Bristol-Myers Squibb Company
Isoxazole o-linked carbamoyl cyclohexyl acids as LPA antagonists

Abstract:

The present invention provides compounds of Formula (Ia) or (Ib) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are each independently CR.sup.6 or N; provided that no more than two of X.sup.1, X.sup.2, X.sup.3, or X.sup.4 are N; L is C.sub.1-4 alkylene substituted with 0 to 4 R.sup.7; R.sup.1 is (--CH.sub.2).sub.aR.sup.9; a is an integer of 0 or 1; R.sup.2 is each independently halo, cyano, hydroxyl, amino, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyallcyl, or haloalkoxy; n is an integer of 0, 1, or 2; R.sup.3 is hydrogen, C.sub.1-6 alkyl, C.sub.1-6 deuterated alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy, and the alkyl, by itself or as part of other moiety, is optionally substituted with deuterium partially or fully; R.sup.4 is C.sub.1-10 alkyl, C.sub.1-10 deuterated alkyl, C.sub.1-10 haloalkyl, C.sub.1-10 alkenyl, C.sub.3-8 cycloalkyl, 6 to 10-membered aryl, 3 to 8-membered heterocyclyl, --(C.sub.1-6 alkylene)-(C.sub.3-8 cycloalkyl), --(C.sub.1-6 alkylene)-(6 to 10-membered aryl), --(C.sub.1-6 alkylene)-(3 to 8-membered heterocyclyl), or --(C.sub.1-6 alkylene)-(5 to 6-membered heteroaryl); wherein each of the alkyl, alkylene, alkenyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, by itself or as part of other moiety, is independently substituted with 0 to 3 R.sup.8; or alternatively, R.sup.3 and R.sup.4, taken together with the N atom to which they are attached, form a 4 to 9-membered heterocyclic ring moiety which is substituted with 0 to 3 R; R.sup.5 and R.sup.6 are each independently hydrogen, halo, cyano, hydroxyl, amino, C.sub.1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R.sup.7 is halo, oxo, cyano, hydroxyl, amino, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R.sup.8 are each independently deuterium, halo, hydroxyl, amino, cyano, C.sub.1-6 alkyl, C.sub.1-6 deuterated alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl, or 5 to 6-membered heteroaryl; or alternatively, two R.sup.8, taken together with the atoms to which they are attached, form a 3 to 6-membered carbocyclic ring or a 3 to 6-membered heterocyclic ring each of which is independently substituted with 0 to 3 R.sup.12; R.sup.9 is selected from --CN, --C(O)OR.sup.10, --C(O)NR.sup.11aR.sup.11b, --CO--NH--CO--R.sup.e, --CO--NH--SO.sub.2--R.sup.e, --CO--NH--SO--R.sup.e, --SO.sub.2--OH, --SO.sub.2--NH--CO--R.sup.e, --P(O)(OH).sub.2, tetrazol-5-yl, --CH.sub.2--CO--NH--CO--R.sup.e, --CH.sub.2--CO--NH--SO.sub.2--R.sup.e, CH.sub.2--CO--NH--SO--R.sup.e, --CH.sub.2--SO.sub.2--OH, --CH.sub.2--SO.sub.2--NH--CO--R.sup.e, --CH.sub.2--P(O)(OH).sub.2, tetrazol-5-ylmethylene; R.sup.e is C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl; R.sup.10 is hydrogen or C.sub.1-10 alkyl; and R.sup.11a and R.sup.11b are each independently hydrogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; and R.sup.12 is halo, cyano, hydroxyl, amino, C.sub.1-6alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl, or 5 to 6-membered heteroaryl. These compounds are selective LPA receptor inhibitors. ##STR00001##