Benzofuran derivatives as sik inhibitors and the use thereof

A compound of Formula (I):

• or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
• wherein:
• X is a divalent heteroaryl ring, a divalent heterocycloalkyl ring, —O—, —CH2—, —NH— or —O—C1-8alkylene-, wherein each of said divalent heteroaryl ring, heterocycloalkyl ring, —CH2—, —NH— or —O—C1-8alkylene is independently optionally substituted with at least one Ra;
• Ra is each independently selected from halogen, —C1-8alkyl, —C1-8haloalkyl, —CN, and —C1-8alkoxy;
• R5 is selected from hydrogen, —C1-8alkyl, —C1-8alkoxy, —C2-8alkynyl, —C1-8haloalkyl, —C3-C8cycloalkyl, 4- to 8-membered heterocycloalkyl, aryl, 5- to 12-membered heteroaryl, —NR5iR5j, —CONR5iR5j, —SR5i, and —NR5iCOR5j;
• wherein said —C1-8alkyl, —C1-8alkoxy, —C2-8alkynyl, —C1-8haloalkyl, —C3-C8cycloalkyl, 4- to 8-membered heterocycloalkyl, aryl, or 5- to 12-membered heteroaryl is independently optionally substituted with at least one R5a,
• wherein said R5a is each independently selected from halogen, oxo, —OH, —CN, —C1-8alkyl, —C1-8haloalkyl, —C1-8alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —NR5bR5c, and —COR5d;
• wherein said —C1-8alkyl, —C1-8haloalkyl, —C1-8alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently optionally substituted with at least one R5g;
• R5b, R5c and R5d are each independently selected from hydrogen, —C1-8alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
• R5g is each independently selected from halogen, oxo, —OH, —CN, —C1-8alkyl, —C1-8haloalkyl, —C1-8alkoxy, C1-8alkyl-CO—, and —NO2,
• wherein said R5i and R5j are each independently selected from hydrogen, —C1-8alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
• wherein said —C1-8alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently optionally substituted with at least one R5m;
• wherein said R5m is each independently selected from halogen, oxo, —OH, —CN, —C1-8alkyl, —C1-8haloalkyl, —C1-8alkoxy, C1-8alkyl-CO—, and —NO2;
• R1 is selected from hydrogen, halogen, —C1-8alkyl, —C1-8haloalkyl, and —C1-8alkoxy;
• X1 is N or CR3 and X2 is N or CR4, with the proviso that X1 and X2 cannot both be N;
• R3 and R4 are each independently selected from hydrogen, halogen (F, Cl, Br or I), —C1-8alkyl (preferably —CH3), —C1-8haloalkyl, —C1-8alkoxy (preferably —OCH3), —CN, and —NR1aR1b(preferably —NHCH3);
• R1a and R1b are each independently selected from hydrogen and —C1-8alkyl (preferably —CH3);
• R2 is
• R6 and R10 are each independently selected from hydrogen, halogen, —C1-8alkyl, —C1-8haloalkyl, and —C1-8alkoxy;
• wherein either
• (A) R7 and R9 are each independently selected from hydrogen, halogen, —C1-8alkyl, cycloalkyl, heterocycloalkyl, —OR7a, —COR7a, —NR7dR7e, —CONR7dR7e, —OH, and —CN;
• wherein said —C1-8alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with at least one R7g;
• wherein R7g is each independently selected from hydrogen, halogen, —C1-8alkoxy, —COC1-8alkyl, —NH2, —OH, and —CN;
• wherein R7a is each independently selected from —C1-8alkyl, C3-8cycloalkyl, and 3- to 10-membered heterocycloalkyl, wherein said —C1-8alkyl, C3-8cycloalkyl, or 3- to 10-membered heterocycloalkyl is optionally substituted with at least one R7b;
• wherein R7b is each independently selected from halogen, —OH, —C1-8alkyl, cycloalkyl, heterocycloalkyl, —NH2, and —C1-8alkoxy, wherein said cycloalkyl, heterocycloalkyl or —C1-8alkoxy is optionally substituted with at least one R7c;
• wherein R7c is each independently selected from halogen, —C1-8alkyl, —CN, and —OH;
• wherein R7d and R7e are each independently selected from hydrogen and —C1-8alkyl, wherein said —C1-8alkyl is optionally substituted with at least one R7f;
• wherein R7f is each independently halogen, —CN, or —OH;
• R72, R73, and R74 are each independently selected from hydrogen, halogen, —C1-8alkyl, —C1-8haloalkyl, and —C1-8alkoxy;
• R71 is selected from 4- to 15-membered monocyclic, spirocyclic, and bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N, O, and S, wherein each of said heterocycloalkyl is independently optionally substituted with at least one R71a;
• R71a is each independently selected from hydrogen, halogen, —C1-8alkyl, —C1-8haloalkyl, —C1-8alkoxy and —NH2;
• R8 is selected from:
• (i) —CN,
• (ii) 5- to 6-membered monocyclic heteroaryl comprising one, two, or three heteroatoms independently selected from N, O, and S;
• wherein said heteroaryl is optionally substituted with at least one R8a;
• wherein R8a is each independently selected from —C1-8alkyl and cycloalkyl;
• and
• (iii) —CONR8bR8c, wherein R8b and R8c are each independently selected from hydrogen, —C1-8alkyl, 5- to 6-membered heterocycloalkyl and C3-C8cycloalkyl, wherein said —C1-8alkyl, 5- to 6-membered heterocycloalkyl or C3-C8cycloalkyl is optionally substituted with at least one R8d, wherein R8d is each independently selected from halogen,
• —OH, —NH2, —CN, —CONH2, aryl, and heteroaryl;
• or
• (B) R8 and R9 together with the atoms onto which they are attached form a fused 5-, 6- or 7-membered heterocycloalkyl
• containing —CONR8b— moiety, wherein said heterocycloalkyl is optionally substituted with at least one R8e;
• R8b is selected from hydrogen, —C1-8alkyl, 5- to 6-membered heterocycloalkyl and C3-C8cycloalkyl, wherein said —C1-8alkyl 5- to 6-membered heterocycloalkyl or C3-C8cycloalkyl is optionally substituted with at least one R8d;
• R8d is each independently selected from halogen, —OH, —NH2, —CN, —CONH2, aryl, and heteroaryl;
• wherein R8e is each independently selected from —C1-8alkyl or cycloalkyl;
• and
• R7 is selected from hydrogen, halogen, —C1-8alkyl, cycloalkyl, heterocycloalkyl, —OR7a, —COR7a, —NR7dR7e, —CONR7dR7e, —OH, and —CN;
• wherein said —C1-8alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with at least one R7g;
• wherein R7g is each independently selected from hydrogen, halogen, —C1-8alkoxy, COC1-8alkyl, —NH2, —OH, and —CN;
• wherein R7a is selected from —C1-8alkyl, C3-8cycloalkyl, and 3- to 10-membered heterocycloalkyl, wherein said —C1-8alkyl, C3-8cycloalkyl, or 3- to 10-membered heterocycloalkyl is optionally substituted with at least one R7b;
• wherein R7b is each independently selected from halogen, —OH, —C1-8alkyl, cycloalkyl, heterocycloalkyl, —NH2, and —C1-8alkoxy, wherein said cycloalkyl, heterocycloalkyl or —C1-8alkoxy is optionally substituted with at least one R7c;
• wherein R7c is each independently selected from halogen, —C1-8alkyl, —CN, and —OH;
• wherein R7d and R7e are each independently selected from hydrogen and —C1-8alkyl,
• wherein said —C1-8alkyl is optionally substituted with at least one R7f,
• wherein R7f is each independently halogen, —CN, or —OH.