US 2008/0175794 A1Published application

Substituted Pyridazinyl- and Pyrimidinyl-Quinolin-4-Ylamine Analogues

AssigneeNeurogen Corporation

InventorsTimothy M. Caldwell, Bertrand L. Chenard, Kevin J. Hodgetts

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Abstract

Substituted pyridazinyl- and pyrimidinyl-quinolin-4-ylamine analogues are provided. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using them to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.

Claims38

Dependent claims

A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
Either (1) A is N and B is CR8 or (2) A is CR5 and B is N;
Y and Z are each independently N or CR1;
Each R1 is independently hydrogen, halogen, cyano, amino, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy or mono- or di-(C1-C4alkyl)amino;
R2 is:
(i) hydrogen or halogen;
or
(ii) C1-C6alkyl, (C3-C7cycloalkyl)C0-C4alkyl, C1-C6alkoxy, C1-C6-aminoalkyl, C1-C6hydroxyalkyl, C2-C6alkyl ether, mono- or di-(C1-C6alkyl)aminoC0-C4alkyl or (4- to 7-membered heterocycloalkyl)C0-C4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, hydroxy, amino, oxo, mono- and di-(C1-C6alkyl)amino, C1-C6alkyl C1-C6alkoxy and C1-C6haloalkyl.
R3 is hydrogen, COOH, C1-C4alkyl, C1-C4alkoxy, C1-C4alkoxycarbonyl or taken together with R2 to form a fused, optionally substituted ring;
R4 is hydrogen, halogen, cyano, amino, COOH, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy or mono- or di-(C1-C4alkyl)amino;
Each R5 is independently hydrogen, halogen, cyano, amino, COOH, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy or mono- or di-(C1-C4alkyl)amino;
R8 is:
(i) hydrogen, hydroxy, halogen, cyano, amino, aminocarbonyl or COOH;
or
(ii) a group of the formula LRa;
Ar is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 6 substituents independently chosen from:
(i) oxo;
(ii) groups of the formula LRa;
and
(iii) groups that are taken together to form a fused, 5- to 7-membered heterocyclic ring that is substituted with from 0 to 3 substituents independently selected from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo, COOH, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkanoyl, C1-C8alkanoyloxy, C1-C8alkoxycarbonyl, C2-C8alkyl ether, C1-C8hydroxyalkyl, C1-C8haloalkyl, phenylC0-C8alkyl, mono- and di-(C1-C6alkyl)aminoC0-C4alkyl, C1-C8alkylsulfonyl and (4- to 7-membered heterocycle)C0-C8alkyl;
L is independently selected at each occurrence from a single covalent bond, O, C(═O), OC(═O), C(═O)O, OC(═O)O, S(O)m, N(Rx), C(═O)N(Rx), N(Rx)C(═O), N(Rx)S(O)m, S(O)mN(Rx) and N[S(O)mRw]S(O)m;
wherein m is independently selected at each occurrence from 0, 1 and 2;
Rx is independently selected at each occurrence from hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkanoyl and C1-C6alkylsulfonyl;
and Rw is hydrogen or C1-C6alkyl;
Ra is independently selected at each occurrence from:
(i) hydrogen, halogen, cyano and nitro;
and
(ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, (C3-C7cycloalkyl)C0-C4alkyl, C1-C8haloalkyl, C2-C8alkyl ether, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C0-C6alkyl, each of which is substituted with from 0 to 6 substituents independently selected from:
(a) hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo, COOH;
and
(b) C1-C8alkyl, C2-C8alkenyl, (C3-C7cycloalkyl)C0-C4alkyl C1-C8alkoxy, C1-C8alkylthio, C1-C8alkanoyl, C1-C8alkanoyloxy, C1-C8alkoxycarbonyl, C2-C8alkyl ether, C1-C8hydroxyalkyl, C1-C8haloalkyl, phenylC0-C8alkyl, mono- or di-(C1-C6alkyl)aminocarbonyl, mono- or di-(C1-C6alkyl)aminoC0-C4alkyl, C1-C8alkylsulfonyl and (4- to 7-membered heterocycle)C0-C8alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, amino, C1-C4alkyl and C1-C4alkoxy.

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Dependencies are inferred from the claim text.

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Abstract

A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:
Either (1) A is N and B is CR8 or (2) A is CR5 and B is N;
Y and Z are each independently N or CR1;
Each R1 is independently hydrogen, halogen, cyano, amino, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy or mono- or di-(C1-C4alkyl)amino;
R2 is:
(i) hydrogen or halogen;
or
(ii) C1-C6alkyl, (C3-C7cycloalkyl)C0-C4alkyl, C1-C6alkoxy, C1-C6-aminoalkyl, C1-C6hydroxyalkyl, C2-C6alkyl ether, mono- or di-(C1-C6alkyl)aminoC0-C4alkyl or (4- to 7-membered heterocycloalkyl)C0-C4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, cyano, hydroxy, amino, oxo, mono- and di-(C1-C6alkyl)amino, C1-C6alkyl C1-C6alkoxy and C1-C6haloalkyl.
R3 is hydrogen, COOH, C1-C4alkyl, C1-C4alkoxy, C1-C4alkoxycarbonyl or taken together with R2 to form a fused, optionally substituted ring;
R4 is hydrogen, halogen, cyano, amino, COOH, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy or mono- or di-(C1-C4alkyl)amino;
Each R5 is independently hydrogen, halogen, cyano, amino, COOH, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy or mono- or di-(C1-C4alkyl)amino;
R8 is:
(i) hydrogen, hydroxy, halogen, cyano, amino, aminocarbonyl or COOH;
or
(ii) a group of the formula LRa;
Ar is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 6 substituents independently chosen from:
(i) oxo;
(ii) groups of the formula LRa;
and
(iii) groups that are taken together to form a fused, 5- to 7-membered heterocyclic ring that is substituted with from 0 to 3 substituents independently selected from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo, COOH, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkanoyl, C1-C8alkanoyloxy, C1-C8alkoxycarbonyl, C2-C8alkyl ether, C1-C8hydroxyalkyl, C1-C8haloalkyl, phenylC0-C8alkyl, mono- and di-(C1-C6alkyl)aminoC0-C4alkyl, C1-C8alkylsulfonyl and (4- to 7-membered heterocycle)C0-C8alkyl;
L is independently selected at each occurrence from a single covalent bond, O, C(═O), OC(═O), C(═O)O, OC(═O)O, S(O)m, N(Rx), C(═O)N(Rx), N(Rx)C(═O), N(Rx)S(O)m, S(O)mN(Rx) and N[S(O)mRw]S(O)m;
wherein m is independently selected at each occurrence from 0, 1 and 2;
Rx is independently selected at each occurrence from hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6alkanoyl and C1-C6alkylsulfonyl;
and Rw is hydrogen or C1-C6alkyl;
Ra is independently selected at each occurrence from:
(i) hydrogen, halogen, cyano and nitro;
and
(ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, (C3-C7cycloalkyl)C0-C4alkyl, C1-C8haloalkyl, C2-C8alkyl ether, mono- and di-(C1-C8alkyl)amino and (3- to 10-membered heterocycle)C0-C6alkyl, each of which is substituted with from 0 to 6 substituents independently selected from:
(a) hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo, COOH;
and
(b) C1-C8alkyl, C2-C8alkenyl, (C3-C7cycloalkyl)C0-C4alkyl C1-C8alkoxy, C1-C8alkylthio, C1-C8alkanoyl, C1-C8alkanoyloxy, C1-C8alkoxycarbonyl, C2-C8alkyl ether, C1-C8hydroxyalkyl, C1-C8haloalkyl, phenylC0-C8alkyl, mono- or di-(C1-C6alkyl)aminocarbonyl, mono- or di-(C1-C6alkyl)aminoC0-C4alkyl, C1-C8alkylsulfonyl and (4- to 7-membered heterocycle)C0-C8alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from hydroxy, amino, C1-C4alkyl and C1-C4alkoxy.

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