US2007032487A1PendingUtilityA1
Inhibitors of phosphatidylinositol 3-kinase
Est. expiryMay 2, 2023(expired)· nominal 20-yr term from priority
Inventors:Ian BruceBernard CuenoudThomas Hugo KellerGaynor Elizabeth PilgrimNicola PressDarren Mark Le GrandCathy RitchieBarbara ValadeJudy Fox HaylerEmma Budd
A61P 37/08A61P 3/04A61P 43/00A61P 9/10A61P 9/00A61P 37/06A61P 29/00A61P 31/04A61P 35/00A61P 3/10A61P 19/10A61P 17/06A61P 1/04A61P 19/02A61P 11/06A61P 11/00A61K 31/5377C07D 417/14A61K 45/06A61K 31/497C07D 417/04A61P 1/00
51
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Compounds of formula I in free or salt form, wherein R 1 , R 2 , R 3 and R 4 have the meanings as indicated in the specification, are useful for treating conditions that are mediated by mediated by phosphatidylinositol 3-kinase. Pharmaceutical compositions that contain the compounds and a process for preparing the compounds are also described.
Claims
exact text as granted — not AI-modified1 . A compound of formula I
in free or salt form, wherein R 1 is C 1 -C 8 -alkylcarbonyl optionally substituted by halo, hydroxy, cyano, amino, carboxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, di(C 1 -C 8 -alkyl)aminocarbonyl, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkoxycarbonyl, a C 3 -C 15 -carbocycle, or by a 5-or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
or R 1 is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or R 1 is aminocarbonyl optionally substituted by a C 3 -C 15 -carbocycle or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
or R 1 is —CO—NR x R y , where R x and R y together with the nitrogen to which they are attached form a 5- to 12-membered N-heterocyclic ring optionally including one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
or R 1 is C 1 -C 8 -alkylaminocarbonyl or C 3 -C 8 -cycloalkylaminocarbonyl in either case optionally substituted in the alkyl group by halo, hydroxy, cyano, amino, carboxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, hydroxy-substituted C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, di(C 1 -C 8 -alkyl) amino-carbonyl, C 1 -C 8 -alkoxycarbonyl, a C 3 -C 15 -carbocycle, a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 8 -alkylaminocarbonyl optionally substituted by hydroxy, or R 1 is C 1 -C 8 -alkylaminocarbonyl or C 3 -C 8 -cycloalkylaminocarbonyl in either case optionally substituted by aminocarbonyl optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
or R 1 is hydrogen or C 1 -C 8 -alkyl;
R 2 is C 1 -C 3 -alkyl;
Y is carbon or nitrogen; and
when R 1 is unsubstituted C 1 -C 8 -alkylcarbonyl and Y is carbon then
R 3 is halo, hydroxy, cyano, amino, carboxy, -SO 2 NH 2 , C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, amino-C 1 -C 8 -alkyl, amino-C 1 -C 8 -alkoxy, C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl)amino, di(C 1 -C 8 -alkyl) aminocarbonyl, di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkyl, di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkoxy, aminocarbonyl, C 1 -C 8 -alkoxycarbonyl, carboxy-C 1 -C 8 -alkyl, carboxy-C 1 -C 8 -alkoxy, a C 3 -C 15 -carbocycle, a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 8 -alkylamino optionally substituted by hydroxy or di(C 1 -C 8 -alkyl)amino,
and R 4 is hydrogen, halo, hydroxy, cyano, amino, carboxy, —SO 2 NH 2 C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, amino-C 1 -C 8 -alkyl, amino-C 1 -C 8 -alkoxy, C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl) amino, di(C 1 -C 8 -alkyl)aminocarbonyl, di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkyl, di(C 1 -C 8 -alkyl) amino-C 1 -C 8 -alkoxy, aminocarbonyl, C 1 -C 8 -alkoxycarbonyl, carboxy-C 1 -C 8 -alkyl, carboxy-C 1 -C 8 -alkoxy, a C 3 -C 15 -carbocycle, a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 8 -alkylamino optionally substituted by hydroxy or di(C 1 -C 8 -alkyl)amino,
otherwise R 3 and R 4 are each independently hydrogen, halo, hydroxy, cyano, amino, carboxy,
C 1 -C 8 -alkylsulfanyl, C 1 -C 8 -alkylsulfinyl, C 1 -C 8 -alkylsulfonyl, —SO 2 NH 2 , C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, amino-C 1 -C 8 -alkyl, amino-C 1 -C 8 -alkoxy, C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl)aminocarbonyl, di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkyl, di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkoxy, C 1 -C 8 -acylamino, aminocarbonyl, C 1 -C 8 -alkoxycarbonyl, carboxy-C 1 -C 8 -alkyl, carboxy-C 1 -C 8 -alkoxy, a C 3 -C 15 -carbocycle, a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, C 1 -C 8 -alkylamino or di(C 1 -C 8 -alkyl) amino each being optionally substituted by amino, hydroxy, di(C 1 -C 8 -alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 8 -alkoxy optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur.
2 . A compound according to claim 1 wherein
R 1 is C 1 -C 8 -alkylcarbonyl optionally substituted by di(C 1 -C 8 -alkyl)amino, C 1 -C 8 -alkylcarbonyl or C 1 -C 8 -alkoxycarbonyl, or R 1 is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or R 1 is —CO—-NR x R y , where R x and R y together with the nitrogen to which they are attached form a 5- to 12-membered N-heterocyclic ring optionally including one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted in the alkyl group by hydroxy, C 1 -C 8 -alkoxy, hydroxy-substituted C 1 -C 8 -alkoxy, di(C 1 -C 8 -alkyl)amino, di(C 1 -C 8 -alkyl)amino-carbonyl, C 1 -C 8 -alkoxycarbonyl, a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 8 -alkylaminocarbonyl optionally substituted by hydroxy, or R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted by aminocarbonyl optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or R 1 is hydrogen; R 2 is C 1 -C 3 -alkyl; Y is carbon or nitrogen; and when R 1 is unsubstituted C 1 -C 8 -alkylcarbonyl and Y is carbon then R 3 is halo, C 1 -C 8 -alkyl or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, and R 4 is hydrogen or C 1 -C 8 -alkyl, otherwise R 3 and R 4 are each independently hydrogen, halo, cyano, C 1 -C 8 -alkylsulfanyl, C 1 -C 8 -alkylsulfinyl, C 1 -C 8 -alkylsulfonyl, C 1 -C 8 -alkyl, C 1 -C 8 -acylamino, a C 3 -C 15 -carbocycle, a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, C 1 -C 8 -alkylamino or di(C 1 -C 8 -alkyl)amino each being optionally substituted by amino, hydroxy, di(C 1 -C 8 -alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 8 -alkoxy optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur.
3 . A compound according to claim 2 wherein
R 1 is C 1 -C 4 -alkylcarbonyl optionally substituted by di(C 1 -C 4 -alkyl)amino, C 1 -C 4 -alkylcarbonyl or C 1 -C 4 -alkoxycarbonyl, or R 1 is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or R 1 is —CO—NR x R y , where R x and R y together with the nitrogen to which they are attached form a 5- to 9-membered N-heterocyclic ring optionally including one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or R 1 is C 1 -C 4 -alkylaminocarbonyl optionally substituted in the alkyl group by hydroxy, C 1 -C 4 -alkoxy, hydroxy-substituted C 1 -C 4 -alkoxy, di(C 1 -C 4 -alkyl)amino, di(C 1 -C 4 -alkyl)amino-carbonyl, C 1 -C 4 -alkoxycarbonyl, a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, C 1 -C 4 -alkylaminocarbonyl optionally substituted by hydroxy, or by C 1 -C 4 -alkoxy, or R 1 is C 1 -C 4 -alkylaminocarbonyl optionally substituted by aminocarbonyl optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or R 1 is hydrogen; R 2 is C 1 -C 3 -alkyl; Y is carbon or nitrogen; and when R 1 is unsubstituted C 1 -C 4 -alkylcarbonyl and Y is carbon then R 3 is halo, C 1 -C 4 -alkyl or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, and R 4 is hydrogen or C 1 -C 4 -alkyl, otherwise R 3 and R 4 are each independently hydrogen, halo, cyano, C 1 -C 4 -alkylsulfanyl, C 1 -C 4 -alkylsulfinyl, C 1 -C 4 -alkylsulfonyl, C 1 -C 4 -alkyl, C 1 -C 4 -acylamino, a C 3 -C 10 -carbocycle, a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, C 1 -C 4 -alkylamino or di(C 1 -C 4 -alkyl)amino each being optionally substituted by amino, hydroxy, di(C 1 -C 4 -alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 4 -alkoxy optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur.
4 . A compound of formula I
in free or salt form, wherein
R 1 is C 1 -C 8 -alkylcarbonyl optionally substituted by halo, hydroxy, cyano, amino, carboxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, di(C 1 -C 8 -alkyl) aminocarbonyl, C 1 -C 8 -alkoxycarbonyl, a C 3 -C 15 -carbocycle, or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
or R 1 is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
or R 1 is aminocarbonyl optionally substituted by a C 3 -C 15 -carbocycle or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
or R 1 is C 1 -C 8 -alkylaminocarbonyl or C 3 -C 8 -cycloalkylaminocarbonyl in either case optionally substituted in the alkyl group by halo, hydroxy, cyano, amino, carboxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, di(C 1 -C 8 -alkyl)amino-carbonyl, C 1 -C 8 -alkoxycarbonyl, a C 3 -C 15 -carbocycle, or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur;
R 2 is C 1 -C 3 -alkyl;
Y is carbon or nitrogen; and
when R 1 is unsubstituted C 1 -C 8 -alkylcarbonyl and Y is carbon then
R 3 is halo, hydroxy, cyano, amino, carboxy, —SO 2 NH 2 , C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, amino-C 1 -C 8 -alkyl, amino-C 1 -C 8 -alkoxy, C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl)amino, di(C 1 -C 8 -alkyl) aminocarbonyl, di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkyl, di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkoxy, aminocarbonyl, C 1 -C 8 -alkoxycarbonyl, carboxy-C 1 -C 8 -alkyl, carboxy-C 1 -C 8 -alkoxy, a C 3 -C 15 -carbocycle, a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 8 -alkylamino optionally substituted by hydroxy,
and R 4 is hydrogen, halo, hydroxy, cyano, amino, carboxy, —SO 2 NH 2 , C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, amino-C 1 -C 8 -alkyl, amino-C 1 -C 8 -alkoxy, C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl) amino, di(C 1 -C 8 -alkyl)aminocarbonyl, di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkyl, di(C 1 -C 8 -alkyl) amino-C 1 -C 8 -alkoxy, aminocarbonyl, C 1 -C 8 -alkoxycarbonyl, carboxy-C 1 -C 8 -alkyl, carboxy-C 1 -C 8 -alkoxy, a C 3 -C 15 -carbocycle, a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 8 -alkylamino optionally substituted by hydroxy,
otherwise R 3 and R 4 are each independently hydrogen, halo, hydroxy, cyano, amino, carboxy, —SO 2 NH 2 , C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, amino-C 1 -C 8 -alkyl, amino-C 1 -C 8 -alkoxy, C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl)amino, di(C 1 -C 8 -alkyl)aminocarbonyl, di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkyl, di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkoxy, aminocarbonyl, C 1 -C 8 -alkoxycarbonyl, carboxy-C 1 -C 8 -alkyl, carboxy-C 1 -C 8 -alkoxy, a C 3 -C 15 -carbocycle, a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 8 -alkylamino optionally substituted by hydroxy.
5 . A compound according to claim 4 wherein
R 1 is C 1 -C 8 -alkylcarbonyl or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted in the alkyl group by C 1 -C 8 -alkoxycarbonyl, di(C 1 -C 8 -alkyl)aminocarbonyl or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur; R 2 is C 1 -C 3 -alkyl; Y is carbon or nitrogen; and when R 1 is unsubstituted C 1 -C 8 -alkylcarbonyl and Y is carbon then R 3 is halo, C 1 -C 8 -alkyl or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, and R 4 is hydrogen or C 1 -C 8 -alkyl, otherwise R 3 and R 4 are each independently hydrogen, halo, C 1 -C 8 -alkyl, C 3 -C 8 -cycloalkyl, a 5-or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 8 -alkylamino optionally substituted by hydroxy or di(C 1 -C 8 -alkyl)amino.
6 . A compound according to claim 5 , in free or salt form, wherein
R 1 is C 1 -C 4 -alkylcarbonyl or a 5- or 6-membered N-heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or R 1 is C 1 -C 4 -alkylaminocarbonyl optionally substituted in the alkyl group by C 1 -C 4 -alkoxycarbonyl, di(C 1 -C 4 -alkyl)aminocarbonyl or by a 5- or 6-membered N-heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur; R 2 is C 1 -C 3 -alkyl; Y is carbon or nitrogen; and when R 1 is unsubstituted C 1 -C 4 -alkylcarbonyl and Y is carbon then R 3 is halo, C 1 -C 4 -alkyl or a 5- or 6-membered N-heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, and R 4 is hydrogen or C 1 -C 4 -alkyl, otherwise R 3 and R 4 are each independently hydrogen, halo, C 1 -C 4 -alkyl, C 3 -C 5 -cycloalkyl, a 5-or 6-membered N-heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 4 -alkylamino optionally substituted by hydroxy or di(C 1 -C 4 -alkyl)amino.
7 . A compound according to claim 1 , which is also a compound of formula XXI
where R 1 , Y, R a and R b are as shown in the following table:
R 1
Y
R a
R b
C
H
H
C
Cl
H
C
H
C
H
C
H
C
H
C
Cl
H
C
Cl
H
C
Cl
H
C
H
C
H
C
H
C
H
C
H
C
H
C
H
H
C
H
H
C
H
H
C
—CH 3
—CH 3
C
—CH 3
—CH 3
C
H
H
C
H
H
C
H
H
C
H
H
N
H
N
H
N
H
N
H
N
—CH 3
H
N
H
8 . A compound according to claim 1 , which is also a compound of formula XXI
where R 1 , Y, R a and R b are as shown in the following table:
R 1
Y
R a
R b
C
—CH 3
—CH 3
C
—CH 3
—CH 3
C
Cl
H
C
Cl
H
C
Cl
H
C
Cl
H
C
Cl
H
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
—CH 3
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
—CH 3
—CH 3
N
—CH 3
—CH 3
N
—CH 3
—CH 3
N
—CH 3
—CH 3
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
9 . A compound according to claims 1 in combination with another drug substance which is an anti-inflammatory, a bronchodilator, an antihistamine, a decongestant or an anti-tussive drug substance.
10 . (canceled)
11 . A pharmaceutical composition comprising as active ingredient a compound according to claims 1 in combination with another drug substance which is an anti-inflammatory, a bronchodilator. an antihistamine, a decongestant or an anti-tussive drug substance, optionally together with a pharmaceutically acceptable diluent or carrier.
12 - 13 . (canceled)
14 . A process for the preparation of a compound of formula I as defined in claim 1 , in free or salt form which comprises the steps of:
(i) (A) reacting a compound of formula II wherein R 2 , R 3 , R 4 and Y are as hereinbefore defined and X is halogen, with a compound of formula III wherein R 1 is as hereinbefore defined; (B) for the preparation of compounds of formula I where R 3 is a 5- or 6-membered N-heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, reacting a compound of formula I wherein R 1 , R 2 , R 4 and Y are as hereinbefore defined and R 3 is chloro or bromo, with a compound of formula IV wherein R 5 and R 6 together form a 5- or 6-membered N-heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur; (C) for the preparation of compounds of formula I where R 3 is C 1 -C 8 -alkylamino optionally substituted by hydroxy or di(C 1 -C 8 -alkyl)amino, reacting a compound of formula I wherein R 1 , R 2 , R 4 and Y are as hereinbefore defined and R 3 is chloro or bromo, with a compound of formula V R 7 −NH 2 V wherein R 7 is C 1 -C 8 -alkyl optionally substituted by hydroxy or di(C 1 -C 8 -alkyl)amino; (D) for the preparation of compounds of formula I where R 1 is C 1 -C 8 -alkylcarbonyl optionally substituted by halo, hydroxy, cyano, amino, carboxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, di(C 1 -C 8 -alkyl)-aminocarbonyl, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkoxycarbonyl, a C 3 -C 15 -carbocycle, or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, reacting a compound of formula VI wherein R 2 3 R 3 , R 4 and Y are as hereinbefore defined, with a compound of formula VII or an amide-forming derivative thereof such as an acid halide or anhydride wherein R 1 is C 1 -C 8 -alkylcarbonyl optionally substituted by halo, hydroxy, cyano, amino, carboxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, di(C 1 -C 8 -alkyl)-aminocarbonyl, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkoxycarbonyl, a C 3 -C 15 -carbocycle, or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur; (E) for the preparation of compounds of formula I where R 1 is C 1 -C 8 -alkylamino-carbonyl optionally substituted by halo, hydroxy, cyano, amino, carboxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, hydroxy-substituted C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, di(C 1 -C 8 -alkyl)aminocarbonyl, C 1 -C 8 -alkoxycarbonyl, a C 3 -C 15 -carbocycle, or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 8 -alkylaminocarbonyl optionally substituted by hydroxy, reacting a compound of formula VI wherein R 2 , R 3 , R 4 and Y are as hereinbefore defined, with a compound of formula VIII O═C═N−R 8 VIII wherein R 8 is C 1 -C 8 -alkyl optionally substituted by halo, hydroxy, cyano, amino, carboxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, hydroxy-substituted C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl) amino, di(C 1 -C 8 -alkyl)aminocarbonyl, C 1 -C 8 -alkoxy-carbonyl, a C 3 -C 15 -carbocycle, a 5-or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 8 -alkylaminocarbonyl optionally substituted by hydroxy; (F) for the preparation of compounds of formula I where R 1 is C 1 -C 8 -alkylamino-carbonyl optionally substituted by halo, hydroxy, cyano, amino, carboxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, hydroxy-substituted C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, di(C 1 -C 8 -alkyl)aminocarbonyl, C 1 -C 8 -alkoxycarbonyl, a C 3 -C 15 -carbocycle, or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 8 -alkylaminocarbonyl optionally substituted by hydroxy, reacting a compound of formula IX wherein R 2 , R 3 , R 4 and Y are as hereinbefore defined and T 1 is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, with a compound of formula X R 9 −NH 2 X wherein R 9 is C 1 -C 8 -alkyl optionally substituted by halo, hydroxy, cyano, amino, carboxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, hydroxy-substituted C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl) amino, di(C 1 -C 8 -alkyl)aminocarbonyl, C 1 -C 8 -alkoxycarbonyl, a C 3 -C 15 -carbocycle, or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 8 -alkylaminocarbonyl optionally substituted by hydroxy; (G) for the preparation of compounds of formula I where R 3 is C 1 -C 8 -alkylsulfinyl or C 1 -C 8 -alkylsulfonyl, oxidising the corresponding C 1 -C 8 -alkylsulfanyl or C 1 -C 8 -alkylsulfinyl respectively; (H) for the preparation of compounds of formula I where R 3 is di(C 1 -C 8 -alkyl)amino optionally substituted by amino, hydroxy, di(C 1 -C 8 -alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, reacting the corresponding compound where R 3 is C 1 -C 8 -alkylsulfinyl or C 1 -C 8 -alkylsulfonyl with a compound of formula Xa or a protected form thereof where R m and R n are independently C 1 -C 8 -alkyl optionally substituted by amino, hydroxy, di(C 1 -C 8 -alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur; (I) for the preparation of compounds of formula I where R 3 is C 1 -C 8 -alkoxy, reacting the corresponding compound where R 3 is C 1 -C 8 -alkylsulfinyl with an alkali metal C 1 -C 8 -alkoxide; (J) for the preparation of compounds of formula I where R 3 is C 1 -C 8 -alkoxy substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, reacting the corresponding compound where R 3 is C 1 -C 8 -alkylsulfinyl with a compound of formula Xb HO−V−T 2 Xb where V is C 1 -C 8 -alkyl and T 2 is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur in the presence of a base; or (K) for the preparation of compounds of formula I where R 3 is cyano, reducing the corresponding compound where R 3 is C 1 -C 8 -alkylsulfonyl with an alkali metal cyanide; and (ii) removing any protecting groups and recovering the resultant compound of formula I in free or salt form.
15 . A pharmaceutical composition comprising as active ingredient a compound according to claim 1 .
16 . A method of treating a disease mediated by phosphatidylinositol 3-kinase in a subject in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula I as defined in claim 1 in free form or in the form of a pharmaceutically acceptable salt.
17 . A method of treating an inflammatory or obstructive airways disease in a subject in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula I as defined in claim 1 in free form or in the form of a pharmaceutically acceptable salt.
18 . A method of treating cancer in a subject in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula I as defined in claim 1 in free form or in the form of a pharmaceutically acceptable salt.Join the waitlist — get patent alerts
Track US2007032487A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.