Patent MX-2020005874-A (MX)
Title: Pyrazole n-linked carbamoyl cyclohexyl acids as lpa antagonists.
Inventor: WANG YING
IPC: C07D401/04
Filed: 2018-12-18
Abstract: The present invention provides compounds of Formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein X<sup>1</sup>, X<sup>2</sup>, X<sup>3</sup>, and X<sup>4</sup> are each independently CR<sup>6</sup> or N; provided that no more than two of X<sup>1</sup>, X<sup>2</sup>, X<sup>3</sup>, or X<sup>4</sup> are N; Q<sup>2</sup> is N or NR<sup>5a</sup>; one of Q<sup>1</sup> and Q<sup>3</sup> is CR<sup>5</sup>, and the other is N or NR<sup>5a</sup>; and the dashed circle denotes optional bonds forming an aromatic ring; Y<sup>1</sup> is O or NR<sup>3</sup>; Y<sup>2</sup> is -CO-, -SO<sub>2</sub>-, or -S(O(NH)-; Y<sup>3</sup> is O or NR<sup>4a</sup>; provided that (1) Y<sup>1</sup> and Y<sup>3</sup> are not both O, and (2) when Y<sup>2</sup> is C(O), Y<sup>1 </sup>is not O; L is a covalent bond or C<sub>1-4</sub> alkylene substituted with 0 to 4 R<sup>7</sup>; R<sup>1</sup> is (-CH<sub>2</sub>)<sub>a</sub>R<sup>9</sup>; a is an integer of 0 or 1; R<sup>2</sup> is each independently halo, cyano, hydroxyl, amino, C<sub>1-6</sub> alkyl, C<sub>3-6</sub> cycloalkyl, C<sub>4-6 </sub>heterocyclyl, alkylamino, haloalkyi, hydroxyalkyi, aminoalkyi, alkoxy, alkoxyalkyl, haloalkoxyalkyl, or haloalkoxy; n is an integer of 0, 1, or 2; R<sup>3</sup> and R<sup>4a</sup> are independently hydrogen, C<sub>1-6</sub> alkyl, haloalkyi, hydroxyalkyi, aminoalkyi, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R<sup>4</sup> is C<sub>1-10</sub> alkyl, C<sub>1-10</sub> haloalkyi, C<sub>1-10</sub> deuterated alkyl, C<sub>1-10</sub> alkenyl, C<sub>3-8 </sub>cycloalkyl, 6 to 10-membered aryl, 3 to 8-membered heterocyclyl, -(Ci-6 alkylene)-(C3-8 cycloalkyl), -(C<sub>1-6 </sub>alkylene)-(6 to 10-membered aryl), -(C<sub>1-6</sub> alkylene)-(3 to 8-membered heterocyclyl), or -(C<sub>1-6</sub> 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; or alternatively, R<sup>3 </sup>and R<sup>4</sup>, taken together with the N and 0 atoms which they are attached, form a 4 to 9-membered heterocyclic ring moiety which is substituted with 0 to 3 R<sup>8</sup>; or alternatively, (R<sup>3</sup> and R<sup>5a</sup>) or (R<sup>3</sup> and R<sup>5</sup>), taken together with the atoms to which they are attached to, form a 5 to 8-membered heterocyclic ring moiety which is substituted with 0 to 3 R<sup>8</sup>; R<sup>5a</sup> is hydrogen, C<sub>1-6</sub> alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R<sup>5</sup> and R<sup>6</sup> are each independently hydrogen, halo, cyano, hydroxyl, amino, alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R<sup>7</sup> is halo, oxo, cyano, hydroxyl, amino, C<sub>1-6</sub> alkyl, C<sub>3-6</sub> cycloalkyl, C<sub>4-6</sub> heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; R<sup>8</sup> are each independently deuterium, halo, hydroxyl, amino, cyano, C<sub>1-6</sub> alkyl, C<sub>1-6</sub> deuterated alkyl, C<sub>2-6</sub> alkenyl, C<sub>2-6</sub> alkynyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, haloalkoxy, phenyl, or 5 to 6-membered heteroaryl; or alternatively, two R<sup>8</sup>, taken together with the atom(s) 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</sup>; R<sup>9</sup> is selected from -CN, -C(O)OR<sup>10</sup>, -C(O)NR<sup>11a</sup>R<sup>11b</sup>, -CO-NH-CO-R<sup>e</sup>, -CO-NH-SO<sub>2</sub>-R<sup>e</sup>, -CO-NH-SO-R<sup>e</sup>,-SO<sub>2</sub>-OH, -SO<sub>2</sub>-NH-CO-R<sup>e</sup>, -P(O)(OH)<sub>2</sub>, tetrazol-5-yl, -CH<sub>2</sub>-CO-NH-CO-R<sup>e</sup>, -CH<sub>2</sub>-CO-NH-SO<sub>2</sub>-R<sup>e</sup>, -CH<sub>2</sub>-CO-NH-SO-R<sup>e</sup>, -CH<sub>2</sub>-SO<sub>2</sub>-OH, -CH<sub>2</sub>-SO<sub>2</sub>-NH-CO-R<sup>e</sup>, -CH<sub>2</sub>-P(O)(OH)<sub>2</sub>, tetrazol-5-ylmethylene; R<sub>e</sub> is C<sub>1-6</sub> alkyl, C<sub>3-6</sub> cycloalkyl, haloalkyl, hydroxyalkyi, aminoalkyi, alkoxyalkyi, or haloalkoxyalkyi; R<sup>10</sup> is hydrogen or C<sub>1-10</sub> alkyl; and R<sup>11a</sup> and R<sup>11b</sup> are each independently hydrogen, C<sub>1-6</sub> alkyl, C<sub>3-6</sub> cycloalkyl, C<sub>4-6</sub> heterocyclyl, alkylamino, haloalkyi, hydroxyalkyi, aminoalkyi, alkoxyalkyi, haloalkoxyalkyi, alkoxy, or haloalkoxy; and R<sup>12</sup> is halo, cyano, hydroxyl, amino, C<sub>1-6 </sub>alkyl, alkylamino, haloalkyi, hydroxyalkyi, aminoalkyi, alkoxyalkyi, haloalkoxyalkyi, alkoxy, haloalkoxy, phenyl, or 5 to 6-membered heteroaryl. These compounds are selective LPA receptor inhibitors.