US 2008/0293709 A1Published application

Novel 2-Amino-Heterocycles Useful in the Treatment of Abeta-Related Pathologies

AssigneeAstraZeneca AB

InventorsJeffrey Albert, Gianni Chessari, Miles Stuart Congreve, Phil Edwards, Christopher Murray, Sahil Patel, Mark Sylvester

Life of this patent

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Abstract

This invention relates to novel compounds having the structural formula I below: and to their pharmaceutically acceptable salts, compositions and methods of use. These novel compounds provide a treatment or prophylaxis of cognitive impairment, Alzheimer Disease, neurodegeneration and dementia.

Claims43

Dependent claims

A compound of formula I

or a pharmaceutically acceptable salt, tautomer, or in vivo-hydrolysable precursor thereof, wherein:
G is O, NR7 or CR8R9;
R1 is H, C1-6 alkyl, C1-6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R14;
R2 is Q or -L-Q;
or R1 and R2 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl group or 3-14 membered heterocycloalkyl group, each substituted by Cy2 and optionally substituted by 1, 2, 3, 4 or 5 A4;
R3, R4, R5 and R6 are, independently, H, CN, NO2, ORa, SRa, OC(O)Ra, OC(O)ORb, OC(O)NRcRd, C(O)Ra, C(O)ORb, C(O)NRcRa, NRcRa, NRcC(O)Ra, NRcC(O)ORd, NRcS(O)2Rb, S(O)Ra, S(O)NRcRd, S(O)2Ra, S(O)2NRcRd, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R14;
R7 is H, C(O)Ra, C(O)ORb, C(O)NRcRd, S(O)Ra, S(O)2Ra, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl are each optionally substituted with 1, 2, 3, 4 or 5 R14;
R8 and R9 are, independently, H, CN, NO2, ORa, SRa, OC(O)Ra, OC(O)ORb, C(O)ORb, OC(O)NRcRd, NRcRd, NRcC(O)Ra, NRcC(O)ORb, NRcS(O)2Rb, S(O)Ra, S(O)NRcRd, S(O)2Ra, S(O)2NRcRd, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R14;
or R8 and R9 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or 3-14 membered heterocycloalkyl group, each optionally substituted by 1, 2 or 3 R14;
R12 and R13 are each, independently, H, halo, C1-4 alkyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa′, SRa′, C(O)Rb′, C(O)NRc′Rd′, C(O)ORa′, OC(O)Rb′, OC(O)NRc′Rd′, NRc′Rd′, NRc′C(O)Rd′, NRc′C(O)ORa′, NRc′S(O)2Rb′, S(O)Rb′, S(O)NRc′Rb′, S(O)2Rb′, or S(O)2NRc′Rd′;
R14 is halo, C1-4 alkyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa′, SRa′, C(O)Rb′, C(O)NRc′Rd′, C(O)ORa′, OC(O)Rb′, OC(O)NRc′Rd′, NRc′Rd′, NRc′C(O)Rd′, NRc′C(O)ORa′, NRc′S(O)2Rb′, S(O)Rb′, S(O)NRc′Rd′, S(O)2Rb′, or S(O)2NRc′Rd′;
Q is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 Cy1 or A1;
L is C2-10 alkenylenyl, C2-10 alkynylenyl, (CR12R13)q, (CR12R13)q1O(CR12R13)q2, (CR12R13)q1S(CR12R13)q2, (CR12R13)q1SO2(CR12R13)q2, (CR12R13)q1SO(CR12R13)q2, (CR12R13)q1CO(CR12R13)q2, (CR12R13)q1NRe(CR12R13)q2, or (CR12R13)q1CONRe(CR12R13)q2;
Cy1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 A2;
Cy2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 A3;
A1 is halo, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, NRcS(O)Rb, NRcS(O)2Rb, S(O)Rb, S(O)NRcRd, S(O)2Rb, S(O)2NRcRd, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, C2-8 dialkylamino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, NRcS(O)Rb, NRcS(O)2Rb, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd;
A2, A3, and A4 are each, independently, halo, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, NRcS(O)Rb, NRcS(O)2Rb, S(O)Rb, S(O)NRcRd, S(O)2Rb, S(O)2NRcRd, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, C2-8 dialkylamino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, NRcS(O)Rb, NRcS(O)2Re, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd;
Ra and Ra′ are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
Rb and Rb′ are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
Rc and Rd are each, independently, H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
Rc′ and Rd′ are each, independently, H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
or Rc′ and Rd′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
Re is H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, or CO—(C1-4 alkyl);
q is 1, 2, 3, 4, 5 or 6;
q1 is 0, 1, 2 or 3;
and
q2 is 0, 1, 2 or 3;
with the provisos:
a) when G is NH or CH2;
R2 is -L-Q;
L is —CH2, —CH═CH—, or —C≡C—;
and R1 is H or methyl, then Q is other than unsubstituted phenyl;
and
b) when G is NR7 or CR8R9;
R7 is H, methyl, or phenyl optionally substituted by halo;
R8 and R9 are each, independently, H or methyl;
R2 is Q;
and R1 is H or methyl, then Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted by at least one Cy3 and optionally substituted by 1, 2 or 3 A4.

36 more elements

A compound of Formula V:

or a pharmaceutically acceptable salt, tautomer, or in vivo-hydrolysable precursor thereof, wherein:
R21 is H, C1-6 alkyl, C1-6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R29;
R22 is Q or -L-Q;
R23, R24, R25 and R26 are, independently, H, Si(C1-10 alkyl)3, CN, NO2, ORa, SRa, OC(O)Ra, OC(O)ORb, OC(O)NRcRd, C(O)Ra, C(O)ORb, C(O)NRcRd, NRcRd, NRcC(O)Ra, NRcC(O)ORb, NRcS(O)2Rb, S(O)Ra, S(O)NRcRd, S(O)2Ra, S(O)2NRcRd, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R29;
R27 and R28 are each, independently, H, halo, C1-4 alkyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa′, SRa′, C(O)Rb′, C(O)NRc′Rd′, C(O)ORa′, OC(O)Rb, OC(O)NRc′Rd′, NRc′Rd′, NRc′C(O)Rd, NRc′C(O)ORa′, NRc′S(O)2Rb′, S(O)Rb′, S(O)NRc′Rd′, S(O)2Rb′, or S(O)2NRc′Rd′;
R29 is halo, C1-4 alkyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa′, SRa′, C(O)Rb, C(O)NRc′Rd′, C(O)ORa, OC(O)Rb, OC(O)NRc′Rd′, NRc′Rd′. NRc′C(O)Rd′, NRc′C(O)ORa′, NRc′S(O)2Rb′, S(O)Rb, S(O)NRc′Rd′, S(O)2Rb′, or S(O)2NRc′Rd′;
Q is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 Cy1 or A1;
L is C2-10 alkenylenyl, C2-10 alkynylenyl, (CR27R28)q, (CR27R28)q1O(CR27R28)q2, (CR27R28)q1S(CR27R28)q2, (CR27R28)q1SO2(CR27R28)q2, (CR27R28)q1SO(CR27R28)q2, (CR27R28)q1CO(CR27R28), (CR27R28)q1, NRe(CR27R28)q2, or (C CR27R28)q1CONRe(C CR27R28)q2;
Cy1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 A2;
A1 is halo, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, NRcS(O)Rb, NRcS(O)2Rb, S(O)Rb, S(O)NRcRb, S(O)2Rb, S(O)2NRcRd, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, C2-8 dialkylamino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, NRcS(O)Rk, NRcS(O)2-1e, S(O)le, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd;
A2 is halo, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, NRcS(O)Rb, NRcS(O)2Rb, S(O)Rb, S(O)NRcRd, S(O)2Rb, S(O)2NRcRd, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, C2-8 dialkylamino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, NRcS(O)Rb, NRcS(O)2Re, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd;
Ra and Ra′ are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
Rb and Rb′ are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
Rc and Rd are each, independently, H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
Rc′ and Rd′ are each, independently, H, C10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
or Rc′ and Rd′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
Re is H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, or CO—(C1-4 alkyl);
q is 1, 2, 3, 4, 5 or 6;
q1 is 0, 1, 2 or 3;
and
q2 is 0, 1, 2 or 3;
with the provisos:
when R21, R23 and R24 are each H, and R22 is Q, then Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted by at least one Cy1 and optionally substituted by 1, 2 or 3 A1;
and
when R21, R23 and R24 are each H, R22 is -L-Q and L is —C≡C—, then Q is other than unsubstituted phenyl.

23 more elements

A compound selected from:

3-(3′-Methoxybiphenyl-3-yl)-3,4-dihydroisoquinolin-1-amine trifluoroacetate;
3-(3-Bromophenyl)-3,4-dihydroisoquinolin-1-amine trifluoroacetate;
3-Biphenyl-3-yl-3,4-dihydroisoquinolin-1-amine trifluoroacetate;
3-Phenyl-3-(trifluoromethyl)-3,4-dihydroisoquinolin-1-amine trifluoroacetate;
3-(3′-Methoxybiphenyl-3-yl)-3-(trifluoromethyl)-3,4-dihydroisoquinolin-1-amine trifluoroacetate;
3-(3-Bromophenyl)-3-(trifluoromethyl)-3,4-dihydroisoquinolin-1-amine trifluoroacetate;
3-(3-Chlorophenyl)-3-phenyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate;
3-(3′-Methoxybiphenyl-3-yl)-3-phenyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate;
3-(3-Bromophenyl)-3-phenyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate;
3-(3′-Methoxybiphenyl-3-yl)-3-methyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate;
3-(3-Bromophenyl)-3-methyl-3,4-dihydroisoquinolin-1-amine;
3-(3-Bromophenyl)-1-(ethylthio)-3-methyl-3,4-dihydroisoquinoline;
3-Biphenyl-3-yl-3-methyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate;
3-[2-(3′-Methoxybiphenyl-3-yl)ethyl]-3-methyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate;
3-[2-(3-Bromophenyl)ethyl]-3-methyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate;
3-[2-(3′-Methoxybiphenyl-3-yl)ethyl]-3-phenyl-3,4-dihydroisoquinolin-1-amine trifluoroacetate;
N-{[1-Amino-3-phenyl-3-(trifluoromethyl)-3,4-dihydroisoquinolin-6-yl]methyl}methanesulfonamide trifluoroacetate;
N-{[1-Amino-3-phenyl-3-(trifluoromethyl)-3,4-dihydroisoquinolin-6-yl]methyl}acetamide trifluoroacetate;
6-(Aminomethyl)-3-phenyl-3-(trifluoromethyl)-3,4-dihydroisoquinolin-1-amine bis trifluoroacetate;
3-Phenyl-6-(1H-tetrazol-5-yl)-3-(trifluoromethyl)-3,4-dihydroisoquinolin-1-amine trifluoroacetate;
1-Amino-3-phenyl-3-(trifluoromethyl)-3,4-dihydroisoquinoline-6-carboxylic acid trifluoroacetate;
1-Amino-3-phenyl-3-(trifluoromethyl)-3,4-dihydroisoquinoline-6-carbonitrile HCl salt;
1-Amino-3-(3′-methoxybiphenyl-3-yl)-3-(trifluoromethyl)-3,4-dihydroisoquinoline-6-carboxamide trifluoroacetate;
1-Amino-3-(3-bromophenyl)-3-(trifluoromethyl)-3,4-dihydroisoquinoline-6-carboxamide trifluoroacetate;
1-Amino-3-(3′-methoxybiphenyl-3-yl)-3-(trifluoromethyl)-3,4-dihydroisoquinoline-6-carboxylic acid trifluoroacetate;
1-Amino-3-(3′-methoxybiphenyl-3-yl)-3-(trifluoromethyl)-3,4-dihydroisoquinoline-6-carbonitrile trifluoroacetate;
1-Amino-3-(3-bromophenyl)-3-(trifluoromethyl)-3,4-dihydroisoquinoline-6-carbonitrile;
2-[2-(3′-methoxybiphenyl-3-yl)ethyl]-2-methyl-1,2-dihydroquinazolin-4-amine trifluoroacetate;
2-[2-(3-Bromophenyl)ethyl]-2-methyl-1,2-dihydroquinazolin-4-amine trifluoroacetate;
2-(3′-Methoxybiphenyl-3-yl)-2-methyl-1,2-dihydroquinazolin-4-amine trifluoroacetate;
2-(3-Bromophenyl)-2-methyl-1,2-dihydroquinazolin-4-amine trifluoroacetate;
4-Amino-2-[2-(3′-methoxybiphenyl-3-yl)ethyl]-2-methyl-1,2-dihydroquinazoline-7-carboxylic acid trifluoroacetate;
4-Amino-2-[2-(3-bromophenyl)ethyl]-2-methyl-1,2-dihydroquinazoline-7-carboxylic acid trifluoroacetate;
2-[2-(3′-Methoxybiphenyl-3-yl)ethyl]-1,2-dimethyl-1,2-dihydroquinazolin-4-amine trifluoroacetate;
2-[2-(3′-Methoxybiphenyl-3-yl)ethyl]-2-methyl-2H-1,3-benzoxazin-4-amine trifluoroacetate;
2-[2-(3-Bromophenyl)ethyl]-2-methyl-2H-1,3-benzoxazin-4-amine trifluoroacetate;
2-(3′-Methoxybiphenyl-3-yl)-2-methyl-2H-1,3-benzoxazin-4-amine trifluoroacetate;
2-(3-Bromophenyl)-2-methyl-2H-1,3-benzoxazin-4-amine;
2-(3-Bromophenyl)-N-methoxy-2-methyl-2H-1,3-benzoxazin-4-amine trifluoroacetate;
2-(3-Bromophenyl)-4-chloro-2-methyl-2H-1,3-benzoxazine;
2-(3-Bromophenyl)-2-methyl-2,3-dihydro-4H-1,3-benzoxazin-4-one;
3-(3′-Methoxybiphenyl-3-yl)-1′H-spiro[cyclohex-2-ene-1,2′-quinazolin]-4′-amine trifluoroacetate;
3-(3′-Methoxybiphenyl-3-yl)-1′H-spiro[cyclohexane-1,2′-quinazolin]-4′-amine trifluoroacetate;
3-Methyl-5-(trimethylsilyl)thiophene-2-carbonitrile;
5-(3-Bromophenyl)-2-(trimethylsilyl)-4,5-dihydrothieno[2,3-c]pyridin-7-amine;
5-(3-Bromophenyl)-4,5-dihydrothieno[2,3-c]pyridin-7-amine trifluoroacetate;
5-(3′-Methoxybiphenyl-3-yl)-4,5-dihydrothieno[2,3-c]pyridin-7-amine trifluoroacetate;
5-Phenyl-5-(trifluoromethyl)-2-(trimethylsilyl)-4,5-dihydrothieno[2,3-c]pyridin-7-amine trifluoroacetate;
5-Phenyl-5-(trifluoromethyl)-4,5-dihydrothieno[2,3-c]pyridin-7-amine;
5-(3-Bromophenyl)-5-(trifluoromethyl)-2-(trimethylsilyl)-4,5-dihydrothieno[2,3-c]pyridin-7-amine trifluoroacetate;
5-(3-Bromophenyl)-5-(trifluoromethyl)-4,5-dihydrothieno[2,3-c]pyridin-7-amine trifluoroacetate;
5-(3′-Methoxybiphenyl-3-yl)-5-(trifluoromethyl)-4,5-dihydrothieno[2,3-c]pyridin-7-amine trifluoroacetate
or a pharmaceutically acceptable salt, an alternative salt, tautomer, or in vivo-hydrolysable precursor thereof.

50 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/093,631Filed 13 Nov 2006
Priority: 15 Nov 2005
Published: 27 Nov 2008
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07D 217/22
Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems: with hetero atoms or with carbon atoms having three…
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…

Family

Application60/737,327Us provisional application · filed 15 Nov 2005
US 2008/0293709 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula I

or a pharmaceutically acceptable salt, tautomer, or in vivo-hydrolysable precursor thereof, wherein:
G is O, NR7 or CR8R9;
R1 is H, C1-6 alkyl, C1-6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-6 alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 R14;
R2 is Q or -L-Q;
or R1 and R2 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl group or 3-14 membered heterocycloalkyl group, each substituted by Cy2 and optionally substituted by 1, 2, 3, 4 or 5 A4;
R3, R4, R5 and R6 are, independently, H, CN, NO2, ORa, SRa, OC(O)Ra, OC(O)ORb, OC(O)NRcRd, C(O)Ra, C(O)ORb, C(O)NRcRa, NRcRa, NRcC(O)Ra, NRcC(O)ORd, NRcS(O)2Rb, S(O)Ra, S(O)NRcRd, S(O)2Ra, S(O)2NRcRd, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R14;
R7 is H, C(O)Ra, C(O)ORb, C(O)NRcRd, S(O)Ra, S(O)2Ra, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl are each optionally substituted with 1, 2, 3, 4 or 5 R14;
R8 and R9 are, independently, H, CN, NO2, ORa, SRa, OC(O)Ra, OC(O)ORb, C(O)ORb, OC(O)NRcRd, NRcRd, NRcC(O)Ra, NRcC(O)ORb, NRcS(O)2Rb, S(O)Ra, S(O)NRcRd, S(O)2Ra, S(O)2NRcRd, C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-10 alkyl, C1-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R14;
or R8 and R9 together with the carbon atom to which they are attached form a 3-14 membered cycloalkyl or 3-14 membered heterocycloalkyl group, each optionally substituted by 1, 2 or 3 R14;
R12 and R13 are each, independently, H, halo, C1-4 alkyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa′, SRa′, C(O)Rb′, C(O)NRc′Rd′, C(O)ORa′, OC(O)Rb′, OC(O)NRc′Rd′, NRc′Rd′, NRc′C(O)Rd′, NRc′C(O)ORa′, NRc′S(O)2Rb′, S(O)Rb′, S(O)NRc′Rb′, S(O)2Rb′, or S(O)2NRc′Rd′;
R14 is halo, C1-4 alkyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa′, SRa′, C(O)Rb′, C(O)NRc′Rd′, C(O)ORa′, OC(O)Rb′, OC(O)NRc′Rd′, NRc′Rd′, NRc′C(O)Rd′, NRc′C(O)ORa′, NRc′S(O)2Rb′, S(O)Rb′, S(O)NRc′Rd′, S(O)2Rb′, or S(O)2NRc′Rd′;
Q is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 Cy1 or A1;
L is C2-10 alkenylenyl, C2-10 alkynylenyl, (CR12R13)q, (CR12R13)q1O(CR12R13)q2, (CR12R13)q1S(CR12R13)q2, (CR12R13)q1SO2(CR12R13)q2, (CR12R13)q1SO(CR12R13)q2, (CR12R13)q1CO(CR12R13)q2, (CR12R13)q1NRe(CR12R13)q2, or (CR12R13)q1CONRe(CR12R13)q2;
Cy1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 A2;
Cy2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1, 2, 3, 4 or 5 A3;
A1 is halo, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, NRcS(O)Rb, NRcS(O)2Rb, S(O)Rb, S(O)NRcRd, S(O)2Rb, S(O)2NRcRd, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, C2-8 dialkylamino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2, 3, 4 or 5 halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, NRcS(O)Rb, NRcS(O)2Rb, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd;
A2, A3, and A4 are each, independently, halo, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, NRcS(O)Rb, NRcS(O)2Rb, S(O)Rb, S(O)NRcRd, S(O)2Rb, S(O)2NRcRd, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, C2-8 dialkylamino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2, 3, 4 or 5 halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, NRcS(O)Rb, NRcS(O)2Re, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd;
Ra and Ra′ are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
Rb and Rb′ are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
Rc and Rd are each, independently, H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
Rc′ and Rd′ are each, independently, H, C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein the C1-10 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with OH, amino, halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;
or Rc′ and Rd′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
Re is H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, or CO—(C1-4 alkyl);
q is 1, 2, 3, 4, 5 or 6;
q1 is 0, 1, 2 or 3;
and
q2 is 0, 1, 2 or 3;
with the provisos:
a) when G is NH or CH2;
R2 is -L-Q;
L is —CH2, —CH═CH—, or —C≡C—;
and R1 is H or methyl, then Q is other than unsubstituted phenyl;
and
b) when G is NR7 or CR8R9;
R7 is H, methyl, or phenyl optionally substituted by halo;
R8 and R9 are each, independently, H or methyl;
R2 is Q;
and R1 is H or methyl, then Q is aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, each substituted by at least one Cy3 and optionally substituted by 1, 2 or 3 A4.

36 more elements

Facts

Application

12/093,631Filed 13 Nov 2006

Priority

15 Nov 2005

Published

27 Nov 2008

Term ends

Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07D 217/22
Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems: with hetero atoms or with carbon atoms having three…
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/28
Drugs for disorders of the nervous system: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents,…