AU2007231842A1 - Derivatives of aryl-quinazoline/aryl-2-amino-phenyl methanone which promote the release of parathyroid hormone - Google Patents

Description

P/00/011 Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT

(ORIGINAL)

Name of Applicant(s): Address: Actual Inventor(s): NOVARTIS AG Lichtstrasse 35, CH-4056 Basel Switzerland ALTMANN, Eva BEERLI, Ren6 GERSPACHER, Marc RENAUD, Johanne WEILER, Sven WIDLER, Leo Address for Service: DAVIES COLLISON CAVE, Patent Trademark Attorneys, of 1 Nicholson Street, Melbourne, 3000, Victoria, Australia Ph: 03 9254 2777 Fax: 03 9254 2770 Attorney Code: DM DERIVATIVES OF ARYL-QUINAZOLINE/ARYL-2-AMINO- PHENYL METHANONE WHICH PROMOTE THE RELEASE OF PARATHYROID HORMONE Invention Title: The following statement is a full description of this invention, including the best method of performing it known to us:- Q:\OPER\AS\2OO7\October\3O36S72I Div filing ipau 23 1007doc DERIVATIVES OF ARYL-QUIN--AZOCLINE/ARYL-2-A11AO'P.1EN METHANON EV WHCH PROMOTE THE RELEASE OF PAR.ATHYROID

HORMONE

This is a divisional of Australian patent application o.20670the entire contents of which are incorporated herein by reference.

This invention relates to 4-ary!-2(lH)-quilazolilofe derivatives and aryl-(2-arni nophenyl)-methanone derivatives and to pharmaceutical uses thereof.

00 4-Ary1-2(1H)-quilazolilofl derivatives and 2 -sub st ituted-4-aryl -quilazolinle derivatives have been described together with their use as promoters of PTH (Parathyroid hormone) release in our co-pending international patent application WO 02/102782.

We have now synthesised additional new 4-aryl-2(lH)-quinazolilofe derivatives and aryl-(2-amino-phenyl)-methaflofe derivatives which have activity as promoters of PTI- release.

Accordingly the invention provides a compound of formula I R3 8 11 6 N3 R1I 5 4 R2 wherein Y is 0 or S; RI represents from I to 3 substituents independently selected from OH, SH, halo,

NO

2 optionally substituted (lower alkyl, lower alkoxy, lower alkenyl, lower alkenyloxy, lower alkyrlyl, lower alkynyloxy, lower alkanoyl, cycloalkyl, lower alkylsulphone, lower alkylsulphoxide or amino); R2 represents from I to 3 substituents selected from halo, optionally substituted (lower alkyl, lower alkenyl, cycloalkyl or lower alkoxy); R3 is 4-32832A -2- A) lower alkyl optionally substituted by 1 to 3 substituents selected from cycloalkyl, lower alkylene, lower alkyl, Br, F, CF3, CN, COOH, lower alkyl- ,carboxylate, OH, lower alkoxy or -Ox-(CH 2 )y-SO,-lower alkyl, wherein x is 0 z or 1, y is 0, 1 or 2 and z is 0, 1 or 2; or tt) B) Benzyl which is a. mono-or di- (preferably mono-) substituted by -Ox-(CH 2 )y-SOz-lower alkyl or -Ox-(CR, wherein x, y and z are as defined 0 above and R, R' or R" is H or lower alkyl (preferably x 0, y 1, R S,R'and R" H), b. substituted by 1 or 2 substituents selected from morpholino-lower Salkoxy, aryl-lower alkoxy, optionally N-lower alkyl substituted arylamino-lower alkoxy, c. substituted at the 2-position by lower alkoxy-, hydroxy-lower alkoxyor lower alkoxy-lower alkoxy, d. substituted on the -CH2- group thereof; or C) optionally substituted (aryl-C 2 -Cs-alkyl, aryl- C 2

-C

8 -alkenyl, heteroarylmethyl or 4-heteroarylbenzyl); or when R1 is 2 substituents one of which is OH, preferably at the 6-position, and the other of which is optionally substituted (lower alkyl, cycloalkyl-lower-alkyl or lower alkenyl), preferably at the 5-position, R3 is H or optionally substituted (lower alkyl, aryl, aryl-lower alkyl, arylcycloalkyl, cycloalkyl-lower alkyl, cycloalkenyl-lower alkyl, hetereoaryl-lower alkyl, hetereoaryl, or carbonyl lower alkyl); or when R1 is 2-propynyloxy and R2 is isopropyl, R3 is also benzyl which is substituted by 1 to 3 substituents selected from lower alkyl, lower alkoxy, halo, halo-lower alkyl, e.g. CF 3 or when R1 is 2-propynyloxy and R2 is isopropyl, R3 is also benzyl which is substituted by OH and a second and optionally third substituent selected from lower alkyl, lower alkoxy, halo, -O-CH(H or lower alkyl)-COO(H or lower alkyl); or when RI is 2-propynyloxy and R2 is cyclopropyl, R3 is also optionally substituted lower alkyl or benzyl (preferably R3 is also benzyl which is substituted by 1 to 3 substituents selected from lower alkyl, lower alkoxy, halo, -O-CH(H or lower alkyl)- COO(H or lower alkyl)); or 4-32832A -3when Y is S and RI is as defined above but not methoxy, R3 is also optionally substituted benzyl; or a compound selected from 4-4iorplpey)1(,-imn-ezl--rp2 Zynyloxy- 1H-quinazolin-2-ofle, 1 (,-ihoobnzl--4iorpy-hnl--rp 2-ynyloxy- 1 H-quinazolin-2 -one, 1 -benzyl-4-(4-isopropyl-pheflyl)6prop- 2 -ynyloxy- I H-quinazoline-2-thione; 1 di-tert-butyl-4-hydroxy-benzyl)4- 4 -isopropyl- N phenyl)-6-prop- 2 -ynyloxy- I H-quinazolin-2 -onie, or I -[3-(2-hydroxy-ethoxy)-bel]l 00 4(-spoyphnl6-rp2ynyl 1 yH-quinazoline-2-thiole; or a pharmaceutical ly-acceptable and -cleavable ester, or acid addition salt thereof; and N- provided that when Y is 0 and R3 is lower alkyl or cycloalkyl, R3 is not isopropyl or cyclopentyl; or provided the compound of formula I is not 4-(4-isopropy1-phenyl)-6-methoxy- 1 pyridin-3-ylmethyl-I1.H.-quinazolin-2-one, 4-(4-isopropy1-phenyl)-6-mTethoxy- 1pyridin-2-ylmethyl- I.H.-quinazolifl-2-one, 1 -(6-chloro-pyridin-3-ylmethyl)- 4 4 isopropyl-phenyl)-6-methoxy-l -quinazolin-2-one, 4-(4-isopropyl-phenyl)- 6 methoxy- 1 -nitro- furan-2-ylmethyl)- 1 .H.-quinazolin-2-one or 1 1.H.-indol-2yl)-ethyl] -4-(4-isopropy1-phenyl)-6-methoxy- I.H quinazolin-2-one, 4-(4-isopropylphenyl)-6-methoxy- I -phenethyl- 1 H-quinazolin-2 -one, 1 -(2-hydroxy-2-phelyl-ethyl)> 4-(4-isopropyl-phenyl)-6-prop 2 -yn~yloxylH-quinazolin-2-one, methanesulfonic acid 2-4(-spoy-hnl--x-6po--nlx-Hqiaoi--ylmethyl]-phenyl ester, or acetic acid 2-4(-spoy-hnl-2oo6po--nlx-H quinazolin- l-yl]-l -phenyl-ethyl ester, 5-allyl-6-hydroxy-l1-isopropyl-4-(4-isopropylphenyl)-l1.H.-quinazolin-2-ofle, 1 -cyclopropylinethy1-4-(o-to1yl)- 6 -nitro- 2 (l H)quinazolinone, 1 -ethy1-4-(o-toly1)-6-chloro- 2 IH)-quinazolinone, 1cyclopropylmethyl-4-(o-toly)- 6 -chloro- 2 (l H)-quinazolinone, 1 -cyclopropylmethyl-4- (o-fluorophenyl)-6-chloro- 2 (l H)-quinazolinone, 1 -cyclopropylmethyl- 4 chlorophenyl)-6-chloro- 2 (l1H)-quinazolinone, 1 -cyclopropylmethyl- 4 chlorophenyl)-6-nitro- 2 I H)-quinazolinone.

Above and elsewhere in the present description the following terms have the following meanings: Halo or halogen denote I, Br, Cl or F. The term "lower" referred 4-32832A -4to above and hereinafter in connection with organic radicals or compounds a respectively defines such as branched or unbranched with up to and including 7, preferably up to and including 4 and advantageously one or two carbon atoms.

A lower alkyl group is branched or unbranched and contains 1 to 7 carbon atoms, Spreferably 1-4 carbon atoms. Lower alkyl represents; for example, methyl, ethyl, propyl, butyl, isopropyl isobutyl, or tertiary butyl. Halo-substituted lower alkyl is C 1

C

7 lower alkyl substituted by up to 6 halo atoms. A lower alkoxy group is branched or o0 unbranched and contains 1 to 7 carbon atoms, preferably 1-4 carbon atoms. Lower Cc alkoxy represents for example methoxy, ethoxy, propoxy, butoxy, isopropoxy, S isobutoxy or tertiary butoxy. A lower alkene, alkenyl or alkenyloxy group is branched Sor unbranched and contains 2 to 7 carbon atoms, preferably 1-4 carbon atoms and contains at least one carbon-carbon double bond. Lower alkene lower alkenyl or lower alkenyloxy represents for example vinyl, prop-1-enyl, allyl, butenyl, isopropenyl or isobutenyl and the oxy equivalents thereof. A lower alkyne, alkynyl or alkynyloxy group is branched or unbranched and contains 2 to 7 carbon atoms, preferably 1-4 carbon atoms and contains at least one carbon-carbon triple bond. Lower alkyne or alkynyl represents for example ethynyl, prop-1-ynyl, propargyl, butynyl, isopropynyl or isobutynyl and the oxy equivalents thereof. (In the present description, oxygen containing substituents, e.g. alkoxy, alkenyloxy, alkynyloxy, carbonyl, etc. encompass their sulphur containing homologues, e.g. thioalkoxy, thioalkenyloxy, thioalkynyloxy, thiocarbonyl, sulphone, sulphoxide etc.). Aryl represents carbocyclic or heterocyclic aryl. Carbocyclic aryl represents monocyclic, bicyclic or tricyclic aryl, for example phenyl or phenyl mono-, di- or tri-substituted by one, two or three radicals selected from lower alkyl, lower alkoxy, aryl, hydroxy, halogen, cyano, trifluoromethyl, lower alkylenedioxy and oxy-C 2

-C

3 -alkylene; or 1- or 2-naphthyl; or 1- or 2-phenanthrenyl.

Lower alkylenedioxy is a divalent substituent attached to two adjacent carbon atoms of phenyl, e.g. methylenedioxy or ethylenedioxy. Oxy-C 2

-C

3 -alkylene is also a divalent substituent attached to two adjacent carbon atoms of phenyl, e.g. oxyethylene or oxypropylene. An example for oxy-C 2

-C

3 -alkylene-phenyl is 2,3- 4-32832A Preferred as carbocyclic aryl is naphthyl, phenyl or phenyl mono-, di- or trisubstituted 0by lower alkoxy, phenyl, halogen, lower alkyl or trifluoromethyl, especially phenyl or phenyl mono- or disubstituted by lower alkoxy, halogen or trifluoromethyl, and in 0 Z particular phenyl.

Heterocyclic aryl represents monocyclic or bicyclic heteroaryl, for example pyridyl, N indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, 00 benzopyranyl, benzothiopyranyl, benzothiadiazolyl, furanyl, pyrrolyl, thiazolyl, Cc oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any said radical substituted, especially mono- or di-substituted as defined above.

Preferably, heterocyclic aryl is pyridyl, pyrimidyl, indolyl, quinoxalinyl, quinolinyl, benzothiadiazolyl, pyrrolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any said radical substituted, especially mono- or di-substituted as defined above.

Cycloalkyl represents a saturated cyclic hydrocarbon optionally substituted by lower alkyl which contains 3 to 10 ring carbons and is advantageously cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl optionally substituted by lower alkyl.

R1 may represent from 1 to 3 substituents; though more preferably represent 1 or 2 substituents. The R1 substituents may be present at any of positions 5, 6, 7 or 8; for instance, at positions 5, 6 or 7, e.g. when R1 represent 2 substituents these may be present at the 5 and 6 or 6 and 7 positions. Preferably one of the Rl substituents is at the 6 position. R1 as optionally substituted (lower alkyl, lower alkoxy, lower alkenyl, lower alkenyloxy, lower alkynyl, lower alkynyloxy, lower alkanoyl or amino) may be substituted by 1 or 2 substituents independently selected from halo, e.g. Cl, lower alkyl, e.g. ethyl or methyl, lower alkenyl, lower alkynly, cyloalkyl, e.g. C 3

-C

6 cycloalkyl, or cyano.

4-32832A -6- In a particular embodiment R1 is2 substituents one of which is OH, preferably at the 6-position, and the other of which is optionally substituted (lower alkyl, cycloalkyl lower alkyl or lower alkenyl), e.g. ethyl, propyl, cyclopropylmethyl or allyl, preferably 0 Z at the Particularly preferred significances for R1 are: propargyloxy, hydroxy, methoxy, N ethoxy, allyloxy, 2-chloroethoxy, isopropoxy, n-propoxy, cyclopropylmethoxy, 3- 0 0 chloropropoxy, 2-methyl-allyloxy, n-butoxy, allyl, amino, acetonitrileoxy, N methylamino, dimethylamino, propargylamino, or allylamino; in particular, e.g. as hereinafter described in the Examples.

R2 represents 1, 2 or 3; for instance, 1 substituent, in the 2-position or 3-position or more preferably in the 4-position, selected from halo, optionally substituted (lower alkyl or amino) in which lower alkyl is preferably unsubstituted, e.g. branched lower alkyl, and amino is preferably mono-or di-substituted by lower alkyl.

Preferred significances for R2 include: methyl, ethyl, isopropyl, t-butyl, cyclopropyl or chloro. Most preferably R2 is isopropyl in the 4-position.

R3 as alkyl substituted by -Ox-(CH 2 )y-SOz-lower alkyl, may be substituted by -SOzlower alkyl, e.g. -S-lower alkyl.

R3 as benzyl which is mono-or di- (preferably mono-) substituted by -Ox-(CH 2 )y-SOzlower alkyl, may be benzyl mono-substituted by -SOz-lower alkyl, e.g. -S(O)-CH 3 or -S(0 2

)-CH

3 R3 as benzyl may be substituted on the -CH 2 group thereof, by 1 or 2 substituents independently selected from halogen, OH, lower alkyl, e.g. methyl, or lower alkoxy, e.g. methoxy.

R3 as optionally substituted (aryl-C 2 -Cs-alkyl, aryl-C 2 -Cs-alkenyl, heteroarylmethyl or 4-heteroarylbenzyl) may be substituted by up to 8, typically up to 5, usually 1, 2 or 3 substituents, independently selected from halo, nitro, cyano, amino, OH, SH, lower 4-32832A -7alkyl, lower alkoxy, lower thioalkoxy, lower alkoxycarbonyl, lower alkylsuiphonyl, lower alkoxysulphonyl, lower alkylcarbonyloxy, trifluoromethyl, optionally halosubstituted aryl, optionally oxo-substituted pyrrolidinyl or -X-A-Z, z wherein in is -CH 2 -CO-NR5-, -NR5-, -CH 2 -NR5-, -CO-CH 2 -S(0 2

-CH

2

CH

2

-CH

2 S(0 2 -SO-NR5-, -S0 2 -NR5-, c-i CO-, NR5S(O)-, NR5S(0 2 or where R5 is H or optionally substituted 00 (lower alkyl, lower alicenyl, lower alkoxy-lower alkyl, aryl lower alkyl or optionally mono-or di-lower alkyl-substituted amino lower alkyl), is CI-Clo alkyl, preferably C 3 -Cs alkyl optionally interrupted by one or more, e.g.

up to 4, preferably 1, 2 or 3, of or -NR5-, or HO-(lower alkoxy)p-, e.g. HO(ethoxy)p, or lower alkoxy-(lower alkoxy)p-, e.g.

methoxy-(ethoxy)p, where p is an integer from I up to and including preferably from 1 up to and including 4, and Z is H, halo, hydroxy, lower alkoxy, lower alkoxy-lower alkoxy, -NR5R5', N+R5R5'R5", -COOH, imidazolyl, optionally R5 substituted -piperazinyl,

CH(COOH)

2 -S0 3 -NR,5-(CH 2 )n-CH2-NR5R5', -NR5-(CH 2 2 morpholino, or tetrahydropyranyl, where R5, R5' and R5" are independently H or optionally substituted (lower alkyl, lower alkoxy-lower alkyl or aryl lower alkyl, e.g. indolylethyl), or R5' or R5" may be linked together in an optionally substituted Nheterocyclic ring containing from 3 to 8 ring atoms one or more of which may comprise a fuirther heteroatom selected from 0, S or -NR5-, wherein R5 is as defined above.

R3 as optionally substituted (aryl-C 2 -C8-alkyl) may be carbocyclic aryl-C 2 -CB-alkyl, e.g. phenyl-C 2 -C8-alkyl, or hetrocyclic aryl-C 2 -Cg-alkyl, e.g. pyridyl-C 2 -C8-alkyl, all optionally substituted.

R3 as optionally substituted (aryl-C 2 -Cg-alkyl) may be arylethyl, aryl propyl, arylbutyl etc, e.g. phenylethyl or pyridylethyl, all optionally substituted.

4-32832A -8- R3 as optionally substituted (aryl-Cz-Cs-alkenyl) may be carbocyclic aryl-C 2 -Cs- Salkenyl, e.g. phenyl-C2-C-alkenyl, or heterocyclic aryl-C 2 -C-alkenyl, e.g. pyridyl-C2- 0 Cs-alkenyl, all optionally substituted.

R3 as optionally substituted (aryl-C 2 -Cs-alkenyl) may be arylvinyl, arylpropenyl, l arylbutenyl etc, e.g. styryl or pyridylvinyl, all optionally substituted.

00 M R3 as optionally substituted (aryl-C 2 -Cs-alkyl and aryl-C 2 -C-alkenyl) may be substituted on the aryl ring preferably by 1, 2 or 3 substituents independently selected from halogen, nitro, cyano, amino, OH, SH, lower alkyl, lower alkoxy, lower alkyl-

SO,-(CH

2 wherein x is 0 or 1, y is 0, 1 or 2 and z is 0, 1 or 2, or

HO-

(lower alkoxy),- or lower alkoxy-(lower alkoxy), as defined above.

R3 as optionally substituted (aryl-C 2 -C-alkyl and aryl-C 2 -Cs-alkenyl) is optionally substituted on the C 2

-C

8 -alkyl or on the C 2

-C

8 -alkenyl by 1 to 6, preferably 1, 2 or 3 substituents independently selected from halogen, nitro, cyano, amino, OH, SH, lower alkyl, lower alkoxy, lower alkyl-SOz-(CH2)y wherein x is 0 or 1, y is 0, 1 or 2 and z is 0, 1 or 2, or HO-(lower alkoxy)p- or lower alkoxy-(lower alkoxy), as defined above. For example, when C 2 -C8-alkyl is ethyl, it may be substituted, e.g. at the 2-position, preferably by 1 or 2 substituents independently selected from halogen, OH, lower alkyl, e.g. methyl, or lower alkoxy, e.g. methoxy.

R3 as heteroarylmethyl is preferably pyridinylmethyl, e.g. pyridin-2-ylmethyl, pyridin- 3-ylmethyl or pyridin-4-ylmethyl, imidazolylmethly, e.g. imidazol-4-ylmethyl, quinoxalinylmethyl, e.g. quinoxalin-6-ylmethyl, thiophenylmethyl, e.g. thiophen-2ylmethyl, pyrazolylmethyl, e.g. pyrazol-3-ylmethyl, pyrimidinylmethyl, e.g. pyrimidinindolylmethyl, or furanylmethyl, e.g. furan-2-ylmethyl.

R3 as heteroarylmethyl is optionally substituted on the heteroaryl ring preferably by 1, 2 or 3 substituents independently selected from halogen, nitro, cyano, amino (optionally substituted by lower alkyl), OH, SH, lower alkyl (optionally substituted by halogen, nitro, amino, OH or SH), lower alkoxy, lower thioalkoxy, hydroxy-lower 4-32832A -9r- alkoxy, lower alkoxy-lower alkoxy, hydroxy-lower alkoxy-lower alkoxy or aryl, or X-A-Z, 1-O-(lower alkoxy)p- or lower alkoxy-(lower alkoxy)p as defined above.

R3 as 4-heteroarylbenzyl may comprise 4-pyrazinylbenzyl, e.g. 4-pyrazin-2-ylbenzyl, or 4-triazolylbenzyl, e.g. 4-(1,2,3)triazol-2-ylbelzyl.

N- Accordingly in particular embodiments the invention provides a compound of formula 00 I M

R

3 c-I8 13 6 N 3

RI

5 4

I

R2 wherein Y is 0 or S; RI and R2 are as defined above for formula I; R3' is A) lower alkyl substituted by I to 3 substituents independently selected from -Slower alkyl, lower alkylene, cycloalkyl, Br, F or CF 3 or B) benzyl which is a. mono-or di- (preferably mono-) substituted by 2 )y-S0,.-lower alkyl, wherein x is 0 or 1, y isO0, 1 or 2 and z isO0, 1 01 2, b. substituted by 1 or 2 substituents selected from morpholino- lower alkoxy, aryl-lower alkoxy, optionally N-lower alkyl substituted arylamnino-alkoxy, c. substituted at the 2-position by lower alkoxy-, hyciroxy-lower alkoxyor lower alkoxy-lower alkoxy; or C) optionally substituted (arylvinyl, arylethyl, heteroarylmethyl or 4heteroarylbenzyl) or 4-32832A r- when R I is 2 substituents one of which is OH, preferably at the 6-position, and the other of which is optionally substituted (lower alkyl or lower alkenyl), preferably at the 5-position, R3' is H or optionally substituted (lower alkyl, aryl, aryl-lower alkyl, Z arylcycloalkyl, cycloalkyl-lower alkyl cycloalkenyl-lower alkyl, hetereoaryl-lower alkyl, hetereoaryl, or carbonyl lower alkyl); or when RI is 2-propynyl and R2 is isopropyl, R3' is also benzyl which is substituted by 1 to 3 substituents selected from lower alkyl, lower alkoxy, halo, halo-lower alkyl, e.g.

00 CF 3 -O-CH(H or lower alkyl)-COO(H or lower alkyl); or when R I is 2-propynyl and R2 is isopropyl, R3' is also benzyl which is substituted by OH and a second and optionally third substituent selected from lower alkyl, lower N alkoxy, halo, -O-CH(H or lower alkyl)-COO(H or lower alkyl); or when RI is 2-propynyl and R2 is cyclopropyl, R3' is also optionally substituted benzyl (preferably R3 is also benzyl which is substituted by 1 to 3 substituents selected from lower alkyl, lower ailcoxy, halo, -O-CH(H or lower alkyl)-COO(H or lower alkyl)); or when X is S and RI is as defined above but not methoxy, R3' is also optionally substituted benzyl; or a compound selected from 4-(4-isopropyl-phenyl)- 1-(3 ,4-diainino-benzyl)-6-proP- 2 ynyloxy- 1H-quinazolin-2-one, 1 (,-ihoobnzl--4iorpy-hnl--rp 2-ynyloxy- 1H-quinazolin-2-one, I ezl4(-sorplpey)6-rp2yyoy 1 H-quinazoline-2-thione; 1 (d-etbtl4hdoybnzl--4iorplpey) 6-prop-2-ynyloxy- 1H-quinazolin-2-orie, or I -[3-(2-hydroxy-ethoxy)-benzyl]-4-(4isopropyl-phenyl)-6-prop- 2 -ynyloxy- 1H-quinazoline-2-thione; or a pharmaceutical ly-acceptable and -cleavable ester, or acid addition salt thereof; and provided that when Y is 0 and R3' is lower alkyl or cycloalkyl, R3' is not isopropyl or cyclopentyl; or provided the compound of formula I' is not 4-(4-isopropyl-phenyl)-6-methoxy-lI pyridin-3-ylmethyl-I1.H.-quinazolin-2-one, 4-(4-isopropyl-phenyl)-6-Inethoxy- 1 pyridin-2-ylmethyl-lI.H.-quinazolin-2-one, 1 -(6-chloro-pyridin-3-ylnlethyl)- 4 4 isopropyl-phenyl)-6-methoxy- I.H.-quinazolin-2-one, 4-(4-isopropyl-phenyl)-6methoxy-l1-(5-nitro-furan-2-ylmethyl)-lI.H.-quinazolin-2-one or 1 1.H.-indol-2- 4-32832A r-yl)-ethyl] -4-(4-isopropyl-phenyl)-6-methoxy-I1.H quinazolin-2-one, 4-(4-isopropylphenyl)-6-methoxy- 1 -phenethyl- I H-quinazol in-2 -one, 1 -(2hydroxy-2-phenyl-ethyl)-4- (4-isopropyl-pheny)-6-prop-2-yflyloxy-l1H-quinazolin-2-one, methanesulfonic acid 2- Z (-spoy-pey)2oo6-rp2yyoy-Hqiaoi--ylmethyl] -phenyl ester, or acetic acid 2-4(-spoy-hnl-2oo6po--nlx-H quinazolin- Il-yl]-lI -phenyl-ethyl ester, 5-allyl-6-hydroxy- 1 -isopropyl-4-(4-isopropyl- (Ni phenyl)- I -quinazolin-2 -one, 1 -cyclopropylmethyl-4-(o-tolyl)- 6 -nitro- 2 (l1H)- 00 quinazolinone, I -Ethyl -4-(o-tolyl)-6-chlorO-2( I H)-quinazolinone, Icyclopropylmethyl-4-(o-tolyl)- 6 -chloro- 2 (l1H)-quinazolinone, 1 -cyclopropylmethyl-4- (o-fluorophenyl)-6-chloro-2(l1H)-quinazolinone, 1 -cyclopropylmethyl-4-(mchlorophenyl)-6-chloro-2( 1H)-quinazolinone, 1 -cyclopropylmethyl- 4 chlorophenyl)-6-nitro- 2 1 H)-quinazolinone.

Accordingly in particular embodiments the invention further provides a compound of formula I" 8 1 6~ 3 4 R21 wherein Y is 0 or S RI is 2 substituents one of which is OH, preferably at the 6-position, and the other of which is optionally substituted (lower alkyl or lower alkenyl), preferably at the position; or R1i" is 2-propynyloxy, preferably at the 6-position; R2" is isopropyl, tert. butyl or cyclopropyl; R3" is benzyl which is substituted by 1 to 3 substituents selected from lower alkyl, lower alkoxy, halo, halo-lower alkyl, e.g. CF 3 or lower alkyl)-COO(H or lower alkyl); -COO(H or lower alkyl); or 4-32832A 12- R3" is benzyl which is substituted by OH and a second and optionally third Ssubstituent selected from lower alkyl, lower alkoxy, halo, -CH(H or lower alkyl)- COO(H or lower alkyl); or S when R1" is 2-propynyl and R2" is cyclopropyl, R3" is benzyl which is substituted by 1 to 3 substituents selected from lower alkyl, lower alkoxy, halo, -CH(H or lower alkyl)-COO(H or lower alkyl)); or N when X is S and Ri" is as defined above but not methoxy, R3" is also optionally 00 substituted benzyl; or

C

a pharmaceutically-acceptable and -cleavable ester, or acid addition salt thereof.

(N

Moreover, further embodiments of the invention are provided as a compound of formula I"' R Il 8 1 4 N S R, 5 4 R2..2 wherein Ri'" is 1 to 2 substituents selected from lower alkoxy, lower alkenoxy, lower alkynoxy, lower alkyl, lower alkenyl, lower alkinyl, OH or halo (preferably RI"' is propynyloxy, preferably at the 6 position); R2"' is 1 to 3 substituents selected from halo, lower alkyl or lower alkoxy, provided one substituent is isopropyl, tert. butyl or cyclopropyl; R4"' is optionally substituted (aryl-lower alkyl, aryl, hetereoaryl, hetereoaryl-lower alkyl, lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, lower alkenyl, lower alkynyl); or a pharmaceutically-acceptable and -cleavable ester, or acid addition salt thereof; provided that the compound of formula is not 4-(4-isopropyl-phenyl)- 2 isopropylsulfanyl-6,7-dimethyoxy-quinazoline.

4-32832A -13- As hereinafter described compounds of formula I may be prepared by cyclisation of a compound of formula II

O

In wherein R1, R2 and R3 are as defined above. Compounds of formula II have activity as promoters of PTH release and are included within the present invention, e.g. for use as PTH release promoters.

As hereinafter described compounds of formula I' may be prepared by cyclisation of a compound of formula II' wherein R1, R2 and R3' are as defined above. Compounds of formula II' have activity as promoters of PTH release and are included within the present invention, e.g. for use as PTH release promoters.

As hereinafter described compounds of formula I" may be prepared by cyclisation of a compound of formula II" 4-32832A -14-

O

O

O

wherein RI", R2" and R3" are as defined above. Compounds of formula II" have activity as promoters of PTH release and are included within the present invention, e.g. for use as PTH release promoters.

As hereinafter described compounds of formula may be prepared by reaction of a compound of formula Il"'a 8 a N halo 7/ R2'" wherein RI"' and R3"' are as defined above, with HS-R4'", wherein R4'" is as defined above.

Alternatively, the compounds of formula may be prepared by reaction of formula l"'b 4-32832A 15 R 4 21"' R211' 00 wherein RI" and are as defined above, with Halo-R4"', wherein is as defined above.

Compounds of formula H a or compounds of formula HI have activity as promoters of PTH release and are included within the present invention, e.g. for use as PTH release promoters.

Accordingly in a further aspect the invention provides a compound of formula II R3

NH

0 RI

I

R2 wherein RI, R2 and R3 are as defined above; provided that the compound of formula HI is not {2-[2-(3,5-dimethoxy-phenyl)- 2 (4-isopropyl-phenyl)-methanone, (4isopropyl-phenyl)- {5mtoy2[pyii- }ehl)aio-hnl -methanone, (4-isopropyl-phenyl)- 5-mtoy2[prii- lehl)aio-hn methanone; or a compound selected from (2[-2hdoyehx)bnylaio 5-rp2yyoy phenyl) -(4-isopropyl-phenyl)-methanone or {2-[(2,3-dimethoxy-quinoxalin- 6 ylmethyl)-amino]-5-prop-2-yfyloxy-phenyl) -(4-isopropyl-phenyl)-methanole; 4-32832A -16- O or a pharmaceutically-acceptable and -cleavable ester, or acid addition salt thereof.

z Preferred significances for R1, R2 and R3 in formula II are as described above for R1, In R2 and R3 in formula I.

CI Particular signifances for R3 in formula II include: 00 Optionally substituted aryl-C 2 -Cs-alkyl; for instance, optionally substituted phenylethyl, e.g. optionally mono-or di-lower alkoxy substituted phenylethyl, in which the ethyl is optionally mono- or di-substituted at the 2-position) by halogen, OH, Slower alkyl methyl) or lower alkoxy methoxy); Optionally substituted heteroarylmethyl; for instance, optionally substituted pyridinylmethyl or quinoxalinylmethyl, e.g. optionally mono-or di-disubstituted by halogen, OH, lower alkyl methyl), lower alkoxy methoxy), hydroxy-lower alkoxy, hydroxy-ethoxy) or lower alkoxy-lower alkoxy methoxy-ethoxy); and Benzyl which is substituted at the 2-position by lower alkoxy-, hydroxy-lower alkoxyor lower alkoxy-lower alkoxy, e.g 2-(2-hydroxy-ethoxy)-benzyl.

Accordingly in particular embodiments the invention provides a compound of formula 1 4 0 R1 5 II' R2 wherein R1 and R2 are as defined above for formula I;

R'

3 is as defined above for formula I' 4-32832A -17- S provided that the compound of formula II' is not {2-[2-(3,5-dimethoxy-phenyl)-2- Smethyl-propylamino]-4,5-dimethoxy-phenyl}-(4-isopropyl-phenyl)-methanone, (4- S isopropyl-phenyl)- 5-methoxy-2- [(pyridin-3-ylmethyl)-amino]-phenyl}-methanone, S (4-isopropyl-phenyl)- {5-methoxy-2-[(pyridin-2-ylmethyl)-amino]-phenyl}t methanone; or a compound selected from {2-[2-(2-hydroxy-ethoxy)-benzylamino]-5-prop-2-ynyloxyphenyl}-(4-isopropyl-phenyl)-methanone or {2-[(2,3-dimethoxy-quinoxalin-6- 0 0 ylmethyl)-amino]-5-prop-2-ynyloxy-phenyl}-(4-isopropyl-phenyl)-methanone; or a pharmaceutically-acceptable and -cleavable ester, or acid addition salt thereof.

N The substituents and optional substituents on R3' are as described above for the optional substituents on R3, including the preferred significances thereof.

In particular the invention includes the compounds of formula I and formula II as hereinafter described in the Examples, or pharmaceutically-acceptable and -cleavable esters, or acid addition salts thereof.

The compounds of formula I and II, and salts and esters thereof, in particular as identified in the Examples are hereinafter referred to as Agents of the Invention.

The Agents of the Invention which comprise free hydroxyl groups may be also used in the form of pharmaceutically acceptable, physiologically cleavable esters, and as such and where novel are included within the scope of the invention. Such pharmaceutically acceptable esters are preferably prodrug ester derivatives, such being convertible by solvolysis or cleavage under physiological conditions to the corresponding Agents of the Invention which comprise free hydroxyl groups. Suitable pharmaceutically acceptable prodrug esters are those derived from a carboxylic acid, a carbonic acid monoester or a carbamic acid, advantageously esters derived from an optionally substituted lower alkanoic acid or an arylcarboxylic acid.

Agents of the Invention may also exist in the form of pharmaceutically acceptable salts, and as such and where novel are included within the scope of the invention.

4-32832A -18- Pharmaceutically acceptable salts include acid addition salts with conventional acids, for example, mineral acids, hydrochloric acid, sulfuric or phosphoric acid, or S organic acids, for example, aliphatic or aromatic carboxylic or sulfonic acids, e.g., S acetic, trifluoroacetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, fumaric, hydroxymaleic, pyruvic, pamoic, methanesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; also amino acids, such as arginine and lysine. For compounds of the invention having O acidic groups, for example, a free carboxy group, pharmaceutically acceptable salts r also represent metal or ammonium salts, such as alkali metal or alkaline earth metal salts, sodium, potassium, magnesium or calcium salts, as well as ammonium N salts, which are formed with ammonia or suitable organic amines.

Agents of the Invention of formula I and II may be prepared as follows: Agents of the invention of formula

I

R3 R 1 I R2 R2 wherein R1, R2 and R3 are as defined above may be prepared by cyclising a compound of formula

II

R3

I

NH

R1

II

4-32832A -19with a condensation reagent such as chlorosulfonyl isocyanate (CISO 2 NCO), sodium Scyanate, benzoyl isothiocyanate in THF, followed by treatment with K 2

CO

3 /methanol S or sodium thiocyanate and acetic acid, and thereafter, if required converting the R1, z R2 or R3 residues into an alternative RI, R2 or R3 residues to give alternative t compound of formula II. For example, in the cyclisation reaction the benzophenone of formula II in solution is treated with a solution of sodium cyanate, e.g. in acetic acid at Sroom temperature.

00 S Benzophenone compounds of formula II may be prepared by treatment of the corresponding amine of formula X O NH 2 R1

X

R2 with the corresponding halide, e.g. bromide, R3Br and a suitable base such as K 2

CO

3 In particular, compounds of formula X where R1 is OH in 6 position and R1 is also 2propenyl, cyclopropyl-methyl or propyl may be prepared as e.g. described in Example for compound 5-allyl-l-benzyl-6-hydroxy-4-(4-isopropyl-phenyl)-lH-quinazolin-2one and following.

Alternatively, compounds of formula II may be prepared by reductive amination of the corresponding aldehyde with the amine X, using Ti (Oi-pr)4 or molecular sieves as dehydrating agent and NaBH(OAc)3 or NaCNBH 3 as the reducing agent. The amine X is obtainable from the corresponding nitro derivative (see below compound of formula XI) by reduction, e.g. with iron in acetic acid.

4-32832A 0

SII

NN z xI In R1 R2 00 Swherein R2 is as previously defined and R1 is an activating group.

0 The compound of formula XI may in turn be obtained by the oxidation, e.g. with N Jones reagent, of the corresponding alcohol which may in turn be obtained by coupling an organometallic compound derived from the corresponding bromide of formula XIII and aldehyde of formulae XII respectively; for instance as described in the Examples 0 H O I0I XII XIII Br R1 R2 In a further alternative, compounds of formula II, in particular where R3 is substituted pyridyl-methyl, may be prepared by reacting the corresponding alcohol, R3-OH, e.g.

pyridyl-methyl-hydroxide, with the corresponding amine of formula X, e.g. in the presence of Hiinig's base and mesyl chloride; for instance as hereinafter described in the Examples.

In a yet further alternative Agents of the Invention of formula II, in which R3 is optionally substituted aryl-lower alkyl may be prepared by alkylation of an Agent of the Invention of formula XX 4-32832A -21 0 3 00

O

o0

(N,

at the 1-position with the corresponding optionally substituted aryl-lower alkylhalide; for instance, in the presence of e.g. LiHMDS and Nal, in solution, e.g. THF/DMF, with mild heating.

Alternatively compounds of formula XXII

'OH

2

XXII

wherein Rx is halo, lower alkyl or lower alkoxy; may be prepared by reacting a compound of formula XX with the corresponding oxirane of formula XXI

XXI

4-32832A -22r- Where Rx is the optional substitution on the phenyl ring; for instance in the presence 0ofbenzyltriethylammonium chloride and potassium carbonate, e.g. as hereinafter described in the Examples. Corresponding compounds of formula II in which R3 is Z optionally substituted styryl may be prepared by treatment of a compound of formula SXXII with a reagent such as trifluoromethanesulphonic anhydride.

IN The compound of formula XX may be prepared from the corresponding compound of 00 formula I in which R3 is H by treatment with a condensation reagent such as sodium Scyanate.

S Agents of the Invention of formula II may be prepared as intermediates in the preparation of Agents of the Invention of formula I, e.g. as described above, or as hereinafter described in the Examples.

Accordingly the Invention includes processes for the preparation of Agents of the Invention of formula I R3 a I N O r/ 2 R1 54 R2 wherein the symbols are as defined above comprising a) cyclising a compound of formula II 4-32832A -23-

O

O

O

0 it o with a condensation reagent such as chlorosulfonyl isocyanate (CISO 2 NCO) or sodium cyanate or sodium thiocyanate; or b) for an Agent of the Invention of formula I, in which R3 is optionally substituted aryl-lower alkyl, alkylation of a compound of formula XX 8 1 1 2

XX

at the 1-position with the corresponding optionally substituted aryl-lower alkylhalide; and thereafter, if required converting the R1, R2 or R3 residues into alternative RI, R2 or R3 residues to give an alternative compound of formula I.

The preparation of Agents of the Invention of formula II as described above is also included within the invention.

Accordingly in a further aspect the invention provides processes for the preparation of Agents of the Invention of formula II 4-32832A -24- R3 8 3 O 2 1 4 O O 6 R1 5

II

R2 00 Swherein R1, R2 and R3 are as defined above comprising alkylation of the corresponding aminobenzophenone compound of formula X

SNH

2 R 2 0 R1 R2 wherein R1 and R2 are as defined above, and thereafter, if required, converting RI, R2 or R3 residues into alternative R1, R2 or R3 residues to give an alternative compound of formula II.

The invention is described by way of illustration only in the following non-limiting Examples which relate to the preparation of compounds of the invention of formulae I and II.

4-32832A 25

EXAMPLES

Example 1: -Dmtoyqio ln6ymty)--4iorplpey6-rp 2-ynyloxy- 1 H-quinazolin-2-one C N >O0 Br N 1(7003 dioxane, 80 C AcOH, NaON rt

I

A. Synthesis of {2-[(2,3-dimethoxy-quinoxalil-6-ylmety1)-ami0] -5-prop-2-ynyloxyphenyl}I -(4-isopropyl-phenyl)-methanofle 4-32832A -26- To a solution of 82 mng (0.280 mrnol) (2-amino-5-propargyloxy-phenyl)-( 4 isopropyl phenyl)-methanone in 3 ml dioxane is added 193 mng (1.40 minol) potassium carbonate and 119 mg (0.419 mmol) 6-Brornomethyl-2,3-dimethoxy-quinoxaline. The Z mixture is stirred at 80 'C for two days, diluted with water and extracted with CH 2

CI

2 Purification of the crude product by chromatography (ethyl acetate/hexanes 1: 1) affords a yellow oil.

'H NMR (300 MHz, CDCl 3 7.04-7.60 (in, 10H), 4.94 2H), 4.52 2H), 4.26 (s, 00 3H), 4.08 3H), 2.96 (hept, lH), 2.48 1H), 1.28 6H).

c-i MS: 496 NI B. Synthesis of 1 (,-iehx-pnxln6ymehl--4iorplpey)6 prop-2-ynyloxy-l1H-quinazolin-214ne 00i To a solution of 52 mg 105 mmol) {2-[(2,3-dimethoxy-quinoxalin-6yhneffiyl)amn]-5-rp2yyoypey) (-spoy-hnl-ehnn in I ml acetic acid is added 14 mng (0.2 10 mnmol) sodium cyanate. After stirring for 2 h the solvent is removed in vacuo and the residue is partitioned between CH 2 C1 2 and water. The organic layer is extracted with 2 M sodium hydroxide and evaporated. Purification of the crude product by flash-chromatography (ethyl acetate/hexanes 9: 1) affords a yellow oil.

'H INMR (300 MHz, CDC1 3 7.78 2H), 7.70 IlH), 7.48 I1H), 7.14-7.51 (mn, 6H), 6.10 2H),4.62 2H), 4.24 3H), 4.18 3H), 3.01 (hept, lH), 2.52 (mn, 1H), 1.32 6H).

MS: 521 4-32832A 27 The (2-amino-5-poaglx-hnl 4ispoy-hnl-ehnn building block is prepared as follows:

HO"'H

0 Nal. N-ethyidiisopropylamnife

NO

acetone Br -0

H

Br Bh~rt<.. 0 0

THF

rt 3 h Jones-feagefli acetone 2 h, fl Fet- FeO h, rt A. Synthesis of 0 11.

H

0 4-32832A 28 A mixture of 25 g (150 nmol) 5-hydroxy-2-nitro-belzaldehyde, 44.9 g (299 mmol) sodium iodide, 44.5 g propargyl bromide (80% in toluene), 42 ml N-ethyl-diisopropylamnine and 400 ml acetone is stirred at rt for 6 d. The reaction mixture is filtered, Z concentrated, taken up in IM aqueous hydrochloric acid and extracted with ethyl acetate to yield 'H NMR (300 MHz, CDCl 3 10.49 IH), 8.19 IH), 7.43 IH), 7.25 2H), ri 4.85 2H), 2.60 IlH).

00 B. Synthesis of (4-isopropyl-phenyl)-(2-nitro-S -propargyloxy-phenyl)-methanol 0

OH

0 To a solution of 30.7 g (150 mmol) 2-nitro-5-propargyloxy-benl~adehyde in 200 ml THY are added at -75 'C during 40 min 200 ml (175 mmol) of a 0.8 8 M solution of 4isopropyl magnesium bromide in THF. After stirring for I h at -75 'C saturated aqueous ammonium chloride solution is added and the reaction mixture is extracted with portions of ethyl acetate. Evaporation of the organic phases yields (4-isopropyl- 'HNMvR (300 MHz, CDCl 3 8.09 I 7.45 I 7.26 2H), 7.19 2H), 6.98 (dd, l1H), 6.52 (broad, IH), 4.80 2H), 2.88 (hept, 1H), 2.71 (broad, lH), 2.56 IH), 1.23 6H).

MS: 308 (100) 294 4-3283 2A 29 C. Synthesis of 4 0 0 00 To an ice cold solution of (4iorplpey)(-ir--rpryoypey) methanol in 200 ml acetone are added dropwise 60 ml Jones reagent. After stirring for 2 h at rt the reaction is quenched by the addition of isopropanol and sodium bisulphite solution Extraction with dichloromethafle affords (4-isopropyl-phenyl)-( 2 'H NMR (300 MI-z, CDC1 3 8.27 1H), 7.70 7.30 2H), 7.18 (dd, 1H), 6.97 4.81 2H), 2.96 (hept, IH), 2.59 lH), 1.27 6H).

D. Synthesis of (2-amino-S -propargyloxy-phenyl)-(4-isopropyl-phenyl)methanone

SNH

2 To a solution of 10.59 g (30.7 mmol) (4-isopropyl-phenyl)-(2-nitro5-propargyloxyphenyl)-methaflone in 250 ml acetic acid are added 13.6 g (246 mmol) iron powder.

After stirring for 20 h at rt the reaction mixture is basified by the addition of 2M sodium hydroxide solution, filtered and extracted with dichloromethane. After purification by chromatography using hexanes ethyl acetate as eluent (2-amnino- -propargyloxy-pheny)(4ioprpypheny)methanone is obtained.

'H NMR (300 MHz, CDCl 3 7.64 2H), 7.30 2H), 7.12 I 7.05 I H), 6.72 IH), 5.71 (broad, 2H), 4.64 2H), 2.98 (hept, IH), 2.48 1H), 1.30 (d, 6H).

MS: 294 4-32832A The (2-amino-4,S -dimethoxy-phenyI)-(4-isopropylphenyl-methanone building block ri is synthesised following the procedure outlined immediately above.

Z MeO ~,NH 2 MeO 00 Example 2: 4-(4-Isopropyl-phenyl)- I (3-methane-sulphoflyl-benzyI-5-propargyloxy phenyl-methanofle NH 0 0 <0 A mixture of 100 mng (0.34 mmol) (2-amino-5-propargyloxy-pheflyl)-(4-isopropylphenyl)-methanone, 80 mng (0.58 mmol) K 2 C0 3 and 77 mg (0.375 mmol) 1-chioromethyl-3-methanesulphofl-benzene in imi dimethylformamide is stirred at 80 'C for 6 h and at 100 'C for 3 h. Then the reaction mixture is poured onto water and extracted with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO 4 filtered and concentrated in vacuo. The residue is purified by flashchromatography on silica gel (hexane:EtOAc 2: 1) to afford the title compound as a yellow foam.

'H-NMR (300 MI-z, DMSO): 8.34 1H), 7.90 IH), 7.80 1H), 7.67 IH), 7.60-7.56 (in, 3H4), 7.39 (in, 2H), 7.09 (dd, 1H), 7.01 1H), 6.70 1H), 4.61-4.53 (in, 4H), 3.54 (in, 1H), 3.19 3H), 2.96 (in, IH), 1.25 6H).

MS: 462 4-32832A -31 The starting materials may be prepared as follows: 0

SO

c n 1 0.267 ml (3.45 mmol) methanesulphonyl-chloride is added to o a solution of 584 mg (3.14 mmol) (3-methanesulphonyl-phenyl)-methanol and 0.66 ml (4.71 mmol) Striethylamine in 6 ml dichloromethane. This reaction mixture is stirred at room temperature for 1 h and at 50 °C for additional 3 h. The reaction mixture is then poured into water and extracted twice with dichloromethane. The combined organic layers are washed with water and brine, dried, filtered and concentrated in vacuo to afford the title compound, which is used in the next step without further purification.

'H-NMR (300 MHz, DMSO): 7.98 (broad s, 1H), 7.86 1H), 7.77 2H), 7.64 (t, 1H), 4.86 2H), 3.21 3H).

B. Synthesis of (3-methanesulphonyl-phenyl)-methanol O, ,O HO s NaBH 4 is added to a solution of 750 mg (4.08 mmol) 3-methanesulphonyl-benzaldehyde in 20 ml ethanol (see P.L. Omstein, T.J. Bleisch, M.B. Arnold, R.A. Wright, B.G. Johnson, J.P. Tizzano, D.R.Helton, M.J. Kallman, D.D. Schoepp, M. Herin, J.

Med. Chem. 1998, 41(3), 358-378 or B. Eistert, W. Schade, H. Selzer, Ber. 1964, 97(5), 1470-81). The reaction mixture is stirred at room temperature for 1 h. The reaction mixture is poured into water and extracted three times with ethyl acetate. The combined organic layers are washed with water and brine, dried, filtered and concentrated in vacuo to afford the title compound, used in the next step without further purification.

4-3283 2A 32 'H-NMR (300 MHz, DMSO): 7.85 (broad s, 111), 7.78 IH), 7.62 211), 7.59 (t, 111), 5.45 3H), 4.58 2H), 3.19 3H).

(NN

00 E xple 3: 49(4mgspr0.21-phefll) 1 ((3isethanelsulphyflyl-beflZY1) 6 PrOuargoloxY 1 Hnzlie--ofgle.-hnlmtaoead1 g 02 ml oimcaaei AHNM mixtur ofIz 97O) 7.9 (0.2 mmol) 7.8~prp1 (del) 77(dme2H), 7.50honm, 2Hz) 7.47(m, 2)gy7.4X(d, H),ymefn and8 17, mg, .5 (0.ad25),mol)8sod cyanat in6 (m H-NM 3020 (sH, 3MSO) 7.95 1251), 7.(d1H,70(d2),.6-50in MS: 487 (M+i1)+ 4-32832A 33 Example 4: 4-(4-Isopropyl-phelyl)- 1 [-2mtaeulhnlehx)-ezl--r 2-ynyloxy- I H-quinazolin- 2 -one HOC, aO NaH DMF. 0 TC cIl-11 HOC, j- 0

H

2 0 2 AcOH, rt HO0 NaBH 4 EtOH, 0.5 h 0 0 I' MeSO 2

CI

Et 3 N, 70 0C

CH

fNH 0 /K 2 C0 3 DMF,. 100 C N H <0 NaOCN AcOH, rt A. Synthesis of 3-(2-methylsulphany1-ethoxy)benzaldehyde 0 Na1H (1.3 g, 54 mmol) is added to a solution of 5.0 g (41 mmol) 3-hydroxybenzaldehyde in 30 ml DNvi at 0 0 C. After stirring for 1 h 4.44 ml (45 mmol) 2chioroethyl methyl sulphide is added. The reaction mixture is warmed to room temperature and stirring is continued for 16 h. Then the reaction mixture is poured onto water and extracted with ethyl acetate. The combined organic layers are washed 4-32832A -34t- with water and brine, dried over MgSO 4 filtered and concentrated in vacuo. The 0residue is purified by flash-chromatography on silica gel (hexane/EtOAc 3:1) to afford the title compound as a colorless oil.

Z 'H-NMR (300 MHz, DMSO-d 6 9.94 1H), 7.51 1H), 7.50 1H), 7.41 (bs, t 1H), 7.27 1H), 4.20 2H), 2.85 2H), 2.18 3H).

N B. Synthesis of 3-(2-methanesulphinyl-ethoxy)-benzaldehyde 00 0

C

o I Is 0 o A solution of 1.6 g (8.15 mmol) 3-(2-methylsulphanyl-ethoxy)-benzaldehyde and 1ml (9.78 mmol) hydrogen peroxide solution in 30 ml acetic acid is stirred for 2 h at room temperature. Then the reaction mixture is poured onto 4N NaOH and extracted with ethyl acetate. The combined organic layers are washed with sodium bisulphite solution, water and brine, dried over MgS04, filtered and concentrated in vacuo to afford the title compound as a colorless solid, sufficiently pure for the next step.

'H-NMR (300 MHz, DMSO-d 6 9.96 1H), 7.52 1H), 7.51 1H), 7.46 (bs, 1H), 7.30 1H), 4.40 2H), 3.26 and 3.08 2H), 2.62 3H).

MS: 213 (M+1) C. Synthesis of [3-(2-methanesulphinyl-ethoxy)-phenyl]-methanol i s

OH

To a solution of 1.1 g (5.18 mmol) 3-(2-methanesulphinyl-ethoxy)-benzaldehyde in ml ethanol (anhydrous) is added NaBH 4 (0.215 g, 5.7 mmol). The reaction mixture is stirred at room temperature for 0.5 h. Then it is poured onto water and extracted with ethyl acetate. The combined organic layers are washed with water and brine, dried 4-32832A over MgSO4, filtered and concentrated in vacuo to afford the title compound as a Scolorless oil that is of sufficient purity for the next step.

'H-NMR (300 MHz, DMSO-d 6 7.20 1H), 6.90 (bs, 1H), 6.88 1H), 6.80 (d, O 1H), 5.18 1H), 4.45 2H), 4.30 2H), 3.25 and 3.04 2H), 2.61(s, 3H).

D. Synthesis of 1-chloromethyl-3-(2-methanesulphinyl-ethoxy)-benzene 00 o CI ci To a solution of 0.7 g (3.27 mmol) and 1.7 ml triethylamine in 30 ml dichloromethane MeSO2C1 (0.315 ml, 4 mmol) is added at 0 OC. The reaction mixture is stirred at 0 °C for 1 h and at room temperature for 70 h. After that the reaction mixture is poured onto water and extracted with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (dichloromethane MeOH 9:1) to afford the title compound as a colorless oil.

'H-NMR (300 MHz, DMSO-d 6 7.28 1H), 7.04 (bs, 1H), 7.02 1H), 6.94 (d, 1H), 4.71 2H), 4.32 2H), 3.26 and 3.04 2H), 2.62(s, 3H) MS: 233 (M+1) E. Synthesis of (4-isopropyl-phenyl)- {2-[3-(2-methanesulphinyl-ethoxy)benzylamino]-5-prop-2-ynyloxy-phenyl} -methanone

N

NH

<0 4-3283 2A -3 The title compound is prepared from 2-mn--rpryoy-hnl-4iorpl C1 phenyl)-methaflofe and I -chloromethyl-3 -methanesulphinyl-ethox y benzene as o described for the preparation of example 2.

Z 'H-NMvR (300 MI-z, DMSO-d 6 8.32 lH), 7.56 2H), 7.38 2H), 7.24 IH), 7.10 (dd, IH), 7.00 (bs, 1H), 6.95 (in, 2H), 6.86 (dd, lH), 6.74 1H), 4.57 2H), 4.42 2H), 4.28 (in, 2H), 3.55 (in, IH), 3.24-3.00 (mn, 2H), 3.00 (in, IH), 2.60 (s, 3H), 1.24 6H).

00 MS: 490 F. Synthesis of 4-(4-Isopropyl-phenYl)- I [3-(2-inethanesulphilyl-ethoxy)-benzyl] -6prop-2-ynyloxy- IH-quinazoline-2-ofle.

0 11 N0 The title compound (yellow oil) is prepared from (4-isopropyl-pheflyl)- inethanesulphiylethoxy)bezylaImino] -5-prop-2-ynyloxy-phenyl)}-iethanone and sodium cyanate as described for the preparation of example 3.

1 H-NMR (300 MHz, DMSO-d 6 7.72 2H), 7.48 2H), 7.46 2H), 7.35 (bs, 11H), 7.24 I1H), 6.94 (bs, 11H), 6.87 (dd, I 6.81 I 5.46 (bs, 211), 4.79 (s, 2H), 4.30 (in, 2H), 3.67 (in, lH), 3.24-3.00 (mn, 2H), 3.02 (mn, IH), 2.61 3H), 1.29 6H).

MS: 515 4-32 83 2A 37 Ex ample 5: 4-(4-Isopropyvl-pheflyl)- 1-[3 -(2-methanesulphony1-ethoxy)-belzyl] -6prop-2-ynyloxy- 1 H-quinazoline-2-ofle.

0 N If0 <0 'H-NMR (300 Miz, DMSO-46): 7.66 211), 7.46 2H), 7.44 2H), 7.30 (bs, 1H1), 7.20 114), 6.95 (bs, IH), 6.87 (in, 1H), 6.76 111), 5.42 2H), 4.75 2H1), 4.27 2H), 3.63 (mn, 1H), 3.56 2H), 3.02 311), 3.00 (in, 1H), 1.24 6H).

MS: 531 I Clrmty- (-ehneupoy-toy-ezn can be prepared from 3 inethanesulpholyl-ethoxy)-beflzaldehyde as described for the preparation of I1chooehl3(-ehnsupiy-toy-ezn (example 4B3)

HOC

H

2 0 2 AcOH, 100 TC 7011 HOC 0 analogous to example 4 7 00 CI N 4-32832A -38- O A solution of 2.0 g (10.2 mmol) 3 2 -methylsulphanyl-ethoxy)-benzaldehyde and 2.3 N ml (22.4 mmol) hydrogen peroxide solution in 10 ml acetic acid is stirred for 2 h at 0 100 Then the reaction mixture is poured onto 2N NaOH and extracted with ethyl Z acetate. The combined organic layers are washed with sodium bisulphite solution, Swater and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane/EtOAc 3:1) to afford the title Scompound as a white crystalline compound.

00 S'H-NMR (300 MHz, DMSO-d 6 9.96 1H), 7.54 (2d, 2H), 7.46 (bs, 1H), 7.32 (m, 1H), 4.42 2H), 3.63 2H), 3.06 3H) MS: 229 (M+1)

(-N

_39 Example 6: 4 (-Isoprcpy! n'-,_Ite~Z~>Yrlthl prop-2-ynyloxyi 1 H-quinazo1ifl-2 -thiole.

N

CICH

2

CN

K

2 C0 3 DMF, 100 *C >0 Bu SnN 3 Xylene reflux

HN-N\

N

N

NH

WN

NN 0 ,,.OMe NH Br 0

K

2 C0 3

KI

ethyl methyl ketone

C

TF. 50 C 0

NCS

4-32832A r A. Synthesis of [2-(4-isopropyl-benzoyl)-4-prop-2-ynyloxy-phenylamino-acetnitrile

N

NH

0 0 00 A mixture of 2.0 g (6.83 mmol) 2-amino-5-propargyloxy-phenyl)-(4-isopropylphenyl)-methanone, 0.516 g (7.5 mmol) chloroacetonitrile and 1.6 g K 2 C0 3 in 20 ml DMF is heated to 100 OC and stirred at this temperature for 20 h. The reaction mixture is cooled to room temperature and poured onto water and extracted with ethyl acetate.

The combined organic layers are washed with water and brine, dried over MgSO 4 filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane/EtOAc 3:1) to afford 1.26 g of the title compound as a yellow crystalline solid.

'H-NMR (300 MHz, DMSO-d 6 7.60 (min, 1H), 7.60 2H), 7.40 2H), 7.28 (dd, 1H), 7.04 (bs, 1H), 6.96 1H), 4.67 2H), 4.42 2H), 3.59 1H), 2.98 1H), 1.25 6H).

MS: 333 B. Synthesis of (4-isopropyl-phenyl)- {5-prop-2-ynyloxy- 2 amino] -phenyl) -methanone HN -N

N

N

NH

0 A solution of 0.82 g (2.47 mmol) [2-(4-isopropyl-benzoyl)-4-prop-2-ynyloxy-phenylamino]-acetonitrile and 0.8 ml (3.31 mmol) Bu 3 SnN 3 in 20 ml m-xylene is stirred at 4-32832A -41 Sreflux temperature for 5 h. Then the reaction mixture is cooled to room temperature 0and 15 ml 2N KOH and 2 ml MeOH are added. This mixture is stirred vigorously for min. After that the phases are separated and to the water layer 4 N HC1 is added Z until a pH -1 is reached. The aqueous layer is extracted with dichloromethane Sisopropanol 3:1. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting solid is Nsuspended in diethyl ether, stirred for 0.5 h, filtered and dried to afford 0.89 g of the 00 title compound as yellow crystals.

(ni 'H-NMR (300 MHz, DMSO-d 6 8.22 1H), 7.59 2H), 7.40 2H), 7.14 (dd, 1H), 7.04 (bs, 1H), 6.72 1H), 4.81 2H), 4.61 2H), 3.59 1H), 2.98 1H), 1.25 6H).

MS: 376 (M+1) C. Synthesis of (4-isopropyl-phenyl)-( 2 {[2-(2-methoxy-ethyl)-2H-tetrazol-5ylmethyl]-amino}-5-prop-2-ynyloxy-phenyl)-methanone.

Ns N

N-\

NH

A mixture of 1.04 g (2.77 mmol) (4-isopropyl-phenyl)- {5-prop-2-ynyloxy-2-[(1H- 0.85 g K 2 CO3, 0.25 g KI and 0.41 g (2.95 mmol) chloroacetonitrile and 40 ml ethyl methyl ketone is stirred at 60 °C for h. The reaction mixture is cooled to room temperature and poured onto water and extracted with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane/EtOAc 2:1) to afford 0.65 g of(4isopropyl-phenyl)-( 2 [2-(2-methoxy-ethyl)-2H-tetrazol-5-ylmethyl]-amino 4-32832A 42 r-2-ynyloxy-phelyl)-methalofe (yellow oil, title compound) and 0.3 g of (4-isopropylphenyl)-(2- [1-(2-methoxy-ethyl)- I H-tetrazol-5 -ylmethyl] -amrino) 1-5 -prop-2-ynyloxyphenyl)-methanone (yellow oil).

Z 'H-NMR (300 MHz, DMSO-d 6 8.32 1H), 7.56 2H), 7.38 21H), 7.18 (dd, 1H), 7.02 (bs, 1H), 6.92 lH), 4.78 2H), 4.72 2H), 4.60 2H), 3.80 2H), 3.55 IH), 3.18 2.96 (in, 1H), 1.24 6H).

Cl MS: 434 00 D. Synthesis of 4-(4-isopropyl-pheflyl)-lI [2-(2-methoxy-ethyl)-2H-tetrazol-S ylmethyl]-6-prop-2-ynyloxy- 1H-quinazolin-2-thione.

N

<0 The title compound (red foam) is prepared from (4-isopropyl-phenyl)-( 2 2 2 ylmethylI -mino)} -5-prop-2-ynyloxy-phenyl)methanone and benzoylisothiocyaflate as described for the preparation of example Ill.

'H-NMR (300 MHz, DMSO-d 6 7.74 2H), 7.73 IH), 7.60 (dd, IHI), 7.48 (d, 2H), 7.41 (mn, 1H), 6.40 (bs, 2H), 4.88 (bs, 2H), 4.77 2H), 3.76 2H), 3.74 (in, 1H), 3.16 3H), 3.00 111), 1.28 6H).

MS: 475 The compounds of the following examples are prepared by analogy: 4-32832A -43- Example 7: 4-(4-Isopropyl-phel)- 1 (3-methane-sulphoflyl-benzyl)- -propargyloxyphenyl-methaflofe NH 0 0 <0 The title compound can be prepared using the synthesis methodology as described using I -chloromethyl-3-methanesu1pnylbenzene (see S.A. Laufer, G.K. Wagner J1 Med. Chem. 2002, 45(13), 2733-40).

MS: 446 Example 8: 4-(4-Isopropy1-phelyl)- 1 -(3-rnethane-sulphinylbbenlYW 6 propargyloxy- I H-quinazolifle-2-ofle <0 -f 0O

N

'H-NMvR (300 MHz, DMSO): 7.70 2H), 7.66 1K), 7.58-7.44 (in, 6H), 7.39 (broad s, IH), 7.35 (broad s, 1K), 5.59 (broad s, 2H), 4.78 2H), 3.67 (in, 1 3.02 (mn, 1 2.72 3H), 1.28 6H).

MS: 471 4-32832A 44 Example 9: 4-(4-Isopropy-phel)-6-prop- 2 -ylloxy I -pyridin-2-ylmethyl- 1 Hquinazolin-2-one 'H NMR (300 MHz, CDC1 3 8.58 111), 7.76 2H), 7.20-7.70 (in, 8H), 5.68 (s, 2H), 4.64 2H), 3.02 (hept, 1H), 2.54 1H), 1.32 6H).

MS: 410 Example 10: 4-(4-Isopropyl-phel)-6-prop- 2 -ylloxy I-(4-[1I,2,3lltriazol-2-ylbenzyl)- 1 H-quinazolin-2-one 'H NMR (300 MHz, CDC1 3 8.04 2H), 7.72-7.80 (in, 3H), 7.20-7.52 (mn, 8H), 5.60 2H), 4.64 2H), 3.02 (hept, 11H), 2.55 (mn, 1H), 1.33 6H).

MS: 476 4-32832A 45 Example 11: 1 (-rm-rpl--(-spoy-hnl)6po--nlx

H-

quinazolin-2-one 00 'HNMR (300 MHz, CDCI 3 7.69 2H4), 7.46 7.53 (mn, 3H), 7.37 211), 4.63 (d, 2H), 4.42 (mn, 211), 3.58 2H), 2.99 (hept, 111), 2.58 (mn, 1H), 2.38 (in, 2H), 1.30 (d, 6H1).

MS: 441 Example 12: 4-(4-Isopropy-phel)-6-prop- 2 -ylloxy I-pyridin-3-ylmethyl- 1Hquinazolin-2-one

SNO

<0 'H NMR (300 MHz, CDCl 3 8.78 11-1), 8.58 1H), 7.90 111), 7.74 2H1), 7.54 111), 7.26-7.44 (mn, 511), 5.60 211), 4.64 2H), 3.01 (hept, 1H), 2.56 (t, 111), 1.32 611).

MS: 410 4-32832A -46- Example 13: 1 -[2-(2-Hydroxy-ethoxy)-benlZl 4-(4-isopropyl-phenfl)-6-prop- 2 ynyloxy- I H-quinazolin-2-crne O Na(OAc) 3

BH

CH

2

CI

rt AcOH-, NaOCN rt A. Synthesis of {2-[2-(2-Hydroxy-ethoxy)-benlam.liflo]5 -prop-2-ynyloxy-phelyl} (4-isopropyl-phenyl)-methalofe 4-32832A -47

NH

0 0 00 To a solution of 100 mg (0.341 mmol) (2-amino-5-propargyloxy-pheflYl)-( 4 isopropyl-phenyl)-methalofe in 1.5 ml CH 2 Cl 2 is added 61 mg (0.36 mniol) 2-(2hydroxyethoxy)benzaldehyde and 84 mg (0.38 mmol) sodium triacetoxyborohydnide.

N1 The mixture is stirred at r.t. for two days, diluted with water and extracted with

CH

2 Cl 2 Purification of the crude product by chromatography (ethyl acetate/hexanes 1: 1) affords a yellow solid.

'H NMR (300 M-Hz, CD 3 OD): 7.56 211), 7.34 211), 7.16-7.30 (in, 2H), 7.06- 7.12 (in, 211), 6.84-7.00 (mn, 3H), 4.50-4.54 (in, 411), 4.12 211), 3.96 2H), 3.00 (hept, 111), 2.92 1H), 1.32 611).

MS: 444 B. Synthesis of 1I2(-yrx-ehx)bny]4-4iorplphnl--rp2 ynyloxy- I H-quinazolin-2-one HO -I Nr

N

<0 To a solution of 85 mng (0.192 minol) f2[-2Hdoyehoy-ezlmn]5 prp2yyoypey)(-spoy-hnl-ehnn in 2 ml acetic acid is added nig (0.383 inmol) sodium cyanate. After stirring for 2 h the solvent is removed in vacuo and the residue is partitioned between CH 2 Cl 2 and water. The organic layer is 4-32832A -48extracted with 2 M sodium hydroxide solution. After evaporation of the organic phase the product is obtained as a yellow oil.

'H NMR (3 00 MHz, CDCl1 3 7.7 6 2H1), 7.2 0-7.5 6 (in, 6H1), 6.94 I1H), 6.86 (d, 1H), 5.62 2H1), 4.04 2H), 3.94 2H), 3.02 (hept, 111), 2.56 (in, 111), 1.32 (d, 6H1).

MS: 469 Example 14: 1 [-2Hdoyehx)-hohn2ymty]4-4iorplpey) 6-prop-2-yniylOXy- IH-quinazolin-2-ofle.

HO

)S\

SN

'H-NMR (300 MHz, CDCl 3 7.64-7.84 (in, 3H), 7.22-7.50 (mi, 4H), 7.12 1IH), 6.76 111), 5.58 2 4.62 211), 4.20 2H), 3.96 2H), 3.42 (broad s, 1H-I), 3.00 (hept, 1H1), 2.54 111), 1.30 6H).

MS: 475 The starting material may be prepared as follows: cu, CuSO 4 LiH ethylene glycol 10000C

HO-N\O

Hyo

O(POC

2 2 000C

HO

0 4-32832A -49- A. Synthesis of 2-(thiophen-3-yloxy)-ethanol O HO O

O

IIn H O To a solution of 1.0 g (4.76 mmol) 3-iodothiophene in 5 ml ethylene glycol is added S109 mg (1.71 mmol) copper powder, 114 mg (0.714 mmol) copper(II)sulphate and 00 M 151 mg (19.0 mmol) lithium hydride. The reaction mixture is heated overnight in a sealed flask at 100 The reaction mixture is filtered through Celite and evaporated.

The resulting oil is then filtered through a 50 g silica pad and eluted with ethyl acetate/hexanes to give after evaporation 750 mg of an orange liquid, which is used without purification directly in the next reaction.

HPLC-MS: t 1.31 min. 145) B. Synthesis of 3-(2-hydroxy-ethoxy)-thiophene-2-carboxaldehyde

HO-O

The crude material (750 mg) obtained in the reaction above is added dropwise at 0 °C to a mixture of 1.15 ml (8.32 mmol) diphosphoryl chloride and 1 ml (13 mmol) DMF.

The reaction mixture is stirred for two hours at room temperature. 50 ml of cold 2N NaHCO 3 solution are added and the resulting mixture is extracted with dichloromethane, dried, filtered through Celite and evaporated in vacuo. Flashchromatography (hexanes/ethyl acetate) gives a yellow oil, which is used without further purification in the reductive amination reaction.

4-32832A r- Example 15: 1 (-hoo4hdoy5mtoybezl--4iorplpey)6 ci prop-2-ynyloxy- I H-quinazolil-2-ofle 0 0 Z 0

OH

OH

,~NH

2 cI O C,

NH

NaBH 3

CN

00 M ~CH 3 OH, AcOH NaOCN AcOH 4-32832A -51 A. Synthesis of -chloro-4-hydroxy- 5 -methoxy-benzylanfo)- 5 -prop -2-ynyloxy- Nphenyl] sopropyl-phenyl)-methalofe Z

OH

NH

0 000 To a stirred mixture of 146.7 mg (0.5 mmol) of (2-amino-5-prop-2-ynyloxy-phelyl)- 4-isopropyl-phenyl)-methalofe and 28.6 p.1 (0.5 mmol) of acetic acid in 1.5 ml of methanol is added 93.3 mg (0.5 mmol) of 5-chiorovanillin followed by 31.4mig mmol) of sodium cyanoborohydride. After stirring for 40 h at the reaction is quenched with IN HCl and subsequently made alkaline with IN aqueous NaOH solution. Methanol is removed in vacuo, the residue diluted with water and extracted twice with ethyl acetate.The combined organic layers are dried (Na 2 SO4) and evaporated. Flash chromatography of the residue (SiO 2 hexane/ethyl acetate) affords the title compound as a yellow solid.

'H-NMR (400 MHz, DMSO-d6): 9.28 1H), 8.20 1H), 7.57 2H), 7.40 2H), 7.13 (dd, IH), 7.02 IH), 6.95 1H), 6.90 1H), 6.76 1H), 4.59 2H), 4.34 3.77 3H), 3.54 1H), 2.97 (in, IH), 1.24 6H).

MS: 464 4-32832A -52- B. Synthesis of 1-(3-chloro-4-hydroxy-5-methoxy-benzyl)-4-(4-isopropyl-phenyl)- 6 prop-2-ynyloxy- H-quinazolin-2-one 0 0 o 0 OH

N

0oo

MN

To a mixture of 43.1 mg (0.093 mmol) of [2-(3-Chloro-4-hydroxy-5-methoxy-benzylamino)-5-prop-2-ynyloxy-phenyl]-(4-isopropyl-phenyl)-methanone in 1ml of acetic acid is added 12.1 mg (0.186 mmol) of sodium cyanate. After stirring for 12 h at r.t.

the solvent is removed in vacuo and the residue partitioned between saturated NaHCO 3 solution and ethyl acetate. The organic layer is separated and the aqueous phase extracted twice with ethyl acetate. The combined organic extracts are dried (Na 2 SO4) and evaporated in vacuo. Flash chromatography (Si02, hexane ethyl acetate) affords the title compound as an amorphous yellow solid.

'H NMR (400 MHz, DMSO-d6): 9.41 1H), 7.73 2H), 7.48 7.58 4H), 7.36 1H), 7.07 1H), 6.84 1H), 5.39 (broad s, 2H), 4.81 2H), 3.81 3H), 3.68 1H), 3.03 1H), 1.29 6H).

MS: 489 (M+1) The compounds of the following examples are prepared in an analogous manner.

4-32832A 53 Example 16: 1-(-toybny)4(-spoy-hnl--rp2yyoy I Hquinazolin- 2 -ofle 'HNMvR (400 MHz, DMSO-d6): 7.73 2H), 7.46-7.50 (in, 3H1), 7.37 I1H), 7.30 1H), 7.23 (dt, 1H), 7.06 1H), 6.76-6.83 (in, 2H), 5.39 (broad s, 2H), 4.79 (d, 2H), 4.16 2H), 3.67 1H), 3.03 (mn, 1H), 1.41 1.29 6H).

MS: 453 Example 17: 1 -Ethoxy-benzyl)4(4isopropy1phenyl)6prop- 2 ynyloxyl

H-

quinazolin-2-one

N

'H NMR (400 MI-z, DMSO-d6): 7.72 2H), 7.46-7.50 (in, 4H), 7.36 1H), 7.22 1H), 6.86 (mn, 1H), 6.79-6.81 (mn, 2H), 5.45 (broad s, 2H), 4.78 2H), 3.97 (q, 2H), 3.66 1H), 3.02 (in, 1H), 1.26-1.30 (mn, 9H).

MS: 453 4-32832A 54 Examnple 18: 1 (-yrx--ehx-ezl--(-spoy-hnl--rp2 ynyloxy- 1 H-quinazolin-2-ofle 'H NMR (400 MHz, DMSO-d6): 9.90 I1H), 7.67 2H), 7.61 I1H), 7.40-7.47 (in, 3H), 7.27 1H), 7.03 IH), 6.43 2H), 5.44 2H), 4.75 2H), 3.65 (s, 3.63 1H), 3.00 (mn, 1H), 1.27 6H).

MS: 455 Example 19: 1-(-toy4mtoybn yl--4iorpl-hnl--rp ynyloxy- 1 H-quinazolin-2-one

N~O

'H NMR (400 MHz, DMSO-d6): 7.71 2H), 7.47-7.55 (mn, 4H1), 7.35 1H), 7.05 111), 6.86 111), 6.73-6.76 (in, 1H), 5.41 (broad s, 2H), 4.79 2H), 3.97 (q, 2H), 3.69 3H), 3.66 (in, 1H), 3.02 (in, 111), 1.26-1.32 (mn, 9H).

MS: 483 4-32832A 55 Example 20: 1 H-Indol-4-ylmethyl)4(4isopropylphenyl)6prop- 2 -yIyloxyl Hquinazolin- 2 -one 'H NMvR (400 MHz, DMSO-d6): 11. 10 I1H), 7.74 2H), 7.49 2H), 7.29-7.42 (in, 5H), 6.96 1H), 6.64 (in, 1H), 6.59 111), 5.74 (broad s, 2H), 4.76 2H), 3.65 1H), 3.03 (in, 1H), 1.29 6H).

MS: 448 Example 21: 1 -(4-Hydroxy-3-mtoybny) -4iorplphnl--rp2 ynyloxy- 1 H-quinazolin-2-oflC 0

I-I

OH

N

'H NMR (400 MHz, DMSO-d6): 7.70 2H), 7.56 1H), 7.45-7.49 (mn, 3H), 7.34 IH), 7.03 111), 6.61-6.69 (in, 2H), 5.37 (broad s, 2H), 4.78 2H), 3.73 (s, 3H), 3.66 lH), 3.01 (mn, 1H), 1.28 6H).

4-32832A 56 Example 22: 1 -(2-Hydroxy4methoxy-bezyl)4(4isopropyphenyl) 6 prop- 2 ynyloxy- 1 H-quinazolin-2-Qfle HO 0, >0 'H1 NMR (400 MI-z, DMSO-d6): 10.05 (broad s, I 7.70 2H), 7.40-7.50 (in, 4H1), 7.35 1H), 6.76 1H), 6.46 III), 6.28 (dd, 1H), 5.29 (broad s, 2H), 4.78 2H), 3.66 (in, 1H), 3.64 3H), 3.02 (in, 111), 1.28 6H).

MS: 455 Example 23: 2-yrx--4(-spoy-hny)2oo6po--nlx-H quinazolin- I ylmethyl1]-belzoic acid methyl ester 'H NMR (400 MI-z, DMSO-d6): 10.44 111), 7.82 IlH), 7.71 2H), 7.47-7.56 (in, 5H), 7.35 111), 6.95 IH), 5.44 (broad s, 2H), 4.78 211), 3.86 3H1), 3.66 IlH), 3.02 (mn, I1H), 1. 28 6H).

MS: 483 4-32832A 57 Example 24: 1 -Chloro-4hydroxy-beflZ4(4isopropylphenyl) 6 prop- 2 CI ynyloxy- IH-quinazolifl- 2 -ofle

OH

N.

00

MN

'H NMR (400 MHz, DMSO-d6): 10.15 1H), 7.70 7.46-7.54 (in, 4H), 7.35 (in, 2H), 7.09 (dd, 1H), 6.90 1H), 5.37 (broad s, 2H), 4.78 2H), 3.66 IH), 3.02 (in, 1H), 1.28 6H).

MS: 459 Example 25: 1 (-hoobnyl--4iorpy-hnl -ro--nlx-Hquinazolin-2-one NCy

N.

<0 'H NMR (400 MI-z, DMSO-d6): 7.74 2H), 7.56 (dd, I 7.47-7.5 1 (in, 3H), 7.40 1H), 7.32 (dt, 1H), 7.25 1H), 7.21 (dt, 111), 6.81 (dd, IH), 5.48 (broad s, 2H), 4.80 2H), 3.69 111), 3.03 (mn, LH), 1.29 6H).

MS: 443 4-32832A-5- Example 26: 1 .(4-Hydroxy-3 ,5 -dimethoxy-benzy)4(4isopropylphenyl)- 6 prop- 2 ynyloxy- I H-quinazolifl-2-ofle 'H NMR (400 MHz, DMSO-d6): 8.34 IH), 7.71 2H), 7.59 1H), 7.46-7.50 (in, 3H), 7.35 1H), 6.66 2H), 5.37 (broad s, 2H), 4.78 2H), 3.68 6H), 3.66 1H), 3.01 (mn, 1H), 1.28 6H).

MS: 485 Example 27: 1 -(2,5-Dmtoybny)4-4iorplpeyl--rp2yyoy I H-quinazolin-2-orne 1'H NMR (400 MHz, DMSO-d6): 7.72 2H1), 7.46-7.49 (mn, 3H), 7.37 I 7.28 1H), 7.02 111), 6.83 (dd, 1H), 6.29 1H), 5.35 (broad s, 2H), 4.78 2H), 3.87 311), 3.67 1H), 3.56 3H), 3.02 (mn, 1H), 1.28 6H).

MS: 469 4-32832A 59 Example 28: 4-4(-spoy-hnl--x--rp2yyoy2-unzln 1ylmethyl]IH-indole-2-carboxylic acid am~ide 'H NMR (400 MIHz, DMSO-d6): 11.50 1H), 8.03 (broad s, 1H), 7.75 2H), 7.50 2H), 7.3 8-7.44 (in, 4H), 7.26-7.32 (in, 2H), 7.04 1H), 6.47 2H), 5.72 (broad s, 2H), 4.78 2H), 3.67 1H), 3.03 (mn, 1H), 1.29 6H).

MS: 491 Example 29: 1 -(2-Ethyl-butyl)-4-(4-isopropy-pheyl)-6-prop-2-yyloxy- I Hquinazolin-2-one IN yO0 <0 'H NMR (400 M4Hz, DMSO-d6): 7.68 2H), 7.55-7.60 (mn, 2H), 7.46 2H), 7.34 1H), 4.80 2H), 4.20 2H), 3.69 1H), 3.01 (mn, 1H), 1.85 (mn, IH), 1.30-1.38 (mn, 4H), 1.28 6H), 0.87 6H).

MS: 403 4-32832A 60 Example 30: 3- [4-(4-Isopropyl-phenyl)-2-oxo-6-prop-2-ynyloxy-21-quilazolil-I 1ylmethyl]-phenoxy} -acetic acid

~~OH

0~ >0 'H NMR (400 M]Hz, DMSO-d6): 7.71 2H), 7.45-7.48 (in, 4H), 7.3 5 I 7.17 (in, 1W), 6.81 (broad s, 1H), 6.69-6.76 (in, 2H), 5.43 (broad s, 2H), 4.77 2H), 4.30 2H), 3.65 1H), 3.01 (mn, 1W), 1.28 6H).

MS: 483 Example 31: 1 -(2,3-Diinethoxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-yfloxy- 1Hquinazolin-2-one 'H NMR (400 MHz, DMSO-d6): 7.72 2H), 7.47-7.50 (in, 3H), 7.32-7.3 7 (in, 2H), 6.91-6.98 (in, 2H), 6.41 (dd, 1H), 5.45 (broad s, 2H), 4.78 2H), 3.87 3H), 3.82 3H), 3.67 1W), 3.02 (in, 1W), 1.28 6H).

MS: 469 4-32832A 61 Example 32: 1 -Dihydro-benzo[ 1,4] dioxin-6-ylmethyl)-4-(4-isopropyl-phenyl)-6prop-2-ynyloxy- I H-quinazolin-2-one 'H NMR (400 MiHz, DMSO-d6): 7.70 2H), 7.46-7.5 1 (in, 411), 7.3 5 I1H), 6.77- 6.82 (mn, 3H), 5.37 (broad s, 211), 4.18 4H1), 3.66 1H), 3.01 (mn, 111), 1.28 (d, 6H).

MS: 467 Example 33: 4-(4-Isopropyl-phenyl)- 1-(4-oxo-4H-chroinen-3-ylmethyl)-6-prop-2ynyloxy-l1H-quinazolin-2-one 'HNMR (400 MHz, DMSO-d6): 8.23 1H1), 8.13 (dd, 1H), 7.82 (dt, 1H1), 7.70 (d, 2H), 7.62-7.65 (in, 2H), 7.47-7.54 (mn, 4H), 7.35 11H), 5.25 2H), 4.80 211), 3.67 (in, 111), 3.02 (in, I1H), 1.28 611).

MS: 477 (M+1) 4 4-32832A 62 Example 34: 4-(4-Isopropyl-phenyl)- 1-(2-methyl-butyl)-6-prop-2-ynyloxy-

IH-

quinazolin-2-one 'HNMR (400 MHz, DMSO-d6): 7.62-7.68 (in, 311), 7.53 (dd, 111), 7.46 2H), 7.33 111), 4.80 2H), 4.14 (in, 2H1), 3.68 1H), 3.00 (in, 1H), 1.92-2.01 (in, 114), 1.37-1.45 (mn, 1H), 1.27 6H), 1.18-1.26 (mn, IH), 0.88 (mn, 6H-).

MS: 389 Example 35: 1 -(2,6-Dichloro-benzy)-4-(4-isopropy1-phel)-6-prop-2-yfloxy- 1Hquinazolin-2-one

I

AN

0I 'H NMR (300 MHz, CDC1 3 7.78 211), 7.44 1H), 7.38 211), 7.15-7.40 (in, 5.90 211), 4.62 211), 3.01 (hept, 111), 2.55 (mn, 1H), 1.31 611).

MS: 477 4-32832A 63 Example 36: 1 -(2,3-Dclr-ezl -(-spoy-hnl)6po--nlx

H-

quinazolin-2-one 'H NMR (400 MI-z, DMSO-d6): 7.74 2H), 7.57-7.60 (in, I 7.46-7.5 1 (mn, 3H), 7.40 IH), 7.31 IH), 7.23 IH), 6.76 IH), 5.49 2H), 4.80 2H), 3.69 IH), 3.03 (mn, IH), 1.29 6H).

MS: 477/479 Example 37: 4-(4-Isopropy-pheny)-6-prop- 2 -yylloxy 1-(3-trifluoromethyl-benzyl)- I H-quinazolin-2-ofle 'H NMIR (400 MHz, DMSO-d6): 7.78 IH), 7.72 2H), 7.64 (in, IH), 7.47-7.5 8 (mn, 6H), 7.38 IH), 5.58 2H), 4.79 2H), 3.67 1H), 3.02 (in, 1H), 1.28 (d, 6H).

MS: 477 0 Mz 4-32832A 64 Example 38: 4-(4-Isopropy-pheny)-6-prop-2-yfloxy-l1-(4-trifluoromethyl-benzyl)- I H-quinazolin-2-one 'HNMR (400 MHz, DMSO-d6): 7.71 (in, 4H), 7.43-7.51 (mn, 6H), 7.37 1H), 5.59 (broad s, 2H), 4.79 2H), 3.67 1H), 3.02 (mn, 1H), 1.28 6H).

MS: 477 Example 39: 1 -Ethoxy-4-hydroxy-benzyl)-4-(4-isopropyl-phelyl)-6-prop- 2 ynyloxy- I H-quinazolin-2-one 'HNMR (400 MHz, DMSO-d6): 8.86 1H), 7.70 2H), 7.46-7.55 (in, 4H), 7.33 1H), 7.00 1H), 6.63-6.70 (mn, 2H), 5.36 (broad s, 2H), 4.78 2H), 3.97 (q, 2H), 3.65 1H), 3.02 (in, IH), 1.29 3H), 1.28 6H).

MS: 469 4-32832A 65 Example 40: 4-(4-lsopropyl-phenyl)- 1-(3 -phenyl-butyl)-6-prop-2-ynyloxy-

IH-

quinazolin-2-one 'H NMvR (400 Miz, DMSO-d6): 7.63 2H), 7.50 (dd, 1H), 7.45 2H), 7.37 (d, 1H), 7.28-7.32 (in, 5H), 7.17-7.21 (in, IH), 4.79 2H), 4.12-4.21 (in, 1H), 3.97-4.04 (mn, 1H), 3.68 111), 2.91-3.03 (mn, 2H1), 1.86-2.01 (in, 2H), 1.27 (in, 9H).

MS: 451 (M+1) 4 Example 41: 1 ,4-Diethoxy-benzy)-4-(4-isopropy-pheyl)-6-prop- 2 -yyloxy 1 Hquinazolin-2-one NyO0 ~~0 'H NMR (400 MHz, DMSO-d6): 7.70 2H), 7.46-7.54 (mn, 4H), 7.3 3 I1H), 7.04 1H), 6.84 1H), 6.71 (dd, 1H), 5.39 (broad s, 2H), 4.78 2H), 3.91-4.00 (in, 4H), 3.65 1H), 3.01 (in, 1H), 1.25-1.30 (mn, 12H).

MS: 497 4-32832A 66 Example 42: 1 (-loo4mtoy-ezl--4iorpy-hnl--rp2 ynyloxy- I H-quinazolin-2-one 'HNMR (400 MHz, DMSO-d6): 7.71 2H), 7.47-7.53 (in, 4H), 7.35 1H), 7.24 (dd, 1H), 7.06-7.13 (mn, 2H), 5.42 (broad s, 2H), 4.78 2H), 3.78 3H), 3.67 (t, 111), 3.02 (in, IH), 1.28 6H).

MS: 457 Example 43: (4[-4Iorplpenl 1x--rp2ynlx-Hqiaoiylmethyl]-phenoxy} -acetic acid 'H NMR (400 MHz, DMSO-d6): 7.69 2H), 7.45-7.52 (mn, 4H), 7.32 1H), 7.20 2H1), 6.79 2H), 5.40 (broad s, 2H), 4.77 2H), 4.33 2H), 3.65 111), 3.01 (mn, lH), 1.28 6H).

MS: 483 4-32832A 67 Example 44: 4-(4-Isopropyl-phenyl)- 1-(4-methoxy-2,3 -dimethyl-benzyl)-6-prop-2ynyloxy- 1 H-quinazolin-2-ofle 'H NMR (400 MHz, DMSO-d6): 7.74 2H), 7.49 2H), 7.44 (dd, 1H), 7.38 (d, IH), 7.21 IH), 6.63 IH), 6.32 1H), 5.37 (broad s, 2H), 4.79 2H), 3.69(t 1H), 3.67 3H), 3.03 (in, LH), 2.32 3H), 2.15 1.29 6H).

MS: 467 Example 45: 1 -(4-Benzyloxy-benzyl)-4-(4-isopropy1-phefl-6-prop-2-ynlloxy- 1 Hquinazolin-2-one 0 N-0To 'H NMvR (400 MHz, DMSO-d6): 7.71 2H), 7.47-7.53 (mn, 4H), 7.24-7.53 (mn, 8H), 6.97 2H), 5.43 (broad s, 2H), 5.05 2H), 4.78 2H), 3.67 I 3.02 (in, I H), 1.28 6H).

MS: 515 4-32832A 68 Example 46: 1 -(3-Hydroxy-6-methyl-pyridil-2-ylmethyl)-4-(4-isopropyl.phel)-6- C) prop-2-ynyloxy- IH-quinazolin-2-one

HO

N0 Z

N

00 'H NMR (400 MHz, DMSO-d6): 10.06 I 7.71 211), 7.44-7.49 (mn, 411), 7.3 1H), 7.12 111), 6.96 1H), 5.46 (broad s, 2H), 4.79 2H), 3.67 1H), 3.02 (in, 1H), 2.14 3H), 1.28 611).

MS: 440 1)+ Example 47: (2[-4Iorplpenl 1x--rp2ynlx-Hqiaoiylmethyl] -6-methoxy-phenoxy) -acetic acid 0 HO'J 0" 0

N

N 0 'H NMR (400 MHz, DMSO-d6): 7.71 2H), 7.62 1H), 7.48 211), 7.43 (dd, 111), 7.33 111), 6.92 (dd, 1H), 6.84 1H), 6.22 1H), 5.68 (broad s, 2H), 4.78 211), 4.68 2H), 3.81 3H), 3.66 111), 3.02 (in, IH), 1.28 6H).

MS: 513 4-32832A 69 Example 48: 4-(4-Isopropyl-phenyl)- I (-etoybezl)61 prylx Hquinazolin-2-one

NO

'H-NMR (300 MHz, CDCI 3 7.75 2H)P 7.49 1H), 7.39 2H), 7.20-7.34 (in, 3H), 6.76-6.92 (in, 3H), 5.53 (broad, 2H), 4.64 2H), 3.77 3H), 3.02 (hept, 1H), 5 I 1. 33 6H).

MS: 439 Example 49: 4-(4-Isopropyl-pheflyl)- I ,4-dimethoxy-benzy)-6-propargyloxy- 1 Hquinazolin-2-one m.p. 97 *C.

'H-NMIR (300 MHz, CDCI 3 7.75 2H), 7.49 (dd, IH), 7.38 2H), 7.32-7.36 (in, 2H), 6.96 I1H), 6.87 (dd, I 6.79 I1H), 5.48 (broad, 2H), 4.64 2H), 3.8 5 (s, 3H), 3.84 3H), 3.02 (hept, 1H), 2.65 1H), 1.32 6H).

MS: 469 4-32832A 70 Example 50: 4-(4-Isopropyl-phenyl)- 1-(4-methoxy-benzyl)-6-propargyloxy-

IH-

quinazolin-2-one 01- N y0

N

'H-NMR (300 MHz, CDCl 3 7.74 2H), 7.48 (broad s, 1H), 7.38 2H1), 7.24-7.34 (in, 411), 6.85 211), 5.49 (broad, 211), 4.64 2H), 3.77 3H), 3.02 (hept, 1H), 2.55 11H), 1.32 6H).

MS: 439 Example 51: 4-(4-Isopropyl-phenyl)- 1 5-dimethoxy-benzyl)-6-propargyloxy- 1 Hquinazolin-2-one 0 N y0 'H-NMR (300 MHz, CDCl 3 7.75 2H), 7.48 1H), 7.38 2H), 7.31 111), 7.29 111), 6.46 211), 6.35 111), 5.48 (broad, 211), 4.65 211), 3.75 611), 3.02 (hept, 11H), 2.55 111), 1.33 6H1).

MS: 469 4-32832A -71- Example 52: 4-(4-Isopropyl-phenyl)- 1 5 -dimethoxy-benzyl)-6-propargyloxy- 1 Hquinazolin-2-one 00 z :1 0

N~

CcCI C-i m.p. 77-78 'C.

'H-NMR (300 MHz, CDC1 3 7.76 2H), 7.47 1H), 7.38 2H), 7.28-7.32 (m, 2H), 6.83 IH), 6.72 (dd, IH), 6.65 1H), 5.54 (broad, 2H), 4.64 2H), 4.12 (q, 2H), 3.85 2H), 3.02 (hept, 1H), 2.54 1H), 1.49 3H), 1.33 6H), 1.28 3H).

MS: 497 Example 53: 4-(4-Isopropyl-phenyl)- 1 -(4-ethoxy-2-hydroxy-benzyl)-6-propargyloxy- 1 H-quinazolin-2-one HO 0 N y0 m.p. 186-187 'C.

'H-NMR (300 MHz, CDCI 3 10.13 (broad, OH), 7.88 1H), 7.71 2H), 7.54 (s, 1H), 7.52 1H), 7.34-7.40 3H), 6.51 1H), 6.42 (dd, 1H), 5.41 (broad, 2H), 4.68 2H), 3.98 2H), 3.01 (hept, 1H), 2.56 IH), 1.38 3H), 1.32 6H).

MS: 469 4-32832A 72 Example 54: 4-(4-Isopropyl-pheflyl)- I (2,4-diethoxy-benzy)-6-propargy1oxy- 1Hquinazolin-2-one 'H-NMR (3 00 MHz, CDCl 3 7.74 2H), 7.46 I 7.3 8 I1H), 7.3 7 2H), 7.29 (dd, I1H), 7.00 I1H), 6.47 I1H), 6.34 (dd, I 5.49 (broad, 2H), 4.64 (d, 2H), 4.13 2H), 3.96 2H), 3.01 (hept, 1H), 2.54 1H), 1.51 3H), 1.38 3H), 1.32 6H).

MS: 497(M+1)+ Example 55: 4-(4-Isopropyl-pbenyl)- 1 (2,4-diethoxy-benl~y)-6-propargy1oxy 1 Hquinazolin-2-one

OPOH

N y0 0 m.p. 199-201 'C.

'H-NMR (300 MHz, CDC1 3 9.15 (broad, OH), 7.85 7.71 2H), 7.49-7.56 (in, 3H), 7.38 2H), 7.01 1H), 6.90 1H), 6.79 (dd, lH), 5.44 (broad, 2H), 4.68 2H), 3.97 2H), 3.02 (hept, IH), 2.57 1H), 1.39 3H), 1.32 6H).

MS: 469 4-3283 2A 73 Example 5 6: 4-(4-Isopropyl-phenyl)- 1 -(2-methoxy-benzyl)-6-prop-2-ynyIoxy- 1 IHquinazolin-2-one 'HNMR (300 MHz, CDC1 3 7.76 2H), 7.48 1H), 7.38 2HW, 7.18-7.32 (in, 3H), 6.76-7.02 (mn, 3H), 5.56 2H), 4.62 2H), 3.96 3H), 3.02 (hept, 1H), 2.56 1H), 1.32 6H).

MS: 439 Example 57: 4-(4-Isopropyl-phenyl)- I-(4-ethoxy-benzyl)-6-propargyloxy- 1Hquinazolin-2-one N y0 <0 in.p. 181-183 'C.

'H-NMR (300 MHz, CDCI 3 7.73 2H), 7.47 1H), 7.37 2H), 7.30 2H), 7.22-7.28 (in, 211), 6.83 2H), 5.47 (broad, 2H), 4.63 2H1), 3.98 2H), 3.01 (hept, 1H), 2.53 (broad, 1H), 1.38 3H), 1.31 6H).

MS: 453 4-32832A 74 r-Example 58: 4-(4-Isopropyl-phenyl)- I-(3-isopropoxy-benzyl)-6-propargyloxy- 1 Hquinazolin-2-one N0 N0 >0 mn.p. 69 TC.

Ni H-NMR (300 MliIz, CDCl 3 7.74 2H), 7.48 I1H), 7.37 2H), 7.28 (td, 1 H), 7.25 1H), 7.19 1H), 6.74-6.88 (in, 3H), 5.50 (broad, 2H), 4.63 2H), 4.50 (hept, 1H), 3.01 (hept, IH), 2.54 IH), 1.32 6H), 1.29 6H).

MS: 467 Example 59: 4-(4-Isopropyl-phenyl)- I-(2,4-diethoxy-benzyl)-6-propargyloxy- 1Hquinazolin-2-one N0 >0 'H-NMR (300 MI-z, CDC1 3 7.74 2H), 7.48 I1H), 7.3 7 2H), 7.26-7.33 (in, 2H), 7.20 lH), 6.83-6.90 (mn, 2H), 6.75-6.80 (in, IH), 5.51 (broad, 2H), 4.63 (d, 2H), 3.87 2H), 3.01 (hept, 1H), 2.54 IH), 1.76 (hex, 2H), 1.32 6H1), 1.00 (t, 3H).

MS: 467 4-32832A 75 Example 60: 1 -(4-Bromo-3-methoxy-benzyI)- 4-(4-isopropy-phel)-6-propargyloxyc-i I H-quinazolin-2-one Br oy z 0 00

M-

m.p. 72-74 'C.

c-i 1 'H-NMR (300 MvHz, CDC1 3 7.76 2H), 7.48-7.54 (in, 2H), 7.38 2H), 7.32 (dd, IH), 7.04 1H), 6.68 (dd, 1H), 6.47 IH), 5.53 (broad s, 2H), 4.65 2H), 3.64 3H), 3.02 (hept, IH), 2.55 1H), 1.32 6H).

MS: 517 519(M+1)+ Example 61: 4-(4-Isopropyl-phenyl)- I-(3-hydroxy-4-methoxy-benzyl)-6propargyloxy- IH-quinazolin-2-one

OH

N y0 mn.p. 112 TC.

'H-NMR (300 MHz, CDCI 3 7.73 2H), 7.47 1H), 7.37 2H), 7.25-7.33 (n 2H), 6.88 1H), 6.82 (dd, IH), 6.77 1H), 5.60 OH), 5.45 (broad s, 2H), 4.63 2H), 3.8 5 3 3. 01 (hept, I1H), 2.5 4 I1H), 1. 32 6H).

MS: 455 4-32832A 76 r- Example 62: 4-(4-Isopropyl-phenyl)-1I-(2-methoxymethoxy-benzyl)-6-prop- 2 ynyloxy- 1 H-quinazolin-2-one 00 >0 'HNMR (300 MHz, CDCI 3 7.76 2H), 7.48 1H), 7.38 2H), 7.10-7.32 (in, 4H), 7.02 1H), 6.86 1H), 5.58 2H), 5.34 2H), 4.62 2H), 3.58 3H), 3.02 (hept, IH), 2.56 1H), 1.32 6H).

MS: 469 Example 63: 1 -(4-Bromo-3-ethoxy-benzyl)- 4-(4-isopropyl-phenyl)-6-propargyloxy- 1 H-quinazolin-2-one Br N 0 m.p. 144-146 'C.

'H-NMR (300 MHz, CDCI 3 7.77 2H), 7.50 1H), 7.49 1H), 7.39 2H), 7.32 (dd, 1H), 7.04 IH), 6.67 (dd, 1H), 6.48 1H), 5.53 (broad s, 2H), 4.65 (d, 2H4), 3.84 2H), 3.02 (hept, 1H), 2.55 IH), 1.32 614), 1.28 3H-).

MS: 532 4-328 32A 77 Example 64: 1 -(4-Chloro-4-methoxy-benzyI)- 4-(4-i sopropyl-phenyl)-6-propargyloxy- 1 H-quinazolin-2-one 011 N y0 m.p. 159-161 'C.

'H-NMR (300 MI-z, CDCl 3 7.74 2H), 7.48 1H), 7.30-7.40 (in, 4H), 7.17-7.28 (in, 2H), 6.86 1H), 5.45 (broad s, 2H), 4.64 2H), 3.86 3H), 3.01 (hept, 1H), 2.54 1H), 1.31 6H).

MS: 487 Example 65: 1 -(3-Chloro-4-methoxy-benzyl)- 4-(4-isopropyl-phenyl)-6-propargyloxy- 1 H-quinazolin-2-one m.p. 147-149 0

C.

'H-NMR (300 MHz, CDCI 3 7.74 2H), 7.49 1H), 7.39 1H), 7.37(d, 2H), 7.30-7.36 (in, 2H), 7.22-7.26 (in, 1H), 7.17 (dd, 1H), 6.85 1H), 5.44 (broad s, 2H), 4.64 2H), 4.07 2H), 3.01 (hept, 1H), 2.55 1H), 1.44 3H), 1.32 6H).

MS: 473 4-32832A 78 Example 66: 1 -(3-Chloro-4,5 -dimethoxy-benzyl)- 4-(4-i sopropyl-phenyl)-6propargyloxy- 1 H-quinazolin-2-one 0 0 ini N0 00 m.p. 80' 0

C.

'H-NMR (300 MIHz, CDCI 3 7.74 2H), 7.51 1H), 7.33-7.41 (in, 3H), 7.28 (s, 1H), 6.88 (dd, 2H), 5.43 (broad s, 2H), 4.65 2H), 3.82 3H), 3.81 3H), 3.01 (hept, 1H), 2.55 1H), 1.32 6H).

MS: 503, 505 Example 67: 1 -(4-Chloro-3-mtoybny 4-4iorplpeyl--rpryoy 1 1--quinazolin-2-one

CI

N0 <0 m.p. 133-135 'C.

'H NMR (300 MHz, CDC1 3 7.74 2H), 7.50 1H), 7.33 2H), 7.22-7.36 3H), 6.97 IH), 6.83 (dd, 1H), 5.49 (broad s, 2H), 4.64 2H), 3.85 3H), 3.01 (hept, 1H), 2.54 1H), 1.32 6H).

MS: 473 4-32832A 79 Example 68: 1 Fur-ezl)4(-spoplpey)6-rpryyI

H-

quinazolin-2-one m.p. 72-73 'C.

'H NMR (300 MHz, CDCl 3 7.74 2H), 7.50 IN), 7.37 2H), 7.30 (td, 2H), 7.18 1H), 7.08 1H), 6.90-7.02 (in, 2H), 5.53 (broad s, 2H), 4.63 2H), 3.01 (hept, 1H), 2.54 1H), 1.31 6H).

MIS: 427 Example 69: 1 -(3,-iloobny)4(-spoyphnl6praglx- I Hquinazolin-2-one m.p. 84 'C.

'H NMIR(300 MHz, CDCl 3 7.74 2H), 7.51 1H), 7.38 2H), 7.33 (dd, IH), 7.02-7.22 (in, 4H), 5.48 (broad s, 2H), 4.64 2H), 3.01 (hept, 1H), 2.55 1H), 1.31 6H).

MS: 445 4-32832A 00 Example 70: 1 (-hoo-ezl-4(-spoplp1yl -rpaglx-Hquinazolin-2-one r cl 'H NMIR (300 MEz, CDCI 3 7.74 2H), 7.51 1H), 7.38 2H), 7.33 (dd, IH), 7.02-7.22 (in, 4H), 5.48 (broad s, 2H), 4.64 2H), 3.01 (hept, 1H), 2.55 1H), 1.31 6H).

MS: 443,445 Example 71: 1-(-loobny)4(-spoy-hnl--rpryoy I Hquinazolin-2-one m.p. 7 1-73 0

C.

'H NMR (300 MI-z, CDC1 3 7.73 2H), 7.48 1H), 7.37 2H), 7.20-7.34 (in, 4H), 7.00 2H), 5.50 (broad s, 2H), 4.63 2H), 3.01 (hept, 1H), 2.54 (broad t, 1H), 1.31 6H).

MS: 427 4-32832A 81- Example 72: 1 r-ezy)4(-sorplp1nl -rpaglx-Hquinazolin-2-one N y0 >0 m.p. I110- 112 'C.

NMR (300 MHz, CDCl 3 7.75 2H), 7.50 111), 7.38 2H), 7.2 1-7.35 (in, 4H), 7.18 2H), 5.51 (broad s, 2H), 4.64 2H), 3.01 (hept, 1H), 2.54 (broad t, 111), 1.32 6H).

MS: 443,445 Example 73: 1 (-rm--yrx--mtoybny)4(-iorplpey)6 propargyloxy- 1 H-quinazolin-2-one m.p. 175-177 0

C.

'H NMR (300 MII-z, CDCl 3 7.74 2H), 7.50 1H), 7.37 2H)7 7.32 2H), 7.07 (broad d, 1H), 6.89 (broad d, IH), 5.42 (broad s, 2H), 4.65 2H), 3.85 3H), 3.01 (hept, 1H), 2.55 (broad t, IR), 1.31 6H).

MS: 533, 535 Example 74: 1 -(3-Bromo- 4 -hb 1,rcx y- e5*.ie'hcxy-'oenzyi>)4-(4-i soprop9 -Phen"Y. -6propargyloxy- I H-quinazolin- 2 one o

O)H

OMe N 1 0O o.- >0 00

MN

C- m.p. 175-177 0

C.

'H NMR (300 MIz, CDCl 3 7.74 2H), 7.50 1H), 7.37 2H), 7.32 2H), 7.07 (broad d, 1W), 6.89 (broad d, 1H), 5.42 (broad s, 2H), 4.65 2H), 3.85 3H), 3.01 (hept, 1W), 2.55 (broad t, IH), 1.31 6H).

MS: 533, 535 Example 75: 1 (4-Bromo-benzyl)-4-(4-isopropyl-phenyl)-6propargyloxy-I H-quinazolin-2-one rj:,Br

N

>0 imp. 122-123 'C.

'H NMR (300 MHz, CDCI 3 7.74 2H), 7.50 1W), 7.45 2W), 7.38 2H), 7.32 (dd, 1W), 7.16-7.22 3H), 5.49 (broad s, 2H), 4.64 2H), 3.02 (hept, 1H), 2.55 (broad t, lH), 1.32 6H).

MS: 487, 489 4-32832A 83 Example 76: 1 -(3-Boobnzl--4ispoy pey)6propargyloxy-l

H-

quinazolin-2-one raBr m.p. 144-146 0

C.

'H NMR (300 MHz, CDCl 3 7.75 2H), 7.51 1H), 7.46 (broad s, 1H), 7.28-7.41 (in, 4H), 7.14-7.25 (in, 3H), 5.51 (broad s, 2H), 4.65 3.02 (hept, 1H), 2.56 (broad t, 1H), 1.32 6H).

MS: 487, 489 1)+ Example 77: 1 -(3-Broino-4,5-dimethoxy-belzyl)-4-(4-isopropylpheflyl)- 6 propargyloxy- 1 H-quinazolin-2-one ~o.

m.p. 132-142 0

C.

'H NMNR (300 MHz, CDCl 3 7.80 2H), 7.56 I1H), 7.43 2H), 7.41 IRH), 7.32 I1H), 7.12 (br d, I1H), 5.48 (broad s, 2H), 4.70 2H), 3.86 6H), 3.06 (hept, 1H), 2.60 (broad t, 1H), 1.36 6H).

MS: 546, 548 4-32832A 84 Example 78: 1 ,4-Dibromo-benzyl)-4-(4-isopropyl-phel)-6-prOpargyloxy- 1 Hquinazolin-2 -one m.p. 86-88 0

C.

'H NMR (300 MHz, CDC1 3 7.75 2H), 7.50-7.61 (in, 3H), 7.32-7.42 (in, 3H), 7.10-7.19 (mn, 2H), 5.46 (broad s, 2H), 4.66 (broad s, 2H), 3.02 (hept, IH), 2.55 (broad, 1H), 1.32 6H).

MS: 565, 567, 569 (Br 2 isotope pattern) Example 79: 1 -(3,4-Dichloro-benzyl)-4-(4-isopropy1-phel)-6-propargy1oxy- 1 Hquinazolin-2-one in.p. 73-74 'C.

'H NN{R (300 MHz, CDC1 3 7.75 2H), 7.52 I1H), 7.3 1-7.44 (mn, 5H), 7.16 (d, 2H), 5.48 (broad s, 2H), 4.65 (broad d, 2H), 3.02 (hept, IH), 2.55 (broad, 1H), 1.32 (d, 6H).

MS: 477, 479, 481 (C0 2 isotope pattern) 4-32832A 85 Example 80: 1 -(4-Methyl-benzyl)-4-(4-i sopropyl-phenyl)-6-propargyloxy- 1Hquinazolin-2-one m.p. 92-93 'C.

'H1 NMR (300 MHz, CDCI 3 7.74 2H1), 7.47 11H), 7.37 2H), 7.29 2H), 7.21 2H), 7.12 2H), 5.51 (broad s, 2H1), 4.63 (broad d, 2H), 3.01 (hept, 1H), 2.55 (broad, 111), 2.31 3H), 1.32 611).

MS: 423 Example 81: 1-(-ehlbny)4(-spoy-hnl--rpryoy I Hquinazolin-2-one m.p. 115-116'C.

'H NMR (300 MI-z, CDC1 3 7.75 2H1), 7.48 IH), 7.38 2H), 7.27-7.34 (in, 2H1), 7.20 1H), 7.03-7.14 (in, 3H), 5.51 (broad s, 211), 4.64 211), 3.02 (hept, 111), 2.54 (broad, IH), 2.31 311), 1.32 611).

MS: 423 4-32832A 86 Example 82: 1 (-ty-eny)4(-iorplp1nl -roaglx-Hquinazolin-2-one >00 mn.p. 75-76 0

C.

'H NMR (300 MHz, CDC1 3 7.74 2H), 7.48 111), 7.38 2H), 7.30 2H), 7.23 2H), 7.14 2H), 5.52 (broad s, 2H), 4.63 2H), 3.02 (hept, 1H), 2.61 (q, 2H), 2.54 (broad t, 1H), 1.32 6H), 1.20 3H).

MS: 437 Example 83: 1 ,4-Dimethyl-benzyl)-4-(4-isopropyl-pheny)-6-prpargy1oxy-

IH-

quinazolin-2-one m.p. 143-144 0

C.

'H NMR (300 MHz, CDC1 3 7.74 2H), 7.47 I1H), 7.3 8 2H), 7.31 (broad d, 2H), 7.02-7.12 (in, 3H), 5.48 (broad s, 2H), 4.63 2H), 3.01 (hept, 1H), 2.54 (broad t, 1H), 2.21 6H), 1.32 6H).

MS: 437 4-3283 2A 87 Example 84: 1 -Cyclopropylmethyl- 4-(4-isopropyl-phenyl)-6-propargyloxy- 1 Hquinazolin-2-one SNyO 'H-NMiR (300 MiHz, CDC1 3 7.70 2H), 7.43-7.50 (in, 3H), 7.38 2H), 7.35 (d, 211), 4.67 2H1), 4.26 2H), 3.00 (hept, 1H), 2.55 IH), 1.30 6H), 0.52-0.67 4H).

MS: 373 Example 85: 1 -(2-Bromo-thiazol-5-ylmethyl)-4-(4-isopropyl-Phel)-6-prop- 2 ynyloxy- 1 H-quinazolin-2-one 'H-NMR (300 MHz, CDCI 3 7.66-7.72 (mn, 3H), 7.32-7.52 (in, 5H), 5.54 2 H), 4.66 2 2.98 (hept, 1H), 2.54 1H), 1.32 6H).

MS: 496 4-32832A 88 Example 86: 1 (,-ihootipe--lehl)4(-spoy-hnl--rp2 ynyloxy- IH-quinazolin-2-one 'H-NMR (300 MHz, CDC1 3 7.76 2H), 7.36-7.54 (in, 5H), 6.96 1H), 5.48 (s, 2H), 4.62 2H), 3.02 (hept, lH), 2.58 1H), 1.32 6H).

MS: 483 (M+1)4 Example 87: 4-(4-Isopropyl-phenyl)- 1-(5 -methyl-thiophen-2-ylmethyl)-6-prop- 2 ynyloxy- IH-quinazolin-2-one r S11

SNO

1 H-NMR (300 MHz, CDCl 3 7.72 2H), 7.30-7.60 (in, 5H), 6.96 IH), 6.58 (d, IH), 5.54 2H), 4.64 2H), 3.02 (hept, LH), 2.54 IH), 2.42 3H), 1.30 (d, 6H).

MS: 429 4-32832A 00 89 Example 88: 4-(4-Isopropyl-phenyl)-6-prop- 2 -yfloxy-l1-quinolin-2-ylmethyl- 1Hquinazolin-2-one

N

'H-NMR (300 MHz, CDCl 3 8.16 2H), 7.62-7.82 (in, 5H), 7.56 2H), 7.26-52 4H), 5.92 2H), 4.62 2H), 3.02 (hept, 1H), 2.52 1H), 1.32 6H).

Example 89: 4-(4-Isopropyl-phenyl)-6-prop-2-yyloxy-l1-12-(2,6,6-trimethylcyclohex-l1-enyl)-ethyl]- IH-quinazolin-2-one <00 'H-NMR (300 MHz, CDCI 3 7.72 211), 7.42-7.50 (mn, 3H), 7.42 2H), 4.68 (d, 211), 4.26 211), 3.02 (hept, 1H), 2.56 111), 2.50 2H), 1.98 2H), 1.93 3H), 1.62 2H), 1.48 2H), 1.32 6H), 1. 16 3H).

MS: 469 4-32832A 90 Ex ample 90: 4-Ethyl-4- sopropyl-benzoyl)-4-prop-2-yyloxy-pheflylamilo] methyll -hex anoic acid 'H-NMR (300 M]Hz, CDCI 3 7.62 21-1), 7.36-7.82 (in, 5H), 4.58 2H), 2.84-3.08 (in, 3H), 2.48 IH), 2.32 (in, 2H), 1.74 (mn, 211), 1.42 (in, 411), 1.32 611), 0.82 (in, 6H).

MS: 450 Example 91: 4-(4-Isopropyl-pheny)-6-propargyloxy-l1-(3,3,3 -trifluoro-propyl)- 1Hquinazolin-2-one Fd 0 'H-NMR (300 MIHz, CDCl 3 7.69 2H), 7.51 11H), 7.49 (dd, 1H1), 7.37 2H), 7.33 111), 4.68 211), 4.47-4.56 (mn, 2H), 3.01 (hept, 111), 2.60-2.78 (in, 2H1), 2.57 1H), 1.31 6H).

MS: 415 (M+I1)+ 4-32832 A -91r- Example 92: 1 -(3,3-Dmty btl--(-spoplp1 l--rpaglx-Hquinazolin-2-one N0 SyO X N c-Io 00

M-

'H-NMR (300 MI-z, CDC1 3 7.68 2H), 7.42-7.48 (mn, 2H), 7.35 2H), 7.32 (d, 1H), 4.66 2H), 4.25-4.35 (mn, 2H), 3.00 (hept, 111), 2.56 IH), 1.66-1.74 (in, 2H), 1.31 6H1), 1.10 911). in. p. 69 0

C

MS: 403 Example 93: 1 (,-iehlpn--nl--4ispoy-hnl--rp2yyoy IlH- quinazolin-2-one

KNO

1 H NMR (300 MI-z, CDCl 3 7.78 2H), 7.36-7.52 (mn, 5H), 5.90 (mn, 1H), 5.12 (in, 2H), 4.68 211), 4.32 (broad s, 2H), 3.02 (hept, 1H), 2.58 (in, 11H), 2.18 2H), 1.32 6H), 1.02 6H).

MS: 415 4-32832A 92 Example 94: 1- -Dim ethyl -I -phenyl -I H-pyrazol1-4-ylmethyl)-4-(4- isopropyl phenyl)-6-prop-2-ynyloxy- I H-quinazolin-2-one

/N

N 'H NMR (300 MHz, CDCl 3 7.78 2H), 7.52 1H), 7.26-7.50 (in, 9H), 5.48 (s, 2H), 4.66 2H), 3.02 (hept, 111), 2.56 (in, 1H), 2.32 3H), 2.22 3H), 1.32 (d, 6H).

MS: 503 Example 95: 1 -(5-Bromo-thiophen-2-ylmethyl)-4-(4-isopropyl-phelyl)-6-prop- 2 ynyloxy- I H-quinazolin-2-one 'H NMR (300 MHz, CDCI 3 7.68 2H), 7.3 1-7.50 (in, 5H), 7.34 2H), 6.94 (d, iN), 6.88 IH), 5.52 2H), 4.64 2H), 3.00 (hept, IN1), 2.56 (in, 1H), 1.30 (d, 6H).

MS: 495 4-32832A 93 Example 96: 1 -(5-Hydroxymethyl- furan-2-ylmethyl)-4-(4-isopropyl-phelYl)- 6 -prop- 2 ynyloxy- 1 H-quinazolin-2-one 0O

OH

>0 'H NMR (300 MHz, CDCI 3 7.70 2H), 7.62 1H), 7.42-7.52 (in, 2H), 7.38 (d, 211), 6.38 1H), 6.22 1H), 6.96 (dd, 1H), 5.48 2H), 4.52-4.70 (in, 4H), 3.02 (hept, 1H), 2.58 IH), 1.32 6H).

MS: 429 Example 97: 1 -(2-Butyl-5-chloro- 1H-imidazol-4-ylmethyl)-4-(4-isopropyl-phefl)- 6 prop-2-ynyloxy- 1H-quinazolin-2-one 'H NMIR (300 MHz, CDC1 3 7.72 IH), 7.46-7.60 (in, 3H), 7.38 2H), 5.36 (s, 2H), 4.66 2H), 3.00 (hept, 111), 2.70 (in, 2H), 2.56 1H), 1.66 (mn, 2H), 1.30 (d, 6H), 0.86 3H).

MS: 489 4-32832A 94 Example 98: 4-(4-Isopropyl-phenyl)- 1-(6-methoxy-pyridifl-3 -ylmethyl)-6-prop-2ynyloxy- IH-quinazolin- 2 -one I N N 0 >0 00 'H NMv~R (300 MHz, CDCl 3 8.22 (in, 1H), 7.64-7.78 (mn, 3H), 7.50 1H), 7.30-7.42 (in, 4H), 6.72 1H), 5.48 2H), 4.66 2H), 3.94 3H), 3.02 (hept, 1H), 2.56 (t 1H), 1.32 6H).

MS: 440 Example 99: 7-[4-(4-Isopropyl-phenyl)-2-oxo-6-prop-2-yyloxy- 2 H-qui2zolifl 1ylmethyl]- IH-indole-2-carbonitrile

NC

HN

N y0 >0 'H NMR (300 MHz, CDCl 3 11.52 1H), 7.92 1H), 7.74 2H), 7.64 2H), 7.46-7.54 (mn, 2H), 7.38 2H), 7.12-7.26 (mn, 2H), 6.76 (broad s, 2H), 4.64 2H), 3.02 (hept, 1H), 2.56 (t 1H), 1.32 6H).

MS: 473 4-32832A Example 100: 1 -(2,4-Diamino-pyrimidin-5-ylmethyl)-4-(4-is0prpy1-phel)-6-prop- 2-ynyloxy- I H-quinazolin-2-one

H

2 N N *"NH 2 Ny

K

0 'H NMR (300 MJ-z, CD 3 OD): 7.40-7.80 (mi, 8H), 5.36 2H), 4.74 2H), 2.98- 3.12 (in, 2H), 1.32 6H).

MS: 441 Example 101: 1 -(6-Hydroxymethyl-pyridin-2-ylmethyl)-4-(4-isopropyl-phel)lY& prop-2-ynyloxy- 1H-quinazolin-2-one 'H NMR (300 MHz, CDCI 3 7.76 2H), 7.64 I1H), 7.20-7.52 (in, 6H), 7.16 (d, 1H), 5.64 2H), 4.76 2H), 4.64 2H), 3.02 (hept, 1H), 2.56 1H), 1.32 (d, 6H).

MS: 440 (M+1) 4-32832A -96- Example 102: 1-(3,5-Di-te t-butyl-4-hydroxy-benzyl)-4 2-ynyloxy- I H-quinazolin-2-one 00 N0 00 'H NMiR (300 Mi~z, CDCI 3 7.76 2H), 7.30-7.52 (mn, 5H), 7.16 2H), 5.44 (s, 2H), 4.66 2H), 3.02 (hept, 1H), 2.56 IH), 1.30 6H).

MS: 537 Example 103: 4-[4-(4-Isopropyl-phenyl)-2-oxo-6-prop-2-yfloxy-2H-Uuinazolifl 1ylmnethyl]-2,2-dimethy-oxazolidile-3-carboxylic acid tert-butyl ester <00 'H NN4R (300 MHz, CDCI 3 8.20 1H), 7.70 2H), 7.30-7.58 (mn, 4H), 4.94 (dd, IH), 4.66 2H), 4.31 2H), 4.20 (in, 1H), 3.84 (dd, 1H), 3.00 (hept, IH), 2.56 (t, IH), 1.40-1.64 (in, 15 1.32 6H).

MS: 532 4-32832A -97r-Example 104: 4-(4-lsopropyl-phenyl)-1I-(4-methylamino-2-methylsulphalpyrimidin-5-ylmethyl)-6-prop- 2 -ynlolxy-I H-quinazolin-2-one 0HN N yS N y0

N

'H NMR (3 00 MHz, CDC1 3 8.18 11H), 7.86 I1H), 7.72 2H), 7.64 I H), 7.52 111), 7.44 (dd, 1H1), 7.38 2H), 5.34 (broad s, 2H), 4.64 2H), 3.02 (hept, 111), 2.96 3H), 2.58 1H), 2.50 311), 1.32 6H).

MS: 486 Example 105: 4-(4-Isopropyl-phenyl)- 1- 4-[2-(methyl-pyridin-2-yl-amilo)-ethoxy]benzyl -6-prop-2-ynyloxy- 1 H-quinazolin-2-one N y 0

N

<0 'HNMR (300 MHz, CDCI 3 8.12 (dd, 111), 7.74 2H1), 7.20-7.50 (in, 7H1), 6.84 (d, 2H), 6.46-6.56 (mn, 2H), 5.46 (broad s, 211), 4.64 211), 4.36 211), 3.92 2H), 3.12 3H1), 3.02 (hept, 1H), 2.54 1H), 1.40-1.64 (mn, 15 1.32 6H).

MS: 559 4-32832A 98 Example 106: 4-(4-Isopropyl-phenyl)- 1 (2-methyI-hex-4-eny)-6-prop- 2 -ylloxy-lIHquinazolin-2-one 'HNMR (300 MHz, CDCI 3 7.72 2H), 7.30-7.52 (in, 5H), 5.42 (in, 2H), 4.64 (d, 2H), 4.24 (in, 2H), 3.00 (hept, lH), 2.58 IH), 2.00-2.22 (in, 3 1.62 3H), 1.30 6H), 0.98 3H).

MS: 415 Example 107: 4-(4-Isopropyl-phenyl)-6-prop- 2 -yylloxy 1-(4-pyrazin-2-yl-benzyl)- 1 H-quinazolin-2-one 'H NMR (300 MHz, CDCI 3 8.88 1Hf), 8.60 IH), 8.46 1H), 7.88 2H), 7.76 7.20-7.5 8 (in, 6H), 5.62 (broad s, 2H), 4.64 2H), 3.02 (hept, IH), 2.56 IH), 1.32 6H).

MS: 487 00 4-32832A 99 Example 108: 4-(4-Isopropyl-pheflyl)-l1-(3-methylsulphanyl-propyl)-6-prop- 2 ynyloxy- I H-quinazolin-2-one

KNXN

'H NMR (300 MJ-z, CDCl 3 7.72 2H), 7.48 7.52 (in, 3H), 7.38 2H), 4.69 2H), 4.43 (dd, 2H), 3.58 2H), 3.03 (hept, IH), 2.71 (in, 2H), 2.58 (mn, 1H), 2.08- 2.32 (mn, 5H), 1.31 6H).

MS: 407 (lvl±)+ Example 109: 4-(4-Isopropy-pheny)-6-prop-2-yfloxy-lI-thiophen-2-ylinethyl- 1Hquinazolin-2-one qNy 'H NMR (300 MHz, CDCl 3 7.72 2H), 7.39-7.51 (mn, 3H), 7.38 2H), 7.21 (dd, IH), 7.18 (dd, 1H), 6.96 (dd, 1H), 5.65 2H), 4.66 2H), 3.00 (hept, 1H), 2.58 (t, 1H), 1.31 6H).

MS: 415 4-3283 2A 100 r-Example 110: 1 -Benzyl-4-(4-isopropyl-phenyl)-6-prop-2-yfloxy- IH-quinazoline-2thione InNH

N

0 0 0 -N 60 *C0 00 To a solution of 140 mg (0.365 mmol) (2-benzylamino-5-propargyloxy-phenyl)-(4isopropyl-phenyl)-methanone in 5 ml acetic acid is added 68 mg (0.695 mnmol) potassium thiocyanate. The reaction is stirred for two days at 60 The solvent is removed and the residue is extracted with water/dichioromethane. After evaporation of the organic phase the crude product is purified by flash-chromatography (MeOH/CH 2

CI

2 1:9) to give 25 mg of a yellow oil.

'H NMR (300 MHz, CDC1 3 7.82 2H), 7.52 IH), 7.20-7.43 (in, 9H), 6.22 (broad s, 2H), 4.64 2H), 3.02 (hept, 1H), 2.56 1H), 1.32 6H).

MS: 425 (M+1) t Example 111: 4-(4-Isopropyl-phenyl)-1-(3-methane-sulphonyl-belzyl)-6propargyloxy- 1 H-quinazoline-2-thione.

0 ra so 2 Me N NCS ra SO.Me NH N. IfN 0 THF, 50 >01 N

I

A solution of 1.87 g (4.06 inmol) 4-(4-isopropyl-phenyl)-l-(3-methane-sulphonyl- (example 2) and 0.72 g (4.42 inmol) benzoylisothiocyanate in 9 ml TI-F is stirred at 50 'C for 2 h. Then the reaction mixture is cooled to room temperature and K 2 C0 3 (1.2 g suspended in 17 ml MeOH) is added and stirring is continued for 20 h. After that the reaction mixture is poured 4-32832A-10r- onto water and extracted with ethyl acetate. The combined organic layers are washed N with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The >0 residue is purified by flash-chromatography on silica gel (hexane/EtOAc 1:1) to Z afford the title compound as a dark yellow foam.

tcn) 'H-NMR (300 MHz, DMSO-d 6 7.88 I 7.78 IfH), 7.75 2H), 7.58-7.38 (in, 7H), 4.80 3.48 (mn, 1H), 3.18 3H), 2.99 (in, IH), 1.22 6H).

(N

Ill- MS: 503 00 The compounds of the following examples are prepared by analogy: Example 112: 4-(4-Isopropyl-phenyl)-6-prop-2-yyloxy-l -thiophen-2-ylmethyl-l1H quinazoline-2-thione

NS

'H NMR (300 MI-z, CDCl 3 7.76 2H), 7.64 1H), 7.50 1H), 7.44 (dd, 11H), 7.38 2H), 7.12-7.30 (in, 2H), 6.88 (in, IH), 6.32 (broad s, 2H), 4.68 2H), 3.02 (hept, I1H), 2.5 8 I1H), 1. 32 6H).

MS: 431 4-32832A 102 Example 113: 1 [-2Hdoyehx)-ezl--4iorpy-hnl--rp ynyloxy- 1 H-quinazoline-2-thiofle ra0 7 -N OH 1 H-NMR (300 MHz, CDCI 3 7.82 2H), 7.52 (in, I1H), 7.20-7.42 (in, 5H), 6.76- 6.94 (in, 3H), 6.18 (broad s, 2 4.66 2 4.03 2H), 3.92 2H), 3.00 (hept, IH), 2.56 1H), 1.30 6H).

MS: 485 Example 114: 1 -Benzyl-4-(4-isopropyl-pheflY)6-ethoxy- 1 H-quinazoline-2-thionle 'H NMIR (3 00 MHz,CDCI3): 7.76 2H), 7.3 9 7.2 3 (in, I OH), 6.21 broad, I1H), 3.76 3H), 3.00 (hept, IH), 1.30 6H).

MS: 401 4-32832A 103 Example 115: 4-(4-1sopropy1-pheflyl)- I [2-(2-methoxy-ethoxy)-pyridil- 3 -ylmethyl]-6propargyloxy- I H-quinazolifl-2-thiofle 00 'H-NM4R (300 MI-z, CDC1 3 7.76 2H), 7.44-7.55 (mn, 3H), 7.32-7.38 (in, 3H), 6.91 1H), 6.68 1H), 4.66 2H), 4.35-4.40 (in, 2H), 3.64-3.69 (mn, 2H), 3.40,(s, 3H), 2.99 (hept, 1H), 2.55 IH), 1.30 6H).

MS: 500 Example 116: 4-(4-Isopropyl-pheflYl) 1 [2-(2-inethoxy-ethoxy)-pyridifl 3 -ylmnethyl]-6propargyloxy- 1 H-quinazolin-2-th10fle SNyS in.p. 174-175 'C.

'H-NMR (300 MHz, CDCl 3 7.72 7.42-7.52 (mn, 3H), 7.33 4.69 (d, 2H), 2.99 (hept, IH), 2.57 1H), 1.85 (very broad, 2H), 1.29 6H), 1. 12 9H).

MS: 419 4-3283 2A 104 Example 117: 1 -Benzo[ 1,2,5 ]thiadiazol-5 -ylmethyl-4-(4-isopropyl-pheflyl)- 6 propargyloxy- 1 H-quinazolifl-2-thiofle m.p. 102-106 0

C.

'H-NMR (300 MHz, CDCI 3 8.02 1 7.81 211), 7.70 (broad s, I 7.63 (dd, 114), 7.55 1H), 7.39 2H1), 7.26-7.35 (in, 2H1), 4.66 2H), 3.02 (hept, IH), 2.55 11H), 1.32 611).

MS: 483 Example 118: Acetic acid 2- {3[-4iorplpey)6po--nlx--hoo 2H-quinazolin- I -ylmethyl]-phenoxy} -ethyl ester 0 'H-NMR (300 MHz, CDC1 3 7.79 2H), 7.52 (in, 111), 7.21-7.41 (mn, 5H1), 6.76- 6.93 (mn, 3H), 6.18 (bs, 2 4.66 2 4.37 2H1), 4.12 2H), 3.04 (hept, 111), 2.58 111), 2.08 3H), 1.32 611).

MS: 527 4-32832A 105 Example 119: 1 2 ,3-Dimethoxy-quifoxlna6iflmethy)-4(4isopropylphenyl)- 6 prop-2-ynyloxy- 1H-quinazoline S N 0 11 N :(0

NS

'H-NMR (300 MHz, CDCl 3 7.80 2H), 7.70 I1H), 7.52 I1H), 7.16-7.40 (in, 6H), 6.76 (bs, 2H), 4.64 2 4.22 3H), 4.18 3H), 3.00 (hept, 1ff), 2.52 (t, 1H), 1.30 6H).

MS: 537 Example 120: 1 [-2Hdoy-toy-hohe- lehl-4-(4-isopropyl-phenyl)- 6-prop-2-ylyloxy- 1 H-quinazoline-2-thiofle r)S KNy <0 'H-NMR (300 MHz, CDC1 3 8.02 1H), 7.76 2H), 7.42-7.52 (mn, 3H), 7.38 (d, 2H1), 7.16 1H), 6.80 111), 6.22 (bs, 2 4.64 2H), 4.28 2H), 4.08 (in, 2H), 3.00 (hept, 1H), 2.56 IH), 1.30 6H).

MS: 491 4-32832A-10- Example 121: I-spoy--4ispoy hnl-6po--nlx-H-quinazoline- 2-thione.

0Y NZ Lawesson's reagent N ,S 7 z benzene, 70 OC 00 0 A suspension of 50 mg 139 mniol) 1 -isopropy1-4-(4-isopropy[-phefl)- 6 -prop- 2 ci ynyloxy-1H-quiflazolifle- 2 -one ad 56 mg(0.139 mo)Lwso' egn n2m benzene is heated to 70 TC overnight. The reaction mixture is extracted (water/dichioromethafle) and the organic layer is dried and evaporated.

Flash-chromatography (hexanes/ethyl acetate) yields the product as an orange oil.

'H-NMIR (300 MI-z, CDC1 3 7.78 2H), 7.46 1H), 7.42 (dd, IH), 7.36 2H), 6.52 (hept, 1H), 4.72 2H), 3.02 (hept, 1H), 2.58 1H), 1.78 6W4), 1.30 6H).

4-32832A-10- Example 122: 1 ezl--4cclpoy-pey) -rprg 1x-H-quinazolin-2one Br 2 FeBr.

CC!

4 0 TC Br 1) Mg, THIF 0 CHO *C rt Jones reagent acetone 0 T rt, 2h

NH

2 N0 2 <0 Fe acetic acid 45-50CT,5 h ll.l0 benzaldehyde sodium cyanobomohydlde acetic acid, MeOH rt, 5 h

I

ro 0 0 NaON acetic acid rt, 8 h 4-32832A 108 r- A. Synthesis of 1-bromo-4-cyclopropyl-benzene

O

0Br A solution of 5.0 g (42.3 mmol) cyclopropyl benzene and 300 mg of the catalyst N iron(Im) bromide in 30 ml carbon tetrachloride is cooled to 0 oC and treated dropwise 00 S with 6.76 g (42.3 mmol) bromine (diluted with an equal volume of CC14). The CS bromination is complete after V 2 h. Extractive workup with dichloromethane and Saqueous sodium thiosulphate solution affords a yellow oil, which is purified by flash C-I chromatography (petroleum ether to yield a slightly yellow liquid.

'H-NMR (300 MHz, CDC1 3 7.35 2H), 6.93 2H),1.80-1.90 1H), 0.94-1.01 2H), 0.63-0.70 2H).

B. Synthesis of (2-nitro-5-propargyloxyphenyl)-(4-cyclopropyl-phenyl)-methanol

NO,

2 S OH A suspension of 407 mg (16.7 mmol) magnesium turnings in 5 ml anhydrous THF is treated with a solution of 1-bromo-4-cyclopropyl-benzene in 20 ml THF at such a rate to maintain gentle reflux. Stirring is continued for another V2 h after complete addition. The resulting Grignard reagent is then slowly added to a solution of 2-nitroin 30 ml THF at -75 The reaction is kept between °C and -65 °C throughout the addition, followed by slow warming to rt. The mixture is then poured into saturated aqueous ammonium chloride solution and extracted with diethyl ether. Purification of the crude product by flash chromatography (hexane/ dichloromethane) yields a yellow brown oil.

'H-NMR (300 MHz, CDCb1): 8.06 1H), 7.41 1H), 7.21 2H), 7.01 2H), 6.97 (dd, 1H), 6.49 1H), 4.78 1H), 2.68 OH), 2.55 IH), 1.82-1-92 (m, 1H), 0.91-0.99 2H), 0.64-0.70 2H).

4-32832A 109- C. Synthesis of (2-nitro-5-propargyloxyphenyl)-(4-cyclopropyl-phenyl)-methanone N> NO 2 0 00 A solution of 2.8 g (8.66 mmol) of the alcohol prepared in step B in 20 ml acetone is treated dropwise with 4.3 ml 2.6 M Jones reagent. An exothermic reaction occurs and the mixture turns dark. After 2 h the chromium salts formed are separated and rinsed several times with dichloromethane. The combined organic phases are concentrated and the crude product obtained is purified by chromatography (hexane/dichloromethane) to yield white crystals.

m.p. 107 oC.

'H-NMR (300 MHz, CDCI 3 8.24 1H), 7.64 2H), 7.16 (dd, 1H), 7.09 2H), 6.95 1H), 4.80 1H), 2.58 1H), 1.89-1-99 1H), 1.03-1.12 2H), 0.75- 0.83 2H).

MS: 322 (M+1) D. Synthesis of (2-amino-5-propargyloxyphenyl)-(4-cyclopropyl-phenyl)-methanone

NH

2 A solution of 2.2 g (6.85 mmol) of (2-nitro-5-propargyloxyphenyl)-(4-cyclopropylphenyl)-methanol (step C above) in 40 ml glacial acetic acid is heated to 50 OC and treated with 3.06 g (8 equiv.) of iron powder. After 5 h stirring at that temperature the reaction is complete. The green-grey suspension is cooled to rt, diluted by the addition of 500 ml water and 200 ml ethyl acetate and filtered through a pad of Celite. The 4-32832A -110- Slayers are separated and the organic phase washed with water and sat. bicarbonate N, solution. The yellow and sticky crude product is purified by chromatography (dichloromethane/MeOH) to yield a viscous yellow oil.

Z 'H-NMR (300 MHz, CDCl 3 8.60 2H), 7.07-7.14 3H), 7.04 (dd, 1H), 6.71 (d, 1H), 5.67 (broad, 2H), 4.53 2H), 2.48 1H), 1.91-1-2.01 1H), 1.02-1.11 (m, 2H), 0.76-0.83 2H).

MS: 292 (M+1) 00 I E. Synthesis of (2-benzylamino-5-propargyloxyphenyl)-(4-cyclopropyl-phenyl)- Smethanone

NH

0 0 A mixture of 490 mg (1.68 mmol) of the aniline prepared in step D, 256 al benzaldehyde and 150 .ll AcOH in 5 ml MeOH is treated with 200 mg 95 sodium cyanoborohydride. Temperature is kept around rt by a cooling bath. After 5 hours the reaction mixture is distributed between water and ethyl acetate. The crude orange oil obtained after concentration i.V. is purified by chromatography (hexane/ethyl acetate) to yield a yellow solid. m.p. 116-118 °C.

'H-NMR (300 MHz, CDCl 3 8.24 1H), 7.64 2H), 7.16 (dd, 1H), 7.09 2H), 6.95 1H), 4.80 1H), 2.58 1H), 1.89-1.99 1H), 1.03-1.10 2H), 0.76- 0.83 2H).

MS: 382 (M+1) 4-32832A r- F. Synthesis of 1 ezl4(4ccorpl-hnl--roaglx H-quinazolin-2one N 0

KN

S0 00 A solution of 460 mg (1.21 mmol) of (2-benzylamino-5-propargylOXYPhenyl)-( 4 cyclopropyl-phenyl)-methalone (step E) and 118 mg (1.81 mmol) sodium cyanate in ml glacial acetic acid is stirred at rt for 8 h. Then the mixture is diluted with water and ethyl acetate. The layers are separated and the organic phase is washed with water and bicarbonate solution. Chromatography (dichloromethanelMeOH) of the crude product affords a yellow foam. m.p. 112-113 TC.

'H-NMR (300 M~z, CDCl 3 7.72 2H), 7.46 111, 7.18-7.35 (in, 9H), 5.56 (broad, 2H1), 4.63 2H), 2.55 1H), 1.95-2.05 (mn, 111), 1.05-1.12 (in, 2H1), 0.79- 0.86 (in, 2H).

MS: 407 The compounds of the following examples are prepared by analogy: 4-32832A 112- Example 123: 4-(4-Cyclopropyl-phenyl)- 3-dimethyl-butyl)-6-propargyloxy-

IH-

quinazolin-2-one m.p. 159-160 0

C.

'H-NMvR (3 00 MIHz, CDC1 3 7.65 7.41-7.47 (in, 2H), 7.31 I1H), 7.18 (d, 2H), 4.66 211), 4.26-4.34 (mn, 2H), 2.56 1H), 1.92-2.04 (in, 1H), 1.65-1.75 (in, 2H), 1. 10 9H), 1.02-1.08 (in, 2H1), 0.76-0.83 (in, 2H1).

MS: 401 (M+1) 4 Example 124: 4-(4-Cyclopropy1-phel)Y 1 (3-ethoxy-4-inethoxy-beflzyl)&6 propargyloxy- I H-quinazolin-2-ofle in.p. 66-68 0

C.

'H-NMR (300 MiHz, CDC1 3 7.70 211), 7.42-7.46 (in, 111), 7.27-7.36 (in, 2H), 7.19 211), 6.94 1H), 6.85 (dd, 111), 6.78 111), 5.45 (broad, 211), 4.62 211), 4.04 2H), 3.82 3H), 2.54 111), 1.93-2.04 (mn, 1H), 1.41 311), 1.03-1.11 (in, 2H), 0.77-0.84 (mn, 2H).

MS: 481 4-32832A -113- Ex ample 125: 4-(4-Cyclopropyl-pheflyl)-l1 isopropyl-6-propargyloxy- 1H-quinazolin- 2-one SyO

N

mn.p. 124-125 'C.

'H-NMR (300 MiHz, CDC1 3 7.68 2H), 7.54 1H), 7.36-7.44 (in, 2H), 7.18 (d, 2H), 5.20 (broad hept, 1H), 4.66 2H), 2.56 1.93-2.04 (in, 1W, 1.69 6H), 1.03-1.11 (in, 2H), 0.77-0.83 (in, 2H).

MS: 359 Example 126: 1 ezl4(4ccorpl-hnl--roaglx H-quinazolin-2thione

N

NS

S0 m.p. 104-106 'C.

'H-N MR (300 MHz, CDCl 3 7.77 2H), 7.49 1IH), 7.23-7.37 (mn, 7H), 7.20 (d, 6.22 (broad, 2H), 4.66 2H), 2.57 1H), 1.94-2.05 (mn, 111), 1.05-1.13 (in, 2H), 0.78-0.85 (in, 2H).

MS: 423 4-32832A -114- Example 127: 2- 3[-4Iorplphnl--x--rprglx-Hqiaoiylmethyl] -peonly) -butyric acid raOH

.NH

qCHO

OH

Ti('PrO) 4 NaBH(OAc) 3

CH

2

CI

2 rt NaOCN AcOH OlEt 0 NaH DMF, rt 0 NaOHEtOH *C I 4-32832A A. Synthesis of -hydroxy-befl amJfinlo)- 5 prop argyl oxy-phenyli-(4-i sopropyl- Cl phenyl)-methanone

OH

NH

0 00 i To a solution of 267 mg (0.91 mmol) [2-(3-hydroxy-benzylamiflo)-5- propargyloxyphenyl]-(4-isopropylbphefyl)methanone in 5 Ml CH 2

CI

2 are added 122 mg (1.00 mmol) 3-hydroxy-benzaidehyd and 404 p1l( 1 3 7 nimol) tetra-isopropoxy-titaflium.

The deep red solution is stirred for 6 h at rt. Then 289 mg (1.37 mmol) sodium triacetoxyborohydride and 200 p1l EtOH are added and stirring is continued overnight.

The resulting yellow-orange suspension is distributed between water and CH 2

CI

2 Filtration of the organic layer through Hiflo is followed by washing with bicarbonate solution and concentrated The crude product is purified by chromatography (hexane/ethyl acetate) to yield a red oil.

'H-NM.R (300 MHz, CDC1 3 8.57 (broad t, NH), 7.61 2H1), 7.30 2H), 7.17-7.24 (in, 214), 7.07 (dd, 114), 6.94 1H1), 6.84 (broad s, 1H), 6.72 1H1), 6.65 1H), 4.78 (broad s, OH), 4.5 1-4.53 (in, 2H), 4.43 2H), 2.99 (hept, 111), 2.47 11H), 1.39 6H).

MS: B. Synthesis of 1 (-yrx-ezl-4(-spoy-hny)6poaglx

H-

quinazolin-2-one 4-32832A -116-

OH

N 0 00 A solution of 3.0 g (7.51 mmol) of the product prepared in step A in 45 ml AcOH is N treated with 732 mg (11.3 mmol) sodium cyanate. The dark red solution is stirred for S2 h at rt. The resulting yellow-orange suspension is diluted with water and filtered.

N The orange product is washed well with water and diethyl ether to yield an orange solid. m.p. 230 °C.

'H-NMR (300 MHz, DMSO-d 6 9.36 (broad, OH), 7.68 2H), 7.36-7.49 4H), 7.31-7.34 1H), 7.04-7.12 1H), 6.64 (dd, 2H), 6.58 1H), 5.39 (broad s, 2H), 4.76 2H), 3.65 1H), 2.99 (hept, 1H), 2.47 1H), 1.26 6H).

MS: 539 C. Synthesis of 2- 3-[4-(4-isopropyl-phenyl)-2-oxo-6-propargyloxy-2H-quinazolin-1ylmehtyl]-peony}-butyric acid ethyl ester N O

O

o C A suspension of 200 mg (0.47 mmol) of the phenol prepared in step B in 3 ml DMF is cooled with an ice/water bath and treated with 27 mg (0.61 mmol) sodium hydride. A yellow solution formed to which 83 1l (0.56 mmol) 2-bromo-butyric acid ethyl ester is added after 15 minutes. Rapid reaction sets in and after another 15 minutes the reaction mixture is hydrolyzed by the addition of 2 ml water and 5 ml ethyl acetate.

4-32832A -117- 0 Extractive work-up affords a yellow resin, which is chromatographed (hexane/ethyl acetate).

'H-NMR (300 MHz, CDCI 3 7.75 2H), 7.48 1H), 7.38 2H), 7.30 (dd, 1H), Z 7.22 1H), 7.19 1H), 6.91 1H), 6.85 (broad s, 1H), 6.72 (dd, 1H), 5.50 0 (broad, 2H), 4.63 2H), 4.51 1H), 4.14 2H), 3.02 (hept, 1H), 2.54 1H), 1.94 (quint, 2H), 1.32 6H), 1.20 3H), 1.05 3H).

i MS: 539 (M+1) 00 I D. Synthesis of 2-{3-[4-(4-Isopropyl-phenyl)-2-oxo-6-propargyloxy-2H-quinazolin-1- 0 ylmethyl]-phenoxy} -butyric acid O OH 0

N

A solution of 140 mg (0.26 mmol) of the ester prepared in step D in 3 ml MeOH is treated with 2 ml 2N NaOH. After heating to 70 OC for 2 h, the reaction mixture is distributed between ethyl acetate and water. The aqueous phase is adjusted to pH 1 by the addition of 1 N HC1. The crude product is chromatographed (MeOH/CH 2 C2) to give the corresponding acid. m.p. 189 OC (dec.).

'H-NMR (300 MHz, DMSO): 7.70 2H), 7.40-7.50 4H), 7.34 1H), 7.11 (t, 1H), 6.77 (broad s, 1H), 6.69 2H), 5.40 (broad, 2H), 4.76 2H), 4.29 (broad t, 1H), 3.65 2H), 3.01 (hept, 1H), 1.67-1.86 1H), 1.27 6H), 0.92 3H).

MS: 511 The compound of the following example is prepared by analogy: 4-32832A -18 Example 128: 2- 3[-4Iorplphnl--x--rpaglx-Hqiaoin-I ylmethyl]-pheloxyl 2-methy1-propioflic acid Ny~o 0 S 0 'IH-NMR (300 MHz, CDC1 3 7.73 2H), 7.47 IH), 7.37 2H), 7.30 (dd, 1H), 7.22 (dd, 1H), 7.16 IH), 6.98 1H), 6.85 (broad s, 1H), 6.79 1H), 5.47 (broad, 4.63 2H1), 3.00 (hept, 111), 2.53 (broad t, 1H), 1.50 6H1), 1.31 (d, 6H1).

MS: 511 4-32832A-19 Example 129: 4-(4-Isopropyl-phelyl)-lI [2-(2-methoxy-ethoxy)pyridn3-ymethyl- 6 prop-2-ylyloxy- I H-quinazolifl-2-ofle

N_

0 NaBH 4 EtOH, RT CI N HO0 LIHCU, CUSOD 4 Methoxyethall 10000C 0N.

HO 0 7 00 Diisopropyiethylamlifle dioxane, rt, 5 min.

100 18 h NaOCN, AcOH rt, 2 h 15, 0 4-32832A -120- A. Synthesis of (2-chloro-pyridin-3-yl)-methanol C N Z HO N STo a solution of ethyl 2-chloronicotinate (Ig, 5.39 mmol) in 10 ml EtOH at room temperature is added 2.04 g (53.9 mmol) NaBH 4 over 30 minutes in several portions.

4 The solution is stirred for. The excess borohydride is quenched by the addition of 00 methanol. The solvents are evaporated and the residue partitioned between

C

I dichloromethane and water. The aqueous Phase is extracted 3 x with 10 ml of dichloromethane. The combined organic layers are washed with brine, dried with 1 N MgSO4, filtered and evaporated in vacuo to yield a light yellow oil.

'H-NMR (300 MHz, CDCl 3 8.42 1H), 8.04 1H), 7.40 1H), 5.41 3H) 4.82 2H).

MS: 144 (M+1) B. Synthesis of [2-(2-methoxy-ethoxy)-pyridin-3-yl]-methanol

N

HO N.

153 mg (19.2 mmol) LiH is added to 10 ml methoxyethanol and the mixture is stirred for 5 min until evolution of gas ceases. 690 mg (4.81 mmol) (2-Chloro-pyridin-3-yl)methanol is added followed by 110 mg (1.73 mmol) Cu and 115 mg (0.721 mmol) CuSO4 and the mixture is stirred at 100 0 C. After 2 days the reaction is cooled to r.t.

and filtered with help of methanol. After evaporation ether is added to the residue and extracted twice with brine, then dried with Na 2

SO

4 filtered and evaporated until constant weight is reached.

'H-NMR (300 MHz, CDCI 3 8.22 1H), 7.74 1H), 7.04 1H), 5.44 3H) 4.82 2H), 4.68 2H), 3.92 2H), 3.58 3H).

MS: 184 (M+1) 4-32832A 121 C. Synthesis of (4-isopropyl-phenyl)-( 2 [2-(2-methoxy-ethoxy)-pyridin-3-ylmethyl]- O amino) -5-prop-2-ynyloxy-phenyl)-methanone 0 I O N N

NH

00

O

>0 To a solution of 400 mg (2.18 mmol) [2-(2-methoxy-ethoxy)-pyridin-3-yl]-methanol in 4 ml dioxane at r.t. is added 1.12 ml (6.55 mmol) Hinig's base followed by 170 jl (2.18 mmol) mesyl chloride and the mixture is stirred for 5 min. 641 mg (2.18 mmol) (2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone is added to this mixture with the addition of 1 ml of dioxane. The reaction mixture is then heated to 100 oC and stirred overnight. The mixture is partitioned between ether/water and the organic layer is washed with brine, dried with Na 2

SO

4 filtered and evaporated. Flashchromatography (ethyl acetate/ether 1:1) yields a yellow oil 'H NMR (300 MHz, CDC1 3 8.04 1H), 7.56-7.64 3H), 7.30 2H), 7.20 (d, 1H), 7.08 (dd, 1H), 6.84 (dd, 1H), 6.70 1H), 4.58 2H), 4.46 2H), 3.80 (m, 2H), 3.44 3H), 2.98 (hept, 1H),1.32 6H).

MS: 459 (M+l) 4-3283 2A 122 D. Synthesis of 4-(4-isopropyl-phenyl)- I -methoxy-ethoxy)-pyridifl- 3 -ylm ethyl] Cl 6-prop-2-yriyloxy- 1 H-quinazolin-2-ofle 0 N) s- N >0 00 To a solution of 200 mg (0.436 mmol) (4-Isopropyl-phenyl)-(2- {[2-(2-methoxyethoxy)-pyridin-3 -ylmethyl] -aminlo} 5 prop-2-ynyloxy-pheflyl)-methaflofe in 1.5 ml acetic acid is added 28 mg (0,436 mnmol) sodium cyanate. After stirring for 2 h the solvent is removed in vacuo and the residue is partitioned between CH 2 C1 2 and water.

The organic layer is dried and evaporated. Purification of the crude product by flashchromatography

(CH

2 Cl 2 /ether 3:7) affords a yellow oil.

'H NMR (300 MI-z, CDC1 3 8.06 111), 7.74 2H), 7.30-7.52 (in, 6H), 6.78 (dd, I1H), 5.64 2H), 4.62-4.66 (in, 4H), 3.84n(dd, 2H4), 3.50 3H), 3.02 (hept, I H), 2.56 1H), 1.32 6H).

MS: 484 4-32832A 123 Example 130: Synthesis of 1- [6-(2-hydroxy-ethoxy)-pyridif-2-ylmethyl- 4 4 isopropyl-phenyl)-6-propargyloxy- H-quinazolin-2-one pOCI K2CO3 HO N COON HCOOH C1 N COd H 2 CA N COCH

THF

,Ia BuO N COOH me -I 1K 2 C0 3 acetone t BuO N CH0 Dess-Martin 'DuO N CH 2 OH 'uO N COO~e TI(OYPr)d NsBH(OAc 3

CHPCI

NaOCN AcOH

F

3

CCOOH

CHCI,

KCOS

a/,cetone 4-32832A -124r A. Synthesis of 6-chloro-pyridine-2-carboxylid acid 0 CI N COOH A suspension of 4.0 g (28.8 mmol) of 6-hydroxypicolinic acid, 6.0 ml phosphorus oxychloride and 20 g phosphorus pentachloride is slowly heated to 90 oC within 00 hours. Stirring is continued for another 12 h. After cooling to r.t. the mixture is N quenched by careful addition of 1.4 ml formic acid. Concentration under HV affords S5.36 g of a dark solid which is subjected to hydrolysis in water (50 ml) in the presence I of 5.56 g (40 mmol) potassium carbonate. Extractive work-up with petroleum ether/ water and cone. i.v. results in a slightly yellow solid. m.p. 188-190 oC.

'H-NMR (300 MHz, CDC13): 8.17 (dd, 1H), 7.93 1H), 7.62 (dd, 1H).

MS: 158 (M+1) B. Synthesis of 6-tert-butoxy-pyridine-2-carboxylic acid t BuO N COOH A solution of 2.70 g (17.1 mmol) of 6-chloro-pyridine-2-carboxylic acid in 200 ml THF is heated for 19 h to reflux. Then the mixture is poured into water and adjusted to neutral pH by the addition of citric acid. Extractive workup with ethyl acetate yields a slightly yellow solid.

'H-NMR (300 MHz, CDC13): 7.72 2H), 6.94 (dd, 1H), 1.64 9H).

MS: 140 butene] 4-32832A 125 r C. Synthesis of 6-tert-butoxy-pyridine-2-carboxylic acid methyl ester 00

(N

S'BuO cooMe A yellow suspension of 2.60 g (13.3 mmol) of 2-tert-butoxy-pyridine-2-carboxylic acid and 2.8 g (20 mmol) potassium carbonate in 40 ml acetone is treated at r.t. with S 2.64 g (18.6 mmol) of iodomethane. After stirring for 4 h at 40 OC the mixture is N distributed between water and ethyl acetate. Concentration of the organic layer affords Sa yellow oil.

N 'H-NMR (300 MHz, CDCI 3 7.58-7.64 2H), 6.81 (dd, 1H), 3.94 3H), 1.64 (s, 9H).

MS: 154 butene] D. Synthesis of (6-tert-butoxy-pyridin-2-yl)-methanol t BuO N CH 2

OH

A solution of 2.32 g (11.1 mmol) of the ester from step C in 25 ml of ethanol is reduced by portion wise addition of 2.09 g (55. 4 mmol) of sodium borohydride.

HPLC analysis after stirring at r.t. for 12 hours shows complete reaction. The mixture is diluted with methanol and extracted with ethyl acetate water to yield a yellow oil.

'H-NMR (300 MHz, CDC1 3 7.61 (dd, 1H), 6.74 (dd, 1H), 6.56 (dd, 1H), 4.65 (d, 2H), 3.42 1H), 1.60 (s,9H).

E. Synthesis of 6-tert-butoxy-pyridin-2-carbaldehyd BuO N CHO 4-32832A 126- 1.65 g (9.10 mmol) of the alcohol obtained in step D in 50 ml dichloromethane is N oxidised with 3.86 g (9.10 mmol) of Dess-Martin periodinane. The reaction is complete after 12 h. The reaction mixture is extracted with ethyl acetate aqueous Z sodium thiosulphate solution and the organic layer concentrated i.V. Flashchromatography of the crude product (petroleum ether ethyl acetate) affords a yellow oil.

'H-NMR (300 MHz, CDC1 3 9.91 1H), 7.67 1H), 7.50 (dd, 1H), 6.86 (dd, 1H), 00 S 1.66 9H).

CI MS: 124 butene] I F. Synthesis of {2-[(6-tert-butoxy-pyridin-2-ylmethyl)-amino]-5-propargyloxyphenyl} -(4-isopropyl-phenyl)-methanone N OtBu

NH

A solution of 600 mg (2.05 mmol) of (2-amino-5-propargyloxy-phenyl)-4-isoproylphenyl)-methanone and 403 mg (2.25 mmol) of the aldehyde obtained in the step above in 18 ml dichloromethane is treated with 872 mg (3.07 mmol) of titanium(IV)isopropoxyde. The imine obtained after stirring overnight is reduced with 650 mg (3.07 mmol) of sodium triacetoxyborohydride in the presence of 2.4 ml of EtOH. The crude product after extractive workup with ethyl acetate petroleum ether is purified by flash chromatography (ethyl acetate petroleum ether) to yield a yellow oil.

'H-NMR (300 MHz, CDC1 3 7.61 2H), 7.46 (dd, 1H), 7.30 2H), 7.21 1H), 7.04-7.11 1H), 6.86 1H), 6.72 1H), 6.63 1H), 4.53 2H), 4.48 2H), 2.99 (hept, 1H), 2.48 1H), 1.60 9H), 1.34 6H).

MS: 457 (M+1) 4-32832A 127 G. Synthesis of 1-[(-etbtx-yidn2ymty)4(-iorplpey)6 propargyloxy- 1 H-quinazolin-2-ofle A solution of 120 mg (0.26 mmol) of the starting material (step F) in 3 ml acetic acid is cyclised with 21 mg (0.315 mmol) sodium cyanate overnight to afford the quinazolinone after flash-chromatography (hexane ethyl acetate). m.p. 62-65 'C.

'H-NMR (300 MHz, CDC1 3 7.72 2H), 7.46-7.50 (in, 2H1), 7.43 111), 7.39 (d, 2H), 7.31 (dd, 1H), 6.90 111), 6.52 111), 5.56 (broad s, 2H), 3.03 (hept, 111), 2.55 1H), 1.41 9H1), 1.33 611).

MS: 482 H. Synthesis of 1I(-etprdn2ymehl -4iorplphnl--rpryoy I H-quinazolin-2-ofle N OH Ny0

N

A mixture of 60 mg 13 mraol) of the t-butyl ether (step G) in 6 ml dichioromethafle is treated with 15 p1l trifluoroacetic acid and stirred overnight at rt. Extractive workup with aqueous sodium bicarbonate solution dichioromethane yields a yellow solid.

m.p. 219-222 'C.

4-32832A 128- 'H-NMR (300 MHz, CDC1 3 7.76 2H), 7.55 1H), 7.32-7.48 5H), 6.50 (d, 1H), 6.23 1H), 5.38 (broad s, 2H), 4.69 2H), 3.04 (hept, 1H), 2.58 1H), 1.34 S 6H).

Z MS: 426 (M+1) I. Synthesis of Synthesis of 1-[6-(2-hydroxy-ethoxy)-pyridin-2-ylmethyl]-4-(4 Sisopropyl-phenyl)-6-propargyloxy- 1 H-quinazolin-2-one 00 OO

OH

N

0 A suspension of 40 mg (0.094 mmol) of the pyridyl-alcohol obtained in step H, 16 mg (0.132 mmol) 2-bromoethanol and 19 mg (0.141 mmol) potassium carbonate in 4 ml acetone is stirred overnight at 70 OC. The crude product obtained after extraction with ethyl acetate /water is purified by flash chromatography (hexane ethyl acetate) to yield a yellow oil.

'H-NMR (300 MHz, CDCl 3 7.74 2H), 7.32-7.56 6H), 6.92 1H), 6.68 (d, 1H), 5.53 (broad s, 2H), 4.66 2H), 4.38-4.52 2H), 3.91 (broad, 2H), 3.02 (hept, 1H), 2.75 (broad, OH), 2.56 1H), 1.33 6H).

MS: 470 (M+1) 4-32832A 129- Example 131: 1 [-hooprdn3ymtyl--4iorplpey)6 prop argyl oxy- I1H-quinazolin-2-ofle N H 0 00 0nNC

I

NBS

cc", Br n N

C

KCO,

DMEU

NaOCN AcOH A. Synthesis of 2-brornomethyl-2-chloro-pyridifle Br

I

N CI A solution of 1.28 g (10.0 mmol) 2-chloro-5-methyl-pyridifle in 25 ml carbon tetrachloride is treated with 1.79 g (10.0 mmol) of freshly recrystallised N-bromosuccinimid and 30 mg benzoyl peroxide. The mixture is heated to reflux for 17 h and filtered. The filtrate is washed with water and concentrated. Flash chromatography (hexane ethyl acetate) results in a white low melting solid. m.p. 40-43 'C.

MS: 210 208 (100), 206 (75) (chloro-bromo isotope pattern) 4-32832A -130 B. Synthesis of {2-[(6-chloro-pyridin-3-ylmethy1)-amiloI-S -propargyloxy-phenyl)}- (4-isopropy1-pheny1)-methalofe 7 CI

NH

0 00 To a solution of 323 mg (1 .10 mmnol) of (2-amino-5 -propargyloxy-phenyl)- 4 isopropyl-phenyl)-methalofe and 250 mg (1.21 mmol) of 2-bromomethyl-2-chloropyridine (step A) in 2 ml 1 ,3-dimethyl-2-imidazolidiflofe (DMEU) 213 mg (1.54 nimol) of potassium carbonate are added. The reaction is complete after stirring for 2 h at 60 The cooled yellow suspension is distributed between ethyl acetate and bicarbonate solution. Flash chromatography (hexane ethyl acetate) affords a yellow solid. m.p. 96 'C.

'H-NMR (3 00 Mliz, CDCl 3 8.49 111), 8.40 I 7.67 (dd, I1H), 7.61 2H), 7.31 211), 7.30 1H), 7.23 1H1), 7.08 (dd, 1H), 6.59 1H), 4.53 2H1), 4.48 2H1), 2.99 (hept, 1H), 2.48 111), 1.31 6H).

MS: 419 4-32832A 131 0 C. Synthesis of 1-[(6-chloro-pyridin-3-ylmethyl)-4-(4-isopropyl-phenyl)-6- C, propargyloxy- H-quinazolin-2-one oNy SA solution of 320 mg (0.764 mmol) of the starting material (step B) in 4 ml acetic acid is cyclised with 74 mg (1.15 mmol) sodium cyanate. A thick suspension results after 3 h. Distribution between ethyl acetate and aqueous bicarbonate solution, concentration of the organic layer and flash chromatography (hexane ethyl acetate) of the crude product yields the title quinazolinone in the form of a yellow solid. m.p. 210 oC.

'H-NMR (300 MHz, CDCl 3 8.44 1H), 7.72 2H), 7.67 (dd, 1H), 7.61 1H), 7.38 2H), 7.36 (dd, 1H), 7.27 1H), 7.21 1H), 5.51 (broad, 2H), 4.65 2H), 3.01 (hept, 1H), 2.55 1H), 1.31 6H).

MS: 444 (M+1) 4-32832A 132 Example 132: (4-Isopropy-phenyl)-(2- {[6-(2-methoxy-ethoxy)-pyfl din-2-ylmethyl]amino) -5 .propargyloxy-phenyl)-methalofle N OBu .NH rN OH I A

,NH

FCCOOH

CH

2 01 2 0

K

2 c0 3 acetone A. Synthesis of {2..[(6..hycroxy-pyridifl-3-ylmethyl)-amiflo] -5-propargyloxy-phenyl) (4-isopropy1-pheny1)-nmethaflofe

NOH

NH

4zV 0 A solution of 120 mg (0.263 mmol) of {2..[(6.tert-butoxy-pyridifl-2-ylmethyl)-amino]- -propargyloxy-phenyl) (4-isopropyl-phenyl)-methalone (see above in 3 m.l dichioromethane is treated with 30 jAl tnifluoroacetic acid and stirred overnight.

4-32832A 133 Workup with ethyl acetate and aqueous bicarbonate solution and flash chromatography of the crude product results in a yellow solid. m.p. 189-193 'C.

0 'H-NMR (300 MHz, CDCl 3 7.65 2H), 7.40 (dd, 1H), 7.33 2H), 7.24 111), Z 7.08 (dd, 111), 6.58 1H), 6.45 1H), 6.24 111), 4.55 2H), 4.40 2H), 3.01 (hept, 111, 2.49 111), 1.32 611).

MS: 401 00 B. Synthesis of Synthesis of (4-isopropy-phenyl)-( 2 {[6-(2-methoxy-ethoxy)-PYrldiflc-i 2-yhmethy1] -amino) -5-propargyloxy-pheny1)-methaflone N 0

NH

0 A suspension of 50 mg 125 nimol) of the pyridyl-alcohol obtained in step A, 13 Al 13 7 mmol) 2-bromoethyl methyl ether and 26 mg 187 mrnol) potassium carbonate in 6 ml acetone is stirred overnight at 70 The crude product obtained after extraction with ethyl acetate water is purified by flash chromatography (hexane ethyl acetate) to yield a yellow oil.

'H-NMR (300 MHz, CDC1 3 8.83 NH), 7.62 2H), 7.52 (dd, 1H), 7.30 2H), 7.21 IlH), 7. 10 (dd, I1H), 6.90 1lH), 6.69 (dd, 2H), 4.60 (dd, 2H), 4.5 3 2H), 4.48 2H), 3.78(dd, 211), 3.44 3H), 2.99 (hept, 1H), 2.48 IH), 1.31 6H).

MS: 459 4-32832A 134 Example 133: 1- (2-Hydroxy-pyridin-3 -ylmethy1)-4-(4-isopropy-pheflyl)- 6 CI propargyloxy- I H-quinazolin-2-ofle Z

N

00 A solution of 290 mg (0.63 5 mmol) of {2-[(2-tert-butoxy-pyridifl-3-ylmethyl)amino] -5 propargyloxy-pheny} -(4-isopropyl-phel)-methalofe and in 7 ml acetic acid is reacted with 50 mg (0.762 mmol) sodium cyanate. After stirring overnight the mixture is distributed between ethyl acetate and aqueous bicarbonate solution. The organic layer is concentrated to yield the title compound in the form of a yellow solid.

m.p. 121-123 'C.

'H-INMR (300 MiHz, CDCI 3 7.74 2H), 7.48-7.55 (in, 3H), 7.32-7.43 (mn, 4H), 6.26 1H), 5.48 2H), 4.66 2H, 3.02 (hept, IH), 2.66 1H), 1.33 6H).

MS: 426 The compounds of the following examples are prepared by analogy to the example described above: 4-32832A -135 Example 134: 4-(4-Isopropyl-phelyl)- I (5-methoxy-pynidil-2-ylmethyl)- 6 C1propargyloxy- IH-quiflazolin 2 one o~ 0I

N

N0 000 mn. p. 136-137 'C 'H-NMR (300 MHz, CDCI 3 8.25 (dd, 1H), 7.68-7.74 (in, 3H), 7.42-7.48 (in, 2H), 7.34-7.41 (mn, 3H), 7.14 (dd, I 5.60 (broad, 4..65 2H), 3.84 3H), 3.02 (hept, IH), 2.65 1H), 1.33 6H).

MS: 440 Example 135: 4-(4-Isopropyl-pheyl) 1 -(6-iethy1-pyridifl-2-ylinethyl)- 6 propargyloxy- 1H-quinazolin-2-ofle

N

N0 m. p. 165-166 'C 'H-NMR (300 MHz, CDCI 3 7.75 2H), 7.45-7.55 (in, 3H), 7.38 2H), 7.34 (dd, I1H), 7.10 I 7.05 I1H), 5.62 (broad, 2H), 4..65 2H), 3.02 (hept, I1H), 2.60 3H), 2.55 1H), 1.33 6H).

MS: 424 4-32832A 136- Example 136: 1 (-hooprdn4ymtyl--4iorplpey)6 propargyloxy- I H-quinazolin-2-ofle 'H-NMR (300 MHz, CDCI 3 8.35 1H), 7.77 211), 7.57 1H), 7.41 2H), 7.3 7 (dd, IlH), 7.24 1 7.16 I1H), 7.06 I1H), 5.62 (broad s, 2H), 4.67 (d, 2H), 3.04 (hept, 1H), 2.57 1H), 1.34 6H).

MS: 444 Example 137: 1 (-hooprdn3ymtyl--4iorplpey)6 propargyloxy- IH-quinazolin-2-ofle CIp 'H-NMR (300 MHz, CDC1 3 8.84 I 7.77 2H), 7.65 IlH), 7.41 2H), 7.31-7.39 (in, 2H), 7.16 (dd, 1H), 7.07 1H), 5.61 2H), 4.67 2H), 3.91 (broad, 2H), 3.04 (hept, IH), 2.56 111), 1.33 6H).

MS: 444 4-32832A 137 Example 138: 4-(4-Isopropyl-phenyl)-1- {6-[2-(2-methoxy-ethoxy)-ethoxy]-pyri~din-2ylmethyl)-6-propargyloxy- I H-quinazolin-2-ofle N0 Z

N

00 'H-NMR (300 lfz, CDCl 3 7.74 2H), 7.47-7.65 (in, 311), 7.38 2H), 7.35 (dd, 6.93 1H1), 6.66 111), 5.52 (broad, 4.66 2H), 4.41 (dd, 211), 3.78 (dd, 2H), 3.79 (dd, 2H1), 3.65-3.7 1 (in, 2H), 3.54-3.60 (in, 211), 3.39 3H), 3.02 (hept, I1H), 2.5 7 I 1. 33 611).

MS: 528 Example 139: 4-(4-Isopropyl-phenyl)- I [6-(2-methoxy-ethoxy)-ethoxy)-pyrdifl 2 ylmethyl)-6-propargyloxy-l H-quinazolin-2-one N 0 N0 'H-NMR (300 MHz, CDC1 3 7.74 2H), 7.47-7.63 (mn, 311), 7.39 211), 7.34 (dd, IH), 6.92 111), 6.69 111), 5.53 (broad, 211), 4.66 211), 4.38-4.43 (in, 211), 3.66-3.71 (in, 211), 3.42 3H), 3.02 (hept, IH), 2.56 111), 1.33 6H).

MS: 484 4-32832A 138 Example 140: 5-Allyl- I -benzyI-6-hydroxy-4(4isopropylphenyI)-l H-quinazolin-2one O 2 0

HO

H

allyl bromide Nal

DIEA

acetone rt, 18 h

N

2

H

THF

*78*C, I h .N0 2 -01-1 Jones reagent acetone O'C to RT, 2 h~ DIMEU /water z microwave 180*C, 30 min Fe acetic acid rt, 16 h benzaldehyde sodium cyanoborohydride acetic acid 1 ,2-dichloroethafle rt, 16 hi

NH

0

HO

NaOCN acetic acid rt, 16 h 4-32832A -139 A. Synthesis of 5 -allyloxy-2-nitro-beflzaldehyde 0- 00 To a solution of 25 g (150 mmol) 5-hydroxy-2-nitro-benladehyde and 44.89 g (299 mmol) sodium iodide in 400 ml acetone are added 51.2 ml (299 mmol) IN- 0_ ethyldiisopropylalifle and 25.3 ml (299 mmol) allyl bromide. After stirring for 18 h at r.t. the reaction mixture is filtered and the solvent is evaporated. Extraction of the residue with I M aqueous hydrochloric acid dichioromethane followed by N chromatography (hexane ethyl acetate) yields 5.-allyloxy-2-nitro-benzaldehyde.

'H NMR (300 MHz, CDCl 3 10.45 1H), 8.15 IH), 7.32 IH), 7.16 (dd, IH), 6.03 (ddt, 1H), 5.45 (dq, IH), 5.37 (dq, 1H), 4.69 (dt, 2H).

B. Synthesis of (5-allyloxy-2-nitrophenyl)(4isopropylphenyl)-methanol

OH

A solution of 4-isopropylpheflhagflesium bromide prepared from 2.35 g (96.5 mmol) magnesium and 18.15 g (96.5 mmol) I1-bromo-4-isopropylbenzene in 80 ml THIF is added slowly at -78 TC to a solution of 20 g (96.5 mmol) 5-allyloxy-2-nitrobenzaldehyde in 200 ml THF. After allowing the reaction mixture to warm up to r.t.

saturated aqueous amnmonium chloride solution is added. Extraction with ethyl acetate followed by chromatographic purification on silica (hexane ethyl acetate) yields allyloxy-2-nitro-phefyl)(4isopropyl1phenyl)-methanol.

'H NMvR (300 MIHz, CDC1 3 8.05 IH), 7.34 IH), 7.25 2H), 7.16 2H), 6.88 (dd, lH), 6.50 IH), 6.01 (ddt, IH), 5.40 1H), 5.33 1H), 4.62 2H), 2.88 (hept, 1H), 1.22 6H).

MS: 310 4-32832A -140- C. Synthesis of (5-allyloxy-2-nitro-phenyl)-(4-isopropyl-phenyl)-methanone

NO

2 In

CI

A solution of 16.38 g (50 mmol) (5-allyloxy-2-nitro-phenyl)-(4-isopropyl-phenyl)- 00 methanol in 60 ml acetone is treated at 0 OC with 20 ml (53.4 mmol) Jones reagent.

After stirring for 2 h at r.t. isopropanol, an aqueous solution of sodium bisulphite and saturated aqueous ammonium chloride solution are added. Extraction with dichloromethane affords (5-allyloxy-2-nitro-phenyl)-(4-isopropyl-phenyl)-methanone.

'H NMR (300 MHz, CDCI 3 8.24 1H), 7.69 2H), 7.30 2H), 7.09 (dd, 1H), 6.89 1H), 6.03 (ddt, 1H), 5.43 (dq, 1H), 5.36 (dq, 1H), 4.65 (dt, 2H), 2.97 (hept, 1H), 1.27 6H).

D. Synthesis of (5-allyloxy-2-amino-phenyl)-(4-isopropyl-phenyl)-methanone

NH

2 -0 0 To an ice chilled solution of 16 g (5-allyloxy-2-nitro-phenyl)-(4-isopropyl-phenyl)methanone in 65 ml acetic acid are added 21.8 g iron powder. A precipitate that is formed is brought into solution by addition of additional acetic acid. After stirring for 16 h at r.t. the reaction mixture is filtered and basified by addition of aqueous potassium hydroxide solution. Extraction with dichloromethane yields (5-allyloxy-2amino-phenyl)-(4-isopropyl-phenyl)-methanone.

'H NMR (300 MHz, CDC1 3 7.62 2H), 7.31 2H), 7.03 6.98 (min, 2H), 6.71 (d, 1H), 5.98 (ddt, 1H), 5.32 (dd, 1H), 5.25 (dd, 1H), 4.39 2H), 2.99 (hept, 1H), 1.31 6H).

MS: 296 4-32832A -141- E. Synthesis of (2-allyl-6-amino-3-hydroxy-phenyl)-(4-isopropyl-phenyl)-methanone

SNH,

0HO SIn a sealed tube a mixture of 50 mg (0.17 mmol) (5-allyloxy-2-nitro-phenyl)-( 4 00 isopropyl-phenyl)-methanone, 1 ml DMEU and 1 ml water is heated by microwave N irradiation to 180 0 C for 30 min. Water is evaporated and the resulting solution is purified by reversed phase preparative HPLC to yield the rearranged product.

'H NMR (300 MHz, CDCl 3 7.79 2H), 7.30 2H), 6.81 1H), 6.60 IH), 5.80 (ddt, 1H), 5.03 (dq, 1H), 5.01 (dq, 1H), 3.16 (dt, 2H), 2.97 (hept, IH), 1.28 (d, 6H).

MS: 296 F. Synthesis of 2 -allyl-6-benzylamino-3-hydroxy-phenyl)(4isopropyl-phenyl) methanone 7

IN

NH

HO

To a solution of 39 mg (0.13 mmol) (2-allyl-6-amino-3-hydroxy-phenyl)-(4-isopropylphenyl)-methanone and 13.34 pl1(13 mmol) benzaldehyde in 1.3 ml 1,2-dichlorethane and 0.3 g molecular sieves (4 A pore size) are added after 1 h 13 mg (0.18 mmol) sodium cyanoborohydride and 7.55 jil acetic acid (0.13 mmol). After stirring for 16 h at r.t. 1 M hydrochloric acid is added to destroy the excess of hydride equivalents. By adding 1 M NaOH the mixture is basified. The crude product obtained by extraction with dichloromethane is purified by reversed phase preparative chromatography.

4-32832A 142 'H 7NMR (300 MHz, CDCI 3 7.78 2H1), 7.31 2H), 7.28 7.16 (in, 5H1), 6.82 (d, CK1 1IH), 6.56 IH), 5.79 (ddt, 111), 5.02 (dd, 111), 5.01 (dd, 111), 4.22 2H), 3.17 (d, o 2H), 2.99 (hept, 1H), 1.30 6H).

ZMS: 386 G. Synthesis of 5 -allyl-l1 benzyl-6-hydroxy-4(4-isopropyl-phenyl)-l H-quinazolin-2one 00

N-I

N.

HO

A solution of 15 mg (39 jtmol) (2-ally1-6-benzylamfino-3hydroxy-phenyl)( 4 isopropyl-phenyl)-methalone and 2.5 mg sodium cyanate in 0.2 ml acetic acid is stirred at r.t. for 16 h. Aqueous sodium hydroxide solution is added and the product is extracted with dichioromethane.

'H NMvR (300 MHz, CDC1 3 7.48 2H), 7.33 -7.24 (in, 8H), 7.14 1H), 5.65 (ddt, I 5.52 211), 5. 10 (dd, 11H), 4.95 (dd, I1H), 3.20 2H), 2.97 (hept, I1H), 1.28 6H).

MS: 411 The compounds of the following examples are prepared by analogy to the example described above: 4-32832A 143 Example 141: 5-Allyl- 1 -[-2clr-toy--ehx-ezl--yrx--4 isopropyl-phenyl)- 1 H-quinazolifl-2-ofle 'H NMR (300 MHz, d 6 DMSO): 9.66 1H), 7.31 (in, 4H), 7.25 2H), 6.99 2H), 6.85 1H1), 6.69 lH), 5.47 5.32 (in, ifH), 5.29 2H), 4.64 1H), 4.30 (d, IH), 4.14 2H), 3.86 2H), 3.67 3H), 3.03 2H), 2.94 (hept, 1H), 1.21 (d, 6H).

MS: 519 1 (isotop pattern for one chioro atom) Example 142: 5-ly--yrx--4iorplpey) -thiophen-2-ylnlethyl- 1 Hquinazolin-2-one 1H NMIR (300 MHZ, CDC1 3 7.45 2H1), 7.39 1H), 7.31 7.23 (mn, 31H), 7.20 (dd, I1H), 7.11 (in, I1H), 6.93 (dcl, I1H), 5.69 5.60 (mn, I1H), 5.61 2H), 5.13 (dt, IlH), 5.00 (dt, Ili), 3.17 2H), 2.95 (hept, IH), 1.26 6H).

MS: 417 4-32832A -144- Example 143: 5 -Allyl-6-hydroxy-4-(4-isopropyl-PhenylD-l-(3 -methylsuiphailylbutyl)- 1 H-quinazolin-2-ofle 'H NMR (300 MHz, CDCl 3 7.47 2H), 7.3 8 2H), 7.25 7.22 (in, 2H), 6.3 5 (s, broad, I1H), 5.63 (ddt, I 5.05 I 4.90 I1H), 4.40 2H), 3.20 (dd, 1 3.18 (dd, 1H1), 2.94 (hept, 1H), 2.88 2.76 (mn, 1H), 2.13 3H), 2.11 1.87 (in, 2H), 1.88 3H), 1.25 6H).

MS: 423 Example 144: 5-AllyI-6-hydroxy-4-(4-isopropyl-phenylD- 1-(1 -methyl-2-phenylethyl)- 1 H-quinazolin-2-onle 'HNMR (300 MHz, CDCl 3 7.47 7.43 (in, 3H), 7.32 7.11 (in, 8H), 6.88 (broad, IH), 5.63 (ddt, 1H), 5.00 (dd, IH), 4.88 (in, IH), 4.83 (dd, lH), 3.52 (dd, 1H), 3.42 (dd, 1H), 3.22 (dd, IH), 3.18 (dd, IH), 2.94 (hept, IH), 1.71 3H), 1.26 6H).

MS: 439 4-32832A 145 Example 145: 5 All6hdox--4ioroy hnl--pyridin-3-ylmethyl- 1Hquinazolifl- 2 -ofle 'H NMR (300 MHz, d 6 DMSO): 9.74 1H), 8.56 1H), 8.46 (dd, IH), 7.61 (dt, 1H), 7.39 7.31 (in, 7H), 5.51 5.41 (mn, 3H), 4.70 (dd, 1H), 4.35 (dd, 1W), 3.08 (d, 2H), 2.98 (hept, 1H), 1.25 6H1).

MS: 412 Example 146: 5-Allyl-6-hydroxy-l 1 doy--ehx-bny)4(4iorpl phenyl)-1 H-quinazolifl-2-ofle- 'H NMR (300 MHz, d 6 DMSO): 9.71 1H), 8.93 1W), 7.35 7.30 (in, 6H), 6.95 1W), 6.68 6.57 (in, 2H), 5.44 (in, 1W), 5.30 2H), 4.68 lH), 4.33 1H), 3.70 3H), 3.06 (in, 2H), 2.97 (in, 1H), 1.25 614).

MS: 457 4-328-2A -146- Example 147: 5-Allyl-6-hydroxy-l-[2-(2-hydroxy-ethoxy)-bel]-4-(4-isopropyl- 00 N~ phenyl)- I H-quinazolin-2-one

OO

IN 0 00

HO

lH NMR (300M1z, d 6 DMSO): 9.70 1H), 7.38 2H), 7.35 2H), 7.30 IH), 7.22 (td, IH), 7.17 1H), 7.05 1H), 6.80 IH), 6.74 (dd, 11), 5.47 (ddt, II), 5.38 4.96 1H), 4.70 (dd, 1H), 4.36 (dd, IH), 4.12 2H), 3.79 2H), 3.09 2H), 2.98 (hept, IH), 1.25 6H).

MS: 471 Example 148: 5-Allyl-6-hydro xy-l-[3-(2-hydroxy-ethoxy phenyl)- I H-quinazolin-2-one ra H Ny0 SNy

HO

'H NMR (300 MHz, d 6 DMSO): 9.71 1H), 7.38 2H), 7.35 2H), 7.30 1H), 7.24 7.18 2H), 6.82 6.76 3H), 5.46 (ddt, 1H), 5.39 2H), 4.83 1H), 4.70 (dd, IN), 4.35 (dd, IH), 3.91 2H), 3.66 2H), 3.08 2H), 2.98 (hept, 1I), 1,25 6H).

MS: 471 4-3283 2A 147 Example 149: 5-Allyl- 1 -dim ethoxy-b efzyl)-hydrox y4(4isopropyl phenyl)lH-quinazolin-2-ofle 0 N Y0

HO

00 'H NMR (300 MHz, d 6 DMSO): 9.72 1H), 7.37 2H), 7.35 2H), 7.31 1H), 7.22 1H), 6.36 (in, 3H), 5.47 (ddt, 1H), 5.34 2H), 4.70 (dd, 1H), 4.34 (dd, 1H), 3.67 6H1), 3.08 2H), 2.98 (hept, IH), 1.25 611).

MS: 471 Example 150: 1 ezl6hdrx--4iopoy-hnl)5poy H-quinazolin-2one NH 1) H 2 /Raney N! HO 0 normal pressure, rt, 2h HO

.N

2) NaOCN/ AcOH N rL 2.5 h A solution of 200 mng (519 iimol) (2-allyl-6-benzylamino-3-hydroxy-phenyl)-( 4 isopropyl-phenyl)-methalone in 6 ml methanol is hydrogenated in the presence of Raney nickel catalyst during 2 h at normal pressure. The catalyst is filtered off and the filtrate is evaporated. A 100 mng portion of the residue is dissolved in 0.6 ml acetic acid and treated with 16.7 mg (258 iimol) sodium cyanate. for 2.5 h at The crude product obtained after extraction with dichioromethane aqueous sodium bicarbonate is triturated with ethyl ether and dichloromethane containing a small amount of methanol.

4-32832A 148 'H NMR (300 MHz, d 6 DMSO):9.58 1H), 7.41 7.16 (in, I 1H), 5.43 2H), 2.99 ri (hept, 1H), 2.19 (in, 2H), 1.25 6H), 1.18 (in, 2H), 0.36 3H).

0 MS: 413 The compound of the following example is prepared by analogy to the example described above: 00 Example 151: 6-yrx--sbtl4(-spoy-hnl--rplI-unzln 2-one N Y0

HO

'H NMR (300 MII-z, CDC1 3 7.44 2H), 7.36 1H), 7.27 2H), 7.11 I H), 5.7 (broad, 1H), 4.17 2H), 2.96 (hept, 1H), 2.86 (dd, 2.26 (hept, 1H), 1.31 1.19 (mn, 2H), 1.27 6H), 1.01 6H), 0.46 3H).

MS: 379 4-3283 2A 149 Example 152: 5-Cyclopropylmethyl-l1-(3 ,3-dimethy1-butyl)-6-hydroxy-4-( 4 -isopropyI- C1 phenyl)- I H-quinazolin-2-ofle Z 1) 3,3-dimethylbutyric aldehydle InNH, NH, NaCNBH, dizmtw acetk acid I 0 1 .2-dichloroethane

Y

HO 0 Pd(OAc) 2 HO 18 hr.t.

H

HO diethy4 ether

H

r.t,16 h 2) sodium cyanate 00 t.3h A. Synthesis of (6-amino-2-cyclopropylhnethyl-3hydroxy-phefyl)(4isopropylphenyl)methanone

NH

0

HO

A diazomethane solution is freshly prepared by adding 515 mg (5 mmol) N-nitroso-Nmethylurea .in small portions to a stirred mixture of 50 ml diethyl ether and 17.5 ml aqueous potassium hydroxide solution at 5 Ten minutes after the last addition, the organic layer is separated off and dried over solid potassium hydroxide.

This diazomethane solution is added to a concentrated solution of 1.00 g (3.39mmol) (2-allyl-6-amnino-3-hdoypey) 4iorplphnl-ehnn in diethyl ether containing 152 mg (0.68 mnmol) Pd(OAc) 2 After stirring for 16 h at r.t. the reaction mixture is filtered, evaporated to dryness and purified by flash column chromatography.

'H NMR (300 MI-z, CDCl 3 7.78 2H), 7.29 2H1), 6.77 IlH), 6.5 5 111), 4.70 1H), 3.40 (broad, 2H), 2.96 (hept, 1H), 2.35 2H), 1.27 6H), 0.88 (in, IH), 0.38 (in, 2H), 0.09 (in, 2H).

MS: 3 10 1)+ 4-32832A 150- S B. Synthesis of 5-cyclopropylmethyl- -(3,3-dimethyl-butyl)-6-hydroxy- 4 4 isopropyl-phenyl)-1 H-quinazolin-2-one 0 0 N 0

HO

oo00 A mixture of 100 mg (0.32 mmol) 6 -amino-2-cyclopropylmethyl-3-hydroxy-phenyl)- ,I (4-isopropyl-phenyl)methanone, 40.5 pl (0.32 mmol) 3,3-dimethylbutyric aldehyde and 28.5 mg (0.45 mmol) NaCNBH 3 in 0.5 ml 1,2-dichloroethane containing 18.5 pl (0.32 mmol) acetic acid is stirred for 18 h at To destroy the excess of hydride 0.1 M hydrochloric acid is added first before by the addition of 0.1 M aqueous sodium hydroxide the mixture is made alkaline. The intermediate is extracted with dichloromethane and purified by preparative reversed phase HPLC.

A 50 mg (0.13 mmol) portion of this intermediate is dissolved in 0.1 ml acetic acid and treated with 8.3 mg (0.13 mmol) sodium cyanate. After stirring for 3 h at r.t. the reaction mixture is extracted with dichloromethane and aqueous bicarbonate solution.

The residue obtained after evaporation of the organic phases is triturated with diethyl ether to obtain the pure title compound.

'H NMR (300 MHz, CDC13): 7.44 2H), 7.42 1H), 7.26 2H), 7.17 1H), 6.18 1H), 4.28 2H), 2.96 (hept, 1H), 2.34 2H), 1.72 2H), 1.28 6H), 1.09 9H), 0.70 1H), 0.35 2H), -0.08 2H).

MS: 419 (M+1) The compounds of the following examples are prepared by analogy to the example described above: 4-32832A-15- 0 Example 153:1 -Benzyl-5-cycopropymethyb6hydroxy4(4-isopropylIphenyl)l

H-

NI quinazolin-2-one NN y0

HO

00 'H NMR (300 MHz, CDCl 3 8.0 (broad 111), 7.47 2H), 7.29 7.22 (in, 8H1), 7.01 111), 5.49 2H), 2.96 (hept, 111), 2.36 2H), 1.27 6H1), 0.69 (in, 1H), 0.17 (in, 211), 18 (mn, 2H).

MS: 425 Examnple 154: 5-Cyclopropylmethyl- 1-(3 ,4-dimethoxy-benlZY)-6-hydroxy- 4 4 isopropyl-phenyl)- 1 H-quinazolil-2-ofle 01.

N y0

N

111 NMR (300 MHz, d 6 DMSO): 9.58 1H), 7.33 4H1), 7.27 111), 7.24 111), 6.98 111, 6.84 1H1), 6.69 (dd, 1H), 5.33 2H), 3.67 3H), 3.66 311), 2.95 (hept, 1H1), 2.20 2H), 1.22 611), 0.60 (in, 111), 0.05 (in, 211), -0.36 (mn, 2H).

MS: 485 4-3283 2A 152 Example 155: 5-ylpoymty--yrxy4(-spoy hnl--(3-methoxybenzyl)- 1 H-quinazolin-2-ofle 'HNMR (300 MIHz, d 6 DMSO): 9.60 1H), 7.35 2H), 7.33 2W), 7.28 111), 7.20 1H), 7.18 111), 6.82 6.74 (in, 3H), 5.87 2H), 3.67 3H), 2.96 (hept, IH), 2.21 2H), 1.22 6H), 0.61 (in, 1H), 0.05 (mn, 2H), -0.35 (mi, 2H).

MS: 455 Example 156: 5-Cyclopropylmethyl- 1 ,5-diinethoxy-benzyl)-6-hydroxy-4-( 4 isopropyl-phenyl)-l1H-quinazolin-2-one 'H NMR (300MHz, d 6 DMSO): 9.60 111), 7.34 4H), 7.28 1H), 7.17 1H), 6.35 3H), 5.32 2H), 3.65 6H), 2.95 (hept, 1H), 2.21 2H), 1.22 6H), 0.61 (mn, 1H), 0.05 (in, 2H), -0.36 (mn, 2H).

MS: 485 4-32832A-15 Example 157: 5-Cyclopropylmethylb6hydroxy I -(4-hydroxy-3-methoxy-beflzyl)- 4 (4-isopropyl-phelYl)- I H-quinazolin-2-oflC

OH

0 N y0

HO

NMR (300 MHz, 46DMSO): 9.59 1H), 8.91 IH), 7.33 4H), 7.28 1Kf), 7.27 I1-H), 6.94 I1H), 6.65 I1H), 6.60 (dd, I1H), 5.28 2H), 3.68 3H), 2.95 (hept, 1H), 2.20 2H), 1.22 6K), 0.60 (in, 1H), 0.04 (in, 2H), -0.36 (mn, 211).

MS: 471 4-32832A 154- Example 158: 1 ,4-Dimethoxy-phelyl)-propyl)]F 4-(4-isopropyl-pheflyl)-6propargyloxy- I H-quinazolin-2-ofle 0

M

0

OH

01-1* Dlborane OH Dess-Mortin (1 M in THF) I" periodiflane 0

CH

2

CI,

Meo

CHO

MeO 0 1

,NH

NaOCN 0- 0 ,N ys 4-32832A 155 A. Synthesis of 3-(3,4-dimethoxy-phenyl)-propan-l-ol 0 MeO Z OMe t A solution of 6.0 g (28.5 mmol) 3-(3,4-dimethoxyphenyl)-propionic acid in 120 ml anhydrous THF is cooled to 0 oC and treated within 15 minutes with 42.75 ml borane THF complex (1 M solution). Stirring is continued overnight at rt. The resulting clear 0 0 solution is cooled with an ice/water bath and hydrolyzed by the addition of 100 ml saturated ammonium chloride solution. Extractive work-up with diethyl ether Sfurnishes a colourless oil, which is purified by chromatography (hexane/ ethyl acetate) Ci to yield a colourless oil.

'H-NMR (300 MHz, CDCl 3 6.76-6.80 1H), 6.70-6.74 2H), 3.86 3H), 3.85 3H), 3.67 2H), 2.62-2.69 2H), 1.82-1.93 2H).

MS: 197 (M+1) B. Synthesis of 3-(3,4-dimethoxy-phenyl)-propionaldehyde

CHO

MeOj c OMe A solution of 2.0 g (10.2 mmol) of the aldehyde prepared in step A in 40 ml CH 2

C

2 is oxidised in the dark by the addition of 4.32 g (10.2 mmol) Dess-Marin periodinane.

The reaction is complete after 30 minutes. The suspension formed is taken up into ml CH 2 C1 2 and washed twice with sodium bicarbonate and 20 sodium thiosulphate solution. Concentration of the organic layer affords a beige crude product which is purified by chromatography (hexane/ethyl acetate) to yield a yellow oil.

'H-NMR (300 MHz, CDCl 3 9.80 1H), 6.70-6.81 5H), 3.86 3H), 3.85 (s, 3H), 3.87-3.94 2H), 2.72-2.80 2H).

MS: 193 (M+1) 4-3283 2A 156 r-C. Synthesis of ,4-dimethoxy-phelyl)-propylwnlino] -5-propargyloxy-phenyl (4-isopropyl-phefl-methalone 00

NH

To a solution of 298 mg (1.02 mmol) 2-rnino-propargyloxy-pheflyl)(4isopropylphenyl)-methaflone in 6 ml CH 2 C1 2 are added 217 mg 12 mmol) 3 -(3,4-dimethoxyphenyl)-propiolaldehYde and 450 jil (1.52 mmol) tetra-isopropoxy-titaflium. The deep red solution is stirred for 7 h at rt. Then 323 mg (1.52 mmol) sodium triacetoxyborohydride and 300 .il EtOH are added and stirring is continued overnighit. The reaction mixture is extracted with water and CH 2 Cl 2 and concentrated The crude product is purified by chromatography (hexane/ethyl acetate) to yield a yellow oil.

'H-NMiR (300 MiHz, CDC1 3 8.24 (broad t, NHl), 7.67 2H), 7.28 2H), 7.17 (d, 1H), 7.11 (dd, 1H), 6.65-6.80 (in, 4H), 4.51(d, 2H), 3.85 3H), 3.84 3H), 3.22 (q, 2H), 2.97 (hept, IH), 2.72 2H), 2.46 IH), 2.00 (quint, 2H), 1.28 6H).

MS: 472 4-32832A 157 D. Synthesis of 1 ,4-dimethoxy-pheflyl)-propyl4(4isopropyl-phenyl)- 6 propargyloxy- 1 H-quinazolin-2-ofle A solution of 338 mg (0.72 mmol) of the product prepared in step C in 6 ml AcOH is treated with 70 mg (1.1 mmol) sodium cyanate. The mixture is stirred for 1. 5 h at rt. A yellow product results after work-up with ethyl acetate/water, which is purified by chromatography

(CH

2 Cl 2 IMeOH) to afford a yellow foam.

'H-NMR (300 MIHz, CDC1 3 7.67 2H), 7.45 1H), 7.36 1H), 7.35 2H), 7.12 1H), 6.74-6.80 (in, 3H), 4.64 2H), 4.25-4.33 (broad mn, 2H), 3.86 3H), 3.85 3H), 2.99 (hept, IH), 2.77 2H), 2.55 IH), 2.14 (quint, 2H), 1.30 6H).

MS: 497 E. Synthesis of 1 ,4-dimethoxy-phenyl)-propy1-4-(4isopropyl-phenyl> 6 propargyloxy- 1 H-quinazolin-2-thione A mixture of 130 mng (0.26 mrnol) of the quinazolinone prepared in step D and 122 mng (0.30) inmol Lawesson reagent in 5 ml benzene is stirred for 2 h at 70 The solution turns slightly red. Equal amounts of Lawesson reagent are added after a total 4-32832A 158- O of 3 and 5 h, but the reaction remained incomplete. After extractive work-up with N ethyl acetate and water, followed by chromatography of the crude material 0 (hexane/ethyl acetate) the intermediate is obtained as a yellow oil.

Z 'H-NMR (300 MHz, CDC13): 7.71 2H), 7.47 1H), 7.30-7.40 4H), 7.16 (d, 1H), 6.82 2H), 4.67 2H), 3.89 3H), 3.87 3H), 2.99 (hept, 1H), 2.83 (t, 2H), 2.57 1H), 2.28 (broad, 2H), 1.29 6H).

SMS: 513 (M+1) 00 The compound of the following example is prepared by analogy: Example 159: 4-(4-Isopropyl-phenyl)-1-(3-phenyl-propyl)-6-propargyloxy-1Hquinazolin-2-one

NO

'H-NMR (300 MHz, CDC1 3 7.69 2H), 7.46 1H), 7.28-7.38 5H), 7.18-7.26 3H), 7.06 1H), 4.66 2H), 4.26-4.34 2H), 3.00 (hept, 1H), 2.84 2H), 2.55 1H), 2.16 (quint, 2H), 1.31 6H).

MS: 437 (M+1) 4-32832A 159- Example 160: {2-1j2-(3,4dmtoypey) phenyl) (4-isopropyl-phefl)-methalofe cl-%yI LIDA 0 DIBAHa N HMPA/THF 0 toluene 1 75T.,18h 1-1 5*C,20 h

U

00 Dess-Martin reagent rt, 1h N H -O)I

O

NaCNBFj AcOH molecular sieves

CICK

2 Cl, 2

CI

rt, 4 days A. Synthesis of 2-(3,4-dimethoxy-pheflyl)-2-methyl-propioflic acid ethyl ester

I

0 A solution of 2.00 g (8.92 mmol) ethyl-3,4-dimethoxyphenyl acetate, 2.85 ml (17.84 mmol) HMPA and 3.34 ml (53.52 mmol) methyl iodide in 50 ml THIF is treated at with 51.9 ml (35.7 minol) of a LDA solution prepared in THF. After 18 h stirring at -75TC the cold reaction mixture is poured into an aqueous saturated ammonium chloride solution and extracted with ethyl acetate. After evaporation the crude dimethylated compound still containing some HMPA is obtained and is directly further transformed as described below.

'HNMR (300 MI-z, CDCI 3 6.8 8 (dd, IlH), 6.86 I 6.82 I 4.12 2H1), 3.87 3H), 3.87 3H), 1.57 6H), 1.20 3H).

4-32832A -160- O B. Synthesis of 2-(3,4-dimethoxy-phenyl)-2-methyl-propan- -ol 0

OH

00 3H), 3.60 2H), 1.34 6H).

A solution of 909 mg (ca. 2 mmol) of the crude product described directly above in ml toluene is treated twice with 2.69 mi (3.2 mmol) of 1.2 M DIBAH solution in toluene at 5°C. After stirring for 20 h saturated ammonium chloride solution is added.

She reaction mixture is filtered and extracted with diethyl ether to obtain after Sevaporation of the solvent 2-(3,4-dimethoxy-phenyl)-2-methyl-propan-i-ol.

0'H NMR (300 MHz, CDC1 3 6.94 91 2H), 6.85 1H), 3.90 3H), 3.88 (s, 3H), 3.60 2H), 1.34 6H).

C. Synthesis of2-(3,4-dimethoxy-phenyl)-2-methyl-propionaldehyde A solution of 100 mg (0.476 mmol) 2-(3,4-dimethoxy-phenyl)-2-methyl-propan- 1-ol in 1 ml dichloromethane is treated with 202 mg (0.476 mmol) Dess-Martin reagent at rt. After 1 h aqueous sodium bicarbonate and sodium thiosulphate solutions are added and the product is extracted with dichloromethane. The organic layers are evaporated and the aldehyde is obtained in a sufficient purity to be used in reductive aminations.

'H NMR (300 MHz, CDC13): 9.44 1H), 6.88 1H), 6.83 (dd, 1H), 6.74 1H), 3.88 6H), 1.46 6H).

4-3283 2A 161 D. Synthesis of 1 2- [2-(3,4dmtoypey)2mty -poy dmtoy phenyl (4-isopropy1-phel1)-methalofe Z

N

00 0 0 After one hour stirring a mixture of 143 mg (0.476 mmol) (2-amnino-4,5-dirnethoxypheny1)-(4-isoprpy1-phel)-metha1one, 98 mg (0.476 mmol) 2-(3 ,4-dimethoxypheny1)-2-methyl-propioflaldehyde, 1. 1 g molecular sieves 4 A pore size, 5 ml 1,2dichioroethane and 31 ILI (0.476 mmol) acetic acid 41 mg (0.666 mmol) NaCNBH 3 are added. Over the duration of 4 days three additional portions of31111l acetic (0.476 mmol) and 41 mg NaCNBH 3 (0.666 mmol) are added. Excess hydride is destroyed by addition of I M hydrochloric acid and the reaction mixture is basified by means of 1 M sodium hydroxide. (2[-34Dmtoypey)2mty-rplmn]45 dimethoxy-phenyl)} (4-isopropyl-phenyl)-methalone is isolated by filtration followed by extraction with dichioromethane and reversed phase preparative 1{PLC.

'HNMR (300 MI-z, CDCl 3 7.50 2H), 7.28 2H), 7.13 7.00 (in, 3H), 6.84 (d, 6.14 IH), 3.90 3.88 3H), 3.86 3H), 3.66 31H), 3.35 2H), 2.97 (hept, 111), 1.52 6H), 1.29 6H).

MS: 492 The compounds of the following examples is prepared by analogy to the example described above.

4-32832A 162 Example 161: ,5-Dimethoxy-phelyl)-ethylalilo] -4,5 -dimethoxy-phenyl)}-(4isopropyl-phenyl)-methalofe NH I 0 0 1 'H NMR (300 MHz, CDC1 3 7.53 7.30 2H), 7.06 I 6.46 2H), 6.35 1H), 6.22 1H), 3.93 3H), 3.79 6H), 3.68 3H), 3.50 2H), 3.03 2.94 (in, 3H), 1.31 6H).

MS: 464 Example 162: {4,5-Dimethoxy-2-1 2 3 -methoxy-pheny1)-2-mel-Ypropylamino] phenyl} -(4-isopropy1-phenyl)-inethalofe 'H NMR (300 MHz, CDC1 3 7.51 2H), 7.29 2H), 7.25 I1H), 7.05 (in, 1H), 7.02 1H), 6.99 1H), 6.75 (dd, 1H), 6.30 1H), 3.91 3H), 3.78 3H), 3.67 3H), 3.40 2H), 1.53 6H), 1.30 6H).

MS: 462 4-32832A 163 Example 163: ,5 -Dimethoxy-phel)-2-methyl1proPYlamino]-S -prop-2ynyloxy-phenyl) (4-isopropy1-phefl)-methanofle 00

MC~

'H NMIR (300 Mliz, CDC1 3 7.56 2M1, 7.28 211), 7.16 111), 7.11 (dd, 111), 6.87 IH), 6.68 2H), 6.30 111), 4.54 2H1), 3.77 611), 3.36 211), 2.98 (hept, 1H), 2.48 1H1), 1.48 611), 1.30 611).

MS: 486 Example 164: {2-112-(3 ,5-Dimethoxy-phefl)-ethylamiflo]5prop-2-ynyoxy-phenyl} (4-isopropyl-phel)-methannfe 'H NMR (300 MHz, CDCI 3 7.59 211), 7.30 2H), 7.20 1H), 7.15 (dd, I1H), 6.82 111), 6.44 211), 6.84 1H), 4.55 2H) 3.79 611), 3.48 211). 3.03 2.93 (in, 311), 2.49 111), 1,31 H).

MS: 458 (M+1) 4 4-32832A 164 Example 165: ,4-Dimethoxy-phefl)ethyI amilo] 4,5 dimehoxy-phenyl isopropyl-phenyl)-methalofe 'H NMR (300 MHz, CDC1 3 7.56 2H), 7.32 2H), 7.08 1H), 6.84 6.83 (mn, 3H), 6.67 (broad, IH), 3.97 3H); 3.87 3H), 3.87 3H), (3.72 s, 3H), 3.49 (t, 2H), 3.08 2H), 2.99 (hept, I 1. 31 6H).

MS: 464 Example 166: 4-Ethyl-4- [-4iorplbezy)45dmthx-hnlmn] methyl) -hexanenitrile 'H NMR (300 MHz, CDCI 3 9.18 (in, broad, 1H), 7.55 2H), 7.30 2H), 7.09 (s, IH), 6.19 IH), 3.98 3H), 3.69 3H), 3.01 2H), 2.97 (hept, 1H), 2.34 2.28 (in, 2H), 1.85 1.80 (mn, 2H), 1.49 4H1), 1.29 6H), 0.88 6H).

4-32832A 165 Example 167: 1- ,5 -Dimethoxy-phelyl)-ethyl] -4-(4-isopropy1-phefl)-6-prop-2ynyloxy- 1H-quinazolin-2-ofle NaON AcOH rt, 1 h A solution of 15 mg (33 jimo1) {2-[2-(3,5-dimethoxy-pheflyl)-ethylamifloI-5-prop- 2 ynyloxy-phenyl) -(4-isopropy1-phenyl)methanone and 2.1 mng (3 3 /Amol) NaOCN in 300 tdI acetic acid is stirred for 1 h at rt. The solvent is evaporated and the product is recrystallised from CH 2

CI

2 /diethyl ether.

'H NMR (300 MHz, CDC1 3 7.70 2H), 7.49 1H), 7.43 (dd, lH), 7.37 2H), 7.34 IH), 6.50 2H), 6.36 IH), 4.68 2H), 4.48 (dd, 2H), 3.80 6H), 3.09 2.97 (in, 3H), 2.57 1H), 1.32 6H).

MS: 483 Example 168: ,5-Dimethoxy-phenyl)-2-methylbpropylamino- 4 -hydroxymethoxy-phenyl) (4-isopropyl-pheny1)-methalone o 0

H

Et-SNa

DMF

1 1oC, 5 h molecular sieves rt, 90 min NaCNBH, AcOH rt, 16 h 4-32832A -166 A. Synthesis of (2aio4hdoy5mtoyphnl-4iorplpey) C1 methanone HO NH 2 0 0N 00 A mixture of 1.34 g (4.48 mmol) (2-amino-4,5-dimethOXy-phelyl)-( 4 -iSOPrOPYlphenyl)-methaflofe, 1. 88 g sodium ethanethiolate and 10 ml DM4F are heated for 5h to 11 0 0 C. Saturated aqueous bicarbonate solution (10 ml) and 100 ml water are added.

The product is extracted with GH 2 C1 2 and chromatographed on silica (hexane ethyl acetate).

'HNMR (300 MHz, CDCl 3 7.56 2H), 7.30 2H), 6.96 1H), 6.31 1H), 3.70 3H), 1.30 6H).

MS: 286 B. Synthesis of ,5-dimethoxy-phenyl)-2-methyl-propylamiflo]- 4 -hydroxy-S methoxy-phenyl) -(4-isopropyl-phefl)-methanofle 1 1 0 0 1N A mixture of 41.1 mg (144 A~mo1) (2-amino-4-hydroxy-5-methoxy-pheflyl)-( 4 isopropyl-phenyl)-methanofle, 45 mg (21 61imol) 2-(3 ,5-dimethoxy-phenyl)-2-methylpropionaldehyde, 180 mg molecular sieves (pore size 4A) and 0.50 ml CH 2

CI

2 is stirred for 90 min before 8.23 jAl (144 pmol) and 22 mg NaCNBH 3 are added. After 16 h the excess of reducing agent is destroyed by addition of 1 M hydrochloric acid and 4-32832 A 167 *the mixture is basified with 1 M sodium hydroxide solution. The product is extracted N1 with CH 2

CI

2 and purified by reversed phase preparative HPLC.

o NMR (300 MHz, d 6 DMSO): 10.07 1H), 8.71 broad, 1H), 7.40 2H), 7.31 Z 2H), 6.84 111), 6.56 2H), 6.33 1H), 6.26 IH), 3.71 6H), 3.50 (s, 3H), 3.27 2H), 2.94 (hept, IH), 1.35 6H), 1.23 6H).

MS: 478 00 The compound of the following example is prepared by analogy to the example described above: Example 169: (2-Benzo[ 1,3]dioxol-5-y1ethy)[5hydroxy2(4isopropylbenzoyl)- 4 methoxy-phenyl]-ammnonium; chloride 0 HO NH 2

CI

0 0 'H NMR (300 MHz, CD 3 OD): 7.71 2H), 7.44 2H), 7.19 I1H), 6.98 (in, I1H), 6.79 IH), 6.75 2H), 5.90 2H), 3.79 3H), 3.63 2H), 3.08 2.99 (mn, 3H), 1 .32 6H).

MS: 434 4-32832A 168 Example 170: [2-(Cyclopropylnmethyl-amiflo)-4-hydroxy-5methoxy-phenyl] isopropyl-phenyl)-methalofe 'H NMR (300 MHz, CDCl 3 9.17 (broad I 7.5 5 2H), 7.29 2H), 7.04 (s, 111), 6.39 1H), 6.15 1H), 3.71 3H), 3.07 2H), 2.98 (hept, 1H), 1.30 (d, 6H), 1.19 (in, 1H), 0.60 (in, 2H), 0.31 (mn, 2H).

Example 171: 1 [-yrx--246timty-hnl-ty)4-4iorplpey) 6-prop-2-ynyloxy- 1H-quinazolin-2-one 0N N ~TEBA,

K

2 C0 N I N dioxane 0+ 90-C, 8hN 00 A mixture of 0.5g (1.57 ninol) 4-4iorplpey)6po--nlx-H quinazolin-2-one, 0.254 g (1.57 inmol) mesityl oxirane, 35.7 mg 157 inmol) benzyltriethylammoliuml chloride and 21.7 mng 157 minol) potassium carbonate is stirred in I ml dioxane at 90"C for 6 days. The reaction mixture is extracted with water dichioroinethane and, after evaporation of the organic phases, the residue is purified by preparative reversed phase 1{PLC.

4-32832A 169 r- '1 H NMR (300 MI-z, CDCl 3 7.72 2H), 7.54 IlH), 7.50 I1H), 7.43 (dd, I H), c-i 7.38 2H), 6.88 2H), 5.66 (dd, 1H), 4.93 lH), 4.68 2H), 4.37 (dd, 1H), >0 3.02 (hept, lH), 2.60 6H), 2.57 1H), 2.28 3H), 1.33 6H).

Z MS: 481 The compound of the following example is prepared by analogy to the example 00 described above: Example 172: 1 ,5 -Di fluoro-phenyl)-2-hydroxy-ethyl] -4-(4-isopropyl-phenyl)-6c-i prop-2-ynyloxy- 1H-quinazolin-2-ofle F F

OH

'H NMR (300 MI-z, CDCl 3 7.67 2H), 7.49 7.43 (in, 3H), 7.3 7 2H), 7. 10 (in, 2H), 6.74 (tt, IH), 5.81 (dd, 1H), 4.68 2H), 4.51 (dd, 2H), 4.38 (dd, 2H1), 3.01 (hept, I 2.5 7 I1H), 1. 32 6H).

MS: 475 4-32832A -170- Example 173: 4-(4-IsopropyI-phel)6-prop2-ynyloxy-l -[(E)-2-(2,4,6-trimethyl- O phenyl)-vinyl]-l H-quinazolin-2-ofle OH tifluoromethafle suiphonic anhydride 00 N 0 1 ,2-dichloroethane 15min. N C A .N A X 0 N0 A solution of 50 mg 104 mmol) I -[2-hydroxy-2-(2,4,6-trlmethyl-phenyl)-ethyl V.4- (4-isopropyl-phel)-6-prop-2-yfloxy-lH-quinazolin-2-ofle and 34.3 Al (0.208 mmol) trifluorometharie suiphonic anhydride in 0.5 ml 1,2 dichioroethane is heated to 0 C for 15 min. Extraction with dichioromethane aqueous NaH-C0 3 followed by preparative reversed phase HPLC yielded the title compound.

1 H NMR (300 MHz, CDC1 3 7.76 2H), 7.68 lH), 7.51 1H), 7.41 (dd, 1H), 7.40 2H), 7.03 1H), 6.94 2H), 6.71 1H), 4.69 2H), 3.03 (hept, 1H), 2.58 11H), 2.47 6H), 2.32 3H), 1.33 6H).

MS: 463 The compounds of the following examples are prepared by analogy to the example described above: 4-32832A 171- Example 174: 4-(4-IsopropyI-pheflyl)6prop- 2 ynyloxy I -((E)-styryl)- IH-quinazolin- 2-one 'HNMR (300 MHz, CDC1 3 7.78 2H), 7.64 1H), 7.56 -7.53 (in, 2H), 7.51 (d, 1H), 7.43 7.35 (mn, 6H), 7.25 1H), 7.03 1H), 4.70 2H), 3.03 (hept, 1H), 2.58 IH), 1.34 6H).

MS: 421 Example 175: 1 -Chloro-4-methoxy-pheflyl)vifl]4(4isopropyl-phenyl)- 6-prop-2-ynyloxy- 1 H-quinazolin-2-ofle 1HNMR (300 MIEZ, CDCl 3 7.77 2H1), 7.60 I 7.59 1H), 7.51 IlH), 7.41 7.37 (in, 4H), 7.13 1H), 6.96 1H), 6.92 1H), 4.70 2H), 3.95 (s, 3H), 3.03 (hept, IH), 2.58 1H), 1.33 6H1).

MS: 487 485 (100) (chlorine isotope pattern) 4-32832A 172- Example 176: 1 ,5-Dimethyl-phelyl)-vilYl] -4-(4-isopropy-phefyl)6prop- 2-ynyloxy-l H-quinazolin-2-ofle 'H-NMR (300 MHz, CDCl 3 7.78 2H), 7.64 1H), 7.50 111), 7.40 2H), 7.37 (dd, 1H), 7.23 1H), 7.17 2H), 7.00 1H), 6.93 IH), 4.69 2H), 3.03 (hept, IH), 2.58 1H), 2.36 6H), 1.33 6H1).

MS: 449 (M+I1)+ Example 177: 2-Benzylsulphanl14-(4-isopropyl1phelY)6prop- 2 -yIyloxyquinazoline 1) benzOy4 iSOV00ICP2flt8

THF

r. h 2) KCO

MGOH

18hi benzy4 bromidde

DIEA

r.L, 18h 4-32832A 173- A. Synthesis of 4-(4-isopropyI-pheflyl)-6-prop- 2 -ynyloxy 1 H-quinazoline-2-thiofle: A solution of 0.5 g (1.71 mmol) (2-amino-5-prop-2-yfloxy-phenyl)-( 4-isopropylphenyl)-methanofle and 0.23 ml (1.71 mmol) benzoyl isothiocyanate in 5 ml THF is stirred for 3 h at r.t. before 0.23 5 g potassium carbonate and 5 ml methanol are added.

After stirring for 18 h, the reaction mixture is acidified with 0. 1 M aqueous hydrochloric acid and extracted with dichioromethane. After evaporation of the organic phases, the residue is triturated with diethyl'ether to give the title compound.

'H NMR (300 MHz, d 6 DMSO): 13.79 IH), 7.70 2H), 7.54 2H), 7.44 2H), 7.32 IH), 4.80 2H), 3.69 1H), 2.99 (hept, 1H), 1.24 6H).

MS: 335 B. Synthesis of 2-benzylsulphanyl-4-(4-isopropylphenyl)6-prop- 2 -yryloxyquinazoline N S

N

To a solution of 100 mg (299 pimol) 4-4iorplpey)6po--nlx-IH quinazoline-2-thione in 2 ml THF are added 35.5 jil (299 gmol) benzyl bromide and 76 gIl (448 g.mol) DIEA. After stirring for 18 h at r.t. the reaction mixture is extracted with dichloromethane and water. After evaporation of the organic layers the crude 4-32832A -174- S product is purified by flash chromatography using hexanes ethyl acetate 20:1 as eluent.

O 'H NMR (300 MHz, CDCl 3 7.88 1H), 7.72 2H), 7.53 7.48 4H), 7.40 (d, 2H), 7.32 7.19 3H), 4.71 2H), 4.56 2H), 3.02 (hept, 1H), 2.58 1H), 1.33 6H).

00 The compounds of the following examples are prepared by analogy to the example C, described above: Example178: 4-(4-Isopropyl-phenyl)-2-isopropylsulphanyl-6-prop-2-ynyloxyquinazoline

Y

NYS

N

'H NMR (300 MHz, CDC1 3 7.83 (dm, 1H), 7.73 2H), 7.57 7.51 2H), 7.39 2H), 4.70 2H), 4.13 (hept, 1H), 3.01 (hept, 1H), 2.57 1H), 1.50 6H), 1.32 6H).

4-32832A 175- 0 Example 179: 2-Isobutylsulphanyl-4-(4-isopropyl-phenyl)-6-prop- 2 -ynyloxy- C quinazoline Ny 00 1H 8'H NMR (300 MHz, CDC13): 7.84 (dd, 1H), 7.75 2H), 7.51 (dd, 1H), 7.49 1H), 7.40 2H), 4.72 2H), 3.22 2H), 3.03 (hept, 1H), 2.58 1H), 2.08 (nonet, 1H), 1.34 6H), 1.10 6H).

The Agents of the Invention, as defined above, of formula I or II, particularly as exemplified, in free or pharmaceutically acceptable acid addition salt form, exhibit pharmacological activity and are useful as pharmaceuticals, e.g. for therapy, in the treatment of diseases and conditions as hereinafter set forth.

Inositol phosphate formation assay: To determine antagonistic activity at the human parathyroid calcium-sensing receptor (PcaR), compounds are tested in functional assays measuring the inhibition of calcium-induced inositol phosphate formation in CCL39 fibroblasts stably transfected with human PcaR.

Cells are seeded into 24 well plates and grown to confluence. Cultures are then labelled with 3 H]inositol (74 Mbq/ml) in serum-free medium for 24 h. After labelling, cells are washed once with a modified Hepes-buffered salt solution (mHBS: 130 mM NaC1, 5.4 mM KC1, 0.5 mM CaCl 2 0.9 mM MgSO 4 10 mM glucose, mM HEPES, pH 7.4) and incubated with mHBS at 37 C in the presence of 20 mM LiCI to block inositol monophosphatase activity. Test compounds are added 3 minutes before stimulating PcaR with 5.5 mM calcium and incubations continued for further 4-32832A 176- 20 min. Thereafter, cells are extracted with 10 mM ice-cold formic acid and inositol N, phosphates formed are determined using anion exchange chromatography and liquid scintillation counting.

0 z Assay for intracellular free calcium: An alternative method to determine antagonism at the PcaR consists in measuring the N inhibition of intracellular calcium transients stimulated by extracellular calcium.

00 CCL39 fibroblasts stably transfected with human PcaR are seeded at 40'000 cells CI /well into 96-well Viewplates and incubated for 24 hours. Medium is then removed r- 0and replaced with fresh medium containing 2 tM Fluo-3 AM (Molecular Probes, N Leiden, The Netherlands), In routine experiments, cells are incubated at 37 5

CO

2 for 1 h. Afterwards, plates are washed twice with mHBS and wells are refilled with 100 1I mHBS containing the test compounds. Incubation is continued at room temperature for 15 minutes. To record changes of intracellular free calcium, plates are transferred to fluorescence-imaging plate reader (Molecular Devices, Sunnyvale,

CA,

USA). A baseline consisting in 5 measurements of 0.4 seconds each (laser excitation 488 nm) is recorded. Cells are then stimulated with calcium (2.5 mM final), and fluorescence changes recorded over a period of 3 minutes.

When measured in the above assays, Agents of the Invention typically have in the range from about 50 gM down to about 10 nM or less.

It is now well established that controlled treatment of patients with parathyroid hormone (PTH) and analogues and fragments thereof can have a pronounced anabolic effect on bone formation. Thus compounds which promote PTH release, such as the Agents of the Invention may be used for preventing or treating conditions of bone which are associated with increased calcium depletion or resorption or in which stimulation of bone formation and calcium fixation in the bone is desirable.

Thus in a further aspect the invention includes a method for preventing or treating bone conditions which are associated with increased calcium depletion or resorption or in which stimulation of bone formation and calcium fixation in the bone 4-32832A -177is desirable in which an effective amount of an Agent of the Invention is administered to a patient in need of such treatment.

0 Z In a yet further aspect the invention includes a pharmaceutical composition for preventing or treating bone conditions which are associated with increased calcium depletion or resorption or in which stimulation of bone formation and calcium fixation in the bone is desirable comprising an Agent of the Invention in admixture with a 00 Spharmaceutically acceptable excipient, diluent or carrier.

SAgents of the Invention are accordingly indicated for preventing or treating all C, bone conditions which are associated with increased calcium depletion or resorption or in which stimulation of bone formation and calcium fixation in the bone is desirable, e.g. osteoporosis of various genesis juvenile, menopausal, postmenopausal, post-traumatic, caused by old age or by corticosteroid therapy or inactivity), fractures, osteopathy, including acute and chronic states associated with skeletal demineralisation, osteo-malacia, periodontal bone loss or bone loss due to arthritis or osteoarthritis or for treating hypoparathyroidism.

Further diseases and disorders which might be prevented or treated include e.g.

seizures, stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage such as in cardiac arrest or neonatal distress, epilepsy, neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease, dementia, muscle tension, depression, anxiety, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, neuroleptic malignant syndrome, congestive heart failure; hypertension; gut motility disorders such as diarrhoea, and spastic colon and dermatological disorders, e.g. in tissue healing, for example bums, ulcerations and wounds.

The Agents of the Invention are particularly indicated for preventing or treating osteoporosis of various genesis.

4-32832A -178- For all the above uses, an indicated daily dosage is in the range from about 0.03 to Cabout 300 mg preferably 0.03 to 30, more preferably 0.1 to 10 mg of a compound of S the invention. Agents of the Invention may be administered twice a day or up to twice a week.

The Agents of the Invention may be administered in free form or in pharmaceutically Sacceptable salt form. Such salts may be prepared in conventional manner and exhibit 00 the same order of activity as the free compounds. The present invention also provides Ca pharmaceutical composition comprising an Agent of the Invention in free base form Sor in pharmaceutically acceptable salt form in association with a pharmaceutically Nacceptable diluent or carrier. Such compositions may be formulated in conventional manner. The Agents of the Invention may be administered by any conventional route, for example parenterally e.g. in form of injectable solutions or suspensions, enterally, e.g. orally, for example in the form of tablets or capsules or in a transdermal, nasal or a suppository form.

In accordance with the foregoing the present invention further provides: an Agent of the Invention or a pharmaceutically acceptable salt thereof for use as a pharmaceutical; a method for preventing or treating above mentioned disorders and diseases in a subject in need of such treatment, which method comprises administering to said subject an effective amount of an Agent of the Invention or a pharmaceutically acceptable salt thereof; c) an Agent of the Invention or a pharmaceutically acceptable salt thereof for use in the preparation of a pharmaceutical composition e.g. for use in the method as in b) above.

According to a further embodiment of the invention, the Agents of the Invention may be employed as adjunct or adjuvant to other therapy, e.g. a therapy using a bone 179resorption irmibitor, for exam.le as in osteoporosis therapy, in particular a therapy C employing calcium, a calcitonin or an analogue or derivative thereof, e.g. salmon, eel O or human calcitonin, a steroid hormone, e.g. an estrogen, a partial estrogen agonist or estrogen-gestagen combination, a SERM (Selective Estrogen Receptor Modulator) e.g. raloxifene, lasofoxifene, TSE-424, FC1271, Tibolone (Livial vitamin D or an analogue thereof or PTH, a PTH fragment or a PTH derivative e.g. PTH

PTH

S PTH PTH PTH (1-31)NH2 or PTS 893.

S When the Agents of the Invention are administered in conjunction with, e.g. as an 0 adjuvant to bone resorption inhibition therapy, dosages for the co-administered inhibitor will of course vary depending on the type of inhibitor drug employed, e.g.

whether it is a steroid or a calcitonin, on the condition to be treated, whether it is a curative or preventive therapy, on the regimen and so forth.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (5)

180- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: O 1. A compound of formula I R3 8 1 1 77 N Y 6 3 C~ 3 R1 5 4 I 00 C R2 wherein Y is O or S; R1 represents from 1 to 3 substituents independently selected from OH, SH, halo, NO 2 optionally substituted (lower alkyl, lower alkoxy, lower alkenyl, lower alkenyloxy, lower alkynyl, lower alkynyloxy, lower alkanoyl, cycloalkyl, lower alkylsulphone, lower alkylsulphoxide or amino); R2 represents from 1 to 3 substituents selected from halo, optionally substituted (lower alkyl, lower alkenyl, cycloalkyl or lower alkoxy); R3 is a) lower alkyl optionally substituted by 1 to 3 substituents selected from cycloalkyl, lower alkylene, lower alkyl, Br, F, CF 3 CN, COOH, lower alkyl- carboxylate, OH, lower alkoxy or -O,-(CH 2 )y-SOz-lower alkyl, wherein x is 0 or 1, y is 0, 1 or 2 and z is 0, 1 or 2 or b) Benzyl which is a. mono-or di- (preferably mono-) substituted by -O,-(CH 2 )y-SO,-lower alkyl or -O0-(CR, R')y-COO-R, wherein x, y and z are as defined above and R or R' is H or lower alkyl, 30 b. substituted by 1 or 2 substituents selected from morpholino-lower alkoxy, aryl-lower alkoxy, optionally N-lower alkyl substituted arylamino-lower alkoxy, c. substituted at the 2-position by lower alkoxy-, hydroxy-lower alkoxy- or lower alkoxy-lower alkoxy, 181 d. substituted on the -CH 2 group thereof; or 0 c) optionally substituted (aryl-C 2 -C8-alkyl, aryl- C 2 -Cg-alkenyl, heteroarylmethyl or 4-heteroarylbelzyl); or Z when RI is 2 substituents one of which is OH, preferably at the 6-position, and the V) other of which is optionally substituted (lower alkyl, cycloalkyl-lower-alkYl or lower alkenyl), preferably at the 5-position, R3 is H or optionally substituted (lower alkyl, N- aryl, aryl-lower alkyl, arylcycloalkyl, cycloalkyl-lower alkyl, cycloalkenyl-lower alkyl, 00 hetereoaryl-lower alkyl, hetereoaryl, or carbonyl lower alkyl); or M when RI is 2-propynyloxy and R2 is isopropyl, R3 is also benzyl which is substituted N- by I to 3 substituents selected from lower ailkyl, lower alkoxy, halo, halo-lower alkyl, e.g. CF 3 or when RI is 2-propynyloxy and R2 is isopropyl, R3 is also benzyl which is substituted by OH and a second and optionally third substituent selected from lower alkyl, lower alkoxy, halo, -O-CH(H or lower alkyi)-COO(H or lower alkyl); or when RI is 2-propynyloxy and R2 is cyclopropyl, R3 is also optionally substituted lower alkyl or benzyl (preferably R3 is also benzyl which is substituted by 1 to 3 substituents selected from lower alkyl, lower alkoxy, halo, -O-CH(H or lower alkyl)- COO(H or lower alkyl)); or when Y is S and RI is as defined above but not methoxy, R3 is also optionally substituted benzyl; or a compound selected from 4-(4-isopropyl-phenYl) 1 ,4-diamino-benzyl)-6-prop- 2 ynyloxy- 1H-quinazolin-2-ofle, 1 (,-ihoobnzl--4iorpy-hnl--rp 2-ynyloxy- IH-quinazolin-2-one, 1 -beflzyl-4-(4-isopropy-pheflyl)&6prop 2 -y1yloxy- 1 H-quinazoline-2-thione; 1 -(3,5itr-uy 4hdoybny)--4iorpl phenyl)-6-prop-2-ynyloxy-l H-quinazolin-2-ofle, or I -[3.(2-hydroxy-ethoxy)-benzyl]. 4-(4-isopropyl-pheflyl)-6-prop- 2 -yIyloxy H-quinazoline-2-thione; or a pharmaceuticallyacceptable and -cleavable ester, or acid addition salt thereof; and provided that when Y is 0 and R3 is lower alkyl or cycloalkyl, R3 is not isopropyl or cyclopentyl; or 1S2 provided the compound of formula I is not 4 -(4-isopropyl1-pheflyl)-6-methoxy- I- Spyridin-3 -ylmethyl H. -quinazolin-2-ofle, 4-(4-isopropyI-phelyl)6-methoxy- pyridin-2-ylmethyk 1. .quinazolii-2- one, 1 -(6-chloro-pyridin-3-ylmethyl)A4-( 4 Z isopropyI-phenl)l>.methoxy-l .H quinazolifl-2-one, 4-(4-isopropyl-phenyl)- 6 mehx-1-5-ir-frn2ylehl-IH qiaoi--n or 1-[2-(1.H.-ifldol-2- yl)-ethyl] -4-(4-isopropylpheflY)6methoxy- 1.H. -quinazolin-2-one, 4-(4-isopropyl- CI phenyl)-6-methoxy-l -phenethyl- IH-quinazolifl- 2 -ofle, 1 .(2-hydroxy-2-phel-lethyO)- 00 4 4 -isopropy1-pheflyl)6prop-2ynyloxyl H-quinazolifl-2-ofle, methanesulfonic acid 2-4(-spoy-hny)2oo6po--nyoy2-unzln -ylmethyl)-pheflyl ester, or acetic acid 2-4(-spoy-hnl-2oo6po--nlx-H N- quinazolin- 1-yl]-l -phenyl-ethyl ester, 5-allyl-6-hydroxy I -isopropyl-4-(4-isopropyl- phenyl)-l1.H.-quinazolifl- 2 -ofle, I -cyclopropylmethyl4(o-tolyl)6niro- 2 (l H)- quinazoliflofe, 1 -ethyl-4-(o-tolyl)-6chloro- 2 (l H)-quinazolilOfe, 1- cyclopropylmethyl4(0401ly)6chl0r0- 2 (lH)-quinazoliflofe, I -cyclopropylmethy1- 4 (o-fluorophenyl)-6-chloro- 2 (I H)-quinazOlilofe, I -cyclopropylmethyl- 4 chloropheflyl)-6-chloro- 2 (l H)-quinazoliflofe, I -cyclopropylmethyl- 4 chlorophenyl)-6-flitro- 2 (l H)-quinazolinofle. 2. A compound according to claim 1 of formula F' R 3 8 1 7 N~ 6 3 Ri 5 4 R2 wherein Y is 0 or S; RI and R2 are as defined in claim 1; R3' is a) lower alkyl substituted by 1 to 3 substituents independently selected from -S- lower alkyl, lower alkylene, cycloalkyl, Br, F or CF 3 or 1S3 b) benzyl which is a. onoor i-(Preferably mono-) substituted by -0OK(CH )YSO-lower alkyl, wherein x is 0 or 1, y is 0, 1 or 2 and z is 0, 1 or 2, Zb. substituted by I or 2 substituents selected from morpholino-lower alkoxy, aryl-lower alkoxy, optionally N-lower alkyl substituted ai-ylamino-alkoxy, (1c. substituted at the 2-position by lower alkoxy-, hydroxy-lower alkoxy- 00 or lower alkoxy-lower alkoxy; or c) optionally substituted (arylvinyl, arylethyl, heteroarylmethyl or 4- *heteroarylbeflzyl) or when R I is 2 substituents one of which is OH, preferably at the 6-position, and the other of which is optionally substituted (lower alkyl or lower alkenyl), preferably at the 5-position, R3 is H or optionally substituted (lower alkyl, aryl, aryl-lower alkyl, arylcycloalkyl, cycloalkyl-lower alkyl cycloalkenyl-lower alkyl, hetereoaryl -lower alkyl, hetereoaryl, or carbonyl lower alkyl); or when RI is 2-propynyl and R2 is isopropyl, R3 is also benzyl which is substituted by I to 3 substituents selected from lower alkyl, lower alkoxy, halo, halo-lower alkyl, e.g. CF 3 -O-CH(H or lower alkyl)-COO(H or lower alkyl); or when RI is 2-propynyl and R2 is isopropyl, R3 is also benzyl which is substituted by OH and a second and optionally third subtituent selected from lower alkyl, lower alkoxy, halo, -O-CH(H or lower alkyl)-COO(H or lower alkyl); or when RI is 2-propynyl and R2 is cyclopropyl, R3 is also optionally substituted benzyl (preferably R3 is also benzyl which is substituted by 1 to 3 substituents selected from lower alkyl, lower alkoxy, halo, -O-CH(H or lower alkyl)-COO(H or lower alkyl)); or when X is S and RI is as defined above but not methoxy, R3 is also optionally substituted benzyl; or a compound selected from 4-(4-isopropyl-pheflyl) 4 I (3,4-diamiflo-beflzyl)- 6 -prop- 2 ynyloxy- 1 H-quinazolin-2-one, 1-26dclr-ezl--4-spoy-hnl--rp 2-ynyloxy-l H-quinazolin- 2 -one, I ezl4(-sorplpey)6-rp2yyoy 1 H-quinazoline-2-thione; 1-3itr-uy--yrx-ezl--4iorplpey) 6-prop-2_ynyloxy- IH-quinazolin- 2 -ofle, or I -[3-(2-hydroxyethoxy)-benzyl- 4 4 isopropyl-pheflylY6prop-2ynyloxy-I H-quinazoline-2-thione;

184- or a harmceuticaiIy-acceptable and -cleavable ester, or acid additionsatheof S and 'l provided that when X is 0 and R3 is lower alkyl or cycloalkyl, R3 is not isopropyl or cyclopentyl; or (N provided the compound of formula F' is not 4 -(4-isopropyl-phenyl)6methoxy- 0C) pyridin-3 -ylmethyl- I.H.-quinazolin-2-ofle, 4 -(4-isopropylphenyI-6-methoxy- 1- pyridin-2-ylmethyll .H.-quinazolin- 2 -ole, I (6-chloro-pyridin3-ylmethyl)- 4 4 isopropyl-phenyl)&6methoxy-I.H quinazolil- 2 -ofle, 4-(4-isopropyI-pbeflyl)- 6 N- methoxy-l -(5-nitro-furan-2-ylmethyl.H.-quinazolin- 2 -oflC or .H-.-indol-2- yl)-ethyl]-4-(4-isopropylphenyl)6methoxyl-I quinazolin-2-one, 4-(4-isopropyl- phenyl)-6-tnethoxy-l-phenethyl- 1H-quinazolifl-2-one, 1 -(2hydroxy-2-phefl-ethy1>- 4 4 -isopropyl-phenyl)-6-prop-2i-r1loxy-IH-quinazolifl- 2 -ofle, methanesulfonic acid 2- [4(-spoy-hnl--x--po--nlx-Hqiaoi--ylmethyl]-phelyl ester, or acetic acid 2 4 4 -isopropylphefyl)2oxo6-prop2-ynyoxy- 2 H- quinazolin- I -yIll -phenyl -ethyl ester, 5-allyl-6-hydroxy 1 -isopropyl-4-(4-isopropyl- phenyl)- i.H.-quinazolin- 2 -ofle, 1 -cycopropylmethy-4(otol)6nito 2 (l H)- qu inazolinofle, I -Ethyl -4-(otolyl) -6-chloro- 2 (l H)-quinazol inone, I cyclopropylmethyl(otolyl)6chloro- 2 (lH)-quinazoliflofe, 1 -cyclopropylmethyl- 4 (o-fluorophenyl)-6chloro 2 (l H)-quinazolinofle, 1 -cyclopropylmethyb 4 chlorophenl)l>&chloro- 2 (l H)-quinazolilofe, 1 -cyciopropylmethyl- 4 chloropheflyl)6-nitro- 2 (l I-quinazoliflone. 3. A compound of formula 11 R3 NH 0 wherein RI, R.2 and R3 are as defined in claim I; or 0 a compound selected from 2 -[2-(2hydroxyethoxy)benzyl amino] -5 Prop 2 ynyoxy- Sphenyl (4-isopropyl-Phelyl)-methaflone or ,3-dimethoxY-quiloxalifl- 6 Zylmethyl)-amino-5-Prop-2-ynyloxy-phenyl (4-isopropyl-phelyl)-methalone; or a pharmaceuticallyacceptable and cleavable ester, or acid addition salt thereof, NI and 00 M provided that the compound of formula Hl is not {2-[2(3,dimethoxy-phenyl)-2- methyl -propyl amino]-4,5 dimethoxy-phenyl) }(4-isopropyl phelyl)-methanofle, (4- isopropyl-pheflyl)- t 5 methoxy-2[(pyrdin3 ylmethYl) aio] phenyl I -methanone, (4-isopropyl-phelYl)- Smethoxy-2[(pyfldin-2-ylmethyl)-aminoi-phenyl methanone. 4. A compound according to claim 3 of formula HI' 2 13 i 1 NH 4 0 6 Ri 5 I R2 wherein RI and R2 are as defined in claim 1 and R3' is as defined in claim 2; or a compound selected from 2-[2(2hydroxyethoxy)-benzylamino]-5-prop-2-ynyloxy- phenyl (4-isopropyl-phelYl)-methanofle or ,3-dimethoxy-quinoxalil1-6 ylmethyl)-amiflo]-5prop2ynyloxy-phenyl} (4-isopropyl-phel)lmethanone; or a pharmaceutically-acceptable and -cleavable ester, or acid addition salt thereof; and

186- 0 0 provided that the compound of formula II' is not {2-[2-(3,5-dimethoxy-phenyl)-2- -(4-isopropyl-phenyl)-methanone, (4- 5 isopropyl-phenyl)- {5-methoxy-2-[(pyridin-3-ylmethyl)-amino]-phenyl }-methanone, M (4-isopropyl-phenyl)- {5-methoxy-2-[(pyridin-2-ylmethyl)-amino]-phenyl} methanone. A compound according to anyone of claims 1 to 4 for use as a pharmaceutical. 6. The use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for preventing or treating bone conditions which are associated with increased calcium depletion or resorption or in which stimulation of bone formation and calcium fixation in the bone is desirable; or for the prevention and treatment of seizures, stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage, epilepsy, neurodegenerative diseases, Alzheimer's disease, Huntington's disease and Parkinson's disease, dementia, muscle tension, depression, anxiety, panic disorder, obsessive- compulsive disorder, post-traumatic stress disorder, schizophrenia, neuroleptic malignant syndrome, congestive heart failure; hypertension; gut motility disorders, diarrhoea, spastic colon disorder, dermatological disorders, burns, ulcerations, wounds; osteoporosis, juvenile osteoporosis, menopausal osteoporosis, post-menopausal osteoporosis, post- traumatic osteoporosis, fractures, osteopathy, osteomalacia, periodontal bone loss or bone loss due to arthritis or osteoarthritis or for treating hypoparathyroidism. 7. A method for preventing or treating bone conditions which are associated with increase calcium depletion or resorption or in which stimulation of bone formation and calcium fixation in the bone is desirable; or for the prevention and treatment of seizures, stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage, epilepsy, neurodegenerative diseases, Alzheimer's disease, Huntington's disease and Parkinson's disease, dementia, muscle tension, depression, anxiety, panic disorder, obsessive- compulsive disorder, post-traumatic stress disorder, schizophrenia, neuroleptic malignant -187- z syndrome, congestive heart failure; hypertension; gut motility disorders, diarrhoea, spastic Scolon disorder, dermatological disorders, burns, ulcerations, wounds; osteoporosis, juvenile osteoporosis, menopausal osteoporosis, post-menopausal osteoporosis, post- traumatic osteoporosis, fractures, osteopathy, osteomalacia, periodontal bone loss or bone 00 5 loss due to arthritis or osteoarthritis or for treating hypoparathyroidism; in which an Mc effective amount of a compound according to any one of claims 1 to 4 is administered to a patient in need of such treatment. 8. A pharmaceutical composition for preventing or treating bone conditions which are associated with increased calcium depletion or resorption or in which stimulation of bone formation and calcium fixation in the bone is desirable; or for the prevention and treatment of seizures, stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage, epilepsy, neurodegenerative diseases, Alzheimer's disease, Huntington's disease and Parkinson's disease, dementia, muscle tension, depression, anxiety, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, neuroleptic malignant syndrome, congestive heart failure; hypertension; gut motility disorders, diarrhoea, spastic colon disorder, dermatological disorders, bums, ulcerations, wounds; osteoporosis, juvenile osteoporosis, menopausal osteoporosis, post-menopausal osteoporosis, post-traumatic osteoporosis, fractures, osteopathy, osteomalacia, periodontal bone loss or bone loss due to arthritis or osteoarthritis or for treating hypoparathyroidism; comprising a compound according to any one of claims 1 to 4 in admixture with a pharmaceutically acceptable excipient, diluent or carrier. 9. The process for the preparation of a compound according to claim 1

188- R3 8 1 00 0 0', wherein the symbols are as defined in claim 1 comprising a) cyclising a compound of formula II with a condensation reagent such as chlorosulfonyl isocyanate (CISO 2 NCO) or sodium cyanate or sodium thiocyanate; or b) for an Agent of the Invention of formula I, in which R3 is optionally substituted aryl-lower alkyl, alkylation of a compound of formula XX H 8 I N 0 6 RI XX R2 at the 1-position with the corresponding optionally substituted ylhalide;

189- and thereafter, if required converting the RI, R2 or R3 residues into alternative RI, R2 or R3 residues to give an alternative compound of formula I. A process for the preparation of a compound of formula II R3 2 I wherein RI, R2 and R3 are as defined in claim 1 comprising alkylation of the corresponding aminobenzophenone compound of formula X Wherein R1 and R2 are as defined in claim 1, and thereafter, if required, converting Rl, R2 or R3 residues into alternative RI, R2 or R3 residues to give an alternative compound of formula II. 0- 190- O 11. A compound according to any one of claims 1 to 4 substantially as hereinbefore i described with reference to anyone of the examples. 12. A process according to claim 9 or claim 10 substantially as hereinbefore described 1" 5 with reference to any one of the examples. 00 (N,