Substituted amino acids as integrin inhibitors

A compound of formula (I):

• or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
• wherein:
• G is —C(O)R2 or R3;
• L1 is C2-C4 alkylene, wherein the C2-C4 alkylene is optionally substituted by 1 or more independently selected R4 substituents;
• L2 is a bond or C1-C3 alkylene, wherein the C1-C3 alkylene is optionally substituted by 1 or more independently selected R4 substituents;
• L3 is C2-C4 alkylene, wherein the C2-C4 alkylene is optionally substituted by 1 or more independently selected R4 substituents;
• Y is a bond or C3-C5 cycloalkylene, wherein the C3-C5 cycloalkylene is optionally substituted by 1 or more independently selected Ya substituents;
• each Ya is independently ═O or R4;
• R1 is:
• wherein the 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl or the 1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl is optionally substituted by 1 or more independently selected R4 substituents;
• R2 is C1-C6 alkyl, NR2gR2h, OR21, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C6-C14 aryl, or 5- to 10-membered heteroaryl
• wherein the C1-C6 alkyl is optionally substituted by 1 or more independently selected R2a substituents;
• wherein the C3-C8 cycloalkyl is optionally substituted by 1 or more independently selected R2b substituents;
• wherein the 3- to 12-membered heterocyclyl is optionally substituted by 1 or more independently selected R2c substituents;
• wherein the C6-C14 aryl is optionally substituted by 1 or more independently selected R2d substituents;
• and
• wherein the 5- to 10-membered heteroaryl is optionally substituted by 1 or more independently selected R2e substituents;
• each R2a is independently ═O or R4;
• each R2b is independently ═O or R4;
• each R2c is independently ═O or R4;
• each R2d is independently ═O or R4;
• each R2e is independently ═O or R4;
• R2f is C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C6-C14 aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C6-C14 aryl, or 5- to 10-membered heteroaryl is optionally substituted by 1 or more independently selected R2i substituents;
• R2g is H, D, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C6-C14 aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C6-C14 aryl, or 5- to 10-membered heteroaryl is optionally substituted by 1 or more independently selected R2j substituents;
• R2h is H, D, C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C6-C14 aryl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C6-C14 aryl, or 5- to 10-membered heteroaryl is optionally substituted by 1 or more independently selected R2j substituents;
• each R2i is independently ═O or R4;
• each R2j is independently ═O or R4;
• R3 is C1-C6 alkyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C6-C14 aryl, or 5- to 10-membered heteroaryl;
• wherein the C1-C6 alkyl is optionally substituted by 1 or more independently selected R3a substituents;
• wherein the C3-C8 cycloalkyl is optionally substituted by 1 or more independently selected R3b substituents;
• wherein the 3- to 12-membered heterocyclyl is optionally substituted by 1 or more independently selected R3c substituents;
• wherein the C6-C14 aryl is optionally substituted by 1 or more independently selected R3d substituents;
• and
• wherein the 5- to 10-membered heteroaryl is optionally substituted by 1 or more independently selected R3e substituents;
• each R3a is independently ═O or R4;
• each R3b is independently ═O or R4;
• each R3c is independently ═O or R4;
• each R3d is independently ═O or R4;
• each R3e is independently ═O or R4;
• each R4 is independently D, halogen, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C(NH)OR5, C(O)R5, C(O)NR6R7, C(O)OR5, P(O)(OR5)(OR6), NR6R7, NR5C(O)R6, NR5C(O)NR6R7, NR5C(O)OR6, NR5S(O)R6, NR5S(O)2R6, OR5, OC(O)R5, SR5S(O)R5, S(O)NR6R7, S(O)2R5, S(O)2NR6R7, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C6-C14 aryl, or 5- to 10-membered heteroaryl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C6-C14 aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted by 1 or more independently selected R4a substituents;
• each R4a is independently D, halogen, CN, C1-C6 alkyl, C(O)R8, C(O)OR8, P(O)(OR8)(OR9), NR8R9, NR8C(O)OR10, OR8, ═O, —S(O)R8, S(O)2R8, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, C6-C14 aryl, or 5- to 10-membered heteroaryl, wherein each C1-C6 alky, 3- to 12-membered heterocyclyl, C6-C14 aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted by 1 or more independently selected R4b substituents;
• each R4b is independently D, halogen, C1-C6 alkyl, OH, OD, or ═O, wherein each C1-C6 alkyl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of:
• D, halogen, OH, OD, and ═O;
• each R5 is independently H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C14 aryl, or 5- to 10-membered heteroaryl wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 10-membered heterocyclyl, C6-C14 aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted by 1 or more independently selected R5a substituents;
• each R5a is independently D, halogen, CN, C1-C6 alkyl, P(O)(OR11)(OR12), NR11R12, OR10, ═O, or 3- to 12-membered heterocyclyl, wherein each C1-C6 alkyl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of:
• D, halogen, OH, OD, and ═O;
• each R6 is independently H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-C14 aryl, or 5- to 10-membered heteroaryl,
• wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-C14 aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of:
• D, halogen, CN, C1-C6 alkyl, NR11R12, OR10, and ═O;
• and
• wherein each C1-C6 alkyl substituent is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of:
• D, halogen, OH, OD, and ═O;
• each R7 is independently H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-C14 aryl, or 5- to 10-membered heteroaryl,
• wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-C14 aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of:
• D, halogen, CN, C1-C6 alkyl, NR11R12, OR, and ═O;
• and
• wherein each C1-C6 alkyl substituent is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of:
• D, halogen, OH, OD, and ═O;
• or
• R6 and R7, together with the atom to which they are attached, form a 3- to 10-membered heterocyclyl;
• wherein the 3- to 10-membered heterocyclyl is optionally substituted by 1 or more substituents independently selected from the group consisting of:
• D, halogen, C1-C6 alkyl, NR11R12, OR10, and ═O;
• and
• wherein each C1-C6 alkyl substituent is optionally and independently substituted by 1 or more substituents independently selected form the group consisting of:
• D, halogen, OH, OD, and ═O;
• each R8 is independently H, D, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein each C1-C6alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of:
• D, halogen, and ═O:
• each R9 is independently H, D, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein each C1-C6alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of:
• D, halogen, and ═O;
• each R10 is independently H, D, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein each C1-C6alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of:
• D, halogen, and ═O;
• each R11 is independently H, D, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of:
• D, halogen, and ═O;
• and
• each R12 is independently H, D, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein each C1-C6alkyl, C2-C6 alkenyl, and C2-C6 alkynyl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of:
• D, halogen, and ═O;
• or
• R11 and R12, together with the atom to which they are attached, form a 3- to 6-membered heterocyclyl;
• wherein the 3- to 6-membered heterocyclyl is optionally substituted by 1 or more substituents independently selected from the group consisting of:
• D, halogen, C1-C6 alkyl, and ═O;
• and
• wherein the C1-C6 alkyl substituent is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of:
• D, halogen and ═O;
• with the provisos that:
• (i) if
• is
• then R2 is not tetrahydropyranyl;
• wherein the tetrahydropyranyl is substituted by 1, 2, or 3 independently selected R2c′ substituents;
• wherein each R2c′ is independently R4′;
• wherein each R4′ is selected from the group consisting of:
• D, 3- to 12-membered heterocyclyl, C6-C14 aryl, and 5- to 10-membered heteroaryl;
• and
• wherein each 3- to 12-membered heterocyclyl, C6-C14 aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted by 1 or more independently selected R4a substituents;
• (ii) if
• is
• then R2 is not phenyl;
• wherein the phenyl is substituted by 1, 2, or 3 independently selected R2d′ substituents;
• wherein each R2c′ is independently R4′;
• wherein each R4′ is independently selected from the group consisting of:
• D, 3- to 12-membered heterocyclyl, C6-C14 aryl, and 5- to 10-membered heteroaryl;
• and
• wherein each 3- to 12-membered heterocyclyl, C6-C14 aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted by 1 or more independently selected R4a substituents;
• or
• (iii) if
• is
• then R2 is not pyridyl;
• wherein the pyridyl is substituted by 1, 2, or 3 independently selected R2e′ substituents;
• wherein each R2e′ is independently R4′;
• wherein each R4′ is independently selected from the group consisting of:
• D, 3- to 12-membered heterocyclyl, C6-C14 aryl, and 5- to 10-membered heteroaryl;
• and
• wherein each 3- to 12-membered heterocyclyl, C6-C14 aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted by 1 or more independently selected R4a substituents.