Substituted pyrazolo [1,5-a]pyrimidines having multimodal activity against pain

A compound of Formula (I):

• or a pharmaceutically acceptable salt or stereoisomer thereof,
• wherein:
• X is a bond, —(CH2)p—, —(CH2)p—NRx—(CH2)q—, —(CH2)p—NRx—CH(CH3)—, or —(CH2)p—O—(CH2)q—;
• Rx is H, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR13R13′, O(haloalkyl), and OR13;
• each R13 is independently H or C1-6 alkyl;
• each R13′ is independently H or C1-6 alkyl;
• R1 is H, halogen, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, NR6R6′, OR6, cycloalkyl, heterocyclyl, or aryl;
• wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR11R11′, O(haloalkyl), and OR11;
• and
• wherein the cycloalkyl, heterocyclyl, or aryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, haloalkyl, alkyl(cycloalkyl), (CH2)rNR11R11′, (CH2)rOR11, C(CH3)2OR11, C(O)R11, C(O)NR11R11′, C(O)OR11, NR11C(O)R11′, NR11C(O)NR11′R11″, NR11S(O)2R11′, NR11S(O)2NR11′R11″, O(haloalkyl), OCH2CH2OR11, ═O, SR11, S(O)R11, S(O)2R11, S(O)2NR11R11′, and heterocyclyl;
• R6 is H, C1-6 alkyl, alkyl(cycloalkyl), alkyl(heterocyclyl), alkyl(aryl), C2-6 alkenyl, C2-6 alkynyl, O(haloalkyl), cycloalkyl, heterocyclyl, or aryl;
• wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR13R13′, O(haloalkyl), and OR13;
• and
• wherein the cycloalkyl of alkyl(cycloalkyl), heterocyclyl of alkyl(heterocyclyl), aryl of alkyl(aryl), cycloalkyl, heterocyclyl, or aryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, haloalkyl, alkyl(cycloalkyl), (CH2)rNR14R14′, (CH2)rOR14, C(CH3)2OR14, C(O)R14, C(O)NR14R14′, C(O)OR14, NR14C(O)R14′, NR14C(O)NR14′R14″, NR14S(O)2R14′, NR14S(O)2NR14′R14″, O(haloalkyl), OCH2CH2OR14, ═O, SR14, S(O)R14, S(O)2R14, S(O)2NR14R14′, and heterocyclyl;
• each R14 is independently H, C1-6 alkyl, cycloalkyl, heterocyclyl, or aryl;
• each R14′ is independently H, C1-6 alkyl, cycloalkyl, heterocyclyl, or aryl;
• each R14″ is independently H, C1-6 alkyl, cycloalkyl, heterocyclyl, or aryl;
• R6′ is H, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR13R13′, O(haloalkyl), and OR13;
• or
• R6 and R6′, taken together with the nitrogen atom to which they are attached, form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, haloalkyl, alkyl(cycloalkyl), (CH2)rNR14R14′, (CH2)rOR14, C(CH3)2OR14, C(O)R14, C(O)NR14R14′, C(O)OR14, NR14C(O)R14′, NR14C(O)NR14′R14″, NR14S(O)2R14′, NR14S(O)2NR14′R14″, O(haloalkyl), OCH2CH2OR14, ═O, SR14, S(O)R14, S(O)2R14, S(O)2NR14R14′, and heterocyclyl;
• each R11 is independently H, C1-6 alkyl, alkyl(cycloalkyl), alkyl(heterocyclyl), alkyl(aryl), cycloalkyl, heterocyclyl, or aryl;
• each R11′ is independently H, C1-6 alkyl, alkyl(cycloalkyl), alkyl(heterocyclyl), alkyl(aryl), cycloalkyl, heterocyclyl, or aryl;
• each R11″ is independently H, C1-6 alkyl, alkyl(cycloalkyl), alkyl(heterocyclyl), alkyl(aryl), cycloalkyl, heterocyclyl, or aryl;
• R2 is H, halogen, C1-6 alkyl, alkyl(cycloalkyl), C2-6 alkenyl, C2-6 alkynyl, OR7, O(haloalkyl), or cycloalkyl;
• wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR21R21′, O(haloalkyl), and OR21;
• and
• wherein the cycloalkyl of alkyl(cycloalkyl) or cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, haloalkyl, (CH2)rNR21R21′, (CH2)rOR21, C(CH3)2OR21, C(O)R21, C(O)NR21R21′, C(O)OR21, NR21C(O)R21′, NR21C(O)NR21′R21″, NR21S(O)2R21′, NR21S(O)2NR21′R21″, O(haloalkyl), OCH2CH2OR21, ═O, SR21, S(O)R21, S(O)2R21, and S(O)2NR21R21′;
• R7 is H, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR13R13′, O(haloalkyl), and OR13;
• each R21 is independently H or C1-6 alkyl;
• each R21′ is independently H or C1-6 alkyl;
• each R21″ is independently H or C1-6 alkyl;
• R3 is H, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, OR8, or O(haloalkyl), wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR31R31′, O(haloalkyl), and OR31;
• R8 is H, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR13R13′, O(haloalkyl), and OR13;
• each R31 is independently H or C1-6 alkyl;
• each R31′ is independently H or C1-6 alkyl;
• R4 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, or aryl;
• wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR41R41′, O(haloalkyl), and OR41;
• and
• wherein the cycloalkyl, heterocyclyl, or aryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, C1-6 alkyl, haloalkyl, (CH2)rNR41R41′, (CH2)rOR41, C(CH3)2OR41, C(O)R41, C(O)NR41R41′, C(O)OR41, NR41C(O)R41′, NR41C(O)NR41′R41″, NR41S(O)2R41′, NR41S(O)2NR41′R41″, O(haloalkyl), OCH2CH2OR41, ═O, SR41, S(O)R41, S(O)2R41, and S(O)2NR41R41′;
• each R41 is independently H or C1-6 alkyl;
• each R41′ is independently H or C1-6 alkyl;
• each R41″ is independently H or C1-6 alkyl;
• R5 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or O(haloalkyl), wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR51R51′, O(haloalkyl), and OR51;
• R5′ is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or O(haloalkyl), wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR51R51′, O(haloalkyl), and OR51;
• each R51 is independently H or C1-6 alkyl;
• each R51′ is independently H or C1-6 alkyl;
• m is 1, 2, 3, or 4;
• n is 1 or 2;
• p is 0, 1, 2, 3, or 4;
• q is 0, 1, 2, 3, or 4;
• each r is independently 0, 1, 2, or 3;
• and
• t is 0 or 1;
• with the proviso that the following compound is excluded: