Granzyme b directed imaging and therapy

A compound of Formula II:

• or a pharmaceutically acceptable salt thereof, or a stereoisomer or tautomer thereof, wherein:
• m is 0, 1, or 2;
• n is 1, 2, or 3;
• R1 and R2 are each independently selected from the group consisting of:
• hydrogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C6-10 aryl, HET and —NR10R12, wherein each C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and hydroxy, and each C6-10 aryl and HET are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl and C1-4 haloalkyl;
• or R1 and R2 may come together, with the carbon atom to which they are attached, to form a 5-6 membered cycloalkyl or 5-6 heterocycloalkyl group, each of which may be optionally substituted with 1, 2, or 3 R10 groups;
• each R3 and R7 is independently selected from the group consisting of hydrogen, C1-4 alkyl and C1-4 haloalkyl;
• X is selected from the group consisting of CH2, O, S, SO2, and NR4, with the proviso that, when X is CH2, at least one of R1 and R2 is —NR10R12, and at least one of R10 and R12 is —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl or —C(O)HET;
• R4 is selected from the group H, C1-4 alkyl and C1-4haloalkyl;
• each R5, R6, R8′ and R8 is independently selected from the group consisting of hydrogen, halo, COOH, hydroxy, OC1-4 alkyl, C1-4 alkyl and C1-4haloalkyl;
• R9 is COOR3, —O—C1-4 alkyl, —O—C1-4 haloalkyl, —B(OR13′)2, —PO(OR13″)2, or HET, wherein the HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl and C1-4 haloalkyl;
• R10 is selected from the group consisting of hydrogen, C1-4alkyl, —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl, —C(O)HET and —C(O)C1-4 alkyl;
• wherein the C1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups:
• wherein the —C(O)C1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2, HET, —O—C1-4 alkyl and C6-10 aryl;
• wherein the —O—C1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2 and C6-10 aryl;
• wherein the C6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C1-4 alkyl, —O—C1-4 haloalkyl and halo groups;
• each HET is an independently selected mono- or bicyclic 5-10-membered heteroaryl or a mono- or bicyclic 5-10 membered heterocycloalkyl group, wherein each HET comprises 1, 2, 3, or 4 heteroatoms selected from O, S and N and is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C1-4 alkyl, —O—C1-4 haloalkyl, halo, hydroxy and oxo groups;
• R11 is selected from hydrogen, C1-4 alkyl and C1-4haloalkyl;
• R12 is selected from the group consisting of hydrogen, C1-4 alkyl, —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl, —C(O)HET and —C(O)C1-4 alkyl;
• wherein the C1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups;
• wherein the —C(O)C1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2, HET, —O—C1-4 alkyl and C6-10 aryl;
• wherein the —O—C1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2 and C6-10 aryl;
• wherein the C6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C1-4 alkyl, —O—C1-4 haloalkyl and halo groups;
• and
• each of R13, R13′, and R13″, independently, is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 cycloalkyl and HET,
• wherein at least one of R1, R2, R5 and R9 optionally comprises an imaging agent.

A compound of Formula III:

• or a pharmaceutically acceptable salt thereof, or a stereoisomer or tautomer thereof, wherein:
• m is 0, 1, or 2;
• n is 1 or 2;
• R1 and R2 are each independently selected from the group consisting of:
• hydrogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C6-10 aryl, HET and —NR10R12, wherein each C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and hydroxy, and each C6-10 aryl and HET are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl and C1-4 haloalkyl;
• or R1 and R2 may come together, with the carbon atom to which they are attached, to form a 5-6 membered cycloalkyl or 5-6 heterocycloalkyl group, each of which may be optionally substituted with 1, 2, or 3 R10 groups;
• each R3 and R7 is independently selected from the group consisting of hydrogen, C1-4 alkyl and C1-4 haloalkyl;
• X is selected from the group consisting of CH2, O, S, SO2, and NR4;
• R4 is selected from the group H, C1-4 alkyl and C1-4 haloalkyl;
• each R5, R6, R8′ and R8 is independently selected from the group consisting of hydrogen, halo, COOH, hydroxy, OC1-4 alkyl, C1-4 alkyl and C1-4haloalkyl;
• R9 is COOR13, —O—C1-4 alkyl, —O—C1-4 haloalkyl, —B(OR13′)2, —PO(OR13″)2, or HET, wherein the HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl and C1-4 haloalkyl;
• R10 is selected from the group consisting of hydrogen, C1-4 alkyl, —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl, —C(O)HET and —C(O)C1-4 alkyl;
• wherein the C1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups;
• wherein the —C(O)C1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2, HET, —O—C1-4 alkyl and C6-10 aryl;
• wherein the —O—C1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2 and C6-10 aryl;
• wherein the C6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C1-4 alkyl, —O—C1-4 haloalkyl and halo groups;
• each HET is an independently selected mono- or bicyclic 5-10-membered heteroaryl or a mono- or bicyclic 5-10 membered heterocycloalkyl group, wherein each HET comprises 1, 2, 3, or 4 heteroatoms selected from O, S and N and is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C alkyl, —O—C1-4 haloalkyl, halo, hydroxy and oxo groups;
• R11 is selected from hydrogen, C1-4 alkyl and C1-4 haloalkyl;
• R12 is selected from the group consisting of hydrogen, C1-4 alkyl, —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl, —C(O)HET and —C(O)C1-4 alkyl;
• wherein the C1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups;
• wherein the —C(O)C1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2, HET, —O—C1-4 alkyl and C6-10 aryl;
• wherein the —O—C1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2 and C6-10 aryl;
• wherein the C6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C1-4 alkyl, —O—C1-4 haloalkyl and halo groups;
• and
• each of R13, R13′, and R13″, independently, is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 cycloalkyl and HET,
• wherein at least one of R1, R2, R5 and R9 optionally comprises an imaging agent.

A compound of Formula IV:

• or a pharmaceutically acceptable salt thereof, or a stereoisomer or tautomer thereof, wherein:
• m is 0, 1, or 2;
• n is 1 or 2;
• R1 and R2 are each independently selected from the group consisting of:
• hydrogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C6-10 aryl, HET and —NR10R12, wherein each C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and hydroxy, and each C6-10 aryl and HET are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl and C1-4 haloalkyl;
• or R1 and R2 may come together, with the carbon atom to which they are attached, to form a 5-6 membered cycloalkyl or 5-6 heterocycloalkyl group, each of which may be optionally substituted with 1, 2, or 3 R10 groups;
• each R3 and R7 is independently selected from the group consisting of hydrogen, C1-4 alkyl and C1-4haloalkyl;
• X is selected from the group consisting of CH2, O, S, SO2, and NR4;
• R4 is selected from the group H, C1-4 alkyl and C1-4 haloalkyl;
• each R5, R6, R8′ and R8 is independently selected from the group consisting of hydrogen, halo, COOH, hydroxy, OC1-4 alkyl, C1-4 alkyl and C1-4 haloalkyl;
• R9 is COOR13, —O—C1-4 alkyl, —O—C1-4 haloalkyl, —B(OR13′)2, —PO(OR13″)2, or HET, wherein the HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl and C1-4 haloalkyl;
• R10 is selected from the group consisting of hydrogen, C1-4 alkyl, —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl, —C(O)HET and —C(O)C1-4 alkyl;
• wherein the C1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups;
• wherein the —C(O)C1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2, HET, —O—C1-4 alkyl and C6-10 aryl;
• wherein the —O—C1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2 and C6-10 aryl;
• wherein the C6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C1-4 alkyl, —O—C1-4 haloalkyl and halo groups;
• each HET is an independently selected mono- or bicyclic 5-10-membered heteroaryl or a mono- or bicyclic 5-10 membered heterocycloalkyl group, wherein each HET comprises 1, 2, 3, or 4 heteroatoms selected from O, S and N and is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C alkyl, —O—C1-4 haloalkyl, halo, hydroxy and oxo groups;
• R11 is selected from hydrogen, C1-4 alkyl and C1-4 haloalkyl;
• R12 is selected from the group consisting of hydrogen, C1-4 alkyl, —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl, —C(O)HET and —C(O)C1-4 alkyl;
• wherein the C1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups;
• wherein the —C(O)C1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2, HET, —O—C1-4 alkyl and C6-10 aryl;
• wherein the —O—C1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2 and C6-10 aryl;
• wherein the C6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C1-4 alkyl, —O—C1-4 haloalkyl and halo groups;
• and
• each of R13, R13″, and R13″, independently, is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 cycloalkyl and HET,
• wherein at least one of R1, R2, R5 and R9 optionally comprises an imaging agent.

A compound of Formula V:

• or a pharmaceutically acceptable salt thereof, or a stereoisomer or tautomer thereof, wherein:
• m is 0, 1, or 2;
• n is 1 or 2;
• R1 and R2 are each independently selected from the group consisting of:
• hydrogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C6-10 aryl, HET and —NR10R12, wherein each C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and hydroxy, and each C6-10 aryl and HET are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl and C1-4 haloalkyl;
• or R1 and R2 may come together, with the carbon atom to which they are attached, to form a 5-6 membered cycloalkyl or 5-6 heterocycloalkyl group, each of which may be optionally substituted with 1, 2, or 3 R10 groups;
• each R3 and R7 is independently selected from the group consisting of hydrogen, C1-4 alkyl and C1-4 haloalkyl;
• X is selected from the group consisting of CH2, O, S, SO2, and NR4;
• R4 is selected from the group H, C1-4 alkyl and C1-4haloalkyl;
• each R5, R6, R8′ and R8 is independently selected from the group consisting of hydrogen, halo, COOH hydroxy, OC1-4 alkyl, C1-4 alkyl and C1-4 haloalkyl;
• R9 is COOR13, —O—C1-4 alkyl, —O—C1-4 haloalkyl, —B(OR13′)2, —PO(OR13″)2, or HET, wherein the HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl and C1-4 haloalkyl;
• R10 is selected from the group consisting of hydrogen, C1-4 alkyl, —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl, —C(O)HET and —C(O)C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups;
• wherein the —C(O)C1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2, HET, —O—C1-4 alkyl and C6-10 aryl;
• wherein the —O—C1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2 and C6-10 aryl;
• wherein the C6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C1-4 alkyl, —O—C1-4 haloalkyl and halo groups;
• each HET is an independently selected mono- or bicyclic 5-10-membered heteroaryl or a mono- or bicyclic 5-10 membered heterocycloalkyl group, wherein each HET comprises 1, 2, 3, or 4 heteroatoms selected from O, S and N and is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C1-4 alkyl, —O—C1-4 haloalkyl, halo, hydroxy and oxo groups;
• R11 is selected from hydrogen, C1-4 alkyl and C1-4 haloalkyl;
• R12 is selected from the group consisting of hydrogen, C1-4 alkyl, —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl, —C(O)HET and —C(O)C1-4 alkyl;
• wherein the C1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups:
• wherein the —C(O)C1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2, HET, —O—C1-4 alkyl and C6-10 aryl;
• wherein the —O—C1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2 and C6-10 aryl;
• wherein the C6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C1-4 alkyl, —O—C1-4 haloalkyl and halo groups;
• and
• each of R13, R3′, and R13″, independently, is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 cycloalkyl and HET,
• wherein at least one of R1, R2, R5 and R9 optionally comprises an imaging agent.

A compound of Formula VI:

• or a pharmaceutically acceptable salt thereof, or a stereoisomer or tautomer thereof, wherein:
• m is 0, 1, or 2;
• n is 1 or 2;
• R1 and R2 are each independently selected from the group consisting of:
• hydrogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C6-10 aryl, HET and —NR10R12, wherein each C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and hydroxy, and each C6-10 aryl and HET are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl and C1-4 haloalkyl;
• or R1 and R2 may come together, with the carbon atom to which they are attached, to form a 5-6 membered cycloalkyl or 5-6 heterocycloalkyl group, each of which may be optionally substituted with 1, 2, or 3 R10 groups;
• each R3 and R7 is independently selected from the group consisting of hydrogen, C1-4 alkyl and C1-4haloalkyl;
• X is selected from the group consisting of CH2, O, S, SO2, and NR4;
• R4 is selected from the group H, C1-4 alkyl and C1-4 haloalkyl;
• each R5, R6, R8′ and R8 is independently selected from the group consisting of hydrogen, halo, COOH, hydroxy, OC1-4 alkyl, C1-4 alkyl and C1-4haloalkyl;
• R9 is COOR3, —O—C1-4 alkyl, —O—C1-4 haloalkyl, —B(OR13′)2, —PO(OR13″)2, or HET, wherein the HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl and C1-4 haloalkyl;
• R10 is selected from the group consisting of hydrogen, C1-4 alkyl, —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl, —C(O)HET and —C(O)C1-4 alkyl;
• wherein the C1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups;
• wherein the —C(O)C1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2, HET, —O—C1-4 alkyl and C6-10 aryl;
• wherein the —O—C1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2 and C6-10 aryl;
• wherein the C6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C1-4 alkyl, —O—C1-4 haloalkyl and halo groups;
• each HET is an independently selected mono- or bicyclic 5-10-membered heteroaryl or a mono- or bicyclic 5-10 membered heterocycloalkyl group, wherein each HET comprises 1, 2, 3, or 4 heteroatoms selected from O, S and N and is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C alkyl, —O—C1-4 haloalkyl, halo, hydroxy and oxo groups;
• R11 is selected from hydrogen, C1-4 alkyl and C1-4 haloalkyl;
• R12 is selected from the group consisting of hydrogen, C1-4 alkyl, —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl, —C(O)HET and —C(O)C1-4 alkyl;
• wherein the C1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups;
• wherein the —C(O)C1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2, HET, —O—C1-4 alkyl and C6-10 aryl;
• wherein the —O—C1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2 and C6-10 aryl;
• wherein the C6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C1-4 alkyl, —O—C1-4 haloalkyl and halo groups;
• and
• each of R13, R13′, and R13″, independently, is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 cycloalkyl and HET,
• wherein at least one of R1, R2, R5 and R9 optionally comprises an imaging agent.

A compound of Formula VII:

• or a pharmaceutically acceptable salt thereof, or a stereoisomer or tautomer thereof, wherein:
• m is 0, 1, or 2;
• n is 1 or 2;
• R1 and R2 are each independently selected from the group consisting of:
• hydrogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C6-10 aryl, HET and —NR10R12, wherein each C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and hydroxy, and each C6-10 aryl and HET are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl and C1-4 haloalkyl;
• or R1 and R2 may come together, with the carbon atom to which they are attached, to form a 5-6 membered cycloalkyl or 5-6 heterocycloalkyl group, each of which may be optionally substituted with 1, 2, or 3 R10 groups;
• each R3 and R7 is independently selected from the group consisting of hydrogen, C1-4 alkyl and C1-4haloalkyl;
• X is selected from the group consisting of CH2, O, S, SO2, and NR4;
• R4 is selected from the group H, C1-4 alkyl and C1-4 haloalkyl;
• each R5, R6, R8′ and R8 is independently selected from the group consisting of hydrogen, halo, COOH, hydroxy, OC1-4 alkyl, C1-4 alkyl and C1-4 haloalkyl;
• R9 is COOR3, —O—C1-4 alkyl, —O—C1-4 haloalkyl, —B(OR13′)2, —PO(OR13″)2, or HET, wherein the HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl and C1-4 haloalkyl;
• R10 is selected from the group consisting of hydrogen, C1-4 alkyl, —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl, —C(O)HET and —C(O)C1-4 alkyl;
• wherein the C1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups;
• wherein the —C(O)C1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2, HET, —O—C1-4 alkyl and C6-10 aryl;
• wherein the —O—C1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2 and C6-10 aryl;
• wherein the C6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C1-4 alkyl, —O—C1-4 haloalkyl and halo groups;
• each HET is an independently selected mono- or bicyclic 5-10-membered heteroaryl or a mono- or bicyclic 5-10 membered heterocycloalkyl group, wherein each HET comprises 1, 2, 3, or 4 heteroatoms selected from O, S and N and is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C alkyl, —O—C1-4 haloalkyl, halo, hydroxy and oxo groups;
• R11 is selected from hydrogen, C1-4 alkyl and C1-4 haloalkyl;
• R12 is selected from the group consisting of hydrogen, C1-4 alkyl, —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl, —C(O)HET and —C(O)C1-4 alkyl;
• wherein the C1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups;
• wherein the —C(O)C1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2, HET, —O—C1-4 alkyl and C6-10 aryl;
• wherein the —O—C1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2 and C6-10 aryl;
• wherein the C6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C1-4 alkyl, —O—C1-4 haloalkyl and halo groups;
• and
• each of R13, R13′, and R13″, independently, is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 cycloalkyl and HET,
• wherein at least one of R1, R2, R5 and R9 optionally comprises an imaging agent.

A compound of Formula VIII:

• or a pharmaceutically acceptable salt thereof, or a stereoisomer or tautomer thereof, wherein:
• m is 0, 1, or 2;
• n is 1 or 2;
• R1 and R2 are each independently selected from the group consisting of:
• hydrogen, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C6-10 aryl, HET and —NR10R12, wherein each C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and hydroxy, and each C6-10 aryl and HET are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl and C1-4 haloalkyl;
• or R1 and R2 may come together, with the carbon atom to which they are attached, to form a 5-6 membered cycloalkyl or 5-6 heterocycloalkyl group, each of which may be optionally substituted with 1, 2, or 3 R10 groups;
• each R3 and R7 is independently selected from the group consisting of hydrogen, C1-4 alkyl and C1-4haloalkyl;
• X is selected from the group consisting of CH2, O, S, SO2, and NR4;
• R4 is selected from the group H, C1-4 alkyl and C1-4 haloalkyl;
• each R5, R6, R8′ and R8 is independently selected from the group consisting of hydrogen, halo, COOH, hydroxy, OC1-4 alkyl, C1-4 alkyl and C1-4 haloalkyl;
• R9 is COOR3, —O—C1-4 alkyl, —O—C1-4 haloalkyl, —B(OR13′)2, —PO(OR13″)2, or HET, wherein the HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C1-4 alkyl and C1-4 haloalkyl;
• R10 is selected from the group consisting of hydrogen, C1-4 alkyl, —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl, —C(O)HET and —C(O)C1-4 alkyl;
• wherein the C1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups;
• wherein the —C(O)C1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2, HET, —O—C1-4 alkyl and C6-10 aryl;
• wherein the —O—C1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2 and C6-10 aryl;
• wherein the C6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C1-4 alkyl, —O—C1-4 haloalkyl and halo groups;
• each HET is an independently selected mono- or bicyclic 5-10-membered heteroaryl or a mono- or bicyclic 5-10 membered heterocycloalkyl group, wherein each HET comprises 1, 2, 3, or 4 heteroatoms selected from O, S and N and is optionally substituted with 1 or 2 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C alkyl, —O—C1-4 haloalkyl, halo, hydroxy and oxo groups;
• R11 is selected from hydrogen, C1-4 alkyl and C1-4 haloalkyl;
• R12 is selected from the group consisting of hydrogen, C1-4 alkyl, —C(O)C6-10 aryl, —C(O)C6-10 cycloalkyl, —C(O)HET and —C(O)C1-4 alkyl;
• wherein the C1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups;
• wherein the —C(O)C1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2, HET, —O—C1-4 alkyl and C6-10 aryl;
• wherein the —O—C1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R11)2 and C6-10 aryl;
• wherein the C6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(P)C6-10 aryl, —C(O)C6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, —O—C1-4 alkyl, —OC1-4 haloalkyl and halo groups;
• and
• each of R13, R13′, and R13″, independently, is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 cycloalkyl and HET,
• wherein at least one of R1, R2, R5 and R9 optionally comprises an imaging agent.