Quinazoline derivatives as medicaments
First Claim
Patent Images
1. A method to inhibit p38-α
- activity and/or TGF-β
activity, which method comprises contacting said p38-α and
/or TGF-β
with a compound of the formula;
or the pharmaceutically acceptable salts thereofwherein R3 comprises a substituted or unsubstituted aromatic moiety, wherein said aromatic moiety is a monocyclic or fused bicyclic moiety containing 5-12 ring member atoms, wherein optionally one or more of said member atoms can independently be O, S and N;
each Z is CR2 or N, wherein no more than two Z positions in ring A are N, and wherein two adjacent Z positions in ring A cannot be N;
each R2 is either (i) independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyl, wherein each of alkyl, alkenyl, alkynyl and acyl may optionally contain 1-2 O, S or N, aryl and arylalkyl, each of said aryl and arylalkyl optionally containing 1 or more O, S or N and wherein in each of the foregoing other than H may be unsubstituted or substituted with 1-3 substituents selected independently from the group consisting of alkyl, alkenyl, alkynyl, aryl, alkylaryl, aroyl, N-aryl, NH-alkylaryl, NH-aroyl, halo, OR, NR2, SR, —
SOR, —
SO2R, —
OCOR, —
NRCOR, —
NRCONR2, —
NRCOOR, —
NRSOR, —
NRSO2R, —
OCONR2, RCO, —
COOR —
SO3R, —
CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or alkyl (1-4C), and wherein any aryl or aroyl groups on said substituents may be further substituted by alkyl, alkenyl, alkynyl, halo, OR, NR2, SR, —
SOR, —
SO2R, —
OCOR, —
NRCOR, —
NRCONR2 , —
NRCOOR, —
NRSOR, —
NRSO2R, —
OCONR2, RCO, —
COOR, —
SO3R, —
CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or alkyl (1-4C), or (ii) independently selected from the group consisting of halo, OR, NR2, SR, —
SOR, —
SO2R, —
OCOR, —
NRCOR, —
NRCONR2, —
NRCOOR, NRSOR, NRSO2R, —
OCONR2, RCO, —
COOR, —
SO2R, NRSOR, NRSO2R, —
CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or alkyl (1-4C);
wherein L is S(CR22)m, —
NR1SO2(CR22)1, SO2(CR22)m, SO2NR1(CR22)1, NR1(CR22)m, NR1CO(CR22)1, O(CR22)m, or OCO(CR22)1, or
wherein Z is N or CH and wherein m is 0-4 and 1 is 0-3;
R1 is H, aryl or arylalkyl where the aryl moiety may be substituted by 1-3 substituents selected independently from the group consisting of alkyl, alkenyl, alkynyl aryl, alkylaryl, aroyl N-aryl, NH-alkylaryl, NH-aroyl, halo, OR, NR2, SR, —
SOR, —
SO2R, —
OCOR, —
NRCOR, —
NRCONR2, —
NRCOOR, —
NRSOR, —
NRSO2R, —
OCONR2, RCO, —
COOR, —
SO3R, —
CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or alkyl (1-4C); and
wherein any aryl or aroyl groups on said substituents may be further substituted by alkyl, alkenyl, alkynyl, halo, OR, NR2, SR, —
SOR, —
SO2R, —
OCOR, —
NRCOR, —
NRCONR2, —
NRCOOR, —
NRSOR, —
NRSO2R, —
OCONR2, RCO, —
COOR, —
SO2R, —
CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or alkyl (1-4C), n is 1; and
Ar′
is a monocyclic or polycyclic aromatic moiety optionally substituted with 1-3 substituents, wherein two of said substituents may form a 5-7 member cyclic aliphatic ring and wherein Ar′ and
any said substituents thereon forming a cyclic aliphatic ring, may optionally contain one or more ring atoms selected from O, S and N.
1 Assignment
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Accused Products
Abstract
The invention is directed to methods to inhibit TGF-β and/or p38-α kinase using compounds of the formula
or the pharmaceutically acceptable salts thereof
wherein R3 is a noninterfering substituent;
each Z is CR2 or N, wherein no more than two Z positions in ring A are N, and wherein two adjacent Z positions in ring A cannot be N;
each R2 is independently a noninterfering substituent;
L is a linker;
n is 0 or 1; and
Ar′ is the residue of a cyclic aliphatic, cyclic heteroaliphatic, aromatic or heteroaromatic moiety optionally substituted with 1-3 noninterfering substituents.
-
Citations
9 Claims
-
1. A method to inhibit p38-α
- activity and/or TGF-β
activity, which method comprises contacting said p38-α and
/or TGF-β
with a compound of the formula;
or the pharmaceutically acceptable salts thereof wherein R3 comprises a substituted or unsubstituted aromatic moiety, wherein said aromatic moiety is a monocyclic or fused bicyclic moiety containing 5-12 ring member atoms, wherein optionally one or more of said member atoms can independently be O, S and N;
each Z is CR2 or N, wherein no more than two Z positions in ring A are N, and wherein two adjacent Z positions in ring A cannot be N;
each R2 is either (i) independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyl, wherein each of alkyl, alkenyl, alkynyl and acyl may optionally contain 1-2 O, S or N, aryl and arylalkyl, each of said aryl and arylalkyl optionally containing 1 or more O, S or N and wherein in each of the foregoing other than H may be unsubstituted or substituted with 1-3 substituents selected independently from the group consisting of alkyl, alkenyl, alkynyl, aryl, alkylaryl, aroyl, N-aryl, NH-alkylaryl, NH-aroyl, halo, OR, NR2, SR, —
SOR, —
SO2R, —
OCOR, —
NRCOR, —
NRCONR2, —
NRCOOR, —
NRSOR, —
NRSO2R, —
OCONR2, RCO, —
COOR —
SO3R, —
CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or alkyl (1-4C), and wherein any aryl or aroyl groups on said substituents may be further substituted by alkyl, alkenyl, alkynyl, halo, OR, NR2, SR, —
SOR, —
SO2R, —
OCOR, —
NRCOR, —
NRCONR2 , —
NRCOOR, —
NRSOR, —
NRSO2R, —
OCONR2, RCO, —
COOR, —
SO3R, —
CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or alkyl (1-4C), or(ii) independently selected from the group consisting of halo, OR, NR2, SR, —
SOR, —
SO2R, —
OCOR, —
NRCOR, —
NRCONR2, —
NRCOOR, NRSOR, NRSO2R, —
OCONR2, RCO, —
COOR, —
SO2R, NRSOR, NRSO2R, —
CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or alkyl (1-4C);
wherein L is S(CR22)m, —
NR1SO2(CR22)1, SO2(CR22)m, SO2NR1(CR22)1, NR1(CR22)m, NR1CO(CR22)1, O(CR22)m, or OCO(CR22)1, or
wherein Z is N or CH and wherein m is 0-4 and 1 is 0-3;
R1 is H, aryl or arylalkyl where the aryl moiety may be substituted by 1-3 substituents selected independently from the group consisting of alkyl, alkenyl, alkynyl aryl, alkylaryl, aroyl N-aryl, NH-alkylaryl, NH-aroyl, halo, OR, NR2, SR, —
SOR, —
SO2R, —
OCOR, —
NRCOR, —
NRCONR2, —
NRCOOR, —
NRSOR, —
NRSO2R, —
OCONR2, RCO, —
COOR, —
SO3R, —
CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or alkyl (1-4C); and
wherein any aryl or aroyl groups on said substituents may be further substituted by alkyl, alkenyl, alkynyl, halo, OR, NR2, SR, —
SOR, —
SO2R, —
OCOR, —
NRCOR, —
NRCONR2, —
NRCOOR, —
NRSOR, —
NRSO2R, —
OCONR2, RCO, —
COOR, —
SO2R, —
CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or alkyl (1-4C),n is 1; and
Ar′
is a monocyclic or polycyclic aromatic moiety optionally substituted with 1-3 substituents, wherein two of said substituents may form a 5-7 member cyclic aliphatic ring and wherein Ar′ and
any said substituents thereon forming a cyclic aliphatic ring, may optionally contain one or more ring atoms selected from O, S and N.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
and wherein any aryl or aroyl groups on said substituents maybe further substituted by alkyl, alkenyl, alkynyl, halo, OR, NR2, SR, —
SOR, —
SO2R, —
OCOR, —
NRCOR, —
NRCONR2, —
NRCOOR, —
NRSOR, —
NRSO2R, —
OCONR2, RCO, —
COOR —
SO3R, —
CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or alkyl (1-4C).
- activity and/or TGF-β
-
4. The method of claim 3 wherein Ar′
- is phenyl, 2-, 3-, or 4-pyridyl, 2- or 4-pyrimidyl, indolyl, isoquinolyl, quinlyl, benzimdazolyl, bezotriazolyl, benzothiazolyl, benzofuranyl, pyridyl, thienyl, furyl pyrrolyl, thiazolyl, oxazolyl, or imdazolyl, all of which may optionally be substituted.
-
5. The method of claim 1 wherein said optional substituents on R2 are independently selected from the group consisting of R4, halo, OR4, NR42, SR4, —
- OOCR4, —
NROCR4, —
COOR4, R4CO, —
CONR42, —
SO2NR42, CN, CF3, and NO2, wherein each R4 is independently optional substituted alkyl (1-6C), or optionally substituted arylalkyl (7-12C) and wherein two R4 or two substituents on said alkyl or arylalkyl taken together may form a fused aliphatic ring of 5-7 members.
- OOCR4, —
-
6. The method of claim 1 wherein the compound of formula (1) is selected from group consisting of
(a) the compounds listed in Table 2 below, wherein Z5-Z8 are CH; - Z3 is N;
R1 in compound No. 11 is 2-propyl;
R1 in compound No 12 is 4-methoxyphenyl, and R1 in compound No. 41 is 4-methoxybenzyl; and
wherein L, Ar′ and
R3 are as shown in Table 2;
- Z3 is N;
-
7. The method of claim 1 wherein the compound of formula (1) is selected from the group consisting of:
-
-
8. The method of claim 1 wherein
L is -R1N(CH2)n— - wherein R1 is H or is alkyl (1-6C) or arylalkyl optionally substituted on the aryl group with 1-3 substituents independently selected from alkyl (1-6C), halo, OR, NR2, SR, —
OOCR, —
NROCR, RCO, —
COOR, —
CONR2, —
SO2NR2, CN, CF3, and NO2, wherein each R is independently H or lower alkyl (1-4C) and n is 0, 1 or 2; and
(a) Ar′
is phenyl, substituted with at least one group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR2, SR, —
OOCR, —
NOCR, RCO, —
COOR, —
CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or lower alkyl (1-4C), or pyridyl, indolyl, or pyrimidyl each optionally substituted with at least one group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR2, SR, —
OOCR, —
NROCR, RCO, —
COOR, —
CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or lower alkyl (1-4C); and
R3 is phenyl optionally substituted with 1-3 substituents which substituents are selected from the group consisting of alkyl (1-6C), halo, OR, NR2, SR, —
OOCR, —
NROCR, RCO, —
COOR, —
CONR2, —
SO2NR2, CN, CF3, and NO2, wherein each R is independently H or lower alkyl (1-4C);
or(b) Ar′
is phenyl, pyridyl, indolyl, or pyrimidyl, each optionally substituted with a group selected from the group consisting of optionally substituted allyl (1-6C), halo, OR, NR2, SR, —
OOCR, —
NROC, RCO, —
COOR, —
CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or lower alkyl (1-4C); and
R3 is phenyl substituted with 1-3 substituents which substituents arc selected from the group consisting of alkyl (1-6C), halo, SR, —
OOCR, —
NROCR, RCO, —
COOR, —
CONR2, —
SO2NR2, CN, and CF3, wherein each R is independently H or lower alkyl (1-4C);
or(c) Ar′
is phenyl substituted with a group selected from the group consisting of optionally substituted NR2, SR, —
NROCR, RCO, —
CONR2, SO2NR2, CN, and CF3, wherein each R is independently H or lower alkyl (1-4C);
or pyridyl substituted with a group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR2, SR, —
OOCR, —
NROCR, RCO, —
COOR, —
CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or lower alkyl (1-4C);
or indolyl or pyrimidyl, each optionally substituted with a group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR2, SR, —
OOCR, —
NROCR, RCO, —
COOR, —
CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or lower allyl (1-4C); and
R3 is phenyl optionally substituted with 1-3 substituents which substituents are selected from the group consisting of alkyl (1-6C), halo, OR, NR2, SR, —
OOCR, —
NROCR, RCO, —
COOR, —
CONR2, —
SO2NR2, CN, CF3, and NO2, wherein each R is independently H or lower alkyl (1-4C);
or(d) Ar′
is phenyl, pyridyl, indolyl, or pyrimidyl, each optionally substituted with a group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR2, SR, —
OOCR, —
NROCR, RCO, —
COOR, —
CONR2, SO2NR2, CN, CF3, and NO2, wherein each R is independently H or lower alkyl (1-4C); and
R3 is phenyl substituted with 1-3 substituents which substituents are selected from the group consisting of alkyl (1-6C), halo, OR, SR, —
OOCR, —
NROCR, RCO, —
COOR, —
CONR2, —
SO2NR2, CN, CF3, and NO2, wherein each R is independently H or lower alkyl (1-4C).
- wherein R1 is H or is alkyl (1-6C) or arylalkyl optionally substituted on the aryl group with 1-3 substituents independently selected from alkyl (1-6C), halo, OR, NR2, SR, —
-
9. The method of claim 1 wherein the compound of formula 1 is selected from the group consisting of
2-phenyl-4-(4-pyridylamino)-quinazoline; -
2-(2-bromophenyl)-4-(4-pyridylamino)-quinazoline;
2-(2-chlorophenyl)-4-(4-pyridylamino)-quinazoline;
2-(2-fluorophenyl)-4-(4-pyridylamino)-quinazoline;
2-(2-methylphenyl)-4-(4-pyridylamino)-quinazoline;
2-(4-fluorophenyl)-4-(4-pyridylamino)-quinazoline;
2-(3-methoxyaniyl)-4-(4-pyridylamino)-quinazoline;
2-(2,6-dichlorophenyl)-4-(4-pyridylamino)-quinazoline;
2-(2,6-dibrophonyl)-4 -(4-pyridylamino)-quinazoline;
2-(2,6-difluomrophenyl)-4-(4-pyridylamino)-quinazoline;
2-(2-fluorophenyl)-4-(4-pyridylamino)-6,7-dimethoxyquinazoline;
2-(4-fluorophenyl)-4-(4-pyridylamino)-6,7-dimethoxyquinazoline;
2-(2-fluorophenyl)-4-(4-pyridylamino)-6-nitroquinazoline;
2-(2-fluorophenyl)-4-(4-pyridylamino)-6-aminoquinazoline;
2-(2-fluorophenyl)-4-(4-pyxdylamino)-7-aminoquinazoline;
2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(3-methoxybenzylamino)-quinazoline;
2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(4methoxybenzyrlamino)-quinazoiine;
2-(2-fluorophenyl)-4-(4-pyridylamino)-6(2-isobutylamino)-quinazoline; and
2-(2-fluorophenyl)-4-(4-pyridylamino)-6(4methymercaptobenzylamino)-quinazoline.
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Specification