US 7,488,740 B2
Substituted quinolin-4-ylamine analogues
Rajagopal Bakthavatchalam, Madison, Conn. (US); Timothy M. Caldwell, Guilford, Conn. (US); Bertrand L. Chenard, Waterford, Conn. (US); Stéphane De Lombaert, Madison, Conn. (US); and Kevin J. Hodgetts, Killingworth, Conn. (US)
Assigned to Neurogen Corporation, Branford, Conn. (US)
Filed on Jul. 14, 2004, as Appl. No. 10/891,832.
Claims priority of provisional application 60/486948, filed on Jul. 14, 2003.
Prior Publication US 2005/0070547 A1, Mar. 31, 2005
Int. Cl. A61K 31/47 (2006.01); C07D 215/38 (2006.01)
U.S. Cl. 514—313  [514/314; 546/159; 546/160; 546/161] 48 Claims
 
1. A compound of the formula:

OG Complex Work Unit Drawing
or a pharmaceutically acceptable salt thereof, wherein:
at least one of Y and Z is N; and the other of Y and Z is N or CR1;
R1 is hydrogen, halogen, cyano, amino, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy or mono- or di-(C1-C4alkyl)amino;
R2 is: (i) hydrogen, halogen or cyano;
(ii) a group of the formula —Rc—M—A—Ry, wherein:
Rc is C0-C3alkyl or is joined to Ry or Rz to form a 4- to 10-membered carbocycle or heterocycle that is substituted with from 0 to 2 substituents independently chosen from Rb;
M is a single covalent bond, O, S, SO2, C(═O), OC(═O), C(═O)O, O-C(═O)O, C(═O)N(Rz), OC(═O)N(Rz), N(Rz)C(═O), N(Rz)SO2, SO2N(Rz) or N(Rz);
A is a single covalent bond or C1-C8alkyl substituted with from 0 to 3 substituents independently chosen from Rb; and
Ry and Rz, if present, are:
(a) independently hydrogen, C1-C8alkyl, C2-C8alkyl ether, C2-C8alkenyl, a 4- to 10-membered carbocycle or heterocycle, or joined to Rc to form a 4- to 10-membered carbocycle or heterocycle, wherein each non-hydrogen Ry and Rz is substituted with from 0 to 6 substituents independently chosen from Rb; or
(b) joined to form a 4- to 10-membered carbocycle or heterocycle that is substituted with from 0 to 6 substituents independently chosen from Rb; such that R2 is not —NH2; or
(iii) taken together with R7 to form a fused 5- to 7-membered ring that is substituted with from 0 to 3 substituents independently chosen from oxo and C1-C4alkyl;
R7 is hydrogen, C1-C4alkyl, C1-C4alkoxy, or taken together with R2 to form a fused, optionally substituted ring;
Ar1 is phenyl or 6-membered heteroaryl, each of which is unsubstituted or substituted ortho to the point of attachment with 1 or 2 substituents independently chosen from groups of the formula LRa;
Ar2 is 6- to 10-membered aryl or 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 6 substituents independently chosen from oxo and groups of the formula LRa;
L is independently selected at each occurrence from a single covalent bond, O, C(═O), OC(═O), C(═O), OC(═O)O, S(O)m, N(Rx), C(═O)N(Rx), N(Rx)C(O═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, C1-C6alkanoyl and C1-C6alkylsulfonyl; and Rw is hydrogen or C1-C6alkyl;
Rais independently selected at each occurrence from:
(i) hydrogen, halogen, cyano and nitro; and
(ii) C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, 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
Rb; and
Rb is independently chosen at each occurrence from hydroxy, halogen, amino, aminocarbonyl, cyano, nitro, oxo, COOH, C1-C8alkyl, C1-C8alkoxy, C1-C8alkylthio, C1-C8alkanoyl, C1-C8alkanoyloxy, C1-C8alkoxycarbonyl, C2-C8 alkyl ether, C1-C8hydroxyalkyl, C1-C8haloalkyl, phenylC0-C8alkyl, mono- and di-(C1-C6alkyl)aminoC0-C4alkyl, C1-C8alkylsulfonyl and (4- to 7-membered heterocycle)C0-C8alkyl.