IP Library › Granted Patent US 8,501,754

Granted Patent B2

US 8,501,754 · App. 12/668,864 · Granted Aug 6, 2013

Quinazolinamide derivatives

Inventors: Hans-Michael Eggenweiler (Darmstadt, DE); Christian Sirrenberg (Darmstadt, DE); Hans-Peter Buchstaller (Griesheim, DE)

Assignee: MERCK PATENT GmbH

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Quick Facts

Patent No.: US 8,501,754
App. No.: 12/668,864
Granted: Aug 6, 2013
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

Novel quinazolinamide derivatives of the formula (I), in which R 1 -R 3 have the meanings indicated in Claim 1 , are HSP90 inhibitors and can be used for the preparation of a medicament for the treatment of diseases in which the inhibition, regulation and/or modulation of HSP90 plays a role.

Claims (601)

1. A compound of formula I

in which

R 1 denotes H, A, (CH 2 ) n CONH 2 , (CH 2 ) n CONHA, (CH 2 ) n CONAA′, Hal, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA′, CN, NO 2 , (CH 2 ) n Ar, OAr, (CH 2 ) n COOH, (CH 2 ) n COOA, (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n Het, COHet, C≡C—CH 2 SiA 2 A′, C≡CH, C≡C-A, CH═CH—Ar 1 , CH═CH—COOA, CH 2 CH(OH)CH 2 OH, O(CH 2 ) n OH, NH(CH 2 ) n OH, O(CH 2 ) n OA, NH(CH 2 ) n OA, O(CH 2 ) n NHA, NH(CH 2 ) n NHA, NR 4 R 5 , (CH 2 ) n COOA, (CH 2 ) n CONH(CH 2 ) 2 CN, NH(CH 2 ) n Ar or CH═CH—COOH,

R 2 denotes H, A, (CH 2 ) n Ar, (CH 2 ) n Het, (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n NHHet, (CH 2 ) n SA or (CH 2 ) n CH(OH)Ar,

R 3 denotes A, (CH 2 ) n Ar, (CH 2 ) n Het, (CH 2 ) n CN, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA′, (CH 2 ) n OH, (CH 2 ) n OA or (CH 2 ) n NHHet,

R 2 and R 3 , together with the N atom to which they are bonded, also denote a saturated, unsaturated or aromatic mono- or bicyclic heterocycle, which may contain a further 1 to 3 N, O and/or S atoms and is unsubstituted or mono-, di- or trisubstituted by Hal, A, (CH 2 ) n OH, (CH 2 ) n OA and/or ═O (carbonyl oxygen),

R 4 , R 5 each, independently of one another, denote (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n NH 2 , (CH 2 ) n NHA or (CH 2 ) n NAA′,

Ar denotes phenyl, naphthyl, tetrahydronaphthyl or biphenyl, each of which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, (CH 2 ) n OA, (CH 2 ) n OH, (CH 2 ) n CN, SA, SOA, SO 2 A, NO 2 , C≡CH, (CH 2 ) n COOH, CHO, (CH 2 ) n COOA, CONH 2 , CONHA, CONAA′, NHCOA, CH(OH)A, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA′, (CH 2 ) n NAAr 1 , O(CH 2 ) n Het 1 , (CH 2 ) n Het 1 , COO(CH 2 ) n Ar 1 , (CH 2 ) n NHSO 2 A, (CH 2 ) n OAr 1 , O(CH 2 ) n Ar 1 , SO 2 NH(CH 2 ) n NH 2 , SO 2 NH 2 , SO 2 NHA, SO 2 NAA′, CONHAr 1 , CONH(CH 2 ) n COOA, CONH(CH 2 ) n COOH, NHCO(CH 2 ) n COOA, NHCO(CH 2 ) n COOH, CONH(CH 2 ) n NH 2 , CONH(CH 2 ) n NHA, CONH(CH 2 ) n NAA′, CONH(CH 2 ) n CN, NHCOHet, SO 2 Het, COHet and/or (CH 2 ) n CH(NH 2 )COOH,

Ar 1 denotes phenyl which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Hal and/or OA,

Het denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono-, di- or trisubstituted by A, (CH 2 ) n OA, (CH 2 ) n OH, Ar 1 , SH, S(O) m A, Hal, NO 2 , CN, COA, CHO, COOA, COObenzyl, CONH 2 , CONHA, CONAA′, SO 2 NH 2 , (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA′, NHSO 2 A and/or ═O (carbonyl oxygen),

Het 1 denotes a mono- or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms, which may be unsubstituted or mono- or disubstituted by A, OA, OH, Hal, CN and/or ═O (carbonyl oxygen),

A, A′ each, independently of one another, denote

unbranched or branched alkyl having 1-10 C atoms, in which 1-3 non-adjacent CH 2 groups are each optionally replaced by O, S, SO, SO 2 , NH, N-methyl, or N-ethyl and/or, in addition, 1-5 H atoms are each optionally replaced by F, OH and/or Cl, or

Alk 1 , cyclic alkyl having 3-8 C atoms or cycloalkylalkylene, in which in each case 1-5 H atoms are each optionally replaced by F, OH and/or Cl,

Alk 1 denotes alkenyl or alkynyl having 2-6 C atoms,

m denotes 0, 1 or 2, and

n denotes 0, 1, 2, 3 or 4,

or a pharmaceutically useable salts or stereoisomer thereof, including mixtures thereof in all ratios.

2. The compound according to claim 1 , wherein Het denotes pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, benzo-1,4-dioxanyl, quinolyl, isoquinolyl, quinazolinyl, benzimidazolyl, indazolyl, indolyl, 1,3-dihydroisoindolyl, benzofuranyl, dihydro-benzofuranyl, benzo-1,3-dioxolyl, piperazinyl, pyrazinyl, pyridazinyl, morpholinyl, azepanyl, pyrrolidinyl or piperidinyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, (CH 2 ) n OA, (CH 2 ) n OH, Ar 1 , SH, S(O) n A, Hal, NO 2 , CN, COA, CHO, COOA, COObenzyl, CONH 2 , CONHA, CONAA′, SO 2 NH 2 , (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA′, NHSO 2 A and/or ═O (carbonyl oxygen).

3. The compound according to claim 1 , wherein Het 1 denotes pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, benzimidazolyl, triazolyl, morpholinyl, pyrimidinyl, piperidinyl, pyrrolidinyl or piperazinyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, OA, OH, Hal, CN and/or ═O (carbonyl oxygen).

4. The compound according to claim 1 , wherein

A, A′ each, independently of one another, denote unbranched or branched alkyl having 1-6 C atoms, in which 1-2 CH 2 groups are each optionally replaced by O, NH and/or N-methyl and/or, in addition, 1-5H atoms are each optionally replaced by F, OH and/or Cl,

cyclic alkyl having 3-8 C atoms, in which 1-3H atoms are each optionally replaced by OH.

5. The compound according to claim 1 , wherein n denotes 0, 1 or 2.

6. The compound according to claim 1 , wherein

R 2 and R 3 , together with the N atom to which they are bonded, are 1,3-dihydro-isoindolyl, pyrrolidinyl, azepanyl, piperazinyl, piperidinyl or morpholinyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, (CH 2 ) n OH, (CH 2 ) n OA and/or ═O (carbonyl oxygen).

7. The compound according to claim 1 , wherein R 2 is H, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-(pyridin-2-ylamino)ethyl or benzyl.

8. The compound according to claim 1 , wherein

R 3 denote methyl, ethyl, propyl, butyl, isopropyl, phenyl, benzyl, furyl-2-ylmethyl, HC≡C—CH 2 —, 2-methoxyethyl, 3-trifluoromethylbenzyl, pyridin-2- or 3-ylmethyl, 2-, 3- or 4-fluorobenzyl, 2-, 3- or 4-methoxybenzyl, 2-, 3- or 4-methylbenzyl, 3-chloro-6-methoxybenzyl, N,N-dimethylamino-carbonylmethyl, 4-(1,2,4-triazol-1-ylmethyl)benzyl, 2- or 3-(pyridin-3-yl)-benzyl, 3-(2-morpholin-4-ylethoxy)benzyl, 4-(triazol-1-yl)benzyl, 3-(morpholin-4-yl)benzyl, 3-(pyrimidin-5-yl)benzyl, 3-(morpholin-4-ylmethyl)-benzyl, cyclopropylmethyl, 2-cyanoethyl, 2-dimethylaminoethyl, cyclohexyl, 3- or 4-(methylsulfonylamino)benzyl, 4-(methylsulfonylaminomethyl)benzyl, benzo-1,4-dioxan-6-ylmethyl, morpholin-4-yl, 2-hydroxyethyl, 2-methoxyethyl, 1,3,5-trimethyl-1H-pyrazol-4-ylmethyl, 2-methylsulfanilethyl, 2-hydroxy-2-phenylethyl, 2-(N-ethyl-N-methylamino)ethyl, 2-diethylamino-ethyl, 1-methyl-1H-pyrazol-3-yl, quinolin-5- or 8-yl, 2-methylsulfanilphenyl, biphenyl-2-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 2-(1H-benzimidazol-2-yl)-phenyl, 3,4,5-trimethoxyphenyl, 2-ethynylphenyl or 1-methyl-5-trifluoromethyl-1H-indazol-3-yl.

9. The compound according to claim 1 , wherein

R 1 denotes H, A, (CH 2 ) n CONH 2 , (CH 2 ) n CONHA, (CH 2 ) n CONAA′, Hal, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA′, CN, NO 2 , (CH 2 ) n Ar, OAr, (CH 2 ) n COOH, (CH 2 ) n COOA, (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n Het, COHet, C≡C—CH 2 SiA 2 A′, C≡CH, CC-A, CH═CH—Ar 1 , CH═CH—COOA, CH 2 CH(OH)CH 2 OH, O(CH 2 ) n OH, NH(CH 2 ) n OH, O(CH 2 ) n OA, NH(CH 2 ) n OA, O(CH 2 ) n NHA, NH(CH 2 ) n NHA, NR 4 R 5 , (CH 2 ) n COOA, (CH 2 ) n CONH(CH 2 ) 2 CN, NH(CH 2 ) n Ar or CH═CH—COOH,

R 2 denotes H, A, (CH 2 ) n Ar, (CH 2 ) n Het, (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n NHHet, (CH 2 ) n SA or (CH 2 ) n CH(OH)Ar,

R 3 denotes A, (CH 2 ) n Ar, (CH 2 ) n Het, (CH 2 ) n CN, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA′, (CH 2 ) n OH, (CH 2 ) n OA or (CH 2 ) n NHHet,

R 4 , R 5 each, independently of one another, denote (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n NH 2 , (CH 2 ) n NHA or (CH 2 ) n NAA′,

Ar 1 denotes phenyl which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Hal and/or OA,

Het denotes pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, benzo-1,4-dioxanyl, quinolyl, isoquinolyl, quinazolinyl, benzimidazolyl, indazolyl, indolyl, 1,3-dihydroisoindolyl, benzofuranyl, dihydrobenzofuranyl, benzo-1,3-dioxolyl, piperazinyl, pyrazinyl, pyridazinyl, morpholinyl, azepanyl, pyrrolidinyl or piperidinyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, (CH 2 ) n OA, (CH 2 ) n OH, Ar 1 , SH, S(O) m A, Hal, NO 2 , CN, COA, CHO, COOA, COObenzyl, CONH 2 , CONHA, CONAA′, SO 2 NH 2 , (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA′, NHSO 2 A and/or ═O (carbonyl oxygen),

Het 1 denotes pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, benzimidazolyl, triazolyl, morpholinyl, pyrimidinyl, piperidinyl, pyrrolidinyl or piperazinyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, OA, OH, Hal, CN and/or ═O (carbonyl oxygen),

A, A′ each, independently of one another, denote unbranched or branched alkyl having 1-6 C atoms, in which 1-2 CH 2 groups are each optionally replaced by 0, NH and/or N-methyl and/or, in addition, 1-5H atoms are each optionally replaced by F, OH and/or Cl,

cyclic alkyl having 3-8 C atoms, in which 1-3H atoms are each optionally replaced by OH,

m denotes 0, 1 or 2, and

n denotes 0, 1 or 2.

10. The compound according to claim 1 , wherein

R 1 denotes H, A, (CH 2 ) n CONH 2 , (CH 2 ) n CONHA, (CH 2 ) n CONAA′, Hal, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA′, CN, NO 2 , (CH 2 ) n Ar, OAr, (CH 2 ) n COOH, (CH 2 ) n COOA, (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n Het, COHet, C≡C—CH 2 SiA 2 A′, C≡CH, CC-A, CH═CH—Ar 1 , CH═CH—COOA, CH 2 CH(OH)CH 2 OH, O(CH 2 ) n OH, NH(CH 2 ) n OH, O(CH 2 ) n OA, NH(CH 2 ) n OA, O(CH 2 ) n NHA, NH(CH 2 ) n NHA, NR 4 R 5 , (CH 2 ) n COOA, (CH 2 ) n CONH(CH 2 ) 2 CN, NH(CH 2 ) n Ar or CH═CH—COOH,

R 2 denotes H, methyl, ethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-(pyridin-2-ylamino)ethyl or benzyl,

R 3 denotes methyl, ethyl, propyl, butyl, isopropyl, phenyl, benzyl, furyl-2-ylmethyl, HC≡C—CH 2 —, 2-methoxyethyl, 3-trifluoromethylbenzyl, pyridin-2- or 3-ylmethyl, 2-, 3- or 4-fluorobenzyl, 2-, 3- or 4-methoxy-benzyl, 2-, 3- or 4-methylbenzyl, 3-chloro-6-methoxybenzyl, N,N-di-methylaminocarbonylmethyl, 4-(1,2,4-triazol-1-ylmethyl)benzyl, 2- or 3-(pyridin-3-yl)benzyl, 3-(2-morpholin-4-ylethoxy)benzyl, 4-(triazol-1-yl)benzyl, 3-(morpholin-4-yl)benzyl, 3-(pyrimidin-5-yl)benzyl, 3-(morpholin-4-ylmethyl)benzyl, cyclopropylmethyl, 2-cyanoethyl, 2-dimethylaminoethyl, cyclohexyl, 3- or 4-(methylsulfonylamino)-benzyl, 4-(methylsulfonylaminomethyl)benzyl, benzo-1,4-dioxan-6-ylmethyl, morpholin-4-yl, 2-hydroxyethyl, 2-methoxyethyl, 1,3,5-trimethyl-1H-pyrazol-4-ylmethyl, 2-methylsulfanilethyl, 2-hydroxy-2-phenylethyl, 2-(N-ethyl-N-methylamino)ethyl, 2-diethylaminoethyl, 1-methyl-1H-pyrazol-3-yl, quinolin-5- or 8-yl, 2-methylsulfanilphenyl, biphenyl-2-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 2-(1H-benzimidazol-2-yl)phenyl, 3,4,5-trimethoxyphenyl, 2-ethynylphenyl or 1-methyl-5-trifluoromethyl-1H-indazol-3-yl,

R 2 and R 3 , together with the N atom to which they are bonded, also denote 1,3-dihydroisoindolyl, azepanyl, pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, (CH 2 ) n OH, (CH 2 ) n OA and/or ═O (carbonyl oxygen), R 4 , R 5 each, independently of one another, denote (CH 2 ) n OH, (CH 2 ) n OA, (CH 2 ) n NH 2 , (CH 2 ) n NHA or (CH 2 ) n NAA′,

Ar 1 denotes phenyl which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Hal and/or OA,

Het denotes pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, benzo-1,4-dioxanyl, quinolyl, isoquinolyl, quinazolinyl, benzimidazolyl, indazolyl, indolyl, 1,3-dihydroisoindolyl, benzofuranyl, dihydrobenzofuranyl, benzo-1,3-dioxolyl, piperazinyl, pyrazinyl, pyridazinyl, morpholinyl, azepanyl, pyrrolidinyl or piperidinyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, phenyl, A, (CH 2 ) n OH, (CH 2 ) n OA, COOH, COOA, COObenzyl, CN, COA, CHO, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA′ and/or ═O (carbonyl oxygen),

Het 1 denotes morpholinyl, piperidinyl or pyrrolidinyl, each of which is unsubstituted or monosubstituted by ═O (carbonyl oxygen),

cyclic alkyl having 3-8 C atoms, in which 1-3H atoms may be replaced by OH,

m denotes 0, 1 or 2,

n denotes 0, 1 or 2.

11. The compound according to claim 1 , wherein said compound is selected from the following group:

Compound

No.

Name and/or structure

“A1”

2-Amino-4-methylcarbamoylquinazoline

“A2”

2-Amino-4-ethylcarbamoylquinazoline

“A3”

2-Amino-4-isopropylcarbamoylquinoazline

“A4”

2-Amine-4-isopropylcarbamoylquinazoline

“A5”

2-Amino-4-dimethylcarbamoylquinazoline

“A6”

2-Amino-4-ethylmethylcarbamoylquinazoline

“A7”

2-Amino-4-diethylcarbamoylquinazoline

“A7a”

2-Amino-6-bromo-4-diethylcarbamoylquinazoline

“A8”

2-Amino-4-isopropylmethylcarbamoylquinazoline

“A9”

2-Amino-4-isopropylethylcarbamoylquinazoline

“A10”

2-Amino-4-propylmethylcarbamoylquinazoline

“A11”

2-Amino-4-propylethylcarbamoylquinazoline

“A12”

2-Amino-4-butylmethylcarbamoylquinazoline

“A13”

2-Amino-4-isobutylmethylcarbamoylquinazoline

“A14”

2-Amino-4-cyclopropylmethylcarbamoylquinazoline

“A15”

2-Amino-4-cyclopropylmethymethylcarbamoyl-

quinazoline

“A16”

2-Amino-4-cyclohexylmethylcarbamoylquinazoline

“A17”

2-Amino-4-(3-hydroxypyrrolidin-1-ylcarbonyl)quinazoline

“A18”

2-Amino-4-[(2-cyanoethyl)methylcarbamoylquinazoline

“A19”

2-Amino-4-propargylmethylcarbamoylquinazoline

“A20”

2-Amino-4-[(2-methoxyethyl)methylcarbamoyl]-

quinazoline

“A21”

2-Amino-4-[(2-dimethylaminoethyl)methylcarbamoyl]-

quinazoline

“A22”

2-Amino-4-[(4-methylsulfonylaminobenzyl))methyl- carbamoyl]quinazoline

“A23”

2-Amino-4-[(3-methylsulfonylaminobenzyl))methyl-

carbamoyl]quinazoline

“A24”

2-Amino-4-[(benzo-1,4-dioxan-6-yl)methylcarbamoyl]- quinazoline

“A25”

2-Amino-4-[(4-1,2,4-triazol-1-ylmethylbenzyl)]methyl- carbamoyl]quinazoline

“A26”

2-Amino-4-(furan-2-ylmethylmethylcarbamoyl)- quinazoline

“A27”

2-Amino-4-[(4-1,2,4-triazol-1-ylbenzyl)]methylcarbamoyl]-

quinazoline

“A28”

2-Amino-4-[(2-pyridin-3-ylbenzyl)]methylcarbamoyl]- quinoazline

“A29”

“A30”

“A31”

“A32”

“A33”

“A34”

2-Amino-4-(morpholin-4-ylcarbonyl)quinazoline

“A35”

“A36”

“A37”

“A38”

“A39”

“A40”

“A41”

“A42”

“A43”

“A44”

“A45”

“A46”

“A47”

“A48”

“A49”

“A50”

“A51”

“A52”

“A53”

“A54”

2-Amino-4-(1,3-dihydroisoindol-2-ylcarbonyl)quinazoline

“A55”

2-Amino-4-(5-bromo-1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A56”

2-Amino-4-(5-hydroxy-1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A57”

2-Amino-4-phenylcarbamoylquinazoline

“A58”

2-Amino-4-benzylcarbamoylquinazoline

“A59”

2-Amino-4-benzylmethylcarbamoylquinazoline

“A60”

2-Amino-4-[(3-trifluoromethylbenzyl)methylcarbamoyl]-

quinazoline

“A61”

2-Amino-4-(pyridin-3-ylmethylmethylcarbamoyl)-

quinazoline

“A62”

2-Amino-4-[(3-fluorobenzyl)methylcarbamoyl]quinazoline

“A63”

2-Amino-4-[(4-methoxybenzyl)methylcarbamoyl]-

quinazoline

“A64”

2-Amino-4-[(3-methylbenzyl)methylcarbamoyl]-

quinazoline

“A65”

2-Amino-4-phenylmethylcarbamoylquinazoline

“A66”

2-Amino-4-(furan-2-ylmethylmethylcarbamoyl)-

quinazoline

“A67”

2-Amino-4-(pyridin-2-ylmethylmethylcarbamoyl)-

quinazoline

“A68”

2-Amino-4-[(2-fluorobenzyl)methylcarbamoyl]quinazoline

“A69”

2-Amino-4-[(2-methoxybenzyl)methylcarbamoyl]-

quinazoline

“A70”

2-Amino-4-[(2-methylbenzyl)methylcarbamoyl]-

quinazoline

“A71”

2-Amino-4-benzylethylcarbamoylquinazoline

“A72”

2-Amino-4-[(3-chloro-6-methoxybenzyl)methyl-

carbamoyl]quinazoline

“A73”

2-Amino-4-[(4-fluorobenzyl)methylcarbamoyl]quinazoline

“A74”

2-Amino-4-[(3-methoxybenzyl)methylcarbamoyl]-

quinazoline

“A75”

2-Amino-4-dimethylcarbamoylmethylmethylcarbamoyl- quinazoline

“A76”

2-Amino-4-[(4-methylbenzyl)methylcarbamoyl]-

quinazoline

“A77”

2-Amino-6-methyl-4-diethylcarbamoylquinazoline

“A78”

2-Amino-6-methyl-4-benzylethylcarbamoylquinazoline

“A79”

“A80”

“A81”

“A82”

2-Amino-6-methyl-4-propylethylcarbamoylquinazoline

“A83”

2-Amino-6-methyl-4-(morpholin-4-ylcarbonyl)quinazoline

“A84”

2-Amino-6-methyl-4-isopropylethylcarbamoylquinazoline

“A85”

“A86”

2-Amino-6-methyl-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A87”

“A88”

2-Amino-6-methyl-4-[(1-methyl-1H-pyrazol-3-yl)- carbamoyl]quinazoline

“A89”

2-Amino-6-methyl-4-[(1-methyl-5-trifluoromethyl-1H- indazol-3-yl)carbamoyl]quinazoline

“A90”

2-Amino-6-methyl-4-(5-bromo-1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A91”

2-Amino-6-methyl-4-(5-hydroxy-1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A92”

2-Amino-6-methyl-4-(5-methoxy-1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A93”

2-Amino-6-methyl-4-(5-ethoxy-1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A94”

2-Amino-6-methyl-4-(5-isopropoxy-1,3-dihydroisoindol-2-

ylcarbonyl)quinazoline

“A95”

2-Amino-6-ethyl-4-(5-hydroxy-1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A96”

2-Amino-6-ethyl-4-(5-bromo-1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A97”

2-Amino-6-ethyl-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A98”

2-Amino-6-ethyl-4-diethylcarbamoylquinazoline

“A99”

2-Amino-6-ethyl-4-(pyrrolidin-1-ylcarbonyl)quinazoline

“A100”

2-Amino-6-ethyl-4-(piperidin-1-ylcarbonyl)quinazoline

“A101”

2-Amino-6-ethyl-4-(morpholin-4-ylcarbonyl)quinazoline

“A102”

2-Amino-6-ethyl-4-(azepan-1-ylcarbonyl)quinazoline

”A103”

2-Amino-6-ethyl-4-(2-methylpyrrolidin-1-ylcarbonyl)-

quinazoline

“A104”

2-Amino-6-ethyl-4-(2-methylpiperidin-1-ylcarbonyl)-

quinazoline

“A105”

2-Amino-6-ethyl-4-(4-methylpiperidin-1-ylcarbonyl)-

quinazoline

“A106”

2-Amino-6-ethyl-4-(2,6-dimethylpyrrolidin-1-ylcarbonyl)-

quinazoline

“A107”

2-Amino-6-ethyl-4-(3-methylpiperidin-1-ylcarbonyl)-

quinazoline

“A108”

2-Amino-6-ethyl-4-(3-oxopiperazin-1-ylcarbonyl)-

quinazoline

“A109”

2-Amino-6-ethyl-4-(2-methoxymethylpyrrolidin-1-yl-

carbonyl)quinazoline

“A110”

2-Amino-6-ethyl-4-(2-propylpiperidin-1-ylcarbonyl)-

quinazoline

“A111”

2-Amino-6-ethyl-4-(2-ethylpiperidin-1-ylcarbonyl)-

quinazoline

“A112”

2-Amino-6-propyl-4-(5-bromo-1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A113”

2-Amino-6-propyl-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A114”

2-Amino-6-propyl-4-diethylcarbamoylqquinazoline

“A115”

2-Amino-6-propyl-4-(5-hydroxy-1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A116”

2-Amino-6-isopropyl-4-(5-hydroxy-1,3-dihydroisoindol-2-

ylcarbonyl)quinazoline

“A117”

2-Amino-6-isopropyl-4-(5-bromo-1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A118”

2-Amino-6-isopropyl-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A119”

2-Amino-6-isopropyl-4-diethylcarbamoylquinazoline

“A120”

2-Amino-6-isopropyl-4-(2-propylpiperidin-1-ylcarbonyl)-

quinazoline

“A121”

2-Amino-6-isopropyl-4-(2-ethylpiperidin-1-ylcarbonyl)-

quinazoline

“A122”

2-Amino-6-sec-butyl-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A123”

2-Amino-6-tert-butyl-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A124”

2-Amino-6-bromo-4-benzylmethylcarbamoylquinazoline

“A125”

2-Amino-6-bromo-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A126”

2-Amino-6-bromo-4-(5-bromo-1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A127”

2-Amino-6-chloro-4-(5-bromo-1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A128”

2-Amino-6-chloro-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A129”

2-Amino-6-chloro-4-diethylcarbamoylquinazoline

“A130”

2-Amino-6-iodo-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A131”

2-Amino-6-phenyl-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A132”

2-Amino-6-(3-hydroxymethylphenyl)-4-(1,3-dihydro-

isoindol-2-ylcarbonyl)quinazoline

“A133”

2-Amino-6-(4-hydroxymethylphenyl)-4-(1,3-dihydro-

isoindol-2-ylcarbonyl)quinazoline

“A134”

2-Amino-6-(2-hydroxymethylphenyl)-4-(1,3-dihydro-

isoindol-2-ylcarbonyl)quinazoline

“A135”

2-Amino-6-(4-cyanomethylphenyl)-4-(1,3-dihydro-

isoindol-2-ylcarbonyl)quinazoline

“A136”

2-Amino-6-cyano-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A137”

2-Amino-6-bromo-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A138”

2-Amino-6-phenyl-4-diethylcarbamoylquinazoline

“A139”

2-Amino-6-(butylmethylcarbamoyl)-4-diethylcarbamoyl-

quinazoline

“A140”

2-Amino-6-ethylcarbamoyl-4-diethylcarbamoyl-

quinazoline

“A141”

2-Amino-6-(1,3-dihydroisoindol-2-ylcarbonyl)-4- diethylcarbamoylquinazoline

“A142”

2-Amino-6-((E)-2-methoxycarbonylvinyl)-4-(1,3-dihydro-

isoindol-2-ylcarbonyl)quinazoline

“A142a”

(E)-3-[2-Amino-4-(1,3-dihydroisoindole-2-carbonyl)-

quinazolin-6-yl]acrylic acid

“A143”

2-Amino-6-(2-methoxycarbonylethyl)-4-(1,3-dihydro-

isoindol-2-ylcarbonyl)quinazoline

“A143a”

“A144”

2-Amino-6-((E)-styryl)-4-(1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A145”

2-Amino-6-(2-phenylethyl)-4-(1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A146”

2-Amino-6-(3-trimethylsilanylprop-2-ynyl)-4-(1,3-dihydro-

isoindol-2-ylcarbonyl)quinazoline

“A147”

2-Amino-6-(prop-1-ynyl)-4-(1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A148”

“A149”

“A150”

2-Amino-6-fluoro-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A151”

2-Amino-6-methoxy-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A151a”

2-Amino-6-hydroxy-4-(1,3-dihydroxyisoindol-2-ylcarbonyl)-

quinazoline

“A152”

2-Amino-6-nitro-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A152a”

2,6-Diamino-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A153”

2-Amino-8-methyl-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A240”

“A262”

“A304”

“A310”

“A335”

“A344b”

“A344c”

“A344d”

“A328”

“A535a”

“A535b”

“A918”

2-Amino-6-(2-cyanophenyl)-4-(1,3-dihydroisoindol-2-yl- carbonyl)quinazoline

”A919”

2-Amino-6-(3-cyanomethylphenyl)-4-(1,3-dihydro-

isoindol-2-ylcarbonyl)quinazoline

“A921”

2-Amino-6-(benzofuran-2-yl)-4-(1,3-dihydroisoindol-2-yl- carbonyl)quinazoline

“A922”

2-Amino-6-(pyridin-4-yl)-4-(1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A923”

2-Amino-6-(pyridin-3-yl)-4-(1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A924”

2-Amino-6-(2-ethylphenyl)-4-(1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A925”

2-Amino-6-(3-hydroxyphenyl)-4-(1,3-dihydroisoindol-2-yl-

carbonyl)quinazoline

“A926”

2-Amino-6-(2-piperazin-1-ylmethylphenyl)-4-(1,3-dihydro-

isoindol-2-ylcarbonyl)quinazoline

“A927”

“A928”

“A929”

“A930”

“A931”

“A932”

“A933”

“A936”

“A937”

“A938”

“A939”

“A940”

“A941”

“A942”

“A943”

“A944”

“A945”

“A946”

“A947”

“A948”

“A949”

“A950”

“A951”

“A952”

2-Amino-7-chloro-4-(1,3-dihydroisoindol-2-ylcarbonyl)-

quinazoline

“A953”

“A954”

“A955”

“A956”

“A957”

“A958”

“A959”

“A960”

“A961”

“A962”

“A963”

“A963a”

“A936b”

“A964”

2-Amino-6-(3-hydroxyprop-1-ynyl)-4-(1,3-dihydroisoindol-

2-ylcarbonyl)quinazoline

“A965”

[2-Amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-

6-yl]propynal

“A966”

5-[2-Amino-4-(1,3-dihydroisoindole-2-carbonyl)-

quinazolin-6-yl]-3H-1,2,3-triazole-4-carbaldehyde

“A967”

[2-Amino-6-(5-methylaminomethyl-1H-1,2,3-triazol-4-yl)-

quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone

“A968”

[2-Amino-6-(5-hydroxymethyl-1H-1,2,3-triazol-4-yl)-

quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone

“A969”

2-[2-Amino-4-(1,3-dihydroisoindole-2-carbonyl)-

quinazoline-6-yl]benzaldehyde

“A970”

{2-Amino-6-[2-(4-methylpiperazin-1-ylmethyl)phenyl]-

quinazolin-4-yl}-(1,3-dihydroisoindol-2-yl)methanone

“A971”

“A972”

“A973”

“A974”

“A975”

“A976”

“A977”

“A978”

“A979”

“A980”

{2-Amino-6-[2-(4-methylpiperazine-1-sulfonyl)phenyl]-

quinazolin-4-yl}-(1,3-dihydropisoindol-2-yl)methanone

“A981”

“A982”

“A983”

{2-Amino-6-[2-(4-methylpiperazine-1-carbonyl)phenyl]-

quinazaolin-4-yl}-(1,3-dihydroisoindol-2-yl)methanone

“A984”

“A985”

“A986”

{2-Amino-6-[2-(2-dimethylaminoethoxy)phenyl]-

quinazolin-4-yl}-(1,3-dihydroisoindol-2-yl)methanone

“A987”

“A988”

“A989”

“A990”

“A991”

“A992”

“A993”

“A994”

“A995”

“A996”

“A997”

“A998”

“A999”

“A1000”

“A1001”

“A1002”

“A1003”

“A1004”

“A1005”

“A1006”

“A1007”

“A1008”

“A1009”

“A1010”

“A1011”

“A1012”

and pharmaceutically usable salts and stereoisomers thereof, including mixtures thereof in all ratios.

12. The compound according to claim 1 , wherein

R 1 is H, methyl, ethyl, propyl, isopropyl, tert-butyl, fluoro, bromo, chloro, iodo, cyano, or Ar,

Ar is phenyl which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by A, Hal, (CH 2 ) n OA, (CH 2 ) n OH, (CH 2 ) n CN, SA, SOA, SO 2 A, NO 2 , C≡CH, (CH 2 ) n COOH, CHO, (CH 2 ) n COOA, CONH 2 , CONHA, CONAA′, NHCOA, CH(OH)A, (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA′, (CH 2 ) n NAAr 1 , O(CH 2 ) n Het 1 , (CH 2 ) n Het 1 , COO(CH 2 ) n Ar 1 , (CH 2 ) n NHSO 2 A, (CH 2 ) n OAr 1 , O(CH 2 ) n Ar 1 , SO 2 NH(CH 2 ) n NH 2 , SO 2 NH 2 , SO 2 NHA, SO 2 NAA′, CONHAr 1 , CONH(CH 2 ) n COOA, CONH(CH 2 ) n COOH, NHCO(CH 2 ) n COOA, NHCO(CH 2 ) n COOH, CONH(CH 2 ) n NH 2 , CONH(CH 2 ) n NHA, CONH(CH 2 ) n NAA′, CONH(CH 2 ) n CN, NHCOHet, SO 2 Het, COHet and/or (CH 2 ) n CH(NH 2 )COOH,

R 2 is H or methyl, and

R 3 is methyl, ethyl, propyl, butyl, isopropyl, phenyl, benzyl, furyl-2-ylmethyl, HC≡C—CH 2 —, 2-methoxyethyl, 3-trifluoromethylbenzyl, pyridin-2- or 3-ylmethyl, 2-, 3- or 4-fluorobenzyl, 2-, 3- or 4-methoxybenzyl, 2-, 3- or 4-methylbenzyl, 3-chloro-6-methoxybenzyl, N,N-dimethylaminocarbonylmethyl, 4-(1,2,4-triazol-1-ylmethyl)-benzyl, 2- or 3-(pyridin-3-yl)benzyl, 3-(2-morpholin-4-ylethoxy)benzyl, 4-(triazol-1-yl)benzyl, 3-(morpholin-4-yl)benzyl, 3-(pyrimidin-5-yl)benzyl, 3-(morpholin-4-ylmethyl)benzyl, cyclopropylmethyl, 2-cyanoethyl, 2-dimethylaminoethyl, cyclohexyl, 3- or 4-(methylsulfonylamino)benzyl, 4-(methylsulfonylaminomethyl)benzyl, benzo-1,4-dioxan-6-ylmethyl, morpholin-4-yl, 2-hydroxyethyl, 2-methoxyethyl, 1,3,5-trimethyl-1H-pyrazol-4-ylmethyl, 2-methylsulfanilethyl, 2-hydroxy-2-phenylethyl, 2-(N-ethyl-N-methylamino)ethyl, 2-diethylaminoethyl, 1-methyl-1H-pyrazol-3-yl, quinolin-5- or 8-yl, 2-methylsulfanilphenyl, biphenyl-2-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 2-(1H-benzimidazol-2-yl)phenyl, 3,4,5-trimethoxyphenyl, 2-ethynylphenyl or 1-methyl-5-trifluoromethyl-1H-indazol-3-yl,

R 2 and R 3 , together with the N atom to which they are bonded, can also be 1,3-dihydroisoindolyl, azepanyl, pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal, A, (CH 2 ) n OH, (CH 2 ) n OA and/or ═O (carbonyl oxygen).

13. The compound according to claim 1 , wherein A or A′ are each methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, hexyl, trifluoromethyl, pentafluoroethyl, 1,1,1-trifluoroethyl, 2-methoxyethyl, 3-methylaminopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylmethylene, cyclohexylmethylene, vinyl, propenyl, or ethynyl.

14. The compound according to claim 1 , wherein Het is pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, benzo-1,4-dioxanyl, quinolyl, isoquinolyl, quinazolinyl, benzimidazolyl, indazolyl, indolyl, 1,3-dihydroisoindolyl, benzofuranyl, dihydrobenzo-furanyl, benzo-1,3-dioxolyl, piperazinyl, pyrazinyl, pyridazinyl, morpholinyl, azepanyl, pyrrolidinyl or piperidinyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, (CH 2 ) n OA, (CH 2 ) n OH, Ar 1 , SH, S(O) m A, Hal, NO 2 , CN, COA, CHO, COOA, COObenzyl, CONH 2 , CONHA, CONAA′, SO 2 NH 2 , (CH 2 ) n NH 2 , (CH 2 ) n NHA, (CH 2 ) n NAA′, NHSO 2 A and/or ═O (carbonyl oxygen).

15. The compound according to claim 1 , wherein Het 1 is pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, benzimidazolyl, morpholinyl, pyrimidinyl, piperidinyl, pyrrolidinyl or piperazinyl, each of which is unsubstituted or mono-, di- or trisubstituted by A, OA, OH, Hal, CN and/or ═O (carbonyl oxygen).

16. A pharmaceutical composition comprising at least one compound according to claim 1 and one or more excipients and/or adjuvants.

17. A pharmaceutical composition according to claim 16 , further comprising at least one further medicament active ingredient.

18. A process for the preparation of compounds according to claim 1 , said process comprising:

a) reacting a compound of formula II

in which

R 1 has the meaning indicated in claim 1 , and

L denotes F, Cl, Br, I or a free or reactively modified OH group,

with a compound of formula III

NHR 2 R 3 III

in which

R 2 and R 3 have the meanings indicated in claim 1 ; or

b) reacting a compound of formula IV

in which R 1 , R 2 and R 3 have the meanings indicated in claim 1 ,

with a 1,3-bis(trialkylsilyl)carbodiimide; or

c) converting a radical R 1 in a compound of the formula I is into another radical R 1 by

i) reducing a nitro group to an amino group,

ii) hydrolyzing an ester group to a carboxyl group,

iii) converting an aldehyde group into an alkylated amine by reductive amination,

iv) converting a carboxyl group into a sulfonamidocarbonyl group,

v) converting an acid chloride into an amide,

vi) exchanging a halogen atom with an aryl or alkyl radical,

vii) hydrogenating a double bond,

viii) cleaving an ether,

ix) replacing a halogen atom with an aryl radical (Suzuki coupling),

x) replacing a halogen atom with an alkylamino, arylamino, alkoxy or aryloxy group,

and/or a base or acid of a compound of formula I is converted into one of its salts.

19. A kit comprising consisting of separate packs of

(a) an effective amount of a compound according to claim 1 ,

and

(b) an effective amount of a further medicament active ingredient.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 12, 2010

From: EGGENWEILER, HANS-MICHAEL; SIRRENBERG, CHRISTIAN; BUCHSTALLER, HANS-PETER

To: MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HAFTUNG

Reel/Frame 023769/0355 →

Priority Claims (1)

DE 10 2007 032 739 · Jul 13, 2007 · national

Continuity (1)

Related Publication 20100234324A1 · Sep 16, 2010