US 5,990,109 AGranted

Heterocyclo-substituted imidazopyrazine protein tyrosine kinase inhibitors

AssigneeBristol-Myers Squibb Company

InventorsPing Chen, Derek J. Norris, Joel C. Barrish, Edwin J. Iwanowicz

Life of this patent

Estimating the term…

Abstract

Novel heterocyclo-substituted imidazopyrazines and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of protein tyrosine kinase-associated disorders such as immunologic disorders.

Claims42

Dependent claims

A compound of the following formula I or a salt thereof:

##STR383## where Q, together with the atoms to which it is bonded, forms a 5-, 6- or 7-membered heterocyclic ring;
p is 0 or an integer from 1 to t, where t=3 when Q forms a 5-membered ring, t=4 when Q forms a 6-membered ring, and t=5 when Q forms a 7-membered ring;
each R.sub.1, and R.sub.2 and R.sub.3, are independently selected from:
(1) hydrogen or R.sub.6, where R.sub.6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z.sub.1, Z.sub.2 and one or more groups Z.sub.3 ;
(2) --OH or --OR.sub.6 ;
(3) --SH or --SR.sub.6 ;
(4) --C(O).sub.q H, --C(O).sub.q R.sub.6, or --O--C(O).sub.q R.sub.6, where q is 1 or 2;
(5) --SO.sub.3 H or --S(O).sub.q R.sub.6 ;
(6) halo;
(7) cyano;
(8) nitro;
(9) --Z.sub.4 --NR.sub.7 R.sub.8 ;
(10) --Z.sub.4 --N(R.sub.9)--Z.sub.5 --NR.sub.10 R.sub.11 ;
(11) --Z.sub.4 --N(R.sub.12)--Z.sub.5 --R.sub.6 ;
(12) --SiR.sub.13 R.sub.14 R.sub.15 ;
(13) --P(O)(OR.sub.6).sub.2 ;
(14) any two groups R.sub.1 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the carbon atoms to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
or
(15) any two groups R.sub.1 may, together with the atoms to which they are attached, form a heterocyclo group, which group is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
R.sub.4 and R.sub.5 ;
(1) are each independently hydrogen, R.sub.6, or --C(O)R.sub.6 ;
or
(2) together with the nitrogen atom to which they are attached complete a 3- to 8-membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3, which heterocyclic ring may optionally have fused to it a benzene ring itself unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11 and R.sub.12 ;
(1) are each independently hydrogen or R.sub.6 ;
(2) R.sub.7 and R.sub.8 may together by alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
or
(3) any two of R.sub.9, R.sub.10 and R.sub.11 may together by alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
R.sub.13, R.sub.14 and R.sub.15 are each independently:
(1) alkyl;
or
(2) phenyl;
Z.sub.1, Z.sub.2 and Z.sub.3 are each independently:
(1) hydrogen or Z.sub.6, where Z.sub.6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i);
or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z.sub.1, Z.sub.2 and Z.sub.3 ;
(2) --OH or --OZ.sub.6 ;
(3) --SH or --SZ.sub.6 ;
(4) --C(O).sub.q H, --C(O).sub.q Z.sub.6, or --O--C(O).sub.q Z.sub.6 ;
(5) --SO.sub.3 H or --S(O).sub.q Z.sub.6 ;
(6) halo;
(7) cyano;
(8) nitro;
(9) --Z.sub.4 --NZ.sub.7 Z.sub.8 ;
(10) --Z.sub.4 --N(Z.sub.9)--Z.sub.5 --NZ.sub.7 Z.sub.8 ;
(11) --Z.sub.4 --N(Z.sub.10)--Z.sub.5 --Z.sub.6 ;
(12) --Z.sub.4 --N(Z.sub.10)--Z.sub.5 --H;
(13) oxo;
(14) --O--C(O)--Z.sub.6 ;
(15) any two of Z.sub.1, Z.sub.2, and Z.sub.3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
or
(16) any two of Z.sub.1, Z.sub.2, and Z.sub.3 may together be --O--(CH.sub.2).sub.q --O--;
Z.sub.4 and Z.sub.5 are each independently:
(1) a single bond;
(2) --Z.sub.11 --S(O).sub.q --Z.sub.12 --;
(3) --Z.sub.11 --C(O)--Z.sub.12 --;
(4) --Z.sub.11 --C(S)--Z.sub.12 ;
(5) --Z.sub.11 --O--Z.sub.12 --;
(6) --Z.sub.11 --S--Z.sub.12 --;
(7) --Z.sub.11 --O--C(O)--Z.sub.12 --;
or
(8) --Z.sub.11 --C(O)--O--Z.sub.12 --;
Z.sub.7, Z.sub.8, Z.sub.9 and Z.sub.10 :
(1) are each independently hydrogen or Z.sub.6 ;
(2) Z.sub.7 and Z.sub.8, or Z.sub.6 and Z.sub.10, may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
or
(3) Z.sub.7 or Z.sub.8, together with Z.sub.9, may be alkylene or alkenylene completing a 3- or 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
and
Z.sub.11 and Z.sub.12 are each independently:
(1) a single bond;
(2) alkylene;
(3) alkenylene;
or
(4) alkynylene.

71 more elements

A method for the preparation of a compound of the following formula 9 or salt thereof:

##STR384## where Q, together with the atoms to which it is bonded, forms a 5-, 6- or 7-membered heterocyclic ring;
L.sub.2 represents one or more optionally present leaving groups;
R.sub.2 and R.sub.3 are independently selected from:
(1) hydrogen or R.sub.6,
where R.sub.6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z.sub.1, Z.sub.2 and one or more groups Z.sub.3 ;
(2) --OH or --OR.sub.6 ;
(3) --SH or --SR.sub.7 ;
(4) --C(O).sub.q H, --C(O).sub.q R.sub.6, or --O--C(O).sub.q R.sub.6, where q is 1 or 2;
(5) --SO.sub.3 H or --S(O).sub.q r.sub.6 ;
(6) halo;
(7) cyano;
(8) nitro;
(9) --Z.sub.4 --NR.sub.7 R.sub.8 ;
(10) --Z.sub.4 --N(R.sub.9)--Z.sub.5 --NR.sub.10 R.sub.11 ;
(11) --Z.sub.4 --N(R.sub.12)--Z.sub.5 --R.sub.6 ;
(12) --SiR.sub.13 R.sub.14 R.sub.15 ;
or
(13) --P(O)(OR.sub.6).sub.2 ;
R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11 and R.sub.12 :
(1) are each independently hydrogen or R.sub.6 ;
(2) R.sub.7 and R.sub.8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
or
(3) any two of R.sub.9, R.sub.10 and R.sub.11 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
R.sub.13, R.sub.14 and R.sub.15 are each independently:
(1) alkyl;
or
(2) phenyl;
Z.sub.1, Z.sub.2 and Z.sub.3 are each independently:
(1) hydrogen of Z.sub.6, where Z.sub.6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;
(ii) a group (i) which is itself substituted by one or more or the same or different groups (i);
or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z.sub.1, Z.sub.2 and Z.sub.3 ;
(2) --OH or --OZ.sub.6 ;
(3) --SH or --SZ.sub.6 ;
(4) --C(O).sub.q H, --C(O).sub.q Z.sub.6 ;
(5) --SO.sub.3 H or --S(O).sub.q Z.sub.6 ;
(6) halo;
(7) cyano;
(8) nitro;
(9) --Z.sub.4 --NZ.sub.7 Z.sub.8 ;
(10) --Z.sub.4 --N(Z.sub.9)--Z.sub.5 --NZ.sub.7 Z.sub.8 ;
(11) --Z.sub.4 --N(Z.sub.10)--Z.sub.5 --Z.sub.6 ;
(12) --Z.sub.4 -13 N(Z.sub.10)--Z.sub.5 --H;
(13) oxo;
(14) --O--C(O)--Z.sub.6 ;
(15) any two of Z.sub.1, Z.sub.2, and Z.sub.3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
or
(16) any two of Z.sub.1, Z.sub.2, and Z.sub.3 may together be --O--(CH.sub.2).sub.1 --O--;
Z.sub.4 and Z.sub.5 are each independently:
(1) a single bond;
(2) --Z.sub.11 --S(O).sub.q --Z.sub.12 --;
(3) --Z.sub.11 --C(O)--Z.sub.12 --;
(4) --Z.sub.11 --C(S)--Z.sub.12 --;
(5) --Z.sub.11 --O--Z.sub.12 --;
(6) --Z.sub.11 --S--Z.sub.12 --;
(7) --Z.sub.11 --O--C(O)--Z.sub.12 --;
or
(8) --Z.sub.11 --C(O)--O--Z.sub.12 --;
Z.sub.7, Z.sub.8, Z.sub.9 and Z.sub.10 :
(1) are each independently hydrogen or Z.sub.6 ;
(2) Z.sub.7 and Z.sub.8, or Z.sub.6 and Z.sub.10, may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
or
(3) Z.sub.7 or Z.sub.8 together with Z.sub.9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
and
Z.sub.11 and Z.sub.12 are each independently:
(1) a single bond;
(2) alkylene;
(3) alkenylene;
or
(4) alkynylene;
comprising the step of contacting a compound of the following formula 16 or salt thereof:
##STR385## where L.sub.1 is a leaving group, and Q, L.sub.2, and R.sub.3 are as defined above;
with a base, wherein a copper I salt is optionally employed with said base.

69 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/262,525Filed 4 Mar 1999
Granted: 23 Nov 1999
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 471/14
In which the condensed system contains three hetero rings: ortho-condensed systems
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 11/00
Drugs for disorders of the respiratory system

Family

No related US applications are recorded in the indexed filing history.

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Abstract

A compound of the following formula I or a salt thereof:

##STR383## where Q, together with the atoms to which it is bonded, forms a 5-, 6- or 7-membered heterocyclic ring;
p is 0 or an integer from 1 to t, where t=3 when Q forms a 5-membered ring, t=4 when Q forms a 6-membered ring, and t=5 when Q forms a 7-membered ring;
each R.sub.1, and R.sub.2 and R.sub.3, are independently selected from:
(1) hydrogen or R.sub.6, where R.sub.6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z.sub.1, Z.sub.2 and one or more groups Z.sub.3 ;
(2) --OH or --OR.sub.6 ;
(3) --SH or --SR.sub.6 ;
(4) --C(O).sub.q H, --C(O).sub.q R.sub.6, or --O--C(O).sub.q R.sub.6, where q is 1 or 2;
(5) --SO.sub.3 H or --S(O).sub.q R.sub.6 ;
(6) halo;
(7) cyano;
(8) nitro;
(9) --Z.sub.4 --NR.sub.7 R.sub.8 ;
(10) --Z.sub.4 --N(R.sub.9)--Z.sub.5 --NR.sub.10 R.sub.11 ;
(11) --Z.sub.4 --N(R.sub.12)--Z.sub.5 --R.sub.6 ;
(12) --SiR.sub.13 R.sub.14 R.sub.15 ;
(13) --P(O)(OR.sub.6).sub.2 ;
(14) any two groups R.sub.1 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the carbon atoms to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
or
(15) any two groups R.sub.1 may, together with the atoms to which they are attached, form a heterocyclo group, which group is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
R.sub.4 and R.sub.5 ;
(1) are each independently hydrogen, R.sub.6, or --C(O)R.sub.6 ;
or
(2) together with the nitrogen atom to which they are attached complete a 3- to 8-membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3, which heterocyclic ring may optionally have fused to it a benzene ring itself unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11 and R.sub.12 ;
(1) are each independently hydrogen or R.sub.6 ;
(2) R.sub.7 and R.sub.8 may together by alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
or
(3) any two of R.sub.9, R.sub.10 and R.sub.11 may together by alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
R.sub.13, R.sub.14 and R.sub.15 are each independently:
(1) alkyl;
or
(2) phenyl;
Z.sub.1, Z.sub.2 and Z.sub.3 are each independently:
(1) hydrogen or Z.sub.6, where Z.sub.6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;
(ii) a group (i) which is itself substituted by one or more of the same or different groups (i);
or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z.sub.1, Z.sub.2 and Z.sub.3 ;
(2) --OH or --OZ.sub.6 ;
(3) --SH or --SZ.sub.6 ;
(4) --C(O).sub.q H, --C(O).sub.q Z.sub.6, or --O--C(O).sub.q Z.sub.6 ;
(5) --SO.sub.3 H or --S(O).sub.q Z.sub.6 ;
(6) halo;
(7) cyano;
(8) nitro;
(9) --Z.sub.4 --NZ.sub.7 Z.sub.8 ;
(10) --Z.sub.4 --N(Z.sub.9)--Z.sub.5 --NZ.sub.7 Z.sub.8 ;
(11) --Z.sub.4 --N(Z.sub.10)--Z.sub.5 --Z.sub.6 ;
(12) --Z.sub.4 --N(Z.sub.10)--Z.sub.5 --H;
(13) oxo;
(14) --O--C(O)--Z.sub.6 ;
(15) any two of Z.sub.1, Z.sub.2, and Z.sub.3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;
or
(16) any two of Z.sub.1, Z.sub.2, and Z.sub.3 may together be --O--(CH.sub.2).sub.q --O--;
Z.sub.4 and Z.sub.5 are each independently:
(1) a single bond;
(2) --Z.sub.11 --S(O).sub.q --Z.sub.12 --;
(3) --Z.sub.11 --C(O)--Z.sub.12 --;
(4) --Z.sub.11 --C(S)--Z.sub.12 ;
(5) --Z.sub.11 --O--Z.sub.12 --;
(6) --Z.sub.11 --S--Z.sub.12 --;
(7) --Z.sub.11 --O--C(O)--Z.sub.12 --;
or
(8) --Z.sub.11 --C(O)--O--Z.sub.12 --;
Z.sub.7, Z.sub.8, Z.sub.9 and Z.sub.10 :
(1) are each independently hydrogen or Z.sub.6 ;
(2) Z.sub.7 and Z.sub.8, or Z.sub.6 and Z.sub.10, may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
or
(3) Z.sub.7 or Z.sub.8, together with Z.sub.9, may be alkylene or alkenylene completing a 3- or 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3 ;
and
Z.sub.11 and Z.sub.12 are each independently:
(1) a single bond;
(2) alkylene;
(3) alkenylene;
or
(4) alkynylene.

71 more elements

Facts

Application

09/262,525Filed 4 Mar 1999

Granted

23 Nov 1999

Term ends

Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 471/14
In which the condensed system contains three hetero rings: ortho-condensed systems
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61P 11/00
Drugs for disorders of the respiratory system