	US 7,514,409 B2
	VLA-4 antagonists
William K. Hagmann, Westfield, N.J. (US); Linus S. Lin, Westfield, N.J. (US); Ping Liu, Westfield, N.J. (US); Richard A. Mumford, Red Bank, N.J. (US); Thomas S. Reger, San Diego, Calif. (US); Nicholas D. Smith, San Diego, Calif. (US); Nicholas S. Stock, San Diego, Calif. (US); and Jasmine Zunic, San Diego, Calif. (US)
Assigned to Merck & Co., Inc., Rahway, N.J. (US)
Appl. No. 10/591,820 PCT Filed Mar. 07, 2005, PCT No. PCT/US2005/007252 § 371(c)(1), (2), (4) Date Sep. 07, 2006, PCT Pub. No. WO2005/087760, PCT Pub. Date Sep. 22, 2005.
Claims priority of provisional application 60/615477, filed on Oct. 01, 2004.
Claims priority of provisional application 60/552057, filed on Mar. 10, 2004.
Prior Publication US 2007/0179190 A1, Aug. 02, 2007
Int. Cl. A61K 38/05 (2006.01)

U.S. Cl. 514—19

9 Claims

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A is N or N⁺—O⁻;

X and Y are independently selected from halogen, C_1-3alkyl, and C_1-3alkoxy;

R¹is selected from (1) hydrogen, (2) C_1-10alkyl, (3) —(C_1-10alkyl)-aryl, (4) —(C_1-10alkyl)-O—C_1-10alkyl, (5) —(C_1-10alkyl)-OC(O)—C_1-10alkyl, (6) —(C_1-10alkyl)-OC(O)-aryl, (7) —(C_1-10alkyl)-OC(O)O—C_1-10alkyl and (8) —(C_1-10alkyl)N⁺(C_1-3alkyl)₃; wherein alkyl is optionally substituted with one to three substituents independently selected from R^a, and aryl is optionally substituted with one to three substituents independently selected from R^b;

R²is hydrogen or methyl;

R³and R⁴are independently selected from (1) hydrogen, (2) —NR^dR^e, (3) —NR^dS(O)_mR^e, (4) —NR^dC(O)R^e, (5) —NR^dC(O)OR^e, and (6) —NR^dC(O)NR^dR^e, with the proviso that R³and R⁴are not both hydrogen;

R^ais selected from (1) —OR^d, (2) —NR^dS(O)_mR^e, (3) —NO₂, (4) halogen, (5) —S(O)_mR^d, (6) —SR^d, (7) —S(O)₂OR^d, (8) —S(O)_mNR^dR^e, (9) —NR^dR^e, (10) —O(CR^fR^g)_nNR^dR^e, (11) —C(O)R^d, (12) —CO₂R^d, (13) —CO₂(CR^fR^g)_nCONR^dR^e, (14) —OC(O)R^d, (15) —CN, (16) —C(O)NR^dR^e, (17) —NR^dC(O)R^e, (18) —OC(O)NR^dR^e, (19) —NR^dC(O)OR^e, (20) —NR^dC(O)NR^dR^e, (21) —CR^d(N—OR^e), (22) CF₃, (23) —OCF₃, (24) C_3-8cycloalkyl, and (25) heterocyclyl; wherein cycloalkyl and heterocyclyl are optionally substituted with one to three groups independently selected from R^c;

R^bis selected from (1) a group selected from R^a, (2) C_1-10alkyl, (3) C_2-10alkenyl (4) C_2-10alkynyl, (5) aryl, and (6) —(C_1-10alkyl)-aryl, wherein alkyl, alkenyl, alkynyl, and aryl are optionally substituted with one to three substituents selected from a group independently selected from R^c;

R^cis (1) halogen, (2) amino, (3) carboxy, (4) C_1-4alkyl, (5) C_1-4alkoxy, (6) aryl, (7) —(C_1-4alkyl)-aryl, (8) hydroxy, (9) CF₃, (10) OC(O)C_1-4alkyl, (11) OC(O)NR^fR^g, or (12) aryloxy;

R^dand R^eare independently selected from hydrogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, Cy and —(C_1-10alkyl)-Cy, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from R^c; or

R^dand R^etogether with the atom(s) to which they are attached form a heterocyclic ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from O, S and N—R^h, and wherein said heterocyclic ring is optionally fused with a C_3-8carbocyclic ring or is optional substituted with 1 to 4 groups independently selected from C_1-10alkyl;

R^fand R^gare independently selected from hydrogen, C_1-10alkyl, Cy and —(C_1-10alkyl)-Cy; or

R^fand R^gtogether with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;

R^his selected from R^fand —C(O)R^f;

Cy is selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; and

m is 1 or 2.