Compounds, compositions, and methods

A compound of Formula I:

• or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or solvate thereof, wherein:
• A is C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-10 cycloalkylene, heterocyclylene, arylene, or heteroarylene;
• wherein the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-10 cycloalkylene, heterocyclylene, arylene, or heteroaryl of A is independently optionally substituted with one to five ZA;
• Ring B is a 5- or 6-membered heteroaryl optionally substituted with one to three RB;
• each RB is independently selected from halo, hydroxy, —NH2, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
• wherein each C1-3 alkyl of RB is independently optionally substituted with —NH2, —NHC1-3 alkyl, —N(C1-3 alkyl)2, hydroxy, or C1-3 alkoxy;
• Y1a is —C(O)—, —C(S)—, —S(O)2—, —S(O)(NR)—, or —P(O)R)—;
• Y2 is —O—, —S—, —NR2— or —C(R2)2—;
• wherein the bond between Y1a and Y2 is a single bond;
• and
• Y3 is —NR8—, —O—, —S—, —C(R3)2—, —NR8—C(R3)2—, —O—C(R3)2—, —S—C(R3)2—, —C(R3a)2—C(R)2—, —C(R3a)2—C(R3a)2—C(R3a)2—, or —CR3═CR3—;
• or
• Y1 is —C(O)—, —C(S)—, —S(O)2—, —S(O)(NR6)—, or —P(O)R7)—;
• Y2 is —N— or —CR2—, and
• Y3 is —N— or —CR3—;
• wherein the bond between Y2 and Y3 is a double bond;
• or
• Y1 is —N— or —CR1—;
• Y2 is —N— or —CR2—;
• wherein the bond between Y1a and Y2 is a double bond;
• and
• Y3 is —NR—, —O—, or —S—;
• provided that the ring comprising Y1, Y2, and Y3 contains at least one heteroatom;
• L1a is C1-3 alkylene, C2-3 alkenylene, C2-3 alkynylene, C1-3 heteroalkylene, C3-6 cycloalkylene, or 4-6 membered heterocyclylene;
• wherein the C1-3 alkylene, C2-3 alkenylene, C2-3 alkynylene, C1-3 heteroalkylene, C3-6 cycloalkylene, or 4-6 membered heterocyclylene of L1a is independently optionally substituted with one to five substituents independently selected from halo, oxo, hydroxy, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
• L2 is a bond, —O—, —S—, —NRa—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)NR2a—, —NR2aC(O)—, —OC(O)NR2a—, —NR2aC(O)O—, —NR2aC(O)NR2b—, —S(O)—, —S(O)2—, —S(O)NR2a—, —S(O)2NR2a—, —NR2aS(O)—, —NR2aS(O)2—, —NR2S(O)NR2b—, —NR2aS(O)2NR2b—, C1-6 alkylene, C2-4 alkenylene, C2-6 alkynylene, C1-6 heteroalkylene, C3-6 cycloalkylene, 4-6 membered heterocyclylene, or 5 membered heteroarylene;
• wherein the C1-3 alkylene, C2-3 alkenylene, C2-3 alkynylene, C1-3 heteroalkylene, C3-6 cycloalkylene, 4-6 membered heterocyclylene, or 5 membered heteroarylene of L2 is independently optionally substituted with one to five substituents independently selected from halo, oxo, hydroxy, cyano, —NH2, —NHC1-3 alkyl,
• —N(C1-3 alkyl)2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
• R7 is hydrogen, halo, hydroxy, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy;
• each R2 is independently hydrogen, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, 4 to 6-membered heterocyclyl, or 5 to 6-membered heteroaryl;
• wherein each C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C3-6 cycloalkyl, phenyl, 4 to 6-membered heterocyclyl, or 5 to 6-membered heteroaryl of R2 is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, C1-3 alkoxy, or C1-3 haloalkoxy;
• or R2 and any one or two of R1, R3, R3a, R6, R7, and R8, together with the atoms to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, or heteroaryl;
• wherein the C3-10 cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one to five Z2;
• each R2a and R2b is independently hydrogen, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• wherein each C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R2a and R2b is independently optionally substituted with one to five Z2a;
• or R2a and R2b are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Z2a;
• each R3 is independently hydrogen, hydroxy, —NR3bR3c, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• wherein each C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R3 is independently optionally substituted with one to five Z3;
• or two R3, together with the atom(s) to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• wherein the C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to five Z3;
• or two R3, together with the carbon atom to which both are attached, form an oxo;
• each R3 is independently hydrogen, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• wherein each C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R3a is independently optionally substituted with one to five Z3a;
• or two R3a, together with the atom(s) to which they are attached, form a C3-10 cycloalkyl, heterocyclyl, or heteroaryl;
• wherein the C3-10 cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one to five Z3;
• or two R3a, together with the carbon atom to which both are attached, form an oxo;
• R3b and R3c are each independently hydrogen, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• wherein each C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R3b and R3c is independently optionally substituted with one to five substituents independently selected from halo, hydroxy, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
• or R3b and R3c are taken together with the nitrogen atom to which they are attached to form a heterocyclyl optionally substituted with one to five Z3b;
• R4 is C1-6 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• wherein the C1-6 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R4 is independently optionally substituted with one to five Z4;
• R5 is hydrogen, halo, hydroxy, amino, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• wherein the C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R5 is independently optionally substituted with one to five Z5;
• R6 is hydrogen, C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl;
• wherein the C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl is optionally substituted with one to five substituents independently selected from halo, oxo, hydroxy, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
• R7 is hydroxy, C1-3 alkoxy, C1-3 haloalkoxy, C1-3 alkyl, or C1-3 haloalkyl;
• R8 is hydrogen, —S(O)2—C1-3 alkyl, —S(O)2—C1-3 haloalkyl, C1-3 alkyl, C1-3 haloalkyl C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl;
• wherein the —S(O)2—C1-3 alkyl, —S(O)2—C1-3 haloalkyl, C1-3 alkyl, C1-3 haloalkyl C3-6 cycloalkyl, or 4 to 6-membered heterocyclyl of R7 is optionally substituted with one to five substituents independently selected from halo, oxo, hydroxy, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy;
• each ZA, Z2, Z2a, Z3, Z3a, Z3b, Z4, and Z5;
• is independently halo, cyano, nitro, oxo, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -L-H, -L-C1-6 alkyl, -L-C2-6 alkenyl, -L-C2-6 alkynyl, -L-C1-6 haloalkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl;
• wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of ZA, Z2, Z2a, Z3, Z3a, Z3b, Z4, and Z5 are each independently optionally substituted with one to five Z1a;
• each L is independently —O—, —S—, —NR20—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)NR20—, —NR20C(O)—, —OC(O)NR20—, —NR20C(O)O—, —NR20C(O)NR21—, —S(O)—, —S(O)2—, —S(O)NR20—, —S(O)2NR20—, —NR20S(O)—, —NR20S(O)2—, —NR20S(O)NR21—, or —NR20S(O)2NR21—;
• each R20 and R21 is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• wherein each C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R20 and R21 is independently optionally substituted with one to five Z1a;
• or an R20 and R21 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to five Z1a;
• and
• each Z1a is independently halo, hydroxy, cyano, nitro, oxo, —SH, —NH2, —NH—C1-6 alkyl, —N(C1-6 alkyl)2, —S—C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-6 alkenyl, C2-4 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
• wherein each —NH—C1-6 alkyl, —N(C1-6 alkyl)2, —S—C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C2-4 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1a is independently optionally substituted with one to five substituents independently selected from C1-6 alkyl, oxo, halo, hydroxy, and cyano;
• provided that when Ring B is unsubstituted thiophenyl, then -A-L2-R5 is not unsubstituted thiophenyl or unsubstituted phenyl.