US2011059954A1PendingUtilityA1
Cgrp antagonists
Est. expiryOct 18, 2027(~1.2 yrs left)· nominal 20-yr term from priority
Inventors:Dirk GottschlingGeorg DahmannHenri DoodsAnnekatrin HeimannStephan Georg MuellerKlaus RudolfGerhard SchaenzleDirk Stenkamp
A61P 37/08A61P 3/10A61P 9/00A61P 43/00A61P 25/36A61P 29/00A61P 25/04A61P 25/06A61P 31/04A61P 15/12A61P 11/02C07D 417/14A61P 11/06A61P 19/02A61P 11/00C07D 401/14A61P 1/02A61P 17/00C07D 471/04C07D 405/14C07D 413/14A61P 1/12
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Claims
Abstract
The present invention relates to new CGRP-antagonists of general formula I wherein U, V, X, Y, R 1 , R 2 and R 3 are defined as stated hereinafter, the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, their use and processes for preparing them.
Claims
exact text as granted — not AI-modified1 . A compound of the formula I
wherein
R 1 denotes a group of the formula II
wherein
G-L denotes N, N—C(R 4.1 ) 2 , C═C(R 4.1 ), C═N, C(R 4.1 ), C(R 4.1 )—C(R 4.1 ) 2 , C(R 4.1 )—C(R 4.1 ) 2 —C(R 4.1 ) 2 , C═C(R 4.1 )—C(R 4.1 ) 2 , C(R 4.1 )—C(R 4.1 )═C(R 4.1 ), C(R 4.1 )—C(R 4.1 ) 2 —N(R 4.2 ), C═C(R 4.1 )—N(R 4.2 ), C(R 4.1 )—C(R 4.1 )═N, C(R 4.1 )—N(R 4.2 )—C(R 4.1 ) 2 , C═N—C(R 4.1 ) 2 , C(R 4.1 )—N═C(R 4.1 ), C(R 4.1 )—N(R 4.2 )—N(R 4.2 ), C═N—N(R 4.2 ), N—C(R 4.1 ) 2 —C(R 4.1 ) 2 , N—C(R 4.1 )═C(R 4.1 ), N—C(R 4.1 ) 2 —N(R 4.2 ), N—C(R 4.1 )═N, N—N(R 4.2 )—C(R 4.1 ) 2 or N—N═C(R 4.1 ),
Q-T denotes C(R 5 ) 2 —C(R 5 ) 2 , C(R 5 )═C(R 5 ), N═C(R 5 ), C(R 5 ) 2 —C(═O), C(═O)—C(R 5 ) 2 , C(R 5 ) 2 —S(O) m or C(R s ) 2 —N(R 5 ),
wherein a group C(R 5 ) 2 contained in Q-T may also denote a cyclic group which is selected from among C 3-6 -cycloalkyl, C 5-6 -cycloalkenyl or heterocyclyl, or
wherein in a group C(R 5 ) 2 —C(R 5 ) 2 , C(R 5 )═C(R 5 ) or C(R 5 ) 2 —N(R 5 ) contained in Q-T in each case a group R 5 together with an adjacent group R 5 and the atoms to which these groups are bound may also denote a C 3-6 -cycloalkyl, C 5-6 -cycloalkenyl, heterocyclyl, aryl or heteroaryl group, which may be substituted independently of one another by 1, 2 or 3 substituents R 5.1 ,
R 2 denotes
(a) H,
(b) F, —CN, C 1-3 -alkyl, —CO 2 —R 2.1 or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 2.1 denotes H or C 1-6 -alkyl,
R 3 denotes a 6 or 10-membered aryl group substituted by the groups R 3.1 , R 3.2 and R 3.3 or
a 6-membered heteroaryl group substituted by the groups R 3.1 , R 3.2 and R 3.3 which is attached via a carbon atom,
R 3.1 denotes
(a) H,
(b) halogen, —NH 2 , C 1-4 -alkyl-NH—, (C 1-4 -alkyl) 2 N—, C 1-3 -alkyl-C(O)—NH—, C 1-3 -alkyl-S(O 2 )—NH—, —CN, —OH, —O—C(O)—NH—C 1-3 -alkyl,
(c) C 1-4 -alkyl, R 3.1,1 —C 1-3 -alkylene, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1-3 -alkyl-O—, C 1-3 -alkyl-S(O) m —, cyclopropyl,
(d) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
(e) —C(O)—R 3.1.2 ,
(f) —S(O) 2 —R 3.1.3 ,
R 3.1.1 denotes
(a) H,
(b) C 3-6 -cycloalkyl, C 5-6 -cycloalkenyl,
(c) (R 3.1.1.1 ) 2 N,
(d) a saturated, mono- or diunsaturated 5- or 6-membered heterocyclic group which is substituted at a nitrogen atom by a group R 3.1.1.1 and is substituted at a carbon atom by one or two groups R 3.1.1.2 , or
(e) a heteroaryl group which is substituted at a carbon atom by a group R 3.1.1.2 ,
R 3.1.1.1 independently of one another denotes
(a) H, C 1-4 -alkyl, C 3-6 -cycloalkyl,
(b) heterocyclyl,
(c) aryl-C 0-3 -alkylene or heteroaryl-C 0-3 -alkylene,
R 3.1.1.2 independently of one another denotes
(a) H, F, C 1-3 -alkyl, —CN, —OH, —O—C 1-3 -alkyl, —CO(O)R 3.1.1.2.1 , H 2 N—, (C 1-4 -alkyl)-NH—, (C 1-4 -alkyl) 2 N—,
(b) phenyl or phenyl-CH 2 —,
(c) a C 1-3 -alkyl or —O—C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
R 3.1.1.2.1 denotes H, C 1-6 -alkyl, benzyl,
R 3.1.2 denotes —O—C 1-3 -alkyl, —OH, —NR 3.1.2.1 R 3.1.2.2 ,
R 3.1.2.1 denotes H, C 1-3 -alkyl,
R 3.1.2.2 denotes H, C 1-3 -alkyl,
R 3.1.2.1 and R 3.1.2.1 together may also form a ring which is selected from among azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,
R 3.1.3 denotes —O—C 1-3 -alkyl, —NR 3.1.3.1 R 3.1.3.2 ,
R 3.1.3.1 denotes H, C 1-3 -alkyl,
R 3.1.3.2 denotes H, C 1-3 -alkyl,
R 3.1.3.1 and R 3.1.3.1 together may also form a ring which is selected from among azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,
R 3.2 denotes
(a) H,
(b) halogen, —NH 2 , C 1-4 -alkyl-NH—, (C 1-4 -alkyl) 2 N—, C 1-3 -alkyl-C(O)—NH—, C 1-3 -alkyl-S(O 2 )—NH—, —CN, —OH, —O—C(O)—NH—C 1-3 -alkyl,
(c) C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1-3 -alkyl-O, C 1-3 -alkyl-S(O) m —, cyclopropyl,
(d) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
(e) —C(O)—R 3.2.1 ,
(f) —S(O) 2 —R 3.2.2 ,
R 3.2.1 denotes —O—C 1-3 -alkyl, —OH, —NR 3.2.1.1 R 3.2.1.2 ,
R 3.2.1.1 denotes H, C 1-3 -alkyl,
R 3.2.1.2 denotes H, C 1-3 -alkyl,
R 3.2.1.1 and R 3.2.1.2 together may also form a ring which is selected from among azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,
R 3.2.2 denotes —NR 3.2,2,1 R 3.2,2,2 ,
R 3.2,2,1 denotes H, C 1-3 -alkyl,
R 3.2,2,2 denotes H, C 1-3 -alkyl,
R 3.2,2,1 and R 3.2,2,2 together may also form a ring which is selected from among azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,
R 3.3 denotes
(a) H,
(b) halogen, —NH 2 , C 1-4 -alkyl-NH—, (C 1-4 -alkyl) 2 N—, C 1-3 -alkyl-C(O)—NH—, C 1-3 -alkyl-S(O 2 )—NH—, —CN, —OH, —O—C(O)—NH—C 1-3 -alkyl,
(c) C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1-3 -alkyl-O, C 1-3 -alkyl-S(O) m —, cyclopropyl,
(d) a C 1-3 -alkyl- or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
(e) —C(O)—R 3.3.1 ,
(f) —S(O) 2 —R 3.3.2 ,
R 3.3.1 denotes —O—C 1-3 -alkyl, —OH, —NR 3.3.1.1 R 3.3.1.2 ,
R 3.3.1.1 denotes H, C 1-3 -alkyl,
R 3.3.1.2 denotes H, C 1-3 -alkyl,
R 3.3.1.1 and R 3.3.1.2 together may also form a ring which is selected from among azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,
R 3.3.2 denotes —O—C 1-3 -alkyl, —NR 3.3.2.1 R 3.3.2.2 ,
R 3.3.2.1 denotes H, C 1-3 -alkyl,
R 3.3.2.2 denotes H, C 1-3 -alkyl,
R 3.3.2.1 and R 3.3.2.2 together may also form a ring which is selected from among azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, or
R 3.2 and R 3.3 together with the carbon atoms to which they are attached form a monounsaturated 5-membered or a mono- or diunsaturated 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, while
the heterocycles mentioned previously may contain a carbonyl, thiocarbonyl or cyanimino group adjacent to a nitrogen atom, and
may optionally each additionally be substituted at one or two nitrogen atoms by a group R 3.3.3 and
may optionally each additionally be substituted at one or two carbon atoms by one or two groups R 3.3.4 ,
R 3.3.3 independently of one another denote
(a) C 1-4 -alkyl or
(b) C 3-6 -cycloalkyl,
R 3.3.4 independently of one another denote
(a) C 1-4 -alkyl or
(b) C 3-6 -cycloalkyl,
(c) halogen, CN, —O—C 1-3 -alkyl, —NH 2 ,
(d) a C 1-3 -alkyl- or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two and each methyl group is substituted by up to three fluorine atoms,
R 4.1 independently of one another denote
(a) H,
(b) C 1-6 -alkyl, —CN, —OH, —O—C 1-3 -alkyl,
(c) a C 1-3 -alkyl- or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 4.2 denotes H or C 1-6 -alkyl,
R 5 independently of one another denote
(a) H, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl,
(b) an aryl group optionally substituted by 1, 2 or 3 substituents R 5.2 , wherein the substituents R 5.2 may be identical or different,
(c) a heteroaryl group optionally substituted by 1, 2 or 3 substituents R 5.2 , wherein the substituents R 5.2 may be identical or different,
(d) a heterocyclic group optionally substituted by 1, 2 or 3 substituents R 5.2 , wherein the substituents R 5.2 may be identical or different,
R 5.1 independently of one another denote
(a) H, halogen, C 1-6 -alkyl, C 3-6 -cycloalkyl,
(b) —O—C 1-6 -alkylene-NR 7 R 8 , —O—R 6 , —O—(CH 2 ) s —O—R 6 , —CO 2 —R 6 , —C(O)—NR 7 R 8 , —O—C(O)—NR 7 R 8 , —NR 6 —C(O)—NR 7 R 8 , —NR 7 —C(O)—R 8 , —NR 7 —C(O)—O—R 8 , —SO 2 —NR 7 R 8 , —NR 7 —SO 2 —R 8 , —S(O) m —R 7 , —CN, —NR 7 R 8 , —NR 6 —C(O)—NR 7 R 8 , —O—C(O)—R 6 ,
(c) a C 1-3 -alkyl- or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
(d) an aryl group substituted by 1, 2 or 3 substituents R 6 , wherein the substituents R 6 may be identical or different,
(e) a heteroaryl group substituted by 1, 2 or 3 substituents R 6 , wherein the substituents R 6 may be identical or different,
(f) a heterocyclic group substituted by 1, 2 or 3 substituents R 6 , wherein the substituents R 6 may be identical or different,
R 5.2 independently of one another denote
(a) halogen, C 1-6 -alkyl, C 3-6 -cycloalkyl,
(b) —O—R 6 , —O—(CH 2 ) s —O—R 6 , —CO 2 R 6 , —C(O)—NR 7 R 8 , —O—(CO)—NR 7 R 8 , —N(R 6 )—C(O)—NR 7 R 8 , —N(R 7 )—C(O)—R 8 , —N(R 7 )—C(O)—O—R 8 , —SO 2 —NR 7 R 8 , —N(R 7 )—SO 2 —R 8 , —S(O) m —R 7 , —CN, —NR 7 R 8 , —N(R 6 )—C(O)—NR 7 R 8 , —O—C(O)—R 6 or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 6 denotes
(a) H,
(b) C 1-6 -alkyl, C 3-6 -cycloalkyl, aryl, heteroaryl, benzyl, which may be substituted by a group R 6.1 , or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 6.1 denotes halogen, HO— or C 1-6 -alkyl-O—,
R 7 denotes
(a) H,
(b) C 1-6 -alkyl, C 3-6 -cycloalkyl, aryl, heteroaryl or benzyl, while the groups are unsubstituted or may be substituted by halogen, HO— or C 1-6 -alkyl-O—, or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 8 denotes
(a) H,
(b) C 1-6 -alkyl, C 3-6 -cycloalkyl, aryl, heteroaryl or benzyl, while the groups are unsubstituted or may be substituted by halogen, HO— or C 1-6 -alkyl-O—, or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
R 7 and R 8 together may also form a ring which is selected from among azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein the ring may be unsubstituted or substituted by 1, 2 or 3 substituents R 6 or fluorine, wherein the substituents R 6 are independent of one another,
m denotes one of the numbers 0, 1 or 2,
s denotes one of the numbers 1, 2 or 3,
U denotes N,N-oxide or C—R 9 ,
V denotes N,N-oxide or C—R 10 ,
X denotes N,N-oxide or CR 11 ,
Y denotes N or C—R 12 ,
while at most three of the previously mentioned groups U, V, X or Y simultaneously denote a nitrogen atom,
R 9 denotes
(a) H,
(b) a C 1-6 -alkyl- or C 1-3 -alkyl-O— group which may each be substituted by a group R 9.1 ,
(c) R 9.2 R 9.3 N, R 9.2 R 9.3 N—C 1-3 -alkylene-,
(d) halogen, —CN, —OH, —COOH, C 1-3 -alkyl-O—C 1-3 -alkylene, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-4 -alkylene-, C 1-3 -alkyl-C(O)—O—C 1-3 -alkylene,
(e) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 9.1 denotes H, OH or —O—CH 3 ,
R 9.2 denotes H or C 1-3 -alkyl,
R 9.3 denotes H or C 1-3 -alkyl, or
R 9.2 and R 9.3 together with the nitrogen atom to which they are attached denote a 3- to 6-membered heterocyclic group,
R 10 denotes
(a) H,
(b) a C 1-6 -alkyl- or C 1-3 -alkyl-O— group which may each be substituted by a group R 10.1 .
(c) —NR 10.2 R 10.3 , NR 10.2 R 10.3 —C 1-3 -alkylene-,
(d) halogen, —CN, —OH, C 1-3 -alkyl-O—C 1-3 -alkylene, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-4 -alkylene, C 1-3 -alkyl-C(O)—O—C 1-3 -alkylene,
(e) an aryl-C 0-3 -alkylene-O— group,
(f) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 10.1 denotes H, OH or —O—CH 3 ,
R 10.2 denotes H or C 1-6 -alkyl,
R 10.3 denotes H, C 1-6 -alkyl or —SO 2 —C 1-3 -alkyl, or
R 10.2 and R 10.3 together with the nitrogen atom to which they are attached denote a 3- to 6-membered heterocyclic group,
R 11 denotes
(a) H,
(b) a C 1-6 -alkyl- or C 1-3 -alkyl-O— group which may each be substituted by a group R 11.1 ,
(c) R 11.2 R 11.3 N, R 11.2 R 11.3 N—C 1-3 -alkylene-,
(d) halogen, —CN, —OH, —COOH, C 1-3 -alkyl-O—C 1-3 -alkylene-, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-4 -alkylene-, C 1-3 -alkyl-C(O)—O—C 1-3 -alkylene,
(e) a C 1-3 -alkyl- or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 11.1 denotes H, OH or —O—CH 3 ,
R 11.2 denotes H or C 1-3 -alkyl,
R 11.3 denotes H or C 1-3 -alkyl, or
R 11.2 and R 11.3 together with the nitrogen atom to which they are attached denote a 3- to 6-membered heterocyclic group, and
R 12 denotes H, halogen or C 1-3 -alkyl,
or a tautomer or salt thereof.
2 . A compound of the formula I according to claim 1 , wherein
R 1 denotes a group of the formula II
wherein
G-L denotes N, N—C(R 4.1 ) 2 , C═C(R 4.1 ), C═N, C(R 4.1 ), C(R 4.1 )—C(R 4.1 ) 2 , C(R 4.1 )C(R 4.1 ) 2 —C(R 4.1 ) 2 , C═C(R 4.1 )—C(R 4.1 ) 2 , C(R 4.1 )—C(R 4.1 )═C(R 4.1 ), C(R 4.1 )—C(R 4.1 ) 2 —N(R 4.2 ), C═C(R 4.1 )—N(R 4.2 ), C(R 4.1 )—C(R 4.1 )═N, C(R 4.1 )—N(R 4.2 )—C(R 4.1 ) 2 , C═N—C(R 4.1 ) 2 , C(R 4.1 )—N═C(R 4.1 ), C(R 4.1 )—N(R 4.2 )—N(R 4.2 ), C═N—N(R 4.2 ), N—C(R 4.1 ) 2 —C(R 4.1 ) 2 , N—C(R 4.1 )═C(R 4.1 ), N—C(R 4.1 ) 2 —N(R 4.2 ), N—C(R 4.1 )=N, N—N(R 4.2 )—C(R 4.1 ) 2 or N—N═C(R 4.1 ),
Q-T denotes C(R 5 ) 2 —C(R 5 ) 2 , C(R 5 )═C(R 5 ), N═C(R 5 ), C(R 5 ) 2 —C(═O), C(═O)—C(R 5 ) 2 , C(R 5 ) 2 —S(O) m or C(R 5 ) 2 —N(R 5 ),
while a group C(R 5 ) 2 contained in Q-T may also denote a cyclic group which is selected from among cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine-S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl and piperazinyl, or
in a group C(R 5 ) 2 —C(R 5 ) 2 , C(R 5 )═C(R 5 ) or C(R 5 ) 2 —N(R 5 ) contained in Q-T in each case a group R 5 together with an adjacent group R 5 and the atoms to which these groups are attached may also denote a group selected from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, dioxanyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolinyl, quinolinyl, isoquinolinyl, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine-S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl, which may be substituted independently of one another by 1, 2 or 3 substituents R 5.1 ,
R 4.1 denotes
(a) H,
(b) C 1-6 -alkyl, —CN, —OH, —O—C 1-3 -alkyl,
(c) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 4.2 denotes H or C 1-6 -alkyl,
R 5 denotes
(a) H, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl,
(b) an aryl group optionally substituted by 1, 2 or 3 substituents R 5.2 , wherein the substituents R 5.2 may be identical or different,
(c) a heteroaryl group optionally substituted by 1, 2 or 3 substituents R 5.2 , wherein the substituents R 5.2 may be identical or different,
(d) a heterocyclic group optionally substituted by 1, 2 or 3 substituents R 5.2 , wherein the substituents R 5.2 may be identical or different,
R 5.1 denotes
(a) H, halogen, C 1-6 -alkyl, C 3-6 -cycloalkyl,
(b) —O—C 1-6 -alkylene-NR 7 R 8 , —O—R 6 , —O—(CH 2 ) s —O—R 6 , —CO 2 —R 6 , C(O)—NR 7 R 8 , —O—C(O)—NR 7 R 8 , —NR 7 —C(O)—NR 7 R 8 , —NR 7 —C(O)—R 8 , —NR 7 —C(O)—O—R 8 , —SO 2 —NR 7 R 8 , —NR 7 —SO 2 —R 8 , —S(O) m —R 7 , —CN, —NR 7 R 8 , —NR 6 —C(O)—NR 7 R 8 , —O—C(O)—R 6 ,
(c) a C 1-3 -alkyl- or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
(d) an aryl group substituted by 1, 2 or 3 substituents R 6 , wherein the substituents R 6 may be identical or different,
(e) a heteroaryl group substituted by 1, 2 or 3 substituents R 6 , wherein the substituents R 6 may be identical or different,
(f) a heterocyclic group substituted by 1, 2 or 3 substituents R 6 , wherein the substituents R 6 may be identical or different,
R 5.2 denotes
(a) halogen, C 1-6 -alkyl, C 3-6 -cycloalkyl,
(b) —O—R 6 , —O—(CH 2 ) s —O—R 6 , —CO 2 R 6 , —C(O)—NR 7 R 8 , —O—(CO)—NR 7 R 8 , —N(R 6 )—C(O)—NR 7 R 8 , —N(R 7 )—C(O)—R 8 , —N(R 7 )—C(O)—O—R 8 , —SO 2 —NR 7 R 8 , —N(R 7 )—SO 2 —R 8 , —S(O) m —R 7 , CN, NR 7 R 8 , —N(R 6 )—C(O)—NR 7 R 8 , —O—C(O)—R 6 or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 6 denotes
(a) H,
(b) C 1-6 -alkyl, C 3-6 -cycloalkyl, aryl, heteroaryl, benzyl, which may be substituted by a group R 6.1 , or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 6.1 denotes halogen, HO or C 1-6 -alkyl-O—,
R 7 denotes
(a) H,
(b) C 1-6 -alkyl, C 3-6 -cycloalkyl, aryl, heteroaryl or benzyl, while the groups are unsubstituted or may be substituted by halogen, HO— or C 1-6 -alkyl-O—, or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 8 denotes
(a) H,
(b) C 1-6 -alkyl, C 3-6 -cycloalkyl, aryl, heteroaryl or benzyl, while the groups are unsubstituted or may be substituted by halogen, HO— or C 1-6 -alkyl-O—, or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
R 7 and R 8 together may also form a ring which is selected from among azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein the ring may be unsubstituted or substituted by 1, 2 or 3 substituents R 6 or fluorine, wherein the substituents R 6 are independent of one another,
m denotes one of the numbers 0, 1 or 2 and
s denotes one of the numbers 1, 2 or 3,
or a tautomer or salt thereof.
3 . A compound of the formula I according to claim 1 , wherein
R 1 denotes a group of the formulae
wherein
Q-T denotes C(R 5 ) 2 —C(R 5 ) 2 , C(R 5 )═C(R 5 ), N═C(R 5 ), C(R 5 ) 2 —C(═O), C(═O)—C(R 5 ) 2 , C(R 5 ) 2 —S(O) m or C(R 5 ) 2 —N(R 5 ),
while in a group C(R 5 ) 2 —C(R 5 ) 2 , C(R 5 )═C(R 5 ) or C(R 5 ) 2 —N(R 5 ) contained in Q-T in each case a group R 5 together with an adjacent group R 5 and the atoms to which these groups are attached may also denote a group selected from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, dioxanyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolinyl, quinolinyl, isoquinolinyl, morpholinyl, thiomorpholinyl, thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl, which may be substituted independently of one another by 1, 2 or 3 substituents R 5.1 ,
R 4.1 denotes
(a) H,
(b) C 1-6 -alkyl, —CN, —OH, —O—C 1-3 -alkyl,
(c) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 5 independently of one another denote
(a) H, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl,
(b) an aryl group optionally substituted by 1, 2 or 3 substituents R 5.2 , wherein the substituents R 5.2 may be identical or different,
(c) a heteroaryl group optionally substituted by 1, 2 or 3 substituents R 5.2 , wherein the substituents R 5.2 may be identical or different,
(d) a heterocyclic group optionally substituted by 1, 2 or 3 substituents R 5.2 , wherein the substituents R 5.2 may be identical or different,
R 5.1 denotes
(a) H, halogen, C 1-6 -alkyl, C 3-6 -cycloalkyl,
(b) —O—C 1-6 -alkylene-NR 7 R 8 , —O—R 6 , —CO 2 R 6 , —C(O)NR 7 R 8 , —SO 2 —NR 7 R 8 , —N(R 7 )—SO 2 —R 8 , —S(O) m —R 7 , —CN, —NR 7 R 8 , —O—C(O)—R 6 or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 5.2 denotes
(a) halogen, C 1-6 -alkyl, C 3-6 -cycloalkyl,
(b) —O—R 6 , —O—(CH 2 ) s —O—R 6 , —CO 2 R 6 , —S(O) m —R 7 , —CN, —O—C(O)—R 6 or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 6 denotes
(a) H,
(b) C 1-6 -alkyl, C 3-6 -cycloalkyl, aryl, heteroaryl, benzyl, which may be substituted by a group R 6.1 , or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 6.1 denotes halogen, HO— or C 1-6 -alkyl-O—,
R 7 denotes
(a) H,
(b) C 1-6 -alkyl, C 3-6 -cycloalkyl, aryl, heteroaryl, or benzyl, while the groups are unsubstituted or may be substituted by halogen, HO— or C 1-6 -alkyl-O—, or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 8 denotes
(a) H,
(b) C 1-6 -alkyl, C 3-6 -cycloalkyl, aryl, heteroaryl, or benzyl, while the groups are unsubstituted or may be substituted by halogen, HO— or C 1-6 -alkyl-O—, or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
R 7 and R 8 together may also form a ring which is selected from among azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein the ring may be unsubstituted or substituted by 1, 2 or 3 substituents R 6 , wherein the substituents R 6 are independent of one another,
m denotes one of the numbers 0, 1 or 2 and
s denotes one of the numbers 1, 2 or 3,
or a tautomer or salt thereof.
4 . A compound of the formula I according to claim 1 , wherein
R 1 denotes a group of the formulae
wherein
Q-T denotes C(R 5 ) 2 —C(R 5 ) 2 , C(R 5 )═C(R 5 ), N═C(R 5 ), C(R 5 ) 2 —C(═O), C(═O)—C(R 5 ) 2 , C(R 5 ) 2 —S(O) m or C(R 5 ) 2 —N(R 5 ),
while in a group C(R 5 ) 2 —C(R 5 ) 2 , C(R 5 )═C(R 5 ) or C(R 5 ) 2 —N(R 5 ) contained in Q-T in each case a group R 5 together with an adjacent group R 5 and the atoms to which these groups are attached may also denote a group selected from cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, dioxanyl, phenyl, naphthyl, thienyl, pyridyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, morpholinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl and piperazinyl, which may be substituted independently of one another by 1, 2 or 3 substituents R 5.1 ,
R 4.1 denotes
(a) H,
(b) C 1-6 -alkyl, —CN, —OH, —O—C 1-3 -alkyl,
(c) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 5 independently of one another denote
(a) H, C 1-6 -alkyl, C 3-6 -cycloalkyl,
(b) an aryl group optionally substituted by 1, 2 or 3 substituents R 5.2 , wherein the substituents R 5.2 may be identical or different,
(c) a heteroaryl group optionally substituted by 1, 2 or 3 substituents R 5.2 , wherein the substituents R 5.2 may be identical or different,
(d) a heterocyclic group optionally substituted by 1, 2 or 3 substituents R 5.2 wherein the substituents R 5.2 may be identical or different,
R 5.1 denotes
(a) H, halogen, C 1-6 -alkyl, C 3-6 -cycloalkyl,
(b) —O—C 1-6 -alkylene-NR 7 R 8 , —O—R 6 , —CO 2 R 6 , —C(O)—NR 7 R 8 , —SO 2 —NR 7 R 8 , —NR 7 —SO 2 —R 8 , —S(O) m —R 7 , —CN, —NR 7 R 8 , —O—C(O)—R 6 or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 5.2 denotes
(a) halogen, C 1-6 -alkyl, C 3-6 -cycloalkyl,
(b) —O—R 6 , —O—(CH 2 ) s —OR 6 , —CO 2 R 6 , —S(O) m —R 6 , —CN, —O—C(O)—R 6 or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 6 denotes
(a) H,
(b) C 1-6 -alkyl, C 3-6 -cycloalkyl, aryl, heteroaryl, benzyl, which may be substituted by a group R 6.1 , or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 6.1 denotes halogen, HO— or C 1-6 -alkyl-O—,
R 7 denotes
(a) H,
(b) C 1-6 -alkyl, C 3-6 -cycloalkyl, aryl, heteroaryl, or benzyl, while the groups are unsubstituted or may be substituted by halogen, HO— or C 1-6 -alkyl-O—, or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 8 denotes
(a) H,
(b) C 1-6 -alkyl, C 3-6 -cycloalkyl, aryl, heteroaryl, or benzyl, while the groups are unsubstituted or may be substituted by halogen, HO— or C 1-6 -alkyl-O—, or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
R 7 and R 8 together may also form a ring which is selected from among azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein the ring may be unsubstituted or substituted by 1, 2 or 3 substituents R 6 , wherein the substituents R 6 are independent of one another,
m denotes one of the numbers 0, 1 or 2 and
s denotes one of the numbers 1, 2 or 3,
or a tautomer or salt thereof.
5 . A compound of the formula I according to claim 1 , wherein
R 1 denotes a group of the formula
wherein
R 4.1 denotes
(a) H,
(b) C 1-3 -alkyl, —OH, —O—C 1-3 -alkyl,
(c) a C 1-3 -alkyl- or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 5 denotes
(a) H, C 1-6 -alkyl, C 3-6 -cycloalkyl,
(b) a phenyl group optionally substituted by 1, 2, or 3 substituents R 5.2 , wherein the substituents R 5.2 may be identical or different,
(c) a heteroaryl group optionally substituted by 1, 2 or 3 substituents R 5.2 which is selected from among benzimidazole, benzothiophene, furan, imidazole, indole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene and triazole, wherein the substituents R 5.2 may be identical or different,
(d) a heterocyclic group optionally substituted by 1, 2 or 3 substituents R 5.2 , wherein the substituents R 5.2 may be identical or different,
R 5.1 denotes
(a) H, halogen, C 1-6 -alkyl, C 3-6 -cycloalkyl,
(b) —O—C 1-6 -alkylene-NR 7 R 8 , —O—R 6 , —CO 2 R 6 , —C(O)—NR 7 R 8 , —SO 2 —NR 7 R 8 , —NR 7 —SO 2 —R 8 , —S(O) m —R 7 , —CN, —NR 7 R 8 , —O—C(O)—R 6 or
(c) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 5.2 denotes
(a) halogen, C 1-6 -alkyl, C 3-6 -cycloalkyl,
(b) —O—R 6 , —O—(CH 2 ) s —O—R 6 , —CO 2 R 6 , —S(O) m —R 6 , —CN, —O—C(O)—R 6 or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 6 denotes
(a) H,
(b) C 1-6 -alkyl, C 3-6 -cycloalkyl, aryl, heteroaryl, benzyl, which may be substituted by a group R 6.1 , or
(c) a C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 6.1 denotes HO— or C 1-6 -alkyl-O—,
R 7 denotes
(a) H,
(b) C 1-3 -alkyl, phenyl or benzyl, while the groups are unsubstituted or may be substituted by halogen, HO— or H 3 C—O—,
R 8 denotes
(a) H,
(b) C 1-3 -alkyl, phenyl or benzyl, while the groups are unsubstituted or may be substituted by halogen, HO— or H 3 C—O—, or
R 7 and R 8 together may also form a ring which is selected from among azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, while the ring may be unsubstituted or substituted by a substituent R 6 ,
m denotes one of the numbers 0, 1 or 2, and
s denotes one of the numbers 1, 2 or 3,
or a tautomer or salt thereof.
6 . A compound of the formula I according to claim 1 , wherein
R 1 denotes a group of the formula
or a tautomer or salt thereof.
7 . A compound of the formula I according to claim 1 , wherein R 2 denotes a hydrogen atom,
or a tautomer or salt thereof.
8 . A compound of the formula I according to claim 1 , wherein
R 3 denotes a group of the formula III
A independently of one another denote CH or N,
R 3.1 denotes
(a) H,
(b) halogen, —NH 2 , C 1-4 -alkyl-NH—, (C 1-4 -alkyl) 2 N—, C 1-3 -alkyl-C(O)—NH—, C 1-3 -alkyl-S(O) 2 —NH—, —CN, —OH, —O—C(O)—NH—C 1-3 -alkyl,
(c) C 1-4 -alkyl, R 3.1.1 —C 1-3 -alkylene, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1-3 -alkyl-O—, C 1-3 -alkyl-S—,
(d) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
(e) —C(O)—R 3.1.2 ,
(f) —S(O) 2 —R 3.1.3 ,
R 3.1.1 denotes
(a) H,
(b) C 3-6 -cycloalkyl, C 5-6 -cycloalkenyl,
(c) (R 3.1.1.1 ) 2 N—,
(d) a saturated, mono- or diunsaturated 5- or 6-membered heterocyclic group, which is substituted at a nitrogen atom by a group R 3.1.1.1 and at a carbon atom by one or two groups R 3.1.1.2 , or
(e) a heteroaryl group which is substituted at a carbon atom by a group R 3.1.1.2 ,
R 3.1.1.1 independently of one another denote
(a) H, C 1-4 -alkyl, C 3-6 -cycloalkyl,
(b) heterocyclyl,
(c) aryl-C 0-3 -alkylene or heteroaryl-C 0-3 -alkylene,
R 3.1.1.2 independently of one another denote
(a) H, F, C 1-3 -alkyl, —CN, —OH, —O—C 1-3 -alkyl, —CO(O)R 3.1.1.2.1 , H 2 N, (C 1-4 -alkyl)-NH—, (C 1-4 -alkyl) 2 N—,
(b) phenyl or phenyl-CH 2 —,
(c) a C 1-3 -alkyl or —O—C 1-3 -alkyl group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, or
R 3.1.1.2.1 denotes H, C 1-6 -alkyl, benzyl,
R 3.1.2 denotes —O—C 1-3 -alkyl, —OH, —NR 3.1.2.1 R 3.1.2.2 ,
R 3.1.2.1 denotes H, C 1-3 -alkyl,
R 3.1.2.2 denotes H, C 1-3 -alkyl,
R 3.1.3 denotes —NR 3.1.3.1 R 3.1.3.2 ,
R 3.1.3.1 denotes H, C 1-3 -alkyl,
R 3.1.3.2 denotes H, C 1-3 -alkyl,
R 3.2 denotes
(a) H,
(b) halogen, —NH 2 , C 1-4 -alkyl-NH—, (C 1-4 -alkyl) 2 N—, C 1-3 -alkyl-C(O)—NH—, C 1-3 -alkyl-S(O) 2 —NH—, —CN, —OH, —O—C(O)—NH—C 1-3 -alkyl,
(c) C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1-3 -alkyl-O—, C 1-3 -alkyl-S—,
(d) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
(e) —C(O)—R 3.2.1 ,
(f) —S(O) 2 —R 3.2.2 ,
R 3.2.1 denotes —O—C 1-3 -alkyl, —OH, —NR 3.2.1.1 R 3.2.1.2 ,
R 3.2.1.1 denotes H, C 1-3 -alkyl,
R 3.2.1.2 denotes H, C 1-3 -alkyl,
R 3.2.2 denotes —NR 3.2,2,1 R 3.2,2,2 ,
R 3.2,2,1 denotes H, C 1-3 -alkyl,
R 3.2,2,2 denotes H, C 1-3 -alkyl,
R 3.3 denotes
(a) H,
(b) halogen, —NH 2 , C 1-4 -alkyl-NH—, (C 1-4 -alkyl) 2 N, C 1-3 -alkyl-C(O)—NH—, C 1-3 -alkyl-S(O) 2 —NH—, —CN, —OH, —O—C(O)—NH—C 1-3 -alkyl,
(c) C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1-3 -alkyl-O—, C 1-3 -alkyl-S—,
(d) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
(e) —C(O)—R 3.3.1 ,
(f) —S(O) 2 —R 3.3.2 ,
R 3.3.1 denotes —O—C 1-3 -alkyl, —OH, —NR 3.3.1.1 R 3.3.1.2 ,
R 3.3.1.1 denotes H, C 1-3 -alkyl,
R 3.3.1.2 denotes H, C 1-3 -alkyl,
R 3.3.2 denotes —O—C 1-3 -alkyl, —NR 3.3.2.1 R 3.3.2.2 ,
R 3.3.2.1 denotes H, C 1-3 -alkyl,
R 3.3.2.2 denotes H, C 1-3 -alkyl, or
R 3.2 and R 3.3 together with the carbon atoms to which they are attached form a monounsaturated 5-membered or a mono- or diunsaturated 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, while
the heterocycles mentioned previously may contain a carbonyl, thiocarbonyl or cyanimino group adjacent to a nitrogen atom, and
may optionally each additionally be substituted at one or two nitrogen atoms by a group R 3.3.3 and
may optionally each additionally be substituted at one or two carbon atoms by one or two groups R 3.3.4 ,
R 3.3.3 independently of one another denote
(a) C 1-4 -alkyl or
(b) C 3-6 -cycloalkyl, and
R 3.3.4 independently of one another denote
(a) C 1-4 -alkyl, C 3-6 -cycloalkyl,
(b) halogen, CN, C 1-3 -alkyl-O, —NH 2 ,
(c) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
or a tautomer or salt thereof.
9 . A compound of the formula I according to claim 1 , wherein
R 3 denotes a group of the formulae III
A independently of one another denotes CH or N,
R 3.1 denotes
(a) H,
(b) halogen, —NH 2 , C 1-4 -alkyl-NH—, (C 1-4 -alkyl) 2 N—C 1-3 -alkyl-C(O)—NH—, —CN, —OH, —O—C(O)—NH—C 1-3 -alkyl,
(c) C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1-3 -alkyl-O—, C 1-3 -alkyl-S—,
(d) a C 1-3 -alkyl- or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 3.2 denotes
(a) H,
(b) halogen, —NH 2 , C 1-4 -alkyl-NH, (C 1-4 -alkyl) 2 N—, C 1-3 -alkyl-C(O)—NH—, —CN, —OH, —O—C(O)—NH—C 1-3 -alkyl,
(c) C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1-3 -alkyl-O—, C 1-3 -alkyl-S—,
(d) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 3.3 denotes
(a) H,
(b) halogen, —NH 2 , C 1-4 -alkyl-NH—, (C 1-4 -alkyl) 2 N—, C 1-3 -alkyl-C(O)—NH—, —CN, —OH, —O—C(O)—NH—C 1-3 -alkyl,
(c) C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1-3 -alkyl-O—, C 1-3 -alkyl-S—,
(d) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 3.2 and R 3.3 together with the carbon atoms to which they are attached form a monounsaturated 5-membered or a mono- or diunsaturated 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, while
the heterocycles mentioned previously may contain a carbonyl, thiocarbonyl or cyanimino group adjacent to a nitrogen atom, and
may optionally each additionally be substituted at one or two nitrogen atoms by a group R 3.3.3 and
may optionally each additionally be substituted at one or two carbon atoms by one or two groups R 3.3.4 ,
R 3.3.3 independently of one another denote
(a) C 1-4 -alkyl or
(b) C 3-6 -cycloalkyl, and
R 3.3.4 independently of one another denote
(a) C 1-4 -alkyl, C 3-6 -cycloalkyl,
(b) halogen, CN, C 1-3 -alkyl-O, —NH 2 ,
(c) a C 1-3 -alkyl- or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
or a tautomer or salt thereof.
10 . A compound of the formula I according to claim 1 , wherein
R 3 denotes a group of the formulae III
R 3.1 denotes
(a) H,
(b) F, Cl, Br, —NH 2 , C 1-3 -alkyl-NH, (C 1-3 -alkyl) 2 N, C 1-3 -alkyl-C(O)—NH, —CN, —OH,
(c) C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1-3 -alkyl-O—, C 1-3 -alkyl-S—,
(d) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 3.2 denotes
(a) H,
(b) F, Cl, Br, H 2 N—, (C 1-4 -alkyl)-NH—, (C 1-4 -alkyl) 2 N—, (C 1-3 -alkyl)-C(O)—NH—, —OH,
(c) C 1-4 -alkyl,
(d) a C 1-3 -alkyl- or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 3.3 denotes
(a) H,
(b) F, Cl, Br, H 2 N—, (C 1-4 -alkyl)-NH—, (C 1-4 -alkyl) 2 N—, (C 1-3 -alkyl)-C(O)—NH—, —OH,
(c) C 1-4 -alkyl,
(d) a C 1-3 -alkyl- or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 3.2 and R 3.3 together with the carbon atoms to which they are attached form a monounsaturated 5-membered or a mono- or diunsaturated 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, while
the heterocycles mentioned previously may contain a carbonyl, thiocarbonyl or cyanimino group adjacent to a nitrogen atom, and
may optionally each additionally be substituted at one or two nitrogen atoms by a group R 3.3.3 and
may optionally each additionally be substituted at one or two carbon atoms by one or two groups R 3.3.4 ,
R 3.3.3 independently of one another denote
(a) C 1-4 -alkyl or
(b) C 3-6 -cycloalkyl, and
R 3.3.4 independently of one another denote
(a) C 1-4 -alkyl, C 3-6 -cycloalkyl,
(b) halogen, CN, C 1-3 -alkyl-O—, —NH 2 ,
(c) a C 1-3 -alkyl- or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
or a tautomer or salt thereof.
11 . A compound of the formula I according to claim 1 , wherein
R 3 denotes a group of the formula
or a tautomer or salt thereof.
12 . A compound of the formula I according to claim 1 , wherein
R 3 denotes a group of the formulae III
R 3.1 denotes
(a) H,
(b) F, Cl, Br, —NH 2 , C 1-3 -alkyl-NH—, (C 1-3 -alkyl) 2 N, C 1-3 -alkyl-C(O)—NH—, —CN, —OH,
(c) C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1-3 -alkyl-O—, C 1-3 -alkyl-S—,
(d) a C 1-3 -alkyl- or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 3.2 and R 3.3 together with the carbon atoms to which they are attached form a monounsaturated 5-membered heterocyclic group or a mono- or diunsaturated 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, while
the heterocycles mentioned previously may contain a carbonyl, thiocarbonyl or cyanimino group adjacent to a nitrogen atom, and
may optionally each additionally be substituted at one or two nitrogen atoms by a group R 3.3.3 and
may optionally each additionally be substituted at one or two carbon atoms by one or two groups R 3.3.4 ,
R 3.3.3 independently of one another denote
(a) C 1-4 -alkyl or
(b) C 3-6 -cycloalkyl, and
R 3.3.4 independently of one another denote
(a) C 1-4 -alkyl, C 3-6 -cycloalkyl,
(b) halogen, —CN, —O—C 1-3 -alkyl, —NH 2 ,
(c) a C 1-3 -alkyl- or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases.
13 . Compounds of general formula I according to claim 1 , wherein U, V, X, Y, R 1 and R 2 are defined as in claim 1 , 2 , 3 , 4 , 5 , 6 or 7 and
R 3 denotes a group of general formulae III
R 3.1 denotes
(a) H,
(b) F, Cl, Br, —NH 2 , C 1-3 -alkyl-NH, (C 1-3 -alkyl) 2 N, C 1-3 -alkyl-C(O)—NH, —CN, —OH,
(c) C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1-3 -alkyl-O, C 1-3 -alkyl-S,
(d) a C 1-3 -alkyl- or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 3.2 and R 3.3 together with the carbon atoms to which they are attached form a monounsaturated 5-membered heterocyclic group or a 5-membered heteroaryl group, wherein
the heterocycles mentioned previously may contain a carbonyl, thiocarbonyl or cyanimino group adjacent to a nitrogen atom, and
may optionally each additionally be substituted at one or two nitrogen atoms by a group R 3.3.3 and
may optionally each additionally be substituted at one or two carbon atoms by one or two groups R 3.3.4 ,
R 3.3.3 independently of one another denote
(a) C 1-4 -alkyl- or
(b) C 3-6 -cycloalkyl, and
R 3.3.4 independently of one another denote
(a) C 1-4 -alkyl-, C 3-6 -cycloalkyl-,
(b) halogen, —CN, —O—C 1-3 -alkyl, —NH 2 ,
(c) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
or a tautomer or salt thereof.
14 . A compound of the formula I according to claim 1 , wherein
R 3 denotes a group of the formula IIIa
T denotes O, S, CH 2 , NH or N—R 3.3.3 ,
R 3.1 denotes
(a) H,
(b) F, Cl, Br, —NH 2 , C 1-3 -alkyl-NH, (C 1-3 -alkyl) 2 N, C 1-3 -alkyl-C(O)—NH, —CN, —OH,
(c) C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 1-3 -alkyl-O, C 1-3 -alkyl-S—,
(d) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms, and
R 3.3.3 independently of one another denote
(a) C 1-4 -alkyl or
(b) C 3-6 -cycloalkyl,
or a tautomer or salt thereof.
115 . A compound of the formula I according to claim 1 , wherein
R 3 denotes a group of the formula
or a tautomer or salt thereof.
16 . A compound of the formula I according to claim 1 , wherein
U-V-X denotes —N═N—(C—R 11 )═, —N═(C—R 10 )—N═, —N═(C—R 10 )—(C—H)═, —(N-oxide)=(C—R 10 )—(C—R 11 )═, —(CR 9 )═N—N═, —(CR 9 )═N—(CR 11 )═, —(C—R 9 )═N(oxide)-(C—R 11 )═, —(CR 9 )═(C—R 10 )—N═, —(CR 9 )═(C—R 0 )—(N-oxide)=, or —(CR 9 )═(C—R 10 )—(CR 11 )═, R 9 denotes
(a) H,
(b) a C 1-6 -alkyl- or C 1-3 -alkyl-O— group which may each be substituted by a group R 9.1 ,
(c) R 9.2 R 9.3 N, R 9.2 R 9.3 N—C 1-3 -alkylene-,
(d) halogen, —CN, —OH, —COOH, C 1-3 -alkyl-O—C 1-3 -alkylene-, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-4 -alkylene-, C 1-3 -alkyl-C(O)—O—C 1-3 -alkylene,
(e) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 9.1 denotes H, OH or —O—CH 3 , R 9.2 denotes H or C 1-3 -alkyl, R 9.3 denotes H or C 1-3 -alkyl, or R 9.2 and R 9.3 together with the nitrogen atom to which they are attached denote a 3- to 6-membered heterocyclic group, R 10 denotes
(a) H,
(b) a C 1-6 -alkyl or C 1-3 -alkyl-CO— group which may each be substituted by a group R 10.1 ,
(c) —NR 10.1 R 10.2 , NR 10.1 R 10.2 —C 1-3 -alkylene-,
(d) halogen, —CN, —OH, C 1-3 -alkyl-O—C 1-3 -alkylene, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-4 -alkylene, C 1-3 -alkyl-C(O)—O—C 1-3 -alkylene,
(e) aryl-C 0-3 -alkylene-O—,
(f) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 10.1 denotes H, OH or —O—CH 3 , R 10.2 denotes H or C 1-6 -alkyl, R 10.3 denotes H, C 1-6 -alkyl or —SO 2 —C 1-3 -alkyl, R 11 denotes
(a) H,
(b) a C 1-6 -alkyl- or C 1-3 -alkyl-O— group which may each be substituted by a group R 11.1 ,
(c) R 11.2 R 11.3 N, R 11.2 R 11.3 N—C 1-3 -alkylene-,
(d) halogen, —CN, —OH, —COOH, C 1-3 -alkyl-O—C 1-3 -alkylene, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-4 -alkylene, C 1-3 -alkyl-C(O)—O—C 1-3 -alkylene,
(e) a C 1-3 -alkyl or C 1-3 -alkyl-O— group wherein each methylene group is substituted by up to two fluorine atoms and each methyl group is substituted by up to three fluorine atoms,
R 11.1 denotes H, OH or —O—CH 3 , R 11.2 denotes H or C 1-3 -alkyl, R 11.3 denotes H or C 1-3 -alkyl, or R 11.2 and R 11.3 together with the nitrogen atom to which they are attached denote a 3- to 6-membered heterocyclic group, or a tautomer or salt thereof.
17 . A compound of the formula I according to claim 1 , wherein
the ring
denotes a group of the formula
or a tautomer or salt thereof.
18 . A compound of the formula I according to claim 1 , wherein
R 1 denotes a group of the formula
R 2 denotes H and
R 3 denotes a group of the formula
and the ring
denotes a group of the formula
or a tautomer or salt thereof.
19 . A compound according to claim 1 selected from the group consisting of:
No.
Structure
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(20)
(21)
(22)
(23)
(24)
(25)
(26)
(27)
(28)
(29)
(30)
(31)
(32)
(33)
(34)
(35)
(36)
(37)
(38)
(39)
(40)
(41)
(42)
(43)
(44)
(45)
(46)
(47)
(48)
(49)
(50)
(51)
(52)
(53)
(54)
(55)
(56)
(57)
(58)
(59)
(60)
(61)
(62)
(63)
(64)
(65)
(66)
(67)
(68)
(69)
(70)
(71)
(72)
(73)
(74)
(75)
(76)
(77)
(78)
(79)
(80)
(81)
(82)
(83)
(84)
(85)
or a salt thereof.
20 . A physiologically acceptable salt of a compound according to any one of claims 1 to 18 .
21 . A pharmaceutical composition comprising a compound according to any one of claims 1 to 18 , or a physiologically acceptable salt thereof, and a carrier or diluent.
22 . A method of treating headache, migraine headache and cluster headache which comprises administering to a host suffering from the same a therapeutically effective amount of a compound according to any one of claims 1 to 18 , or a physiologically acceptable salt thereof.
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