3.16 (4H, m), 3.35 (2H, m). 3.50 (3H, s), 3.53-3.SO (SH, m), 3.SO-4.13 (4H, m), 3.90 (6H, s), 5.71 (1H, bs), 7.00 (2H, d), 7.06 (1H, bs), 7.31 (2H, d). Found:

C,61.75; H,6.63; N,12.34; C₂₈H₃₅N₅O₅ O.2.CH₂C1₂ 0.7.H₂O requires C,61.45; H,6.73;

N, 12.71%.

Example 13

4-Amino-5-[3.5-bis(trifluoromethyl)phenyl]-6.7-dimethoxy-2-[4-(4-morpholinecarbonyl)10 1,4-diazepan-1 -ylfquinoline

The title compound was prepared by the method of Example 1(a) from the compound of o

Example 10(c) and 3,5-bis(trifluoromethyl)phenylboronic acid. The crude product was q purified on silica gel, eluting with CH₂Cl₂/MeOH/0.88NH₃ (90/10/1, v/v). The title

O compound (24%) was obtained as a pale yellow foam. R_f 0.50 (CH₂Cl₂/MeOH/0.88NH₃ q

90/10/1, v/v\ MS m/z 628 (MH⁺).'ΗNMR (CDC1₃) δ: 2.06 (2H, m), 3.16 (4H, m), 3.35 to (2H, m), 3.48 (3H, s), 3.61 (6H, m), 3.77 (2H, m), 4.00 (7H, m), 5.80 (1H, s), 7.10 (1H, bs), 7.84 (2H, s), 7.95 (1H, s). Found: C,53.51; H,5.06; N,10.03; C₂₉H_3IN₅O₄F₆ 0.4.CH₂Cl₂ £?

O. 3.MeOH requires C,53.10; H,4.92; N,10.43%. £?

<

Example 14

4-Amino-6,7-dimethoxy-2- [4-(4-morpholinecarbonyl)-1,4-diazepan-1 -yll-5-[(4trifluoromethyl)phenyl] quinoline

The title compound was prepared by the method of Example 1 (a) from the compound of Example 10(c) and 4-(trifluoromethyl)phenylboronic acid. The crude product was purified on silica gel, eluting with CH₂Cl₂/MeOH/0.88NH₃ (90/10/1, v/v). The title compound (10%) was obtained as a pale yellow foam. R_f 0.45 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v).

MS m/z 560 (MH*). ’HNMR (CDC1₃) δ: 2.06 (2H, m), 3.03-4.13 (2H, b), 3.13 (4H, m),

3.34 (2H, m), 3.48 (3H, s), 3.65 (6H, m), 3.76 (2H, m), 4.03 (5H, m), 5.74 (1H, s), 7.16 (1H, bs), 7.50 (2H, d), 7.71 (2H, d). Found: C,56.46; H,5.78; N, 11.43; C_2SH₃₂N₅O₄F₃

0.5.CH₂Cl₂ requires C,56.85; H,5.52; N,11.63%.

Example 15

A.P . ύ ύ 7 1 5

4-Amino-5-(3-chlorophenyl)-6.7-dimethoxy-2-[4-f4-morpholinecarbonyl^x)-1.4-diazepan-lyljquinoline

The title compound was prepared by the method of Example 1(a) from the compound of Example 10(c) and 3-chlorophenyiboronic acid. The crude product was purified on silica gel, eluting with CH₂Cl₂.'MeOH/O.S8 NH₃ (90/10/1, v/v) followed by trituration with ether. The title compound (43%) was obtained as a colourless foam. R_f0.34 (CH₂Cl₂/MeOH'O.88 NH₃ 90/10/1, v/v); MS mb 526, 528 (MH⁺). ‘HNMR (CDCI₃) δ 2.06 (2H, m), 3.15 (4H, m), 3.35 (2H, m), 3.52 (3H, s), 3.40-3.80 (8H, m), 3.99 (7H, m), 5.77 (1H, s), 7.10-7.50 (4H, m), 7.23 (1H, s). Found: C,59.82; H,6.58; N, 11.96. C₂₇H₃₂N₅O₄C1 0.25.CH₂Cl₂

0.5.ether requires C,60.11; H,6.47; N, 11.99%.

Example 16

4-Amino-6.7-dimethoxy-2-[4-(4-morpholinecarbonyl)-1.4-diazepan-l-yl]-5phenvlquinazoline (a) 2.4-Dichloro-6.7-dimethoxy-5-nitroquinazoline

To a suspension of 2,4-dichloro-6,7-dimethoxyquinazoline (30.Og, 0.12 mol) in acetonitrile (550ml) at 0°C was added nitronium tetrafluoroborate (25.9g, 0.19mol) portionwise over 15min. The reaction was stirred for 0.75h and then evaporated under reduced pressure. The resulting solid was suspended in a mixture of saturated aqueous sodium bicarbonate and EtOAc and the solid filtered, dissolved in CH₂C1₂, dried over MgSO₄ and evaporated to give the subtitle compound as a pale yellow solid (27g). Further material was obtained by separating the organic layer of the filtrate, washing with H₂O (lx), saturated brine (lx), drying over MgSO₄ and filtering through a pad of silica. Subsequent evaporation under reduced pressure, trituration with EtOAc and filtration gave the subtitle compound as a pale yellow solid (3.9g, overall yield 88%). R_f 0.24 (ether/hexane 1/1, v/v).

(b) 2.4-Dihydroxy-6.7-dimethoxy-5-nitroquinazoline

The product of step (a) (27.3s, 90mmol) was suspended in a mixture of glacial acetic acid (150ml) and H₂O (5ml) and the reaction mixture was heated to 150°C for 0.5h after which time a further portion of H₂O (5ml) was added and heating continued. After a total of 1.5h heating, a third portion of H₂O (5ml) was added and heating maintained for a further 0.5h.

00600/96 /d/d V

AP. O0715

The reaction mixture was then cooled and the solid was filtered, washed with ether and dried in vacuo at 80°C to give the subtitle compound as a pale yellow solid (22.2g, 93%).

R_f 0.38 (EtOAc/MeOH 95/5, v/v). MS m/z 285 (MNHf).

(c) 5-Amino-2.4-dihydroxy-6.7-dimethoxyquinazoline

A mixture of the product of step (b) (35.Og, O.lSmol) and 10% palladium on carbon (4.0g) was suspended in glacial acetic acid (200ml) and hydrogenated at 50psi (3.4 atm) and 50°C for 2.5 days. The reaction was then cooled, suspended in MeOH/CH₂Cl₂ (1/1,v/v, IL) and filtered. The residue was transferred to a soxhlet apparatus and continually extracted with

MeOH for 3 days. Evaporation afforded a grey solid which was dissolved in 2N NaOH, filtered through a pad of silica, washing with H₂O. The filtrate was then acidified with concentrated HCI. The resulting precipitate was isolated by filtration, washing sequentially with H₂O and acetone, then dried in vacuo at 60°C to give the subtitle compound as a white solid (22.7g, 73%). R_f 0.42 (EtOAc/MeOH 95/5, v/v). MS m/z 238 (MH⁺).

(d) 2.4-Dihydroxy-6.7-dimethoxy-5-iodoquinazoline

To a suspension of the product of step (c) (5.5g, 23.2 mmol) in concentrated HCI (10ml ) at -10°C was added H₂O (10ml), followed by an aqueous solution of sodium nitrite (2.4g, 34.8mmol in 10ml), the temperature being maintained below 0°C. The resultant yellow diazonium salt was cautiously added to a solution of potassium iodide (40.Og, 0.23mol), copper (I) iodide (4.4g, 23mmol) in H₂O (100ml) heated to 90°C and heating was maintained after the addition was complete until gas evolution ceased. The mixture was then cooled, filtered and the solid residue washed sequentially with H₂O and aqueous sodium thiosulphate. The crude product was purified on silica gel, eluting initially with

EtOAc/MeOH (95/5, v/v) followed by EtOAc/MeOH/AcOH (95/5/1, v/v) affording a solid which was suspended in MeOH and filtered to give the subtitle compound as a yellow/orange solid (2.2g, 27%) which was contaminated with the compound of step (b) (0.4g). R_f 0.16 (CH₂Cl₂/MeOH 95/5, v/v). MS m/z 366 (MNH₄ ⁺).

00600/-9 6 /d'd (e) 2.4-Dihydroxy-6.7-dimethoxy-5-pheny]quinazoline

The subtitle compound was prepared by the method of Example 1(a) from the product of step (d) (5.7/1 mixture of compounds, w/w) and phenylboronic acid. The crude product

AP .00715 was purified on silica gel eluting with CH₂Cl₂/MeOH (95/5, v/v) to give the subtitle compound (95%) as an orange powder which was contaminated (5% w/w) with the compound of step (b). R_f 0.16 (CH₂Cl₂/MeOH 95/5, v/v). MS m/z 299 (MH^-).

(f) 2.4-Dichloro-6.7-dimethoxy-5-phenyIquinazoIine

The mixture produced in step (e) (95/5, w/w, 1.75g, 5.6mmol of the subtitle compound of step (e)) was suspended in POC1₃ (10ml, 16.5s, 109mmol) and the mixture treated with Ν,Ν-dimethylaniline (1.86ml, 1.79g, 14./mmol) and heated at reflux for 1.5h. After cooling, excess POC1₃ was evaporated under reduced pressure and the residue azeotroped with toluene (2x) then partitioned between EtOAc and H₂O. The organic layer was separated and washed sequentially with H₂O (3x), saturated brine (lx), dried over MgSO₄and filtered through a pad of silica, washing with EtOAc to give, on evaporation, the subtitle compound as a yellow gum. R_f 0.83 (EtOAc).

(g) 4-Amino-2-chloro-6.7-dimethoxy-5-phenylquinazoline

The product of step (f) was suspended in a saturated solution of ammonia in MeOH and the reaction was stirred under N₂ for 3h after which time CH₂C1₂ was added until all the solid present dissolved. The reaction mixture was then stirred for a further 2.5 days at room temperature, the solvent removed under reduced pressure and the resulting solid suspended in MeOH and isolated by filtration, washing with ether and then drying in vacuo at 60°C. This gave the subtitle compound as a white solid (1.12g, 65% from the product of step (e)). R_f 0.39 (EtOAc). MS m/z 316, 318 (MH⁺).

(h) 4-Amino-6.7-dimethoxy-2-[4-(4-morpholinecarbonyl)-1.4-diazepan-l-yl]-525 phenvlguinazoline

To a solution of the product of step (g) (200mg, 0.63mmol) in n-BuOH (10ml) was added Intermediate 3 (250mg, l.Ommol) and triethylamine (0.22ml, 160mg, 1.58 mmol) and the reaction heated to 100°C under N₂ for 18h. After cooling, the reaction mixture was partitioned between EtOAc and 2N NaOH, the organic layer separated, washed with saturated brine, dried over MgSO₄ and evaporated under reduced pressure. The crude product was purified on silica gel, eluting with EtOAc and the resulting solid was then suspended in a minimal volume of EtOAc, filtered and dried in vacuo at 60°C to give the

AP/P/ 9 6 / 0 0 9 0 0 /0-¹ .00/15 title compound as a white solid (180mg, 58%). Rj- 0.40 (EtOAc/MeOH 95/5, v/v). MS m/z 493 (MH⁺). ‘HNMR (CDC1₃) δ: 2.00 (2H, m), 3.16 (4H, m), 3.35 (2H, m), 3.48 (3H, s), 3.52 (2H, m), 3.65 (4H, m), 3.84 (2H, m), 3.94 (2H, m), 3.97 (3H, s), 4.52 (2H, bs), 6.92 (1H. s), 7.35 (2H, m), 7.40-7.52 (3H, rn). Found: C,62.82; H,6.52; N,16.70; C₂₆H₃₂N₆O₄

0.25.H₂O requires C,62.85; H,6.59; N, 16.91%.

Alternative route to 4-Amino-2-chloro-6,7-dimethoxy-5-phenylquinazoline [the compound of step (g)] (Aa) 4-Amino-6.7-dimethoxy-2-hydroxy-S-phenylquinazoline

Trifluoroacetic acid (8.1ml, O.lOmol) was added dropwise to a stirred solution of the compound of Example 3(f) (12.9g, 0.051mol) and sodium cyanate (6.6g, O.lOmol) in CH₂C1₂ (200ml) and the reaction was left to stir at room temperature under N₂ for 18h, after which time an orange precipitate was formed. The solid was isolated by filtration, washing with hexane, dried by suction and then combined with a mixture of 2N aqueous NaOH (250ml) and MeOH (250ml). The mixture was heated on a steam bath until the solid had dissolved and after cooling, the solution was acidified with concentrated HCl and warmed on a steam bath until dissolution was complete. The solution was cooled and neutralised with K₂CO₃ and the precipitated solid was isolated by filtration, washing with H₂O,

MeOH, CH₂C1₂ and finally ether to give the subtitle compound as a colourless solid (12.4g, 82%). MS m/z 298 (MH⁺).

AP/P/ 96/00900 (Ab) 4-Amino-2-chloro-6.7-dimethoxy-2-hydroxy-5-phenylquinazoline

DMF (6.4ml, 0.083mol) was added dropwise to POC1₃ (19.3ml, 0.21 mol). Once the mixture had cooled, the product of step (Aa) (12.34g, 0.042mol) was added and the temperature was maintained at 90°C for 3h and then stirred at room temperature for 18h after which time, the reaction was cautiously quenched with ice. The reaction was then basified with excess 2N NaOH, the temperature was allowed to reach 60°C and this was maintained for Ih. The reaction mixture was then cooled and the precipitate was isolated by filtration and dried in vacuo at 60°C to afford the subtitle compound as an off-white solid (10.2g, 78%).

k Ρ . 0 ύ 7 1 -5

Example 1 7

4-Amino-6,7-dimethoxy-2-{4-[l-(3S.4S-dihydroxypyrrolidine^>)carbonyll-1.4-diazepan-lyll-5-phenylquinazoline hydrochloride (a) A^/-Benzyl-3S.4S-bis('t-butyldimethylsilyloxy\pyrrolidine

The subtitle compound was prepared by the method of Arakawa et al Chem.Pharm.Bull.,29, 2219 (1991).

(b) l-{l-(3S.4S-Bisft-butyldimethylsilyIoxy)pyrroIidine)carbonyl}-1.4-diazepane

To a stirred solution of the product of step (a) (12.Og, 28mmol) in toluene (150ml) was

Τ. ,·'-’* added a solution of phosgene in toluene (1.93M, 18ml, 34mmol). The resulting suspension was heated at reflux for 6h after which time the solvent was removed under reduced pressure and the residue redissoh/ed in THF (200ml). The solution was cooled to 0°C and then added to a solution of homopiperazine (15.Og, 150mmol) in THF (100ml). The resultant solution was heated to 60°C for lh and stirred at room temperature for 18h. The solvent was removed under reduced pressure and the residue partitioned between CH₂C1₂(200ml) and H₂O (100ml). The organic layer was washed with saturated brine (50ml) and dried over MgSO₄. The solvent was evaporated under reduced pressure and the crude product was purified on silica gel, eluting initially with CH₂Cl₂/MeOH/0.88NH₃(96/3.5/0.5, v/v) followed by CH₂Cl₂/MeOH/0.88NH₃ (92/7/1, v/v) to give the subtitle compound as an oil which slowly crystallised on standing (7.64g, 60%). R_f 0.2 (CH₂Cl₂/MeOH/0.88NH₃ 92/7/1, v/v). MS m/z 459 (MH⁺).

(c) 4-Amino-6.7-dimethoxy-2-{4-[l-(3S.4S-dihydroxypyrrolidine)carbonyl]-1.4diazepan-l-yl}-5-phenylquinazoline hydrochloride

To a solution of the compound of Example 16(g) (200mg, 0.63mmol) and triethylamine (0.22ml, 1.7mmol) in n-BuOH (10ml) was added the product of step (b) (350mg, 0.76mmol) and the reaction mixture was heated to 100°C under N₂ for 18h. The reaction was then cooled and evaporated under reduced pressure and HCI was bubbled through a solution of the residue in CH₂C1₂ for 20min. The reaction mixture was then evaporated under reduced pressure, partitioned between EtOAc and H₂O and the aqueous layer extracted repeatedly with EtOAc. The aqueous layer was then basified with 2N NaOH,

AP/P/ 9 6 / 0 0 9 0 0 extracted with CH₂C1₂ and the organic layer dried over MgSCf and evaporated to give a gum which was treated with ethereal HCI. The resulting precipitate was filtered, washing with ether, to give the title compound as a white foam. (210mg, 61%). R_f 0.1 (CH₂Cl₂/MeOH 95/5, v/v). MS m/z 509 (MH⁺). ‘HNMR (CDC1₃) δ: 1.58-2.23 (2H, bm),

3.03-4.35 (2H, bm), 3.23 (4H, m), 3.48 (3H, s), 3.52 (3H, m), 3.71 (4H, m), 4.02 (3H, s),

4.11 (4H, m), 5.16 (1H, bs), 7.32 (2H, m), 7.52 (3H, m), 8.45 (1H, s), 12.59 (1H, bs). Found: C.55.42; H.6.32; N, 13.90; C₂₆H₃₂N₆O₅ HCI H₂O 0.5EtOAc requires C.55.40; H,6.48; N,13.84%.

Example 18

4-Amino-6.7-dimethoxy-2-[4-(3-hydroxyazetidine-l-carbonyl)-1.4-diazepan-l-yll-5phenylquinazoline hydrochloride

A suspension of the compound of Example 16(g) (205 mg, 0.65mmol) in n-BuOH was treated with homopiperazine (1.3g, 13.0mmol) and the reaction heated to reflux under N₂ for 18h. After cooling, the reaction mixture was partitioned between EtOAc and 2N NaOH, the organic layer separated, washed with H₂O (5x) then evaporated under reduced pressure azeotroping with toluene (3x) to give a foam (280mg). This was dissolved in CH₂C1₂(50ml), triethylamine (0.11ml, 0.78mmol) was added and the solution stirred -with 4A molecular sieves for 2h before adding dropwise over lh to a solution of triphosgene (68.0mg, 0.23mmol) in CH₂C1₂ (10ml) at -5°C. This was then treated with a fine suspension of 2-azetidinol [prepared according to method of Chatterjee et al, J.Chem.Soc.Chem.Commun., 93 (1968)] (142mg, 1.3mmol) and triethylamine (0.32ml, 2.3mmol) in THF, pre-stirred with 4A molecular sieves for 2h. The reaction mixture was subsequently stirred for 3 days at room temperature under N₂ after which time it was partitioned between CH₂C1₂ and IN NaOH, the organic layer washed with saturated brine, dried over MgSO₄ and evaporated. Purification of the crude product on silica gel, eluting initially with EtOAc/MeOH (95/5, v/v) then CH₂Cl₂/MeOH/0.88NH₃ (90/10/1) followed by treatment with ethereal HCI gave the title compound as a white foam (153mg, 46%). MS m/z 479 (MH⁺). ^!HNMR (CDC1₃) δ: 1.61, 1.84 (2H, two m), 3.10 (1H, m), 3.18-3.40 (3H, m), 3.40-3.73 (4H, m), 3.55 (3H, s), 3.90 (3H, bm), 4.10 (3H, s), 4.35 (2H, bm), 5.03 (0.5H, bm), 5.21 (1H, bs), 5.26 (0.5H, bm), 5.66 (0.5H, bm), 6.58 (0.5H, bm), 7.40 (2H,

AP/P/ 9 6 / 0 0 9 0 0 ki³ . 0 0 7 15

m). 7.55 (3H, m), S.50 (1H, bs). 12.97 (1H. bs). Found: C.53.94; H.6.40; N.14.06: C₂₅H₃₀N₆O₄ HCI 0.4.ether 2.5H_;O requires C.54.14; H,6.78; N.14.25%.

Example 19

4-Ammo-2-[4-(1.4-benzodioxan-2-carbonyD-l .4-piperazin-l-yll-6.7-dimethoxv-5phenylquinazoline (a) 4-Amino-6.7-dimeihoxy-5-phenvl-2-n.4-piperazin-l -yDquinazoline

To a stirred suspension of the compound of Example 16(g) (420ms, l.Smmol) in n-BuOH 10 (10ml) was added piperazine (2.29g, 27mmol) and the reaction heated to 80°C for 3h.

After cooling, the reaction mixture was partitioned between EtOAc and 2N NaOH, the organic layer was washed sequentially with H₂O (2x) and saturated brine (lx), then dried over MgSO₄ and evaporated under reduced pressure. The residue was azeotroped with toluene (lx) then CH₂C1₂ (2x) to give the subtitle compound as a foam (455mg, 94%). R_f

0.4 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 366 (MH⁺).

(b) (R/S)-4-Amino-2- {4-(1.4-benzodioxan-2-carbonyl)-1.4-piperazin-1 -yl} -6.7dimethoxy-5-phenylquinazoline

The title compound was prepared by the method of Example 5(e) from the product of step 20 (a) and (R/S)-l,4-benzodioxan-2-carboxylic acid. The title compound (61%) was obtained as a foam. R_f 0.69 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 528 (MH⁺). ’HNMR (CDC1₃) δ: 3.42-4.16 (8H, b) 3.48 (3H, s), 4.00 (3H, s), 4.35 (1H, dd), 4.48 (1H, dd), 4.87 (1H, dd), 5.80 (1H, s), 6.89 (4H, m), 6.97 (1H, s), 7.16 (1H, m), 7.39 (2H, m), 7.50 (3H, m). Found: C,64.31; H.5.58; N,12.61; C₂9H₂₉N₅O₅ 0.2.EtOAc 0.5.H₂O requires C,64.54;

H,5.70; N,12.63%.

Example 20

4-Amino-6.7-dimethoxy-5-(4-fluorophenyl)-2-[4-(4-morpholinecarbonyl)-1.4-diazepan-1yl]quinazoline (a) 2.4-Dichloro-6.7-dimethoxy-5-iodoquinazoline

AP/P/ 96 / 0 0900

AP . ό 0 / ' 5

The subtitle compound was prepared by the method of Example 16(f) from the compound of Example 16(d). The subtitle compound was obtained as a solid (contaminated with

2,4,5-trichloroquinazoline). R_f 0.16 (hexane/EtOAc 4/1, v/v).

(b) 4-Amino-2-chloro-6.7-diraethoxy-5-iodoquinazoline

This was prepared by the method of Example 16(g) from the contaminated product of step (a). The subtitle compound (61% from the compound of Example 16(d)) was obtained as a yellow solid (contaminated with the 5-chloro analogue). R_f 0.11 (hexane/EtOAc 4/1, v/v). MS m/z 366 (MH⁺).

(c) 4-Amino-6.7-dimethoxy-5-iodo-2-[4-(4-morpholinecarbonyl)-1.4-diazepan-lyl]quinazoline

This was prepared by the method of Example 16(h) from the product of step (b) (3/2 mixture, w/w) and Intermediate 3. The crude product was purified on silica gel, eluting initially with hexane followed by EtOAc/hexane (1/1, v/v). The subtitle compound (28% based on the compound of step (b)) was obtained as an orange foam (contaminated with the

5-chloro analogue). R_f 0.41 (EtOAc). MS m/z 543 (MH⁺).

(d) 4-Ammo-6.7-dimethoxy-5-(4-fluorophenyl)-2-[4-(4-morpholinecarbonyl)-1.4diazepan-l-yl]quinazoline

This was prepared by the method of Example 1(a) from the product of step (c) (1.2/1 mixture, w/w) and 4-fluorophenylboronic acid. The crude product was purified on silica gel, eluting initially with hexane/EtOAc (4/1, v/v) followed by EtOAc. The title compound (63% based on the compound of step (c)) was obtained as a white foam. R_f 0.18 (EtOAc). MS m/z 511 (MH⁺). ‘HNMR (CDC1₃) δ: 2.00 (2H, m), 3.14 (4H, m), 3.35 (2H, m), 3.48

AP/P/ 9 6 / 0 0 9 0 0 (3H, s), 3.55 (2H, m), 3.66 (4H, m), 3.84 (2H, m), 3.94 (2H, m), 3.97 (3H, s), 4.52 (2H, bs), 6.90 (1H, bs), 7.16 (2H, m), 7.32 (2H, m). Found: C,60.91; H,6.32; N,15.73;

C₂₆H₃₁N₆O₄F 0.2.EtOAc requires C,60.90; H,6.17: N,15.91%.

Example 21

4-Amino-6.7-dimethoxy-2-{l-[4-(4-morphoIinecarbonyl)piperidine]}-5-phenylquinazo1ine

The title compound was prepared by the method of Example 16(h) from the compound of Example 16(g) and 4-(4-morpholinecarbonyl)piperidine (see US patent 4.022.791). The crude product was purified by column chromatography on silica gel. elutins with CH₂Cl₂/EtOH/0.88 NH₃ (96/3.5/0.5, v/v). Recrystallisation from EtOAc gave the title compound (25%) as a colourless solid. R_f 0.10 (d-RCf/MeOH/O.SS NH-, 96/3.5/0.5 v/v). MS m/'z 478 (MH^T). *Η NMR (CDC1₃) δ: 1.75-1.95 (4H, m), 2.70 (IK, m), 2.90 (2H. m), 3.50 (3H, s), 3.55-3.75 (8H, m), 4.00 (3H, s), 4.60 (2H, m), 6.95 (1H, bs), 7.40 (2H, m), 7.50 (3H, m). Found: C,65.34; H,6.56; N,14.55. C₂₆H₃₁N₅O₄ requires C,65.39; H,6.54; N,14.66%.

Example 22

4-Amino-2-{4-[l-(3S.4S-dihydroxypyrrolidine)carbonyl)]-1.4-diazepan-l-yl}-6.7dimethoxy-5-phenylquinoline (a) 6-{ 1 -[(4-Benzyl)-1.4-diazepan-l -vl]ethylideneamino}-3.4-dimethoxy-2phenvlbenzonitrile

The subtitle compound was prepared by the method of Example 1 (c) from the compound of Example 3(f) and l-acetyl-4-benzyl-l,4-diazepane [Sutton, J. Med. Chem., 13, 1026 (1970)] to give the subtitle compound (83%) as an orange glass. R_f 0.36 (CH₂Cl₂/MeOH

95/5, v/v). MS m/z 469 (MH⁺).

(b) 4-Amino-2-(4-benzyl-l,4-diazepan-l-yI)-6.7-dimethoxy-5-phenylquinoline

A solution of the product of step (a) (440mg, 0.94mmol) in dimethoxyethane (10ml) was treated with potassium ΐ-butoxide (316mg, 2.82mmol) and reaction mixture heated at reflux for 5h. When cool, the mixture was partitioned between EtOAc and H₂O. The organic layer was dried over MgSO4 and evaporated at reduced pressured to an oil. Trituration with MeOH and filtration gave the subtitle compound as a pale pink solid, (300mg, 68%). R_f 0.39 (CH₂Cl₂/MeOH/0.88 NH₃ 92/7/1 v/v). *H NMR (CDC1₃) δ: 1.95(2H, m), 2.65(2H, m), 2.8(2H, m), 3.5(3H, s), 3.65(3H, s), 3.7-3.9(6H, m), 4.00(3H, s),

5.7(lH,s), 7.1 (1H, bs), 7.2-7.35(5H, m), 7.4(5H, m).

AP/P/ 9 6 / 0 0 9 0 0 (c) 4-Amino-2-(l .4-diazepan-l-yl)-6.7-dimethoxy-5-phenylquinoline

A mixture of the product of step (b) (700mg, 1 .Smrnol), palladium hydroxide (20%w/w, 140mg) and acetic acid (0.17ml. 3.0mmol) in EtOH (30ml) was hydrogenated at 345 kPa (5Opsi) and room temperature for 18h. The reaction was filtered through Arbocel® and the filtrate evaporated under reduced pressure to yield the subtitle compound as a buff solid (487mg, 86%). R_f 0.10 (CH₂Cl₂/MeOH/0.88 NH₃ 90/10/1, v/v). ^JH NMR(CDC13) δ:

1.95(2H, m), 2.85(2H, m), 3.05(2H, m), 3.50(3H, s), 3.75-3.85(6H, m), 4.0(3H, s), 5.7(1H, s), 7.15(1H, s), 7.45(5H, m).

(d) 4-Amino-2-(4-chlorocarbonyl-1.4-diazepan-l-yl)-6.7-dimethoxy-5-phenyIquinoline

To a solution of triphosgene (128mg, 0.43mmol) in CH₂C1₂ (10ml) at -10°C was added dropwise a solution of the product of step (c) (442mg, 1.17mmol) and triethylamine (0.195ml, 142mg, 1.4mmol) in CH₂C1₂ (20ml) over lh. The mixture was stirred at -10°C for a further lh and then evaporated under reduced pressure to yield the subtitle compound as a brown foam (514mg, 100%) which was used without further treatment.

(e) 4-Amino-2-{4-[l-(3S.4S-dihydroxypyrrolidine)carbonyl)]-1.4-diazepan-l-yl}-6.7dimethoxv-5 -phenv Iquino line

A mixture of the product of step (d) (257mg,0.58mmol), 3S,4S-bis (t-butyldimethylsilyloxy)pyrrolidine [Nagel, Angew. Chem. Int. Ed. Engl., 22, 435 (1984)] (213mg, 0.64mmol) and triethylamine (0.098ml, 71mg, 0.7mmol) in THF (20ml) was refluxed for 18h. When cool, the mixture was partitioned between EtOAc and aqueous saturated sodium hydrogen carbonate solution. The aqueous layer was washed again with EtOAc and finally CH₂C1₂. The combined organics were dried over MgSO₄ and evaporated at reduced pressure. The crude material was purified on silica gel eluting with a gradient eluent of 3-7% MeOH in

CH₂C1₂. The purified material was treated with a methanolic solution of HCI [prepared by adding acetyl chloride (0.07ml) cautiously to MeOH (3ml)] and stirred at room temperature for 2.5h. The mixture was basified with aqueous saturated NaHCO₃ and evaporated under reduced pressure. The residue was extracted with CH₂C1₂, the extract evaporated under reduced pressure and the crude product purified on silica gel eluting with

CH₂Cl₂/MeOH/ 0.88 NH₃ (92/7/1, v/v) to yield the title compound (30mg, 10%) as a colourless solid. R_f 0.25 (CH₂Cl₂/MeOH/0.88NH₃ 84/14/2, v/v). MS m/z 508 MH⁺. *H

AP/P/ 9 6 / 0 0 9 0 0 /λΡ

NMR(d₆-DMSO) δ: l.S7(2H. m), 3.12(2¾ m), 3.34(3¾ s), 3.4(2H,m), 3.52(3H.m), 3.683.9(8H,m), 4.6(2H,bs), 4.87(2H,m), 5.85(lH.s), 6.93(lH.s), 7.3(2¾ m), 7.45(3H,m).

Example 23

4-Amino-6.7-dimethoxy-2-r4-(4-fluoropiperidinecarbonyl)-1.4-diazepan-l -yll-5phenvlguinoline

A mixture of the compound of Example 22(d) (257mg. 0.58mmol), 4-fiuoropiperidine hydrochloride, [J.Org. Chem. 44. 771 (1979)] (90mg, 0.64mmol) and triethylamine (0.18ml, 1.29mmol) in THF (20ml) was heated at reflux for 18h. When cool the reaction was evaporated under reduced pressure and then partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO₄ and evaporated under reduced pressure. Purification on silica gel eluting with a gradient eluent of 3-7% MeOH in CH₂C1₂ afforded the title compound as a foam (102mg, 35%). R_f 0.31 (CH₂Cl₂/MeOH/0.88NH₃ 92/7/1, v/v). MS m/z 508 (MH⁺). NMR (CDC1₃) δ: 1.751.95(4¾ m), 2.05(2¾ m), 3.1(2¾ m), 3.35(4¾ m), 3.45-4.05(12¾ m), 4.70 and 4.85(1¾ m), 5.70(1¾ s), 7.1(1¾ bs) 7.45(5¾ m). Found: C,64.54; H,6.76; N,12.59. C_2gH₃₄N₅O₃F 0.5EtOAc 0.5.H₂O requires C,64.27; H,7.01; N,12.49%.

Example 24

4-Amino-6.7-dimethoxy-2-[4-(4-morphoIinesulphonyl)-l,4-diazepan-l-yl]-5phenvlguinazoline (a) l-(t-ButyloxycarbonyIl-4-{4-morpholinesuIphonyl}-1.4-diazepane

The subtitle compound was prepared by the method of Intermediate 2 from Intermediate 1 and 4-morpholinesulphonyl chloride [Repine et al J. Med. Chem., 24, 1935 (1991)]. The reaction mixture was partitioned between CH₂C1₂ and IN NaOH . The organic phase was washed again with IN HCI, then H₂O and dried over MgSO₄ and evaporated under reduced pressure. Purification on silica gel eluting with CH₂Cl₂/MeOH/0.88 NH₃ (98/1.25/0.25, v/v) initially and then (96/3.5.0.5, v/v) gave the subtitle compound as a gum (53%). R_f

0.44 (CH₂Cl₂/MeOH/O.S8 NH₃ 96/3.5/0.5, v/v). MS m/z 350 (MH⁺). *H NMR(CDC1₃) δ:

1.4(9¾ s), 1.9(2¾ m), 3.17(4¾ m), 3.22(2¾ m), 3.4(2¾ m), 3.5(2¾ m), 3.73(6¾ m).

AP/P/ 9 6 / 0 0 9 0 0

AP. ΰ y / 5 t.

(b) l-(4-Morphoiinesulphonyl)-1.4-diazepane hydrochloride

The subtitle compound was prepared by the method of Intermediate 3 from the product of step (a). The subtitle compound (97%) was obtained as a white solid. R_f 0.09 (CH₂Cl₂/MeOH/0.88 NH₃ 92/7/1, v/v). MS m/z 250 (MH⁺). NMR(d₆-DMSO) δ: 2.1(2H ,m), 3.1(4H, m), 3.4(4H, m), 3.62(8H, m), 9.2(2H, b).

(c) 4-Amino-6.7-dimethoxy-2-[4-(morpholinesulphonyl)-1.4-diazepan-l-yl]}-5phenvlquinazoline

The title compound was prepared by the method of Example 16(h) from the product of step (b) and the compound of Example 16(g). The mixture was purified on silica gel eluting with 3% MeOH in CH₂C1₂. Evaporation under reduced pressure and recrystallisation from EtOAc/hexane gave the title compound (33%) as a colourless solid. R_f 0.27 (CH₂Cl₂/MeOH 95/5 v/v). MS m/z 529 (MH⁺). 'Η NMR (CDC1₃) δ: 2.03(2H, m),

3.08(4H, m), 3.37(2H, m), 3A7(3H, s), 3.53(2H, m), 3.63(4H, m), 3.9(2H, m), 3.95(2H,

m), 3.98(3H, s), 4.56(2H, s), 6.9(1H, s), 7.37(2H, m), 7.44(3H, m). Found C,56.23; H,6.06; N, 15.56. C₂₅H₃₂N₆O₅S 0.5.H₂O requires C,56.42; H,6.14; N,15.79%.

Example 25

4-Amino-2-(7-aminosulfonyl-1.2-3.4-tetrahydroisoquinolin-2-yl)-6.7-dimethoxy-5phenvlguinazoline

To a solution of the compound of Example 16(g) (500mg,1.6mmol) and triethylamine (0.66ml, 4.8mmol) in a mixture of n-BuOH (10ml) and DMA (3ml) was added 1,2,3,425 tetrahydroisoquinoline-7-sulfonamide hydrochloride (R.G. Pendleton et al, The Journal of Pharmacology and Experimental Therapeutics, 208, 24, 1979) (597mg, 2.4mmol) and the reaction mixture was heated to 100°C under N₂ for 18h. The reaction was then cooled, partitioned between 2N aqueous NaOH and EtOAc, the organic layer was washed with H₂O, dried over MgSO₄ and evaporated under reduced pressure. The residue was triturated with ether/hexane and the resulting solid isolated by filtration to give the title compound as a light yellow solid, (360mg, 46%). Rf 0.62 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 492 (MH⁺). ^!H NMR (D₆-DMSO) δ: 2.87 (2H, dd), 3.37 (3H, s). 3.90 (3H, s), 4.00

0 6 0 0 / 9 6 /d/dV (2H, dd), 4.94 (2H, s), 6.90 (IH, s). 7.20-7.40 (6H. m), 7.45-7.65 (6H, m). Found: C.60.47:

H,5.39, N, 13.72; C₂₅H_2;N₅O.S 0.3.H₂O requires C.60.42; H,5.19. N, 14.09%.

Example 26

4-Amino-6.7-dimethoxy-5-phenyl-2-f3-pyridinemethylamlno1quinazoline

To a solution of the compound of Example 16(g) (300mg, 0.95mmol) and triethvlamine (0.60ml, 5.7mmol) in a mixture of n-BuOH (10ml) and DMA (2ml) was added 3(aminomethyl)pyridine and the reaction mixture was heated to 100°C under N-> for 24h after which time, a further portion of DMA (2ml) was added and heating continued for a subsequent day. The reaction was then cooled, partitioned between H₂O and CH₂CI₂, the organic layer was washed with H₂O, dried over MgSO₄ and evaporated under reduced pressure. The residue was chromatographed on silica, eluting with CH₂Cl₂/MeOH/0.88NH₃(90/10/1, v/v) to give the title compound as a colourless foam, (65mg, 18%). R_f 0.52 (CH₂Cl₂/MeOH/0.88NH₃ 84/14/2, v/v). MS m/z 388 (MH⁺). 'H NMR (CDC1₃) δ: 3.45 (2H, dd), 3.97 (3H, s), 4.65 (2H, bs), 4.71 (2H, bs), 5.40 (IH, bs), 6.94 (IH, s), 7.15-7.30 (2H, m), 7.39 (2H, m), 7.50 (3H, m), 7.71 (IH, d), 8.50 (IH, d), 8.61 (IH, s). Found: C,65.48; H,5.51, N,16.68; C₂₂H₂₁N₅O₂ O.l.MeOH O.25.CH₂C1₂ requires C,65.18; H,5.36,

N, 17.00%.

Example 27

4-Amino-6.7-dimethoxy-5-(4-fluorophenyl)-2-[4-(morpholinecarbonylamino)-lpropaneamino] quinoline

To a solution of the compound of Example 4 (150mg, 0.29mmol) in THF (5ml) at 0°C under N₂ was added a 1.5M solution of lithium diisopropylamide in cyclohexane (0.2ml,

O. 3mmol) and the reaction was allowed to reach room temperature and stirred for lh. This was followed by the addition of further portions of lithium diisopropylamide (0.4ml, 0.6mmol) and a final portion of lithium diisopropylamide (0.2ml, 0.3mmol) after a further

2h. The reaction was then stirred at room temperature for a further 3h, after which time it was quenched with H-Ό, the product extracted into 2N aqueous HCl, the aqueous layer separated, neutralised with sodium bicarbonate, extracted with CH₂C1₂ (3x) dried over

AP/P/ 9 6 / 0 0 9 0 0

MgSO₄ and evaporated under reduced pressure. The resulting residue was purified by chromatography on silica, eluting with CH₂Cl₂/MeOH/0.88NH₃ (90/10/1, v/v) to give the title compound as an off-white solid (82mg, 58%). R_f 0.17 (CH₂Cl₂/MeOH/0.88NH₃90/10/1, v/v). MS m/z 484 (MH'). ’H NMR (CDC1₃) δ: 1.95 (2H, m), 3.27 (2H, m), 3.37 (2H, m), 3.48 (3H, s), 3.55 (2H, m), 3.65 (4H, m), 3.90 (5H, bm), 3.99 (3H, s), 5.08 (1H,

m), 5.70 (1H, s), 7.03-7.23 (3H, m), 7.31-7.44 (2H, m). Found: C,60.72; H,6.37, N,13.38; C₂₅H₃₀N₅O₄F 0.35.ether 0.7.H₂O requires C.60.73; H.6.74, N, 13.41 %.

Example 28

4-Amino-6.7-dimethoxy-5-(3 -fluorophenyl)-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1 vl]quinoline c

c:

To a solution of the compound of Example 10(b) (200mg, 0.37mmol) and 3- ^σfluorophenylboronic acid (62mg, 0.44mmol) in a mixture of toluene (9ml), 1M aqueous c

Na₂CO₃ (1.5ml) and EtOH (5ml) was added tetrakis(triphenylphosphine)palladium (13mg, <x

0.44mmol) and the reaction was heated to reflux for lh. The reaction was then cooled, ¢partitioned between EtOAc and H₂O, the organic layer dried over MgSO₄ and evaporated •-U.

to afford a brown residue. This was dissolved in 1,2-dimethoxyethane, the solution purged β with N₂ and then potassium t-butoxide (124mg, 1.1 mmol) was added and the reaction heated to reflux for lh. After cooling, the reaction mixture was partitioned between EtOAc and H₂O, the organic layer was dried over MgSO₄ and evaporated in vacuo. The product was purified by chromatography on silica gel, eluting with CH₂Cl₂/MeOH/0.88 NH₃(96/3.5/0.5, v/v) to afford the title compound as a brown foam (136mg, 72%). R_f 0.39 (CH₂Cl₂/MeOH/0.88 NH₃ 92/7/1, v/v). MS m/z 510 (MH⁺). ‘HNMR (CDC1₃) δ: 2.03 (2H,

m), 3.16 (4H, m), 3.34 (2H, m), 3.50 (3H, s), 3.59 (2H, m), 3.65 (4H, m), 3.71 (2H, m),

3.80 (2H, bs), 3.94 (2H, m), 3.99 (3H, s), 5.74 (1H, s), 7.06 (1H, bs), 7.10-7.20 (3H, m),

7.41 (1H, s). Found: C,62.70; H,6.22; N,13.18. C₂₇H₃₂N₅O₄F 0.5.H,O requires C,62.53;

H,6.41; N,13.50%.

Example 29

4-Amino-6.7-dimethoxy-2-(l-methylpiperidin-4-yl)-5-pheny1quinoline

5»

The title compound was prepared by the method of Example 5(e) from the compound of Example 8(d) and l-methylpiperidine-4-carboxylic acid [Rogers et al Molecular Pharmacology 36. 333- (1989)]. The product was purified by chromatography on silica gel. eluting with EtOAc/diethylamine (90/10. v/v) to afford the title compound (63%) as an orange solid. R_f 0.15 (CH₂Cl₂/MeOH/O.SS NH₃ 92/7/1, v/v). MS m/z 504 (MH^T). ’HNMR (CDC1₅) δ: 1.35 (4H. m), 2.06 (2H. m). 2.23 (3H, s), 2.30 (2H, m), 2.42 (1H, m), 2.80-2.95 (2H, m), 3.50 (3H, s), 3.59 (2H, m), 3.7S (6H, m), 3.95-4.13 (2H, bs), 4.00 (3H, s). 5.68 (1H, s), 7.13 (1H, bs). 7.38 (2H, m), 7.45 (3H, m). Found: C.67.03; H.7.37; N.12.S7. C₂₉H₃₇N₅O₃ O.S.HiO 0.5.EtOAc requires C,66.88; H,7.60; N, 12.58%.

Example 30

4-Amino-6.7-dimethoxy-2-r3-(morpholinecarbonylamino)ethaneamino]-5phenvlguinazoline (a) 4-Amino-2-(3-aminoethaneamino)-6.7-dimethoxy-5-phenyl-quinazoline

This was prepared by the method of Example 16(h) from the compound of Example 16(g) and 10 mole equivalents of 1,2-ethanediamine, in the presence of catalytic potassium iodide. The subtitle compound (66%) was obtained as a colourless foam. R_f 0.42 (CH₂Cl₂/MeOH/0.88NH₃ 84/14/2, v/v). MS m/z 340 (MH⁺).

(b) 4-Amino-6.7-dimethoxy-2-[3-(morpholinecarbonylamino)ethaneamino]-5phenvlquinazoline

A solution of the product of step (a) (343mg, l.Ommol) in CH₂C1₂ (3ml) at 0°C under N₂was treated with N-methylmorpholine (0.14ml, l.Smmol) followed by the dropwise addition of a solution of 4-morpholinecarbonyl chloride (0.11ml, l.lmmol) in CH₂C1₂(lml). The reaction was allowed to reach room temperature and stirred for 18h. The reaction was then quenched with H₂O, extracted with CH₂C1₂, the organic layer separated, washed with saturated brine, dried over MgSO₄ and evaporated. Purification on silica gel, eluting with (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v) followed by trituration with ether afforded the title compound as a colourless foam (185mg, 34%). R_f 0.45 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 453 (MFT). ^!H NMR (CDC1₃) δ: 3.323.80 (13H, mm), 4.00 (5H, s), 5.34 (3H, b), 5.94 (1H, bs), 7.03 (1H, bs), 7.32 (2H, m), 7.55

AP/P/ 9 6 / 0 0 9 0 0

ΛΡ . !' 7 1 5 (3Η. m). Found: C.53.6S: Η,6.16; N.16.45; C₂₃H_2SN₆O₄ 0.1 .ether CH₂C1₂ requires C.53.77;

H,5.73, N, 16.43%.

Example 31

4-Amino-6.7-dimethoxy-2-[4-fmorpholinecarbonylamino)-l-A^r-methylpropaneamino]-5phenylquinazoline (a) 4-Amino-2-(4-amino-l-A^r-methylpropaneaminoA6-7-dimethoxy-5phenvlguinazoline

This was prepared by the method of Example 16(h) from the compound of Example 16(g) and 10 mole equivalents of N-methyl-l,3-propanediamine, in the presence of catalytic potassium iodide. The subtitle compound (17%) was obtained as a colourless foam. R_f 0.45 (CH₂Cl₂/MeOH/0.88NH₃ 84/14/2, v/v). MS m/z 368 (MH⁺).

(b) 4-Amino-6.7-dimethoxy-2-[4-(morpholinecarbonylamino)-1 -77methylpropaneamino]-5-phenylquinazoline

The title compound was prepared by the method of Example 30(b) from the product of step (a) and 4-morpholinecarbonyl chloride. The crude product was purified on silica gel, eluting with (CE[₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v) followed by trituration with ether to afford the title compound (49%) as a colourless foam. R_f 0.56 (CH₂Cl₂/MeOH/0.88NH₃, 90/10/1, v/v). MS m/z 581 (MH⁺). *H NMR (CDC1₃) δ: 1.81 (2H, m), 3.13 (3H, s), 3.32 (6H, m), 3.50 (3H, s), 3.65 (4H, m), 3.84 (2H, m), 4.00 (3H, s), 4.71 (2H, bs), 5.65 (IH, bs), 7.00 (IH, bs), 7.35 (2H, m), 7.48 (3H, m). Found: C,58.84; H.6.68; N,15.69; C₂₅H₃₂N₆O₄ 0.2.ether O.5.CH₂C1₂ requires C,58.72; H,6.56; N,15.63%.

Example 32 (R/S)-4-Amino-6.7-dimethoxy-5-phenyl-2-[4-(tetrahydrofuran-2-carbonylamino)-l-.Vmethylpropaneamino]quinazoline

The title compound was prepared by the method of Example 5(e) from the product of

Example 31(a) and (R,S)-tetrahydrofuran-2-carboxylic acid. The crude product was purified on silica gel. eluting with (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v) followed by

ΛΡ/Ρ/ 9 fi / 0 0 9 0 0 /,1-

trituration with ether to afford the title compound (57%) as a colourless foam. R_f 0.51 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/3. v/v). MS m/z 466 (MET). 'H NMR (CDC1₃) δ: 1.58 (1H, m), 1.71-1.97 (3H, m). 2.23 (2H, m). 2.94 (1H. in), 3.16 (3H, s), 3.39 (1H, m), 3.50 (3H. s), 3.71 (1H, m), 3.S4 (1H. mi, 3.89-4.05 (2H, m). 4.00 (3H, s), 4.40 (1H, t), 5.15 (2H.

b). 7.05 (1H. bs), 7.40 (2H. mj, 7.50 (3H, m), 8.39 (1H, bs). Found: C,63.71; H,6.85;

N,14.64; C₂₅H₃₁N₅O₄ 0.i.CH₂Cl₂ requires C,63.59; H,6.63; N.14.77%.

Example 33

4-Amlro-6.7-dimethoxy-2-[4-(moppholinecarbonylaminoE1-propaneamino1-510 phenyl quinazoline (a) 4-Amino-2-f4-amino-l-propaneamino)-6.7-dimethoxy-5-phenylauinazoline

The subtitle compound was prepared by the method of Example 16(h) from the compound of Example 16(g) and 10 mole equivalents of 1,3-propanediamine, in the presence of • 15 catalytic potassium iodide. The subtitle compound (72%) was obtained as a colourless foam. Rf 0.11 (CH₂Cl₂/MeOH/0.88NH₃ 84/14/2, v/v). MS m/z 354 (MH⁺).

(b) 4-Amino-6.7-dimethoxy-2-[4-(morpholinecarbonyIamino)-l-propaneamino]-5phenylquinazoline

The title compound was prepared by the method of Example 30(b) from the product of step 3 (a) and 4-morpholinecarbonyl chloride. The crude product was purified on silica gel, eluting with (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v) followed by trituration with ether to afford the title compound (71%) as a colourless solid. R_f 0.40 (CH₂Cl₂/MeOH/0.88NH₃90/10/1, v/v). MS m/z 467 (MH⁺). ^JH NMR (CDC1₃) δ: 1.80 (2H, m), 3.39 (6H, m), 3.50 (3H, s), 3.58 (2H, m), 3.68 (4H, m), 4.00 (3H, s), 4.90-(2H, bs), 5.50 (1H, bs), 5.80 (1H, bs), 6.90 (1H, s), 7.37 (2H, m), 7.52 (3H, m). Found: C,58.69; H,6.49; N,16.53; C₂₄H₃₀N₆O₄ 0.4.CHiC1₂ requires C,58.54; H,6.20; N,16.79%.

to cn £

<

Example 34 (R/S)-4-Amino-6.7-dimethoxy-5-pheny1-2-[4-(tetrahydrofuran-2-carbonylamino^>)-lpropaneamino]quinazoline '«toff

The title compound was prepared by the method of Example 5(e) from the product of Example 33(a) and (R/S)-tetrahvdrofuran-2-carboxylic acid. The crude product was purified on silica gel, eluting with (CH₂Cl₂/MeOH 90/10, v/v) followed by trituration with toluene to afford the title compound (52%) as a colourless foam. R_f 0.70 (CH₂Cl₂/MeOH/0.88NH₃ 84/14/2, v/v). MS m/z 452 (MH). *H NMR (CDC1₃) 6: 1.67 (2H, m), 1.90 (2H, m), 2.23 (2H. m), 3.06 (1H, m), 3.35 (2H, m), 3.50 (3H, s), 3.61 (2H, m), 3.87 (1H, m), 3.99 (3H, s), 4.01 (1H, bs), 4.40 (1H, t), 5.35 (2H, b), 7.03 (1H, bs), 7.39 (2H, m), 7.52 (3H, m), 8.20 (1H, bs). Found: C,63.18; H,6.50; N,14.66; C₂₄H₂₉N₅O₄. O.l.toluene 0.5.H₂O requires C,63.16; H,6.61; N,14.91%.

¹⁰

Example 35

4-Amino-6.7-dimethoxy-5-phenyl-2-[4-f2-pyrimidineamino)-l-propaneaminolquinazoline c

c

The product of Example 33(a) (230mg, 0.65mmol) was added to a solution of 2- c chloropyrimidine (82mg, 0.72mmol) and triethylamine (0.11ml, 0.78mmol) in a mixture of ⁴ n-BuOH (3ml) and DMA (1ml). The reaction was heated to 80°C under N₂ for 18h, after which the reaction was cooled, washed with H₂O, extracted with CH₂C1₂, then washed with ‘ saturated brine. The organic layer was separated and dried over MgSO₄ and the product i

purified by silica gel chromatography, eluting with (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v) followed by trituration with ether. The title compound was obtained as a colourless foam (llOmg, 34%). R_f 0.57 (CH₂Cl₂/MeOH/0.88NH₃ 84/14/2, v/v). MS m/z 432 (MH⁺). *H NMR (CDC1₃) 5: 1.84 (2H, m), 3.41 (2H, m), 3.48 (3H, s), 3.55 (2H, m), 3.99 (3H, s), 6.48.4 (2H, b), 6.42 (1H, t), 6.90 (1H, bm), 7.05 (1H, s), 7.35 (2H, m), 7.52 (3H, m), 8.16 (2H, bs). Found: C,57.75; H,5.70; N,20.04; C₂₃H₂₅N₇O₂ O.75.CH₂C1₂ requires C.57.59; H,5.39;

N, 19.80%.

Example 36

4-Amino-6.7-dimethoxy-5-phenyl-2-[3-(2-pyridyl)ethaneamino1quinazoline

The title compound was prepared by the method of Example 16(h) from the compound of

Example 16(g) and 5 mole equivalents of 2-(2-aminoethyl)pyridine in the presence of catalytic potassium iodide. The product was purified by silica gel chromatography, eluting

AP’) Ο Ο 7 1 5 with (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v) followed by trituration with ether to afford the title compound (31%) as a colourless foam. R_f 0.27 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 402 (MH⁺). 'Η NMR (CDC1₃) δ: 3.09 (2H, t), 3.45 (3H, s), 3.84 (2H, q), 4.00 (3H, s), 5.00 (2H, bs), 6.00-6.60 (1H, b), 6.99 (1H, s), 7.05 (1H, dd), 7.40 (1H, d), 7.35 (2H, m), 7.50 (3H, m), 7.59 (1H, t), 8.55 (1H, d). Found: C,63.48; H,5.84; N,15.77;

C₂₃H₂₃N₅O₂. 0.5.CH₂Cl₂ requires C,63.57; H,5.45; N,15.78%.

Example 37

4-Amino-2-[4-(furan-2-carbonyl)-1.4-piperazin-1 -yl]-6.7-dimethoxy-5-phenylquinazoline

The title compound was prepared by the method of Example 5(e) from the compound of Example 19(a) and fiiran-2-carboxylic acid. The product was purified by chromatography on silica gel, eluting with (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v) followed by trituration with ether to give the title compound (66%) as a foam. R_f 0.67 (CH₂Cl₂/MeOH/0.88NH₃

90/10/1, v/v). MS m/z 460 (MH⁺). Ή NMR (CDC1₃) 5: 3.50 (3H, s), 3.74 (2H, m), 3.804.05 (6H, m), 3.97 (3H, s), 4.66 (2H, bs), 6.48 (1H, bs), 7.00 (2H, m), 7.39 (2H, m), 7.50 (4H, m). Found: C,65.71; H,6.42; N,14.80; C₂₅H₂₅N₅O₄ 0.5.ether requires C,65.30; H,6.09;

N, 14.11%.

Example 38 (R/S)-4-Amino-6,7-dimethoxy-5-phenyl-2-[4-(tetrahydrofuran-2-carbonyl)-1.4-piperazinl-yl]quinazoline

The title compound was prepared by the method of Example 5(e) from the compound of

Example 19(a) and (R/S)-tetrahydrofuran-2-carboxylic acid. The product was purified by chromatography on silica gel, eluting with (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v) followed by trituration with ether to give the title compound (52%) as a foam. R_f 0.58 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 464 (MH⁺). *H NMR (CDC1₃) δ: 1.812.16 (4H, m), 3.09-4.08 (10H, m), 3.50 (3H, s), 4.00 (3H, s), 4.61 (3H, bm), 6.97 (1H, s),

7.37 (2H, m), 7.50 (3H, m). Found: C,63.14; H,6.52; N,14.00; C₂₅H₂₉N₅O₄ 0.2.CH₂Cl₂

O. 3.ether requires C,63.07; H,6.53; N,13.88%.

AP/P/ 9 6 / 0 0 9 0 0

AP.00715

Example 39 (R7S)-4-Amino-6.7-dimethoxy-5-phenyl-2-[4-(tetrahydropyran-2-carbonyl)-1.4-piperazinl-yl]quinazoline

The title compound was prepared by the method of Example 5(e) from the compound of Example 19(a) and (R/S)-tetrahydropyran-2-carboxylic acid [Nelson et al J. Org. Chem. 21, 798 (1956)]. The product was purified by chromatography on silica gel, eluting with (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v) followed by trituration with ether to give the title compound (59%) as a solid. R_f 0.48 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 478 (MH⁺). ^!H NMR (CDC1₃) δ: 1.44-2.02 (6H, m), 3.40-4.16 (10H, m), 3.50 (3H, s), 3.98 (3H, s), 4.11 (1H, dd), 4.60 (2H, bm), 6.94 (1H, s), 7.38 (2H, m), 7.50 (3H, m). Found: C,64.43; H,6.45; N,13.85; C₂₆H₃₁N₅O₄ O.1.CH₂C1₂ 0.3.ether requires C,64.51; H,6.82;

N, 13.71%.

Example 40

4-Amino-6-7-dimethoxy-2-[4-(morpholinecarbonyl)-1.4-piperazin-l -vl]-5phenylquinazoline

Morpholinecarbonyl chloride (0.07ml, 0.66mmol) was added to a stirred solution of the compound of Example 19(a) (220mg, 0.60mmol) and 4-methylmorpholine (0.08ml,

O. 72mmol) in CH₂C1₂ (5ml) at 0°C under N₂. The reaction was stirred for 18h, after which it was washed with H₂O, extracted with CH₂C1₂, washed with saturated brine and the organic layer dried over MgSO₄ and evaporated. The product was purified on silica gel, eluting with (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v) followed by trituration with ether to afford the title compound as a solid (230mg, 70%). R_f 0.45 (CH₂Cl₂/MeOH/0.88NH₃90/10/1, v/v). MS m/z 479 (MH⁺). *H NMR (CDC1₃) δ: 3.30 (12H, m), 3.50 (3H, s), 3.84 (4H, m), 3.98 (3H, s), 4.60 (2H, bm), 6.97 (1H, s), 7.38 (2H, m), 7.48 (3H, m). Found: C,60.33; H,6.24; N,15.43; C₂₅H₃₀N₆O₄ 0.3.CH₂Cl₂ 0.5.ether requires C,60.35; H,6.61; N,15.46%.

Example 41

AP/PZ 9 6 / 0 0 9 0 0

AP.06715

4-Amino-6.7-dimethoxy-5-phenyl-2-[4-f thiomorpholine-1.1 -dioxide-4-carbonyl)-1.4diazepan-1 -yl]quinazoline (a) Thiomorpholine-1.1 -dioxide hydrochloride

2-Chloroethyl chloroformate (0.72ml, 6.7mmol) was added dropwise to a solution of 4methylthiomorpholine-1,1-dioxide (l.Og, 6.7mmol) in toluene (10ml) at 0°C under N₂. After lOmin, the reaction was warmed and maintained at reflux for 2h. On cooling, the reaction mixture was evaporated, partitioned between EtOAc and H₂O, the organic layer separated and washed sequentially with dilute HCI and saturated brine, the organic layer dried over Na₂SO₄ and evaporated. The residue was taken up in MeOH (10ml) and heated at reflux for 2h, after which time the reaction mixture was evaporated and triturated with EtOAc to afford the subtitle compound (415mg, 36%) as a solid. R_f 0.34 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 136 (MH⁺).

(b) 4-Amino-6.7-dimethoxy-5-phenyl-2-[4-(thiomorpholine-l.l-dioxide-4-carbonyl)1,4-diazepan-l -vljquinazoline

The title compound was prepared by the method of Example 18 using the product of step (a) in place of azetidinol. The product was purified by chromatography on silica gel, eluting with (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v) followed by trituration with ether to

W 20 give the title compound (25%) as a foam. R_f 0.58 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v).

MS m/z 541 (MH⁺). ^JH NMR (CDC1₃) δ: 1.97 (2H, m), 3.00 (4H, m), 3.40 (2H, m), 3.50 (3H, s), 3.55-3.73 (6H, m), 3.84 (2H, m), 3.90-4.06 (2H, m), 3.98 (3H, s), 4.59 (2H, bm), 6.90 (IH, s), 7.38 (2H, m), 7.50 (3H, m). Found: C,55.90; H;5.82; N,14.35; C₂₆H₃₂N₆O₅S 0.3.CH₂Cl₂ 0.2.ether requires C,55.82; H,5.98; N,14.40%.

Example 42 (R/S)-4-Amino-6.7-dimethoxy-5-phenyl-2-[4-(tetrahydropyran-2-carbonyl)-1.4-diazepanl-yl]quinazoline

AP/P/ 96/00900 (a) (R/S)-1 -ft-Butyloxycarbonyl)-4-(tetrahydropyran-2-carbonyl)-1,4-diazepane

AP. Ο Ο 715

The subtitle compound was prepared by the method of Example 5(e) with Intermediate 1 and (R/S)-tetrahydropyran-2-carboxylic acid. The subtitle compound (73%) was obtained as a solid. R_f 0.67 (CH₂C1₂). MS m/z 312 (MH⁺).

(b) (R/S)-l -(Tetrahydropyran-2-carbonvl)-l -4-diazepane hydrochloride

The subtitle compound was prepared by the method of Intermediate 3 from the product of step (a). The subtitle compound was obtained in quantitative yield as a hygroscopic solid. MS m/z 213 (MH⁺).

(c) (R/S)-4-Amino-6.7-dimethoxy-5-phenyl-2-[4-(tetrahydropyran-2-carbonyl)-1.4diazepan-1 -yljquinazoline

The title compound was prepared by the method of 16(h) from the product of step (b) and the compound of Example 16(g). The product was purified by chromatography on silica gei, eluting with (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v) followed by trituration with ether to afford the title compound (43%) as a foam. R_f 0.61 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 492 (MH⁺). *Η NMR (CDC1₃) δ: 1.06-2.16 (8H, m), 3.16-4.40 (11H, m), 3.47 (3H, s), 3.98 (3H, s), 4.59 (2H, bm), 6.95 (1H, bs), 7.38 (2H, m), 7.50 (3H, m). Found: C,65.60; H,7.20; N,12.32; C₂₇H₃₃N₅O4 0.8.ether requires C,65.84; H,7.50; N,12.71%.

Example 43 (S)-4-Amino-6.7-dimethoxy-2-[2-(morpholinecarbonyl)pyrrolidin-l-yl]-5phenvlquinazoline

The title compound was prepared by the method of 16(h) from (S)-proline morpholine amide [prepared according to the method of Asami, Bull. Chem. Soc. Jpn., 63, 721 (1990), replacing Cbz-(S)-proline with tBoc-(S)-proline] and the compound of Example 16(g). The product was purified by chromatography on silica gel, eluting with (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v) followed by trituration with ether to afford the title compound (53%) as a foam. R_f 0.39 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 464 (MH⁺). ^!H NMR (CDC1₃) δ: 1.99 (2H, m), 2.02 (2H, m), 3.48 (3H, s), 3.60 (6H, m), 3.84 (4H, m), 3.97 (3H, s), 4.58 (2H, bm), 5.02 (1H, bs), 6.95 (1H, bs), 7.35 (2H, m), 7.47 (3H,

AP/P/ 9 6 / 0 0 9 0 0

AP.00715 in). Found: C,63.68; H;6.54; N,13.92; C₂5H₂₉N₅O₄ 0.5.ether 0.1. CH₂C1₂ requires C,63.72;

H,6.75; N, 13.70%.

Example 44

4-Amino-6.7-dimethoxy-5-phenyl-2-(5.6.7.8-tetrahydro-1.6-naphthyrid-6-yl)quinazoline

The title compound was prepared by the method of 16(h) from 5,6,7,8-tetrahydro-l,6naphthyridine [Shiozawa et al. Chem. Pharm. Bull., 32, 2522 (1984)] and the compound of Example 16(g). The product was purified by chromatography on silica gel, eluting with (CH₂Cl₂/MeOH/0.88NH₃ 93/7/1, v/v) followed by trituration with ether to afford the title compound (33%) as a foam. R_f 0.50 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 492 (MH⁺). *HNMR (CDC1₃) δ: 3.10 (2H, t), 3.48 (3H, s), 3.98 (3H, s), 4.18 (2H, t), 4.66 (2H, bs), 5.00 (2H, s), 7.01 (1H, s), 7.13 (1H, dd), 7.39 (2H, m), 7.50 (4H, m), 8.42 (1H, d). Found: C,68.05; H:5.80; N,15.89; C₂₅H₂₃N₅O₂ 0.1.CH₂Cl₂ 0.4.ether requires C,68.35;

H,6.07; N,15.51%.

Example 45

My (a) l-(t-Butyloxycarbonyl)-3-(AUV-dimethylmethylidene)-4-piperidone

Dimethylformamide dimethyl acetal (5.82ml, 0.044mol) was added to a stirred solution of l-Boc-4-piperidone [Ashwood et al J. Chem. Soc., Perkin 1, 641 (1995)] (8.73g, 0.044mol) in DMF (80ml) and the reaction mixture was heated to 80°C under N₂ for 18h.

After cooling, the DMF was removed under reduced pressure and the residue was partitioned between EtOAc and H₂O, the organic layer washed with H₂O and saturated brine, then dried over MgSO₄ and evaporated to afford the subtitle compound as a solid (8.44g, 76%). R_f 0.33 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 255 (MH⁺).

(b) 6-(t-ButyloxycarbonyB-(5.6.7.8-tetrahydro-1.3.6-triazanaphthalene)

Sodium (762mg, 0.033mol) was added to EtOH (150ml) followed by formamidine acetate (3.45g, 0.033mol) and the reaction was stirred at room temperature under N₂ for 30min. A

AP/P/ 9 6 / 0 0 9 0 0

AP.00715 solution of the product of step (a) (8.43g, 0.033M) in EtOH (50ml) was then added and the reaction heated to reflux for 18h after which time the mixture was cooled and concentrated under reduced pressure. The residue was partitioned between EtOAc and H₂O, the organic layer washed with saturated brine and dried over MgSO₄. Purification on silica gel, eluting with CH₂Cl₂/MeOH (96/4, v/v) afforded the subtitle compound as an oil (5.09g, 65%). R_f0.57 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 236 (MH⁺).

(c) 5.6.7.8-Tetrahvdro-1.3.6-tri azanaphthalene

HCI was bubbled through a solution of the product of step (b) (4.80g, 0.020mol) in a mixture of MeOH and ether (50ml, 1/1, v/v) at 0°C until saturated. The mixture was then allowed to reach room temperature over 2h, after which time a precipitate formed. This was isolated by decanting off the supernatant solution, washing with ether (2x) and drying in vacuo to afford the subtitle compound as a colourless solid (2.85g, 81%). R_f 0.13 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 136 (MH⁺).

(d) 4-Amino-6.7-dimethoxy-5-phenyl-2-(5.6.7.8-tetrahydro-1.3.6-triazanaphth-6yl)quinazoline

The title compound was prepared by the method of 16(h) from the product of step (c) and the compound of Example 16(g). The product was purified by chromatography on silica gel, eluting with (EtOAc/hexane 7/1, v/v) followed by trituration with ether to afford the title compound (42%) as a light yellow foam. R_f 0.48 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 415 (MH⁺). *Η NMR (CDC1₃) δ: 3.03 (2H, t), 3.50 (3H, s), 4.00 (3H, s), 4.21 (2H, t), 4.68 (2H, bs), 5.00 (2H, s), 7.00 (1H, s), 7.37 (2H, m), 7.50 (3H, m), 8.55 (1H, s), 8.99 (1H, s). Found: C,65.77; H,5.48; N,19.31; C₂₃H₂₂N₆O₂ 0.2.ether 0.25.H₂O requires

C,65.90; H,5.69; N,19.37%.

Example 46

4-Amino-6.7-dimethoxy-2-[(4-methanesulfonamido)isoindolin-2-yl]-5-phenylquinazoline (a) 4-Methanesulfonamidophthalimide

Methanesulfonylchloride (2.6ml, 0.034mol) was added dropwise to a stirred suspension of 4-aminophthalimide (5.0g, 0.03 lmol) in pyridine (50ml). The mixture was stirred for 48h

AP/P/ 9 6 / 0 0 9 0 0

AP .06715

	under N₂ at room temperature, after which time the solid formed was isolated by filtration, washing well with H₂O and CH₂C1₂ and then dried in vacuo to afford the subtitle
5	compound as a colourless solid (5.67g, 76%). R_f 0.52 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 241 (MH⁺). (b) 4-fMethanesulfonamidolisoindoline hvdrochloride
10 ©	Borane.THF complex (1M solution in THF, 106ml, O.llmol) was added dropwise to a stirred suspension of the product of step (a) in THF (100ml) and the reaction heated to reflux for 18h. The reaction mixture was then cooled to 0°C and MeOH (50ml) was added cautiously, followed by 6N HCI (70ml). The mixture was then extracted with CH₂C1₂ (3x) and the aqueous layer evaporated to dryness. The residue was taken up into CH₂Cl₂/MeOH (95/5, v/v) and the inorganic solid filtered off. The filtrate was concentrated to give a solid which was triturated with CH₂C1₂ and dried in vacuo to afford the subtitle compound as a
15	colourless solid (2.67g, 46%). R_f 0.09 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 213 (MH⁺).
20 s	(c) 4-Amino-6.7-dimethoxy-2-[(4-methanesulfonamido)isoindolin-2-yl]-5- phenvlguinazoline The title compound was prepared by the method of 16(h) from the product of step (b) and the compound of Example 16(g). The product was purified by chromatography on silica gel, eluting with (EtOAc/hexane 7/1, v/v) followed by trituration with ether to afford the title compound (41%) as a solid. R_f 0.52 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 492 (MH⁺). ^!H NMR (CDC1₃) δ: 3.03 (3H, s), 3.50 (3H, s), 4.00 (3H, s), 4.71 (2H, bs),
25	4.90 (4H, bs), 7.03 (1H, s), 7.13 (1H, d), 7.21 (1H, s), 7.30 (1H, d), 7.40 (2H, m), 7.52 (4H, m). Found: C,59.87; H,5.51; N,12.72; C₂₅H₂₅N₅O₄S 0.8.EtOAc requires C,60.26; H,5.63; N, 12.46%.
30	Example 47 fS')-4-Amino-6.7-dimethoxv-2-[3-(morpholinecarbonvl)pvrrolidin-l-vl]-5- phenvlquinazoline

AP/P/ 9 6 / 0 0 9 0 0 (a) (R/S)-1 -(t-ButyloxycarbonyI)-3-(morpholinecarbonyl)pyiTolidine

AP. Ο Ο 7 f 5

The subtitle compound was prepared by the method of Example 5(e) with (RZS)-l-Bocpyrrolidine-3-carboxylic acid [MacLeod et al J. Med. Chem., 33, 2052 (1990)] and morpholine. The subtitle compound (62%) was obtained as an oil. R_f 0.69 (CH₂Cl₂/MeOH 95/5, v/v). MS m/z 285 (MH⁺).

(b) (R/S)-3-(Morpholinecarbonyl)pyrrolidine hydrochloride

The subtitle compound was prepared by the method of Example 45(c). The subtitle compound (64%) was obtained as a colourless solid. R_f 0.07 (CH₂Cl₂/MeOH/0.88NH₃90/10/1, v/v). MS m/z 185 (MH⁺).

(c) (S)-4-Amino-6.7-dimethoxy-2-[3-(morpholinecarbonyl)pyrrolidm-l-yl]-5phenvlguinazoline

The title compound was prepared by the method of 16(h) from the product of step (b) and the compound of Example 16(g). The product was purified by chromatography on silica gel, eluting with (CH₂Cl₂/MeOH/NH₃ 90/10/1, v/v) followed by trituration with ether to afford the title compound (41%) as a solid. R_f 0.52 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 464 (MH⁺). Ή NMR (CDC1₃) δ: 2.13 (1H, m), 2.35 (1H, m), 3.26(1H, m), 3.47 (3H, s), 3.52-3.76 (10H, m), 3.84 (1H, m), 3.98 (3H, s), 4.00 (1H, m), 4.70 (2H, bs), 7.05 (1H, s), 7.38 (2H, m), 7.45 (3H, m). Found: C,62.55; H,6.28; N,14.27; C₂₅H₂₉N₅O₄ 0.25.

CH₂C1₂ requires C,62.55; H,6.13; N, 14.45%.

Example 48

4-Amino-6.7-dimethoxy-5-(2-methoxyphenyl)-2-(5.6.7.8-tetrahydro-1.6-naphthyrid-6vllquinazoline (a) 4-Amino-6.7-dimethoxy-5-iodo-2-(5.6.7.8-tetrahydro-1.6-naphthyrid-6vDqu-inazoline

The subtitle compound was prepared by the method of 16(h) from l,2,3,4-tetrahydro-l,6naphthyridine and the compound of Example 20(b).The subtitle compound was obtained in quantitative yield as a brown foam. R_f 0.35 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z464(MH⁺).

AP/P/ 96/00900

AP.00715 (b) 4-Amino-6.7-dimethoxy-5-(2-methoxyphenyl)-2-(5.6.7.8-tetrahydro-1.6naphthyrid-6-yl)quinazoline

The title compound was prepared by the method of Example 1(a) with 2methoxyphenylboronic acid and the product of step (a). The product was purified by trituration with EtOAc/hexane to afford the title compound (18%) as an off-white solid. R_f0.33 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 444 (MH⁺). *H NMR (D₆-DMSO) δ: 3.06 (2H, m), 3.50 (3H, s), 3.74 (3H, s), 4.00 (3H, s), 4.21 (2H, m), 4.74 (2H, s), 4.99 (2H, s), 6.90-7.16 (4H, m), 7.22 (IH, d), 7.39-7.55 (2H, m), 8.40 (IH, d). Found: C,66.52; H,5.84; N,14.83; C₂₅H₂₅N₅O₃ 0.5.H₂O 0.1.hexane requires 0,66.67; H,5.73; N,15.20%.

Example 49

4-Amino-l 1 -methoxy-2-[4-(4-morpholinecarbonyl)-1.4-diazepan-1 -vl]-9H[2]benzopvrano- [3,4-c] quinazoline (a) 3 -Benzyloxy-4-methoxy'oenzonitrile

3-Benzyloxy-4-methoxybenzaldehyde (50g, 0.21mol) was added to a solution of sodium acetate (33.9g, 0.41mol) and hydroxylamine hydrochloride (28.73g, 0.41mol) in acetic acid (200ml) and the resulting suspension was heated to reflux for 18h. After cooling, the reaction mixture was partitioned between CH₂C1₂ and H₂O and the aqueous phase was further extracted with CH₂C1₂. The combined organic layers were dried over MgSO₄ and evaporated to afford the subtitle compound as a buff-coloured solid (43.9g, 89%). R_f 0.70 (toluene/EtOAc 4/1, v/v).

AP/P/ 9 6 / 0 0 9 0 0 (b) 5-Benzyloxy-4-methoxy-2-nitro-benzonitrile 25 A solution of the product of step (a) (43.8g, 0.18mol) in glacial acetic acid (87ml) was added dropwise to concentrated nitric acid (70% w/w, 244ml) with periodic cooling to maintain the reaction temperature below 30°C. Once the addition was complete, the reaction was stirred for a further 30min, after which time the mixture was poured into H₂O (IL) and stirred for 30min. The resulting precipitate was isolated by filtration, washing with H₂O followed by drying in vacuo at 50°C to afford the subtitle compound as a white solid (35.1 g, 68%). R_f 0.70 (EtOAc/hexane 1/1, v/v).

AP . Ο Ο 7 1 5 (c) 2-Amino-5-benzyloxy-4-methoxybenzonitrile

To a solution of the product of step (b) (35.0g, 0.12mol) in CH₂C1₂ (500ml) was added tetra-n-butylammonium chloride (20.3g, 0.074mol) followed by a solution of sodium dithionite hydrate (118.0g, 0.61mol) in H₂O (400ml) and the mixture was stirred vigorously for 2h at room temperature. A further quantity of sodium dithionite hydrate (47.2g) was then added and stirring continued for lh. The reaction mixture was then basified with 2N aqueous NaOH and the phases separated. The aqueous layer was extracted twice more with CH₂C1₂ and the combined organic layers dried over MgSO₄ and concentrated in vacuo to a volume of 60ml. Treatment with excess ethereal HCI led to the precipitation of an orange solid which was washed with ether and then dissolved in a mixture of CH₂C1₂ and 2N aqueous NaOH. The phases were separated and the organic layer concentrated in vacuo and then dissolved in EtOAc and passed through a 5cm plug of silica gel, eluting with EtOAc. On evaporation and drying in vacuo, the subtitle compound was obtained as a yellow solid (26.7g, 85%). R_f 0.76 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 255 (MH⁺).

(d) 4-Amino-6-benzyloxy-2-hydroxy-7-methoxyquinazoline

A solution of the product of step (c) (26.7g, O.lOmol) in CH₂C1₂ was treated with sodium cyanate (17.lg, 0.26mol) and trifluoroacetic acid (20.9ml, 0.26mol) was added dropwise to the resulting mixture at room temperature. After 45min, the mixture was diluted with CH₂C1₂ (IL) and stirred for a further 18h. The mixture was then concentrated in vacuo and partitioned between MeOH and 2N aqueous NaOH and stirred for 2h. The MeOH was then removed in vacuo and the yellow solid isolated by filtration, washing sequentially with H₂O, acetone and ether to afford the subtitle compound as a yellow solid (18.0g, 54%). A further quantity of product was obtained by concentration of the filtrate, acidification with concentrated HCI (95ml), wanning on a steam bath for 5min, cooling and neutralisation with solid potassium carbonate. The solid obtained was isolated by filtration, washing sequentially with H₂O, EtOH and ether to afford the subtitle compound as a yellow solid (12.1 lg, 93% combined yield). R_f 0.23 (CH₂Cl₂/MeOH/0.88NH₃ 84/14/2, v/v). MS m/z

298 (MH⁺).

00600/96 /d/dV (e) 4-Amino-6-benzyloxy-2-chloro-7-methoxyquinazoline

AP . 0 0 7 1 5

DMF (7.9ml, O.lOmol) was added dropwise to POC1₃ with stirring. After lOmin, the product of step (d) was added portionwise and the resulting mixture heated at 90°C for 1.5h, then cooled and poured into EtOAc (750ml). The mixture was neutralised by the portionwise addition of aqueous sodium carbonate and the phases were separated. The organic layer was evaporated to dryness and the residue combined with the organic phase which was then treated with aqueous NaOH to basify (pH 10) and the mixture was heated at 90°C for 2h. After cooling, the mixture was partitioned between CH₂C1₂ (IL) and H₂O (IL), the organic phase washed with H₂O, dried over MgSO₄ and evaporated to give a pale yellow solid. Trituration with isopropanol afforded the subtitle compound as a colourless solid (4.64g, 29%). R_f 0.64 (EtOAc/MeOH 95/5, v/v). MS m/z 316, 318 (MH⁺).

(f) 2-Amino-6-benzyloxy-7-methoxy-2-[4-(4-morpholinecarbonyl)-1.4-diazepan-l-yl]

The subtitle compound was prepared by the method of 16(h) from the product of step (e) and the compound of Example 16(g). The product was purified on silica gel eluting with

EtOAc/MeOH (9/1, v/v) to afford the subtitle compound (46%) as a foam. R_f 0.67 (CH₂Cl₂/MeOH/0.88NH₃ 84/14/2, v/v). MS m/z 493 (MH⁺).

(g) 2-Amino-6-hydroxy-7-methoxy-2-[4-(4-morpholinecarbonyl)-l.4-diazepan-1 -yl] The product of step (f) (360mg, 0.73mmol) was dissolved in EtOH (60ml), 10% palladium on charcoal (lOOmg, 0.09mmol) was added and the reaction mixture hydrogenated at room temperature at a pressure of 414 kPa (60psi). for 18h. The reaction mixture was filtered and concentrated in vacuo and the residue purified on silica gel, eluting with CH₂Cl₂/MeOH/0.88NH₃ (92/7/1, v/v) to afford the subtitle compound as a foam (135mg, 47%). R_f 0.33 (CH₂Cl₂/MeOH/0.88NH₃ 84/14/2, v/v). MS m/z 403 (MH⁺).

(h) 2-Amino-6-(o-bromobenzyloxy)-7-methoxy-2-[4-(4-morpholinecarbonyl)-1.4diazepan-l-yl]

Sodium hydride (60% dispersion in mineral oil, lOOmg, 2.5mmol) was added to DMF (20ml) and this was followed by the addition of the product of step (g) (l.Og, 2.5mmol) and the reaction was stirred at room temperature for 20min. o-Bromobenzyl bromide (625mg,

2.5mmol) was then added to the reaction which was left to stir for lh, after which time it was quenched with H₂O, extracted with EtOAc (2x), the combined organic layers washed

0 6 0 0 / 9 6 /d/dV

AP. Ο Ο 7 1 5 with Η₂0, dried over MgSO₄ and evaporated to afford the product as a foam (1.2g, 84%). R_f0.48 (CH₂Cl₂/MeOH/0.88NH₃ 84/14/2, v/v). MS m/z 571, 573 (MH⁺).

(i) 4-Amino-11 -methoxy-2-[4-(4-morpholinecarbony 1)-1,4-diazepan-1 -vl]-9H5 [2jbenzopyrano-[3.4-c]quinazoline

To a solution of the product of step (i) (1.2g, 2.0mmol) in DMA (10ml) was added sodium carbonate (254mg, 2.4mmol) and palladium acetate (45mg, 0.2mmol) and the reaction mixture was heated to 130°C for 48h under N₂. The reaction mixture was then cooled partitioned between EtOAc and H₂O and the organic layer dried over MgSO₄ and evaporated. The product was purified by chromatography on silica gel eluting with CH₂Cl₂/MeOH/0.88NH₃ (95/5/0.5, v/v) followed by trituration with hexane to afford the title compound as a light yellow solid (114mg, 12%). R_f 0.76 (CH₂Cl₂/MeOH/0.88NH₃84/14/2, v/v), MS m/z 491 (MH⁺). *H NMR (CDC1₃) δ: 2.06 (2H, m), 3.18 (4H, m), 3.42 (2H, m), 3.60 (2H, m), 3.68 (4H, m), 3.94 (2H, m), 4.00 (5H, m), 4.90 (2H, bs), 5.09 (2H,

s), 6.87 (1H, s), 7.21-7.52 (4H, m). Found: C,62.18; H,6.34; N,14.66; C₂₆H₃₀N₆O₄.

0.6.hexane 0.5. CH₂C1₂ requires C,61.84; H,6.74; N,14.38%.

Example 50

4-Amino-11 -methoxy-2-[4-(4-morpholinecarbonyl)-1,4-diazepan-1 -vl]-9H20 [2]benzopyrano-[3.4-c]quinoline (a) 3-(o-Bromobenzyloxy)-4-methoxybenzonitrile

To a solution of 2-bromobenzyl alcohol (16.50g, 88.2mmol) in DMF (100ml) was added sodium hydride (60% dispersion in mineral oil, 2.94g, 73.5mmol) and this was followed by

3-fluoro-4-methoxybenzonitrile (8.88g, 58.8mmol) and the resulting mixture was heated to 90°C for 2h under N₂. After cooling, the mixture was partitioned between ether and H₂O, the organic layer washed sequentially with 0.5N HCI and saturated brine and then dried over MgSO₄. Trituration with ether/pentane (1/3, v/v) afforded the subtitle compound as an off-white solid (13.35g, 71%). R_f 0.27 (hexane/EtOAc 5/1, v/v). MS m/z 318, 320 (MH⁺).

(b) l-Cvano-6H-dibenzo[b.d]pyran

00600/96 /d/dV

The subtitle compound was prepared by the method of Example 49(i) from the product of step (a). The product was purified by chromatography on silica gel, eluting with hexane/EtOAc (4/1, v/v) followed by trituration with hexane/EtOAc (4/1, v/v) to afford the subtitle compound (41%) as a colourless solid. R_f 0.16 (hexane/EtOAc, 4/1, v/v). MS m/z

238 (MH⁺).

(c) 1 -Cyano-2-nitro-6H-dibenzo [b.djpvran

The subtitle compound was prepared by the method of Example 16(a) from the product of step (b). The product was purified by chromatography on silica gel, eluting with CH₂C1₂ to afford the subtitle compound (42%) as a pale yellow solid. R_f 0.26 (hexane/ CH₂C1₂ 1/2, v/v). MS m/z 283 (MH⁺).

AP.ϋ ϋ 7 1 5 (d) 2-Amino-l-cvano-6H-dibenzo[b.d]pyran

The subtitle compound was prepared by the method of Example 49(c) from the product of 15 step (c). The product was purified by chromatography on silica gel, eluting with

CH₂Cl₂/MeOH (98/2, v/v) to afford the subtitle compound (85%) as a yellow solid. R_f 0.81 (CH₂Cl₂/MeOH/0.88NH₃ 93/7/1, v/v). MS m/z 253 (MH⁺).

(e) 1 -Cvano-2- {1 - [4-(morpholine-4-carbony 1)-1.4-diazepan-1 -yl] ethvlideneamino} 20 6H-dibenzo [b.djpvran

The subtitle compound was prepared by the method of Example 1(c) from the product of step (d) and Intermediate 4. The product was purified by chromatography on silica gel, eluting with CH₂Cl₂/MeOH (97/3, v/v) to afford the subtitle compound (97%) as a yellow foam. R_f 0.56 (CH₂Cl₂/MeOH/0.88NH₃ 93/7/1, v/v). MS m/z 490 (MH⁺).

(f) 4-Amino-11 -methoxv-2- [4-(4-morpholinecarbonyl)-1.4-diazepan-1 -vl]-9H[2]benzopyrano-[3.4-c]quinoline

The title compound was prepared by the method of Example 1(d) from the product of step (e). The product was purified by chromatography on silica gel, eluting with CH₂Cl₂/MeOH (9/1, v/v) followed by dissolution in CH₂C1₂ and precipitation with toluene to afford the subtitle compound (40%) as a yellow solid. R_f 0.35 (CH₂Cl₂/MeOH/0.88NH₃ 93/7/1, v/v).

MS m/z 490 (MH⁺). ^JH NMR (CDC1₃) δ: 2.10 (2H, m), 3.16 (4H, m), 3.40 (2H, m), 3.65

AP/P/ 9 6 / 0 0 9 0 0

AP. Ο Ο 7 1 5 (6Η, m), 3.77 (2Η, m), 3.98 (2H, m), 4.01 (3H, s), 4.35 (2H, s), 4.90 (1H, d), 5.30 (1H, d), 5.94 (1H, s), 7.05 (1H, s), 7.21-7.52 (4H, m). Found: C,65.86; H,6.33, N,13.30; C₂₇H₃₁N₅O₄. 0.2.toluene 0.5.H₂O requires C,65.98; H,6.55, N, 13.55%.

Example 51

4-Amino-7-methoxy-2-[4-(4-morpholinecarbonyl)-1.4-diazepan-1 -yll-5-phenvl-6-(2.2.2trifiuoroethoxylquinoline (a) 4-Methoxy-3-(2.2.2-trifluoroethoxv)benzoic acid, methyl ester 10 To a mixture of isovanillic acid methyl ester (33.Og, 0.18mol) and potassium carbonate (41.4g, 0.30mol) in DMF (100ml) was added a solution of trifluoroethyl triflate [Burdon et al Tetrahedron 21, 1 (1965)] (65.Og, 0.28mol) in CH₂C1₂. The mixture was stirred at room temperature for 18h then evaporated to 50ml, the mixture partitioned between ether and H₂O, the organic layer washed with H₂O and saturated brine, then dried over MgSO₄ and evaporated. The resulting solid was triturated with hexane to give the subtitle compound as an off-white solid (42.55g, 90%). R_f 0.47 (CH₂C1₂). MS m/z 265 (MH⁺).

(b) 4-Methoxv-3 -(2.2.2-trifluoroethoxy)benzoic acid

The product of step (a) (42.3g, 0.16mol) was dissolved in MeOH (500ml) and 2N aqueous NaOH (160ml, 0.32mol) was added and the mixture stirred at room temperature for 3h and then at 50°C for lh. After cooling, the solution was concentrated in vacuo, treated with 2N HCl and extracted with EtOAc (3x). The combined organic extracts were dried over MgSO₄, filtered and evaporated to give the subtitle compound as a colourless solid (40.4g, quantitative). R_f 0.13 (hexane/EtOAc 1/1, v/v). MS m/z 251 (MH⁺).

00600/96 Zd/dV (c) 2-[4^,-Methoxy-3^l-(2.2.2-trifluoroethoxyphenyl)]-4.4-dimethyl-A²-oxazoline The subtitle compound was prepared by the method of Example 3(a) from the product of step (b). The product was purified on silica gel, eluting with CH₂Cl₂/MeOH (95/5) to give the subtitle compound (80%) as a colourless solid. R_f 0.54 (EtOAc). MS m/z 304 (MH⁺).

(d) 2-[2^l-Iodo-4^l-methoxy-3'-(2.2.2.-trifluoroethoxyphenyl)]-4.4-dimethyl-A--oxazoline

AP. OOM 5

The subtitle compound was prepared by the method of Example 3(b) from the product of step (c). The product was purified on silica gel, eluting with EtOAc/hexane (3/2, v/v) followed by trituration with ether/hexane (1/3, v/v) to give the subtitle compound (26%) as a colourless solid. R_f0.27 (EtOAc/hexane 1/1, v/v). MS m/z 430 (MH⁺).

(e) 2-Iodo-4-methoxy-3-(2.2.2-trifIuoroethoxy)benzonitrile

The subtitle compound was prepared by the method of Example 3(c) from the product of step (d). The product was triturated with ether/hexane (1/3, v/v) to give the subtitle compound (97%) as a colourless solid. R_f 0.50 (EtOAc/hexane 1/1, v/v). MS m/z 358 (MH⁺)· (f) 2-Iodo-4-methoxy-6-nitro-3-(2.2.2-trifluoroethoxy)benzonitrile

The subtitle compound was prepared by the method of Example 3(d) from the product of step (e). The product was triturated with ether to give the subtitle compound (61%) as a colourless solid. R_f 0.25 (EtOAc/hexane 1/2, v/v). MS m/z 403 (MH⁺).

(g) 2-Amino-6-iodo-4-methoxy-5-(2.2.2-trifluoroethoxy)benzonitrile

The subtitle compound was prepared by the method of Example 49(c) from the product of step (f). The subtitle compound (70%) was obtained as a colourless solid. R_f 0.74 (CH₂Cl₂/MeOH/0.88NH₃ 93/7/1, v/v). MS m/z 373 (MH⁺).

s (h) 2-Iodo-4-methoxy-6- {1 -[4-(morpholine-4-carbonyl)-1,4-diazepan-1 yljethylideneamino} -3 -(2,2.2-trifluoroethoxy)benzonitriIe

The subtitle compound was prepared by the method of Example 1(c) from the product of 25 step (g) and Intermediate 4. The product was purified by chromatography on silica gel eluting with CH₂Cl₂/MeOH (9/1, v/v) followed by crystallisation from EtOAc to give the subtitle compound (64%) as a colourless solid. R_f 0.12 (EtOAc). MS m/z 610 (MH⁺).

(i) 4-Amino-5-iodo-7-methoxy-2-[4-(4-morpholinecarbonyl)-1.4-diazepan-l-yl]-630 (2.2.2-trifluoroethoxy)quinoIme

The subtitle compound was prepared by the method of Example 1 (d) from the product of step (h). The product was purified by chromatography on silica gel eluting with

00600/96 /d/dV

AP. Ο Ο 7 1 5

CH₂Cl₂/MeOH (9/1, v/v) to give the subtitle compound (20%) as a colourless solid. R_f 0.15 (CH₂Cl₂/MeOH 9/1, v/v). ’H NMR (CDC1₃) δ: 2.06 (2H, m), 3.16 (4H, m), 3.32 (2H, m), 3.58 (2H, m), 3.65 (4H, m), 3.70 (2H, m), 3.90 (2H, m), 3.97 (3H, s), 4.37 (2H, t), 5.55 (2H, bs), 5.90 (1H, s), 7.05 (1H, bs).

(j) 4-Amino-7-methoxy-2-[4-(4-morpholinecarbonyl)-1.4-diazepan-l-yl]-5-phenyl-6(2.2.2-trifluoroethoxy)quinoline

The subtitle compound was prepared by the method of Example 1(a) from the product of step (i) and phenylboronic acid. The product was purified by chromatography on silica gel eluting with CH₂Cl₂/MeOH (9/1, v/v) to give the subtitle compound (55%) as a foam. R_f0.12 (CH₂Cl₂/MeOH 9/1, v/v). MS m/z 560 (MH⁺). ‘h NMR (CDC1₃) δ: 2.06 (2H, m), 3.16 (4H, m), 3.35 (2H, m), 3.55-3.80 (8H, m), 3.82-4.13 (9H, m), 5.70 (1H, s), 7.65 (1H, bs), 7.37 (2H, m), 7.45 (3H, m).

Example 52

2-Amino-6.7-dimethoxy-5-phenyl-2-(5.6.7,8-tetrahydro-1.3.7-triazanaphth-7yl)quinazoline (a) 1 -Trityl-3-piperidone

Trityl chloride (13.1g, 47.0mmol) was added to a stirred suspension of 3-piperidone hydrochloride (5.79g, 42.7mmol) and triethylamine (14.9ml, 107mmol) in CH₂C1₂ (100ml) and the reaction was stirred for 16h under N₂ at room temperature. The resulting mixture was filtered and the filtrate washed sequentially with H₂O and 5% aqueous citric acid, dried over MgSO₄ and evaporated under reduced pressure. Trituration with pentane afforded the subtitle compound as a colourless solid (4.8g, 33%). R_f 0.23 (CH₂Cl₂/pentane 2/3, v/v). *H NMR (CDC1₃) δ: 2.05 (2H, m), 2.35 (2H, m), 2.45 (2H, m), 2.85 (2H, s), 7.06-7.55 (15H, m).

0 6 0 0 / 9 6 /d/dV (b) 4-(MN-Dimethylmethylidene)-l-trityl-3-piperidone

The subtitle compound was prepared by the method of Example 45(a) from the product of step (a). Crystallisation from ether afforded the subtitle compound (52%) as a colourless

AP.Ο Ο Μ 5 solid. R_f 0.23 (CH₂Cl₂/pentane 2/3, v/v). ^!H NMR (CDC1₃) δ: 2.35 (2H, t), 2.87 (2H, t), 2.97 (2H, s), 3.13 (6H, s), 7.13 (3H, m), 7.24 (7H, m), 7.50 (6H, m).

(c) 7-Trityl-(5.6.7.8-tetrahvdro-l ,3.7-triazanaphthalene)

The subtitle compound was prepared by the method of Example 45(b) from the product of step (b). The product was purified by chromatography on silica gel, eluting with CH₂Cl₂/ether (9/1, v/v) to afford the subtitle compound (51%). R_f 0.33 (CH₂Cl₂/ether 85/15, v/v). 'H NMR (CDC1₃) δ: 2.60 (2H, t), 2.97 (2H, t), 3.58 (2H, s), 7.06-7.37 (8H, m), 7.52 (7H, m), 8.45 (1H, s), 8.90 (1H, s) (d) 5.6.7.8-Tetrahvdro-l ,3.7-triazanaphthalene hydrochloride

The subtitle compound was prepared by the method of Example 45(c) from the product of step (c). The product crystallised from MeOH/ether to afford the subtitle compound (65%) as an orange hygroscopic solid. ^!H NMR (d₆-DMSO) δ: 3.06 (2H, m), 3.40 (2H, m), 4.26 (2H, s), 8.68 (1H, s), 9.00 (1H, s), 9.96 (2H, bs).

(e) 2-Amino-6.7-dimethoxy-5-phenyl-2-(5.6.7,8-tetrahydro-1.3.7-triazanaphth-7yDquinazoline

The title compound was prepared by the method of 16(h) from the product of step '(d) and the compound of Example 16(g). The product was purified by chromatography on silica gel, eluting with CH₂Cl₂/MeOH (95/5, v/v) to afford the title compound (36%) as a foam. R_f 0.16 (CH₂Cl₂/MeOH 95/5, v/v). MS m/z 415 (MH⁺). ’H NMR (CDC1₃) δ: 2.90 (2H, m), 3.50 (3H, s), 4.00 (3H, s), 4.16 (2H, m), 4.65 (2H, bs), 5.05 (2H, s), 7.00 (1H, s), 7.38 (2H, m), 7.50 (3H, m), 8.50 (1H, s), 9.02 (1H, s). Found: C,63.56; H,5.20; N,18.97; C₂₃H₂₂N₆O₂

O.3.CH₂C1₂ requires C,63.49; H,5.17; N,19.06%.

Example 53

4-Amino-6.7-dimethoxy-2-(4-methoxy-5.6.7.8-tetrahydro-1.3.7-triazanaphth-7-yl)-530 phenvlguinazoline (a) 7-Benzyl-4-chloro-5.6,7.8-tetrahydro-1.3.7-triazanaphthalene

AP/P/ 9 6 / 0 0 9 0 0

AP. 0 0 7 15

7-Benzyl-4-hydroxy-5,6,7,8-tetrahydro-l,3,7-triazanaphthalene [Ozdowska et al Rocz. Chem. Ann. Soc. Chim. Pol. 50,1771 (1976)] 95.Og, 15.9mmol) was added to POC1₃ and the mixture heated to 100°C for lh. The reaction was cooled, concentrated under reduced pressure and the residue quenched with ice. After neutralising with K₂CO₃ the product was extracted with CH₂C1_2j, the organic layer washed with H₂O, dried over MgSO₄ and evaporated to give the subtitle compound as a brown oil (3.33g, 81%). R_f 0.45 (CH₂Cl₂/MeOH/0.88NH₃ 92/7/1, v/v).

(b) 7-Benzyl-4-methoxy-5.6.7.8-tetrahydro-l .3.7-triazanaphthalene

Sodium (380mg, 16.5mmol) was added portionwise to MeOH (7ml) and the solution was added dropwise to a solution of the product of step (a) (3.3g, 12.7mmol) in THF (30ml). After stirring at room temperature for 18h, the reaction mixture was concentrated under reduced pressure, partitioned between H₂O and CH₂C1₂, the aqueous layer extracted with CH₂C1₂ and the combined organic layers dried over MgSO₄. Evaporation under reduced pressure afforded the subtitle compound as a brown oil (3.1g, 95%). R_f 0.64 (CH₂Cl₂/MeOH/0.88NH₃ 92/7/1, v/v).

(c) 4-Methoxy-5,6.7.8-tetrahydro-1.3.7-tri azanaphthalene

To a solution of the product of step (b) (3.1g, 12.0mmol) in EtOH (40ml) was added palladium hydroxide (20%, w/w, 614mg) and the mixture was hydrogenated at 345kPa [50psi] pressure for 18h, after which time a further portion of EtOH (40ml) and palladium hydroxide (614mg) was added and the hydrogenation continued for a further 18h. Filtration, evaporation under reduced pressure and chromatography on silica gel, eluting with CH₂Cl₂/MeOH (90/10, v/v) afforded the subtitle compound as a pale orange oil (1.09g, 55%). R_f 0.06 (CH₂Cl₂/MeOH 95/5, v/v). MS m/z 166 (MH⁺).

AP/P/ 9 6 / 0 0 9 0 0 (d) 4-Amino-6.7-dimethoxy-2-(4-methoxy-5.6.7.8-tetrahydro-1.3.7-triazanaphth-7-yl)5-phenvlquinazoline

The title compound was prepared by the method of 16(h) from the product of step (c) and the compound of Example 16(g) in the presence of lmol equivalent of ammonium chloride. The product was purified by chromatography on silica gel, eluting with EtOAc to afford the title compound (10%) as a foam. R_f 0.42 (EtOAc/MeOH 95/5, v/v). MS m/z 445

AP. Ο ο 7 1 5 (ΜΗ⁺). ’Η NMR (CDC1₃) δ: 2.74 (2Η, t), 3.48 (3Η, s), 3.98 (3Η, s), 4.00 (3Η, s), 4.10 (2Η, t), 4.61 (2Η, bs), 4.95 (2H, s), 6.97 (1H, s), 7.38 (2H, m), 7.50 (3H, m), 8.57 (1H, s). Found: C,63.88; H,5.59; N,17.82; C₂₄H₂₄N₆O₃ 0.2.EtOAc 0.3.H,O requires C,63.71; H,5.65; N, 17.98%.

Example 54

4-Amino-6.7-dimethoxy-2-[6-(2-methyl-4.5.6.7-tetrahydrothiazolo-[5.4-c]pyridyl)]-5phenylguinazoline (a) 2-Methyl-4.5.6-7-tetrahydrothiazolo-[5.4-c]pyridine hydrochloride

A mixture of 3-bromo-4-piperidone hydrobromide [Scarponi et al Farmaco, Ed. Sci. 43, 575 (1988)] (2.58g, O.Olmol) and thioacetamide (940mg, 0.013mol) in EtOH (100ml) was heated at reflux for 3h. After cooling, the reaction mixture was cooled and evaporated under reduced pressure and the resulting residue triturated with acetone to afford a solid.

This v-? dissolved in K₂O, washed with EtOAc (3x), the aqueous phase was basified with saturated aqueous Na₂CO₃ and extracted with EtOAc (5x), the combined organic extracts washed with saturated brine and dried over MgSO₄ The product was purified by chromatography on silica gel, eluting with CH₂Cl₂/MeOH/0.88NH₃ (90/10/1, v/v) followed by conversion to the hydrochloride salt with ethereal HCI to give, on filtration and drying in vacuo, the subtitle compound as a white solid (380mg, 20%). R_f 0.67 (CH₂Cl₂/MeOH/0.88NH₃ 90/10/1, v/v). MS m/z 155 (MH⁺)

AP/P/ 0 6/ 00900 (b) 4-Amino-6.7-dimethoxy-2-[6-(2-methyl-4.5.6.7-tetrahydrothiazolo-[5.4c]pyridyl)]-5-phenvlquinazoline

The title compound was prepared by the method of 16(h) from the product of step (a) and the compound of Example 16(g). The product was purified by chromatography on silica gel, eluting with EtOAc, followed by trituration with ether to afford the title compound (11%) as a solid. R_f 0.24 (EtOAc). MS m/z 434 (MH⁺). *H NMR (CDC1₃) δ: 2.66 (3H, s) 2.90 (2H, t), 3.50 (3H, s), 3.97 (3H, s), 4.16 (2H, t), 4.61 (2H, bs), 4.97 (2H, s), 6.95 (1H,

s), 7.38 (2H, m), 7.48 (3H, m).

Example 55

AP. Ο Ο 7 1 5

The compound of Example 17 was tested in the first screen described above (“Contractile responses of human prostate”} and found to have a pA₂ value of 8.5.

Claims

Claims: Having now partirularlv dricnl'rtl and stirrratncd m*/our said invr;iti<.n *r.«l in muniicr die sa.T.? is ?o !'* !T»f«*rn»c4 i;.wc declare dut whai i- ws cci.tn m —·

1. A compound of formula I, <2 *0 wherein

R¹ represents C_M alkoxy optionally substituted by one or more fluorine atoms;

R² represents H or C_b6 alkoxy optionally substituted by one or more fluorine atoms;

R³ represents one or more groups independently selected from H, halogen, C_M alkoxy and CF₃;

R⁴ represents a 4-, 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, 0 and S, the ring being optionally fused to a benzene ring or a 5- or 6membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, CM alkyl, CM alkoxy, halogen, SO2NR⁸R⁹ and NHSO2(C_M alkyl), and when S is a member of the ring system, it may be substituted by one or two oxygen atoms; R⁸ and R⁹ independently represent H or C_M alkyl;

X represents CH or N; and

L is absent, or represents a cyclic group of formula la,

AP/P/ 9 6 / 0 0 9 0 0 (CH₂)„

2. A compound as claimed in claim 1, wherein R¹ represents methoxy.

3. A compound as claimed in claim 1 or claim 2, wherein R represents methoxy.

4. A compound as claimed in claim 1 or claim 2, wherein R² and an R³ group together

15 represent -OCH₂-.

5 pharmaceutically acceptable salt or vice versa.

5 in which R⁴ is as defined in claim 1, A’ represents CO or SO₂ and Lg represents a leaving group;

(c) reacting a compound of formula XVIII,

R¹

RΥΎ Y '*·

AAz

I NHj

XVIII in which R¹, R², R\ X and L are as defined in claim 1, with a compound of formula XIX, B(OH)₂

XIX

R

AP/P/ 96/00900 in which R is as defined in claim 1; or (d) when X represents N, reacting a compound of formula XXII,

XXII in which R¹'³ are as defined in claim 1, with a compound of formula XXIIIa or XXIIIb, as 15 appropriate,

AP. Ο Ο 7 1 5 (ψ„^_ζ/^Αχ ΗΝ__I <CH₂)_m

R⁴

XXIIIa

ΝΖ’ «Χ)_ρ

Ά'

R⁴

XXIIIb in which R⁴, R⁶, R⁷, A, A’, Z, Z’, m, n and p are as defined in claim 1;

(e) when A or A’ represents CO, reacting a compound of formula XXVIIIa or XXVIIIb, as appropriate, • 13 6 7 in which R ', R , R , X, Z, Z’, m, n and p are as defined in claim 1, and Lg is a leaving group, with a compound of formula XXIX,

HR^4a XXIX iO in which R^4a represents the groups defined by R⁴ in claim 1 which contain a nucleophilic nitrogen atom in the ring, this nucleophilic nitrogen atom being attached to H;

(f) conversion of a compound of formula I in which L represents a cyclic group of formula Ia, to a corresponding compound of formula I in which L represents a chain of

15 formula lb in which R⁶ and R⁷ each represent H, by the action of a strong base;

(g) when A or A’ is absent and Z or Z’ represents N, reacting a compound of formula XHIa or XHIb, as defined above, with a compound of formula XXX,

AP/P/ 9 6 / 0 0 9 0 0

R⁴-Hal XXX in which R⁴ is as defined in claim 1 and Hal represents a halogen atom attached to the ring; or (h) when R and one R group together represent -OCH₂-, cyclization of a compound of formula XXXI,

AP. Ο Ο 7 1 5

XXXI in which R¹, R⁴, X and L are as defined in claim 1, and R^3a has the same meaning as R³ in claim 1 except that R² and an R^3a group do not together represent -OCH₂-;

and where desired or necessary converting the resulting compound of formula I into a

5 claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

5. A compound as claimed in any one of the preceding claims, wherein R represents H or 4-fluoro.

6. A compound as claimed in any one of the preceding claims, wherein R⁴ represents a group having the formula II, III, IV, V or VI,

AP/P/ 9 6 / 0 0 9 0 0 wherein

Y represents O, CH₂, SO₂, NR⁵ or CHF; and R⁵ represents H or C_M alkyl.

25

7. A compound as claimed in claim 6, wherein R⁴ represents a group of formula II.

7 \

N Z / \ / to^ (CHA A la in which N is attached to the 2-position of the quinoline or quinazoline ring; A is absent or represents CO or SO₂;

Z represents CH or N;

AP.00715 m represents 1 or 2, and in addition, when Z represents CH, it may represent 0; and n represents 1, 2 or 3, provided that the sum of m and n is 2, 3, 4 or 5; or represents a chain of formula lb, lb in which N is attached to the 2-position of the quinoline or quinazoline ring;

A’ and Z’ have the same significance as A and Z above, respectively;

or a pharmaceutically acceptable salt thereof.

8. A compound as claimed in claim 7, wherein Y represents O.

AP.007 f 5

9. A compound as claimed in any one of the preceding claims, wherein L is absent or represents a group of formula VII,

10 acceptable salt thereof, in the manufacture of a medicament for the treatment of benign prostatic hyperplasia.

10. A pharmaceutical formulation including a compound of formula I, as defined in

11. A compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

12. The use of a compound of formula I, as defined in claim 1, or a pharmaceutically

13 6 7 in which R ’, R , R , X, m, n and p are as defined in claim 1, with a compound of formula

XIV,

A'

R 'Lg

XIV

13. A method of treatment of benign prostatic hyperplasia, which comprises administration of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment.

15

14. A process for the production of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, which comprises:

(a) when X represents CH, cyclizing a compound of formula X,

AP/P/ 96/00900

Τ'-'ίΛ

R*

R²

CN

CH, ^XR⁴ in which R¹ ⁴ and L are as defined in claim 1;

20 (b) when A or A’ is present, and Z or Z’ represents N, reacting a compound of formula

XHIa or XHIb, as appropriate,

AP. Ο Ο 7 1 5

XHIa

R⁷

I

NH z

(CHj) xnib

15. Compounds of formulae X, XHIa, XHIb, XVIII, XXII, XXVIIIa, XXVIIIb and XXXI as defined in claim 12.