	US 7,579,347 B2
	Vanilloid receptor ligands and their use in treatments
Yunxin Y. Bo, Thousand Oaks, Calif. (US); Partha P. Chakrabarti, Simi Valley, Calif. (US); Ning Chen, Thousand Oaks, Calif. (US); Elizabeth M. Doherty, Newbury Park, Calif. (US); Christopher H. Fotsch, Thousand Oaks, Calif. (US); Nianhe Han, Thousand Oaks, Calif. (US); Michael G. Kelly, Thousand Oaks, Calif. (US); Qingyian Liu, Camarillo, Calif. (US); Mark Henry Norman, Thousand Oaks, Calif. (US); Vassil I. Ognyanov, Thousand Oaks, Calif. (US); Xianghong Wang, Moorpark, Calif. (US); and Jiawang Zhu, Simi Valley, Calif. (US)
Assigned to Amgen Inc., Thousand Oaks, Calif. (US)
Filed on Apr. 05, 2005, as Appl. No. 11/100,077.
Application 11/100077 is a division of application No. 10/316295, filed on Dec. 10, 2002.
Claims priority of provisional application 60/339161, filed on Dec. 10, 2001.
Claims priority of provisional application 60/344737, filed on Dec. 21, 2001.
Claims priority of provisional application 60/383331, filed on May 22, 2002.
Claims priority of provisional application 60/402422, filed on Aug. 08, 2002.
Prior Publication US 2005/0227986 A1, Oct. 13, 2005
Int. Cl. C07D 401/04 (2006.01); C07D 401/12 (2006.01); C07D 401/14 (2006.01); C07D 403/04 (2006.01); C07D 403/12 (2006.01); C07D 403/14 (2006.01); A61K 31/4427 (2006.01); A61K 31/4523 (2006.01); A61K 31/47 (2006.01); A61K 31/497 (2006.01); A61K 31/5377 (2006.01); A61P 29/00 (2006.01); A61P 25/04 (2006.01)

U.S. Cl. 514—231.5 [514/252.13; 514/307; 514/311; 514/318; 514/336; 546/268.1; 546/193; 546/152; 546/139; 546/112; 546/113; 544/124; 544/360]

9 Claims

1. A compound having the structure:

wherein:

R²is H;

R³is H or C_1-4alkyl;

(A) R⁴is

wherein

L³is a 2- or 3-atom, unsaturated, bridge containing 1, 2 or 3 carbon atoms and 1 atom independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, ═O, —R^a, —C_1-6alkylOR^a, —C_1-6alkyl, —C(═O)OR^a, —C(═O)NR^aR^a, —C_1-3alkylC(═O)OR^a, —C_1-3alkylC(═O)NR^aR^a, —OC(═O)C_1-6alkyl, —NR^aC(═O)C_1-6alkyl, —C_1-3alkylOC(═O)C_1-6alkyl or —C_1-3alkylNR^aC(═O)C_1-6alkyl, and any nitrogen atoms in the bridge are substituted by H, —C_1-6alkylOR^a, —C_1-6alkyl, —C_1-3alkylC(═O)OR^a, —C_1-3alkylC(═O)NR^aR^a, —C_1-3alkylOC(═O)C_1-6alkyl, —C_1-3alkylNR^aC(═O)C_1-6alkyl, —C(═O)R^cor —C_1-3alkylR^c;

R^bis H, C_1-6alkyl, —C(═O)C_1-6alkyl, C_1-6alkyl-O—R^a; and

Y²is —NR^b— or —O—; or

(B) R⁴is

wherein

L³is a 2- or 3-atom, unsaturated, bridge containing 1, 2 or 3 carbon atoms and 1 or 2 atoms independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, ═O, —OR^a, —C_1-6alkylOR^a, —C_1-6alkyl, —C(═O)OR^a, —C(═O)NR^aR^a, —C_1-3alkylC(═O)OR^a, —C_1-3alkylC(═O)NR^aR^a, —OC(═O)C_1-6alkyl, —NR^aC(═O)C_1-6alkyl, —C_1-3alkylOC(═O)C_1-6alkyl or —C_1-3alkylNR^aC(═O)C_1-6alkyl, and any nitrogen atoms in the bridge are substituted by H, —C_1-6alkylOR^a, —C_1-6alkyl, —C_1-3alkylC(═O)OR^a, —C_1-3alkylC(═O)NR^aR^a, —C_1-3alkylOC(═O)C_1-6alkyl, —C_1-3alkylNR^aC(═O)C_1-6alkyl, —C(═O)R^cor —C_1-3alkylR^c;

R^bis H, C_1-6alkyl, —C(═O)C_1-6allcyl, C_1-6alkyl-O—R^a; and

Y²is —NR^b— or —O—; or

wherein

R^bis H, C_1-6alkyl, —C(═O)C_1-6alkyl, C_1-6alkyl-O—R^a; and

Y²is —NR^b— or —O—; and

R⁵is independently, at each instance, H, C_1-9alkyl, C_1-4haloalkyl, halo, nitro, cyano, —OC_1-6alkyl, —O—C_1-4haloalkyl, —O—C_1-6alkylNR^aR^a, —O—C_1-6alkylOR^a, —NR^aR^a, —NR^a—C_1-4haloalkyl, —NR^a—C_1-6alkylNR^aR^aor —NR^a—C_1-6alkylOR^a; or R⁵is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O, N and S;

R⁷is tert-butyl or CF₃;

R¹⁰is independently, at each instance, H, C_1-9alkyl, —C_1-3alkylOR^a, C_1-4haloalkyl, halo, nitro, cyano, —OR^a, —S(═O)_nC_1-6alkyl, —O—C_1-4haloalkyl, —O—C_1-6alkylNR^aR^a, —O—C_1-6alkylOR^a, —O—C_1-6alkylC(═O)OR^a, —NR^aR^a, —NR^a—C_1-4haloalkyl, —NR^a—C_1-6alkylNR^aR^a, —NR^a—C_1-6alkylOR^a, —C(═O)C_1-6alkyl, —C(═O)OC_1-6alkyl, —OC(═O)C_1-6alkyl, —C(═O)NR^aC_1-6alkyl or —NR^aC(═O)C_1-6alkyl;

R¹²is independently, at each instance, H, C_1-9alkyl, —C_1-3alkylOR^a, C_1-4haloalkyl, halo, nitro, cyano, —OR^a, —S(═O)_nC_1-6alkyl, —O—C_1-4haloalkyl, —O—C_1-6alkylNR^aR^a, —O—C_1-6alkylOR^a, —O—C_1-6alkylC(═O)OR^a, —NR^aR^a, —NR^a—C_1-4haloalkyl, —NR^a—C_1-6alkylNR^aR^a, —NR^a—C_1-6alkylOR^a, —C(═O)C_1-6alkyl, —C(═O)OC_1-6alkyl, —OC(═O)C_1-6alkyl, —C(═O)NR^aC_1-6alkyl or —NR^aC(═O)C_1-6alkyl;

R¹³is independently, at each instance, H, C_1-9alkyl, —C_1-3alkylOR^a, C_1-4haloalkyl, halo, nitro, cyano, —OR^a, —S(═O)_nC_1-6alkyl, —O—C_1-4haloalkyl, —O—C_1-6alkylNR^aR^a, —O—C_1-6alkylOR^a, —O—C_1-6alkylC(═O)OR^a, —NR^aR^a, —NR^a—C_1-4haloalkyl, —NR^a—C_1-6alkylNR^aR^a, —NR^a—C_1-6alkylOR^a, —C(═O)C_1-6alkyl, —C(═O)OC_1-6alkyl, —OC(═O)C_1-6alkyl, —C(═O)NR^aC_1-6alkyl or —NR^aC(═O)C_1-6alkyl;

R¹⁴is independently, at each instance, H, C_1-9alkyl, —C_1-3alkylOR^a, C^1-4haloalkyl, halo, nitro, cyano, —OR^a, —S(═O)_nC_1-6alkyl, —O—C_1-4haloalkyl, —O—C_1-6alkylNR^aR^a, —O—C_1-6alkylOR^a, —O—C_1-6alkylC(═O)OR^a, —NR^aR^a, —NR^a—C_1-4haloalkyl, —NR^a—C_1-6alkylNR^aR^a, —NR^a—C_1-6alkylOR^a, —C(═O)C_1-6alkyl, —C(═O)OC_1-6alkyl, —OC(═O)C_1-6alkyl, —C(═O)NR^aC_1-6alkyl or —NR^aC(═O)C_1-6alkyl;

R^ais independently, at each instance, H, phenyl, benzyl or C_1-6alkyl;

R^bis H, C_1-6alkyl, —C(═O)C_1-6alkyl, C_1-6alkyl-O—R^a;

R^cis phenyl substituted by 0, 1 or 2 groups selected from halo, C_1-3haloalkyl, —OR^aand —NR^aR^a; or R^cis a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0, 1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo, C_1-3haloalkyl, —OR^aand —NR^aR^a;

X is O, S or NR^a;

Y is NH; and

n is independently, at each instance, 0, 1 or 2.