Mk2 inhibitors and methods of making and using the same

A compound of Formula I:

• or a pharmaceutically acceptable salt thereof, wherein
• ring {circle around (A)} is C6-10 aryl, 5- to 10-membered heteroaryl, C3-10 cycloalkyl, or 4- to 10-membered heterocyclyl;
• each R1a is independently halogen, —CD3, C1-6 alkyl, C2-6 alkynyl, C3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, —N(R1a)(R1a), —CN, —OR1a, —C(O)OR1a, —C(O)R1a, —C(O)N(R1a)(R1a), —N(R1a)C(O)—R1a, —N(R1a)C(O)O—R1a, —N(R1a)C(O)N(R1a)(R1a), —N═S(O)(R1a)(R1a), —N(R1a)S(O)2(R1a), —N(R1a)S(O)2N(R1a)(R1a), —N(R1a)S(O)2O(R1a), —OC(O)R1a, —OC(O)OR1a, —OC(O)N(R1a)(R1a), —SR1a, S(O)R1a, —SF5, —S(O)(NR1a)R1a, —S(NR1a)(NR1a)R1a, —S(O)(NR1a)N(R1a)(R1a), —S(O)(N—CN)R1a, —S(O)2R1a, —S(O)2N(R1a)(R1a), —C(O)N(R1a)S(O)2R1a, —S(O)2N(R1a)C(O)R1a, or —P(O)(R1a)2, or two R1 groups taken together with two adjacent atoms of ring {circle around (A)} to which they are attached form a C3-10 cycloalkyl or 4- to 10-membered heterocyclyl, wherein each alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one to three halogen and is further optionally substituted with one to three R1g;
• each R1a is independently H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, C3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, two R1a groups taken together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one to three R1i;
• each R1g is independently —CN, C1-6 alkyl, C2-6 alkynyl, C3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, —OR1h, —N(R1h)(R1h), —C(O)N(R1h)(R1h), —N(R1h)C(O)—R1h, —N(R1h)C(O)O—R1h, —N(R1h)C(O)N(R1h)(R1h), —OC(O)N(R1h)(R1h), —N(R1a)S(O)2(R1a), —S(O)2R1h, or —S(O)2N(R1a)(R1a), wherein each alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one to three R1i;
• each R1h is independently H, C1-6 alkyl, C2-6 alkynyl, C3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, or two Rh groups taken together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocyclyl, wherein each alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted with one to three R1i;
• each R1i is independently halogen, —OH, —NH2, —CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, or —O(C3-6 cycloalkyl);
• L is a bond, —O—, —NRLa—, —C(O)NRLa—, —C(O)—, or C1-3 alkylene, wherein the alkylene is optionally substituted with one to three RLb;
• each RLa is independently H, C1-6 alkyl, C1-6 haloalkyl, or C3-10 cycloalkyl;
• each RLb is independently halogen, —OH, —OCH3, —NH2, or —CN;
• each RY is independently halogen, —OH, —NH2, —CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, or C1-6 haloalkoxy;
• or RY and R1 join together to form a C3-6 cycloalkyl or 4- to 6-membered heterocyclyl, wherein each cycloalkyl and heterocyclyl is optionally substituted with one to three halogen;
• X is CR3 or N;
• R2 is H, halogen, C1-6 alkyl, or C3-6 cycloalkyl, wherein each alkyl and cycloalkyl is optionally substituted with one to three halogen;
• R3 is H, halogen, —CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, or —O(C3-6 cycloalkyl);
• R4 is H, —CN, C1-6 alkyl, C2-6 alkynyl, or C3-10 cycloalkyl, wherein each alkyl, alkynyl, and cycloalkyl is optionally substituted with one to three R4a1;
• each R4a1 is independently halogen, —CN, —OR4a2, or —NR4a2R4a2;
• each R4a2 is independently H, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, —C(O)C1-6 alkyl, —C(O)O(C1-6 alkyl), or —C(O)N(R4a3)2;
• each R4a3 is independently C1-6 alkyl;
• ring {circle around (B)} is C6-10 aryl or 5- to 10-membered heteroaryl;
• each R5 is independently halogen, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, —OR5a1, —N(R5a1)2, —N(R5a1)C(O)(R5a1), —C(O)N(R5a1)2, —N(R5a1)S(O)2(R5a1), —SO2N(R5a1)2, —SO2(R5a1), or —SR5a1, wherein each alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with one to three R5b1;
• each R5a1 is independently H, C1-6 alkyl, C3-10 cycloalkyl, or 4- to 10-membered heterocyclyl, wherein each alkyl, cycloalkyl, and heterocyclyl is optionally substituted with one to three R5b3;
• each R5b1 is independently halogen, —CN, C1-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, 4- to 10-membered heterocyclyl, —OR5b2, or —N(R5b2)2, wherein each alkyl, alkynyl, haloalkyl, cycloalkyl, and heterocycle is optionally substituted with one to three R5b3;
• each R5b2 is independently H, C1-6 alkyl, or C3-10 cycloalkyl, wherein each alkyl and cycloalkyl is optionally substituted with one or two oxo and is further optionally substituted with one to three R5b3;
• each R5b3 is independently halogen, —CN, —OH, —NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-6 cycloalkyl, C3-6 halocycloalkyl, or —O(C3-6 cycloalkyl);
• ring {circle around (C)} is C6-10 aryl, 5- to 10-membered heteroaryl, C3-8 cycloalkyl, or 4- to 10-membered heterocyclyl;
• each R6 is independently oxo, halogen, —NO2, —N3, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, —OR6a1, —N(R6a1)2, —N(R6a1)3+, —C(O)R6a1, —C(O)OR6a1, —C(O)N(R6a1)2, —N(R6a1)C(O)R6a1, —N(R6a1)C(O)OR6a1, N(R6a1)C(O)N(R6a1)2, —N═S(O)(R6a1)2, —N═S(O)N(R6a1)2R6a1, —N(R6a1)S(O)2(R6a1), —N(R6a1)S(O)2N(R6a1)2, —N(R6a1)S(O)2O(R6a1), —OC(O)R6a1, —OC(O)OR6a1, —OC(O)N(R6a1)2, —Si(R6a1)3, —SR6a1, —S(O)R6a1, —SF5, —S(O)(NR6a1)R6a1, —S(NR6a1)2R6a1, —S(O)(NR6a1)N(R6a1)2, —S(O)(N—CN)R6a1, —S(O)2R6a1, —S(O)2N(R6a1)2, —C(O)N(R6a1)S(O)2R6a1, —S(O)2N(R6a1)C(O)R6a1, or —P(O)(R6a1)2, or two R6 groups taken together with two adjacent atoms of ring {circle around (C)} to which they are attached form a C3-10 cycloalkyl or a 4- to 10-membered heterocyclyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one to three halogen and is further optionally substituted with one to three R6b1;
• each R6a1 is independently H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, C3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, or two R6a1 groups taken together with the atom or atoms to which they are attached form a 4- to 10-membered heterocyclyl, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one to three R6b1;
• each R6b1 is independently oxo, halogen, —NO2, —N3, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, —OR6b2, —C(O)—R6b2, —C(O)O—R6b2, —C(O)N(R6b2)2, —N(R6b2)2, —N(R6b2)3+, —N(R6b2)C(O)R6b2, —N(R6b2)C(O)OR6b2, —N(R6b2)C(O)N(R6b2)2, —N═S(O)(R6b2)2, —N(R6b2)S(O)2(R6b2), —N(R6b2)S(O)2N(R6b2)2, —N(R6b2)S(O)2O(R6b2), —OC(O)R6b2, —OC(O)OR6b2, —OC(O)N(R6b2)2, —Si(R6b2)3, —SR6b2, —S(O)R6b2, —SF5, —S(O)(NR6b2)R6b2, —S(NR6b2)2R6b2, —S(O)(NR6b2)N(R6b2)2, —S(O)(N—CN)R6b2, —S(O)2R6b2, —S(O)2N(R6b2)2, —C(O)N(R6b2)S(O)2R6b2, —S(O)2N(R6b2)C(O)R6b2, or —P(O)(R6b2)2, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one to three R6c1;
• each R6b2 is independently H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, C3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one to three R6c2;
• each R6c1 and R6c2 is independently oxo, halogen, —NO2, —N3, —CN, —OH, R6d1, —O(R6d1), —OC(O)(R6d1), —NH2, —NH(R6d1), —N(R6d1)2, —C(O)(R6d1), —C(O)O(R6d1), —C(O)NH2, —C(O)NH(R6d1), —C(O)N(R6d1)2, —NHC(O)(R6d1), —NHC(O)O(R6d1), —NHC(O)NH(R6d1), —SH, —S(R6d1), —NHS(O)(R6d1), —N(R6d1)(S(O)(R6d1), —S(O)N(R6d1)2, —S(O)(R6d1), —S(O)(NH)(R6d1), —S(O)2(R6d1), —S(O)2NH(R6d1), or —S(O)2N(R6d1)2;
• each R6d1 is independently C1-6 alkyl, C3-10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl aryl, and heteroaryl is optionally substituted with one to three R6e1;
• each R6e1 is independently oxo, halogen, —NO2, —N3, —CN, —OH, —NH2, methyl, or halomethyl;
• wherein each heterocyclyl and heteroaryl independently has one to four ring heteroatoms each independently selected from N, O, and S;
• and
• m is 0, 1, 2 or 3;
• n is 0, 1, 2 or 3;
• p is 0, 1, 2 or 3;
• and
• q is 0, 1, 2 or 3.