US2022153745A1PendingUtilityA1
Disubstituted benzothienyl-pyrrolotriazines and their use as fgfr kinase inhibitors
Est. expiryDec 15, 2031(~5.4 yrs left)· nominal 20-yr term from priority
Inventors:Dirk BrohmMelanie HeroultMarie-Pierre CollinWalter HubschMario LobellKlemens LustigSylvia GrünewaldUlf BömerVerena Vöhringer
A61K 31/53C07D 487/04A61K 31/5355C07D 409/14A61K 31/541C07D 409/04A61K 31/5377A61P 35/00A61P 43/00
72
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Claims
Abstract
This invention relates to novel substituted 5-(1-benzothiophen-2-yl) pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives of formula (I) wherein R1 is hydrogen, chloro, methyl or methoxy, R2 is hydrogen or methoxy, with the proviso that at least one of R1 and R2 is other than hydrogen, G1 represents chloro, (C1-C4)-alkyl, (C1-C4)-alkoxycarbonyl, 5-membered aza-heteroaryl, or the group —CH2—OR3, —CH2—NR4R5 or —C(=0)-NR4R6, and G2 represents chloro, cyano, (C1-C4)-alkyl, or the group —CR8AR8B—OH, —CH2—NR9R10, —C(=0)—NR11R12 or —CH2—OR15, having protein tyrosine kinase inhibitory activities, to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds, and to the use of such compounds or compositions for treating proliferative disorders, in particular cancer and tumor diseases.
Claims
exact text as granted — not AI-modified1 - 12 . (canceled)
13 : A process for preparing a compound of formula (I-A):
or an enantiomer, a diastereomer, a hydrate, a solvate, a salt, a hydrate of the salt, or a solvate of the salt thereof,
wherein
R 1 is hydrogen, chloro, methyl or methoxy,
R 2 is hydrogen or methoxy,
with the proviso that at least one of R 1 and R 2 is other than hydrogen,
R 3 is (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl or phenyl, wherein
(i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, (C 1 -C 4 )alkoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, amino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl, (C 3 -C 6 )-cycloalkyl or up to three fluoro atoms,
and
(ii) said (C 3 -C 6 )-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxy and amino,
and
(iii) said phenyl is optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy,
R 9 and R 10 , respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 7-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from the group consisting of N(R 13 ), O, S and S(O) 2 , and which may be substituted on ring carbon atoms with up to three substituents independently selected from the group consisting of fluoro, (C 1 -C 4 )-alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein
R 13 is hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl, formyl or (C 1 -C 4 )-alkylcarbonyl,
the process comprising:
first reacting a 6-substituted 4-aminopyrrolo[2,1-f][1,2,4]triazine of formula (II)
wherein R 3 is as defined above,
with formaldehyde and an amine of formula (III)
wherein R 9 and R 10 are as defined above,
in the presence of an acid to give a compound of formula (IV)
wherein R 3 , R 9 and R 10 are as defined above,
then brominating the compound of formula (IV) to give a compound of formula (V)
wherein R 3 , R 9 and R 10 are as defined above,
and subsequently coupling the compound of formula (V) with a benzothiophen-2-yl boronate of formula (VI)
wherein R 1 and R 2 are as defined above,
and
R 14 is hydrogen or (C 1 -C 4 )-alkyl, or both R 14 residues are linked together to form a —(CH 2 ) 2 —, —C(CH 3 ) 2 —C(CH 3 ) 2 —, —(CH 2 ) 3 —, —CH 2 —C(CH 3 ) 2 —CH 2 — or —C(═O)—CH 2 —N(CH 3 )—CH 2 —C(═O)— bridge,
in the presence of a palladium catalyst and a base to yield the target compound of formula (I-A)
wherein R 1 , R 2 , R 3 , R 9 and R 10 are as defined above.
14 : The process of claim 13 , further comprising:
(i) separating the compound of formula (I-A) into its enantiomers or diastereomers to give an enantiomer or diastereomer thereof, and/or (ii) converting the compound of formula (I-A) into a hydrate, a solvate, a salt, a hydrate of the salt, or a solvate of the salt thereof by treating the compound of formula (I-A) with the corresponding solvent and/or acid or base.
15 : The process of claim 14 , wherein the compound of formula (I-A) is converted into a hydrate, a salt, or a hydrate of the salt thereof.
16 : The process of claim 15 , wherein the salt is a hydrochloride salt, and the hydrate of the salt thereof is a hydrate of a hydrochloride salt.
17 : A process for preparing a compound of formula (I-A):
or an enantiomer, a diastereomer, a hydrate, a solvate, a salt, a hydrate of the salt, or a solvate of the salt thereof,
wherein
R 1 is hydrogen, chloro, methyl or methoxy,
R 2 is hydrogen or methoxy,
with the proviso that at least one of R 1 and R 2 is other than hydrogen,
R 3 is (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl or phenyl, wherein
(i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, (C 1 -C 4 )alkoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, amino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )alkylaminocarbonyl, (C 3 -C 6 )-cycloalkyl or up to three fluoro atoms,
and
(ii) said (C 3 -C 6 )-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxy and amino,
and
(iii) said phenyl is optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy,
R 9 and R 10 , respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 7-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from the group consisting of N(R 13 ), O, S and S(O) 2 , and which may be substituted on ring carbon atoms with up to three substituents independently selected from the group consisting of fluoro, (C 1 -C 4 )-alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein
R 13 is hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl, formyl or (C 1 -C 4 )-alkylcarbonyl,
the process comprising:
first formylating a 6-substituted 4-aminopyrrolo[2,1-f][1,2,4]triazine of formula (II)
wherein R 3 is as defined above,
with N,N-dimethylformamide in the presence of phosphoryl chloride to give an aldehyde of formula (VII)
wherein R 3 is as defined above,
then brominating the compound of formula (VII) to give a compound of formula (VIII)
wherein R 3 is as defined above,
and subsequently coupling the compound of formula (VIII) with a benzothiophen-2-yl boronate of formula (VI)
wherein R 1 and R 2 are as defined above, and
R 14 is hydrogen or (C 1 -C 4 )-alkyl, or both R 14 residues are linked together to form a —(CH 2 ) 2 —, —C(CH 3 ) 2 —C(CH 3 ) 2 —, —(CH 2 ) 3 —, —CH 2 —C(CH 3 ) 2 —CH 2 — or —C(═O)—CH 2 —N(CH 3 )—CH 2 —C(═O)— bridge,
in the presence of a palladium catalyst and a base to give a compound of formula (IX)
wherein R 1 , R 2 and R 3 are as defined above,
and then reacting the compound of formula (IX) with an amine of formula (III)
wherein R 9 and R 10 are as defined above,
in the presence of an acid and a reducing agent to yield the target compound of formula (I-A)
wherein R 1 , R 2 , R 3 , R 9 and R 10 are as defined above.
18 : The process of claim 17 , further comprising:
(i) separating the compound of formula (I-A) into its enantiomers or diastereomers to give an enantiomer or diastereomer thereof, and/or (ii) converting the compound of formula (I-A) into a hydrate, a solvate, a salt, a hydrate of the salt, or a solvate of the salt thereof by treating the compound of formula (I-A) with the corresponding solvent and/or acid or base.
19 : The process of claim 18 , wherein the compound of formula (I-A) is converted into a hydrate, a salt, or a hydrate of the salt thereof.
20 : The process of claim 19 , wherein the salt is a hydrochloride salt, and the hydrate of the salt thereof is a hydrate of a hydrochloride salt.
21 : A process for preparing a compound of formula (I-A):
or an enantiomer, a diastereomer, a hydrate, a solvate, a salt, a hydrate of the salt, or a solvate of the salt thereof,
wherein
R 1 is hydrogen, chloro, methyl or methoxy,
R 2 is hydrogen or methoxy,
with the proviso that at least one of R 1 and R 2 is other than hydrogen,
R 3 is (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl or phenyl, wherein
(i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, (C 1 -C 4 )alkoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, amino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )alkylaminocarbonyl, (C 3 -C 6 )-cycloalkyl or up to three fluoro atoms,
and
(ii) said (C 3 -C 6 )-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxy and amino,
and
(iii) said phenyl is optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy,
R 9 and R 10 , respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 7-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from the group consisting of N(R 13 ), O, S and S(O) 2 , and which may be substituted on ring carbon atoms with up to three substituents independently selected from the group consisting of fluoro, (C 1 -C 4 )-alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein
R 13 is hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl, formyl or (C 1 -C 4 )-alkylcarbonyl,
the process comprising:
first coupling a 6-substituted 4-amino-5-bromopyrrolo[2,1-f][1,2,4]-triazine of formula (XII)
with a benzothiophen-2-yl boronate of formula (VI)
wherein R 1 and R 2 and are as defined above, and
R 14 is hydrogen or (C 1 -C 4 )-alkyl, or both R 14 residues are linked together to form a —(CH 2 ) 2 —, —C(CH 3 ) 2 —C(CH 3 ) 2 —, —(CH 2 ) 3 —, —CH 2 —C(CH 3 ) 2 —CH 2 — or —C(═O)—CH 2 —N(CH 3 )—CH 2 —C(═O)— bridge,
in the presence of a palladium catalyst and a base to give a compound of formula (XIII)
wherein R 1 and R 2 are as defined above,
and then reacting the compound of formula (XIII) with formaldehyde and an amine of formula (III)
wherein R 9 and R 10 are as defined above,
in the presence of an acid to yield a compound of formula (I-C)
wherein R 1 , R 2 , R 9 and R 10 are as defined above,
and subsequently converting the compound of formula (I-C) into the corresponding 6-(halomethyl) derivative of formula (XVI)
wherein R 1 , R 2 , R 9 and R 10 are as defined above, and X is chloro, bromo or iodo, and treating the compound of formula (XVI) with an alcohol of formula (XVII)
R 3A —OH (XVII),
wherein R 3A is R 3 as defined above,
in the presence of a base to yield the target compound of formula (I-A)
wherein R 1 , R 2 , R 3 , R 9 and R 10 are as defined above.
22 : The process of claim 21 , further comprising:
(i) separating the compound of formula (I-A) into its enantiomers or diastereomers to give an enantiomer or diastereomer thereof, and/or (ii) converting the compound of formula (I-A) into a hydrate, a solvate, a salt, a hydrate of the salt, or a solvate of the salt thereof by treating the compound of formula (I-A) with the corresponding solvent and/or acid or base.
23 : The process of claim 22 , wherein the compound of formula (I-A) is converted into a hydrate, a salt, or a hydrate of the salt thereof.
24 : The process of claim 23 , wherein the salt is a hydrochloride salt, and the hydrate of the salt thereof is a hydrate of a hydrochloride salt.
25 : A compound of formula (I):
wherein
R 1 is hydrogen, chloro, methyl or methoxy,
R 2 is hydrogen or methoxy,
with the proviso that at least one of R 1 and R 2 is other than hydrogen;
G 1 is chloro, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxycarbonyl, 5-membered aza-heteroaryl, or the group —CH 2 —OR 3 , —CH 2 —NR 4 R 5 or —C(═O)—NR 4 R 6 , wherein
R 3 is hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl or phenyl,
(i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, (C 1 -C 4 )alkoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, amino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl, (C 3 -C 6 )-cycloalkyl or up to three fluoro atoms,
and
(ii) said (C 3 -C 6 )-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, hydroxy and amino,
and
(iii) said phenyl is optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 )-alkyl and (C 1 -C 4 )alkoxy;
R 4 is hydrogen or (C 1 -C 4 )-alkyl;
R 5 is hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkylcarbonyl, (C 3 -C 6 )-cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein
(i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, (C 1 -C 4 )alkoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl or (C 3 -C 6 )-cycloalkyl,
and
(ii) said (C 3 -C 6 )-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, hydroxy and amino,
and
(iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxy, oxo and amino;
R 6 is hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein
(i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, (C 1 -C 4 )alkoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, amino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl, di-(C 1 -C 4 )-alkylaminocarbonyl or (C 3 -C 6 )-cycloalkyl,
and
(ii) said (C 3 -C 6 )-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, hydroxy and amino,
and
(iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxy, oxo and amino;
or
R 4 and R 5 , or R 4 and R 6 , respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 7-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R 7 ) and O, and which may be substituted on ring carbon atoms with one or two substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein
R 7 is hydrogen, (C 1 -C 4 )-alkyl, formyl or (C 1 -C 4 )-alkylcarbonyl;
and
G 2 is chloro, cyano, (C 1 -C 4 )-alkyl, or the group
—CR 8A R 8B —OH, —CH 2 —NR 9 R 10 , —C(═O)—NR 11 R 12 or —CH 2 —OR 15 , wherein
R 8A and R 8B are independently selected from the group consisting of hydrogen, (C 1 -C 4 )-alkyl, cyclopropyl and cyclobutyl;
R 9 is hydrogen or (C 1 -C 4 )-alkyl;
R 10 is hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkylcarbonyl, (C 3 -C 6 )-cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein
(i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, amino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl or di-(C 1 -C 4 )alkylaminocarbonyl,
and
(ii) said (C 3 -C 6 )-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, hydroxy and amino,
and
(iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxy, oxo and amino;
R 11 is hydrogen or (C 1 -C 4 )-alkyl;
R 12 is hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein
(i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, amino, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl or di-(C 1 -C 4 )alkylaminocarbonyl,
and
(ii) said (C 3 -C 6 )-cycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )alkyl, hydroxy and amino,
and
(iii) said 4- to 6-membered heterocycloalkyl is optionally substituted with one or two substituents independently selected from the group consisting of (C 1 -C 4 )-alkyl, hydroxy, oxo and amino;
or
R 9 and R 10 , or R 11 and R 12 , respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 7-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R 13 ), O, S and S(O) 2 , and which may be substituted on ring carbon atoms with up to three substituents independently selected from the group consisting of fluoro, (C 1 -C 4 )-alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein
R 13 is hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl, formyl or (C 1 -C 4 )alkylcarbonyl;
and
R 15 is (C 1 -C 4 )-alkyl,
with the proviso that G 1 is not chloro when G 2 is chloro or cyano,
or a pharmaceutically acceptable salt, a hydrate, or a solvate thereof.
26 : The compound of claim 25 , wherein:
R 1 is chloro, methyl or methoxy; R 2 is hydrogen or methoxy; G 1 is chloro, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxycarbonyl or 5-membered aza-heteroaryl selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, isoxazolyl and oxadiazolyl, or is the group —CH 2 —OR 3 or —CH 2 —NR 4 R 5 , wherein
R 3 is hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 6 )-cycloalkyl,
wherein said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, (C 1 -C 4 )-alkoxy, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, amino, aminocarbonyl, (C 3 -C 6 )-cycloalkyl or up to three fluoro atoms;
R 4 is hydrogen or (C 1 -C 4 )-alkyl;
R 5 is hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkylcarbonyl, (C 3 -C 6 )-cycloalkyl or 5- or 6-membered heterocycloalkyl, wherein
(i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, hydroxycarbonyl or (C 3 -C 6 )-cycloalkyl,
and
(ii) said 5- or 6-membered heterocycloalkyl is optionally substituted with oxo;
or
R 4 and R 5 are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 6-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R 7 ) and O, and which may be substituted on a ring carbon atom with oxo or hydroxy, and wherein
R 7 is hydrogen or (C 1 -C 4 )-alkyl;
and
G 2 is chloro, cyano, (C 1 -C 4 )-alkyl, or the group
—CR 8A R 8B —OH, —CH 2 —NR 9 R 10 , —C(═O)—NR 11 R 12 or —CH 2 —OR 15 , wherein
R 8A and R 8B are independently selected from the group consisting of hydrogen, (C 1 -C 4 )-alkyl and cyclopropyl;
R 9 is hydrogen or methyl;
R 10 is hydrogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkylcarbonyl, (C 3 -C 6 )-cycloalkyl or 5- or 6-membered heterocycloalkyl, wherein
(i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy or aminocarbonyl,
and
(ii) said 5- or 6-membered heterocycloalkyl is optionally substituted with oxo;
R 11 is hydrogen or methyl;
R 12 is hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 6 )-cycloalkyl or 5- or 6-membered heterocycloalkyl, wherein
(i) said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy,
and
(ii) said 5- or 6-membered heterocycloalkyl is optionally substituted with oxo;
or
R 9 and R 10 , or R 11 and R 12 , respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 6-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R 13 ), O, S and S(O) 2 , and which may be substituted on ring carbon atoms with up to three substituents independently selected from the group consisting of fluoro, (C 1 -C 4 )-alkyl, oxo, hydroxy, amino and aminocarbonyl, and wherein
R 13 is hydrogen, (C 1 -C 4 )-alkyl, cyclopropyl, cyclobutyl, formyl or (C 1 -C 4 )-alkylcarbonyl;
and
R 15 is methyl or ethyl,
with the proviso that G 1 is not chloro when G 2 is chloro or cyano,
or a pharmaceutically acceptable salt, a hydrate, or a solvate thereof.
27 : The compound of claim 25 , wherein:
R 1 is methyl; R 2 is methoxy; G 1 is methyl, oxazol-5-yl or the group —CH 2 —OR 3 or —CH 2 —NR 4 R 5 , wherein
R 3 is hydrogen, (C 1 -C 4 )-alkyl, cyclopropyl or cyclobutyl,
wherein said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, methoxy, ethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, amino, aminocarbonyl, cyclopropyl, cyclobutyl or up to three fluoro atoms;
R 4 is hydrogen, methyl or ethyl;
R 5 is hydrogen, (C 1 -C 4 )-alkyl, acetyl, cyclopropyl, cyclobutyl or 2-oxopyrrolidin-3-yl,
wherein said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy, hydroxycarbonyl, cyclopropyl or cyclobutyl;
or
R 4 and R 5 are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 5- or 6-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from NH and O, and which may be substituted on a ring carbon atom with oxo or hydroxy;
and
G 2 is methyl or the group —CR 8A R 8B —OH, —CH 2 —NR 9 R 10 or —C(═O)—NR 11 R 12 , wherein
R 8A and R 8B are independently hydrogen or methyl;
R 9 is hydrogen;
R 10 is hydrogen, (C 1 -C 4 )-alkyl, acetyl, cyclopropyl, cyclobutyl or 2-oxopyrrolidin-3-yl;
wherein said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy or aminocarbonyl;
R 11 is hydrogen or methyl;
R 12 is hydrogen, (C 1 -C 4 )-alkyl, cyclopropyl, cyclobutyl or 2-oxopyrrolidin-3-yl,
wherein said (C 1 -C 4 )-alkyl is optionally substituted with hydroxy;
or
R 9 and R 10 , or R 11 and R 12 , respectively, are joined and, taken together with the nitrogen atom to which they are attached, form a monocyclic, saturated 4- to 6-membered heterocycloalkyl ring which may contain a second ring heteroatom selected from N(R 13 ), O and S(O) 2 , and which may be substituted on ring carbon atoms with up to three substituents independently selected from the group consisting of fluoro, methyl, oxo, hydroxy, amino and aminocarbonyl, and wherein
R 13 is hydrogen, formyl or acetyl,
or a pharmaceutically acceptable salt, a hydrate, or a solvate thereof.
28 : The compound of claim 25 , wherein:
R 1 is methyl; R 2 is methoxy; G 1 is the group —CH 2 —OR 3 , wherein
R 3 is (C 1 -C 4 )-alkyl optionally substituted with hydroxy, amino or aminocarbonyl;
and
G 2 is the group —CH 2 —NR 9 R 10 or —C(═O)—NR 11 R 12 , wherein
R 9 is hydrogen,
R 10 is 2-oxopyrrolidin-3-yl,
or
R 9 and R 10 are joined and, taken together with the nitrogen atom to which they are attached, form a piperazin-1-yl, 3-oxopiperazin-1-yl or 4-acetylpiperazin-1-yl ring;
R 11 is hydrogen;
R 12 is 2-oxopyrrolidin-3-yl;
or
R 11 and R 12 are joined and, taken together with the nitrogen atom to which they are attached, form a 3-hydroxyazetidin-1-yl, 4-hydroxypiperidin-1-yl or 3-oxopiperazin-1-yl ring,
or a pharmaceutically acceptable salt, a hydrate, or a solvate thereof.Join the waitlist — get patent alerts
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