US2023257388A1PendingUtilityA1
Granzyme b directed imaging and therapy
Est. expiryFeb 13, 2038(~11.6 yrs left)· nominal 20-yr term from priority
C07D 487/06A61K 51/0468C07D 498/06A61B 6/037A61P 37/00C07K 5/0808A61K 38/06A61P 37/02A61K 49/04
66
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Claims
Abstract
Provided herein are heterocyclic compounds useful for imaging Granzyme B. Methods of imaging Granzyme B, combination therapies, and kits comprising the Granzyme B imaging agents are also provided.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula I:
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;
R 1 and R 2 are each independently selected from the group consisting of: hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, HET and —NR 10 R 12 , wherein each C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and hydroxy, and each C 6-10 aryl and HET are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C 1-4 alkyl and C 1-4 haloalkyl;
or R 1 and R 2 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 R 10 groups;
each R 3 and R 7 is independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
X is selected from the group consisting of CH 2 , O, S, SO 2 , and NR 4 , with the proviso that, when X is CH 2 , at least one of R 1 and R 2 is —NR 10 R 12 , and at least one of R 10 and R 12 is —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl or —C(O)HET;
R 4 is selected from the group H, C 1-4 alkyl and C 1-4 haloalkyl;
each R 5 , R 6 , R 8′ and R 8 is independently selected from the group consisting of hydrogen, halo, COOH, hydroxy, OC 1-4 alkyl, C 1-4 alkyl and C 1-4 haloalkyl;
R 9 is COOR 13 , —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, —B(OR 13′ ) 2 , —PO(OR 13 ″) 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, C 1-4 alkyl and C 1-4 haloalkyl;
R 10 is selected from the group consisting of hydrogen, C 1-4 alkyl, —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl, —C(O)HET and —C(O)C 1-4 alkyl; wherein the C 1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups; wherein the —C(O)C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 , HET, —O—C 1-4 alkyl and C 6-10 aryl; wherein the —O—C 1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 and C 6-10 aryl; wherein the C 6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 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 C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, halo, hydroxy and oxo groups;
R 11 is selected from hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
R 12 is selected from the group consisting of hydrogen, C 1-4 alkyl, —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl, —C(O)HET and —C(O)C 1-4 alkyl; wherein the C 1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups; wherein the —C(O)C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 , HET, —O—C 1-4 alkyl and C 6-10 aryl; wherein the —O—C 1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 and C 6-10 aryl; wherein the —O—C 1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 and C 6-10 aryl; wherein the C 6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl and halo groups; and
each of R 13 , R 13′ , and R 13 ″, independently, is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl and HET,
wherein at least one of R 1 , R 2 , R 5 and R 9 optionally comprises an imaging agent.
2 . The compound of claim 1 , wherein X is CH 2 .
3 . The compound of claim 2 , wherein R 1 is —NR 10 R 12 .
4 . The compound of claim 2 , wherein R 2 is C 1-6 alkyl.
5 . The compound of claim 2 , wherein each of R 3 , R 6 , R 7 , R 8 , and R 8′ is H.
6 . The compound of claim 2 , wherein R 9 is HET.
7 . The compound of claim 2 , wherein R 1 is —NR 10 R 12 ; R 2 is C 1-6 alkyl; each of R 3 , R 6 , R 7 , R 8 , and R 8′ is H; and R 9 is HET.
8 . The compound of claim 7 , wherein R 1 is —NR 10 R 12 , in which R 10 is H and R 12 is —C(O)C 1-4 alkyl.
9 . The compound of claim 7 , wherein R 1 is —NR 10 R 12 , in which R 10 is H and R 12 is —C(O)C 6-10 aryl or —C(O)HET.
10 . The compound of claim 7 , wherein R 2 is butyl.
11 . The compound of claim 7 , wherein R 9 is monocyclic heteroaryl.
12 . The compound of claim 7 , wherein R 1 is —NR 10 R 12 , in which R 10 is H and R 12 is —C(O)C 1-4 alkyl, —C(O)C 6-10 aryl, or —C(O)HET; R 2 is butyl; and R 9 is monocyclic heteroaryl.
13 . The compound of claim 12 , wherein R 2 is
and R 9 is
14 . The compound of claim 2 , wherein the compound is one of the following:
15 . The compound of claim 1 , wherein X is O.
16 . The compound of claim 15 , wherein R 1 is —NR 10 R 12 ; R 2 is C 1-6 alkyl; each of R 3 , R 6 , R 7 , R 8 , and R 8′ is H; and R 9 is HET.
17 . The compound of claim 16 , wherein R 1 is —NR 10 R 12 , in which R 10 is H and R 12 is —C(O)C 1-4 alkyl, —C(O)C 6-10 aryl, or —C(O)HET; R 2 is butyl; and R 9 is monocyclic heteroaryl.
18 . The compound of claim 17 , wherein R 2 is
and R 9 is
19 . The compound of claim 15 , wherein the compound is one of the following:
20 . The compound of claim 1 , wherein X is NR 4 , in which R 4 is H or C 1-4 alkyl.
21 . The compound of claim 20 , wherein R 1 is —NR 10 R 12 ; R 2 is C 1-6 alkyl; each of R 3 , R 6 , R 7 , R 8 , and R 8′ is H; and R 9 is HET.
22 . The compound of claim 21 , wherein R 1 is —NR 10 R 12 , in which R 10 is H and R 12 is —C(O)C 1-4 alkyl, —C(O)C 6-10 aryl, or —C(O)HET; R 2 is butyl; and R 9 is monocyclic heteroaryl.
23 . The compound of claim 22 , wherein R 2 is
and R 9 is
24 . The compound of claim 20 , wherein the compound is one of the following:
25 . 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;
R 1 and R 2 are each independently selected from the group consisting of: hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, HET and —NR 10 R 12 , wherein each C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and hydroxy, and each C 6-10 aryl and HET are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C 1-4 alkyl and C 1-4 haloalkyl;
or R 1 and R 2 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 R 10 groups;
each R 3 and R 7 is independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
X is selected from the group consisting of CH 2 , O, S, SO 2 , and NR 4 , with the proviso that, when X is CH 2 , at least one of R 1 and R 2 is —NR 10 R 12 , and at least one of R 10 and R 12 is —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl or —C(O)HET;
R 4 is selected from the group H, C 1-4 alkyl and C 1-4 haloalkyl;
each R 5 , R 6 , R 8′ and R 8 is independently selected from the group consisting of hydrogen, halo, COOH, hydroxy, OC 1-4 alkyl, C 1-4 alkyl and C 1-4 haloalkyl;
R 9 is COOR 13 , —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, —B(OR 13′ ) 2 , —PO(OR 13″ ) 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, C 1-4 alkyl and C 1-4 haloalkyl;
R 10 is selected from the group consisting of hydrogen, C 1-4 alkyl, —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl, —C(O)HET and —C(O)C 1-4 alkyl; wherein the C 1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups; wherein the —C(O)C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 , HET, —O—C 1-4 alkyl and C 6-10 aryl; wherein the —O—C 1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 and C 6-10 aryl; wherein the C 6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 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 C 1 -4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, halo, hydroxy and oxo groups;
R 11 is selected from hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
R 12 is selected from the group consisting of hydrogen, C 1-4 alkyl, —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl, —C(O)HET and —C(O)C 1-4 alkyl; wherein the C 1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups; wherein the —C(O)C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 , HET, —O—C 1-4 alkyl and C 6-10 aryl; wherein the —O—C 1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 and C 6-10 aryl; wherein the C 6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl and halo groups; and
each of R 13 , R 13′ , and R 13 ″, independently, is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl and HET,
wherein at least one of R 1 , R 2 , R 5 and R 9 optionally comprises an imaging agent.
26 . 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; R 1 and R 2 are each independently selected from the group consisting of: hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, HET and —NR 10 R 12 , wherein each C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and hydroxy, and each C 6-10 aryl and HET are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C 1-4 alkyl and C 1-4 haloalkyl;
or R 1 and R 2 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 R 10 groups;
each R 3 and R 7 is independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
X is selected from the group consisting of CH 2 , O, S, SO 2 , and NR 4 ;
R 4 is selected from the group H, C 1-4 alkyl and C 1-4 haloalkyl;
each R 5 , R 6 , R 8′ and R 8 is independently selected from the group consisting of hydrogen, halo, COOH, hydroxy, OC 1-4 alkyl, C 1-4 alkyl and C 1-4 haloalkyl;
R 9 is COOR 13 , —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, —B(OR 13′ ) 2 , —PO(OR 13 ″) 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, C 1-4 alkyl and C 1-4 haloalkyl;
R 10 is selected from the group consisting of hydrogen, C 1-4 alkyl, —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl, —C(O)HET and —C(O)C 1-4 alkyl; wherein the C 1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups; wherein the —C(O)C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 , HET, —O—C 1-4 alkyl and C 6-10 aryl; wherein the —O—C 1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 and C 6-10 aryl; wherein the C 6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 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 C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, halo, hydroxy and oxo groups;
R 11 is selected from hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
R 12 is selected from the group consisting of hydrogen, C 1-4 alkyl, —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl, —C(O)HET and —C(O)C 1-4 alkyl; wherein the C 1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups; wherein the —C(O)C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 , HET, —O—C 1-4 alkyl and C 6-10 aryl; wherein the —O—C 1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 and C 6-10 aryl; wherein the C 6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl and halo groups; and
each of R 13 , R 13′ , and R 13 ″, independently, is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl and HET,
wherein at least one of R 1 , R 2 , R 5 and R 9 optionally comprises an imaging agent.
27 . 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;
R 1 and R 2 are each independently selected from the group consisting of: hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, HET and —NR 10 R 12 , wherein each C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and hydroxy, and each C 6-10 aryl and HET are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C 1-4 alkyl and C 1-4 haloalkyl;
or R 1 and R 2 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 R 10 groups;
each R 3 and R 7 is independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
X is selected from the group consisting of CH 2 , O, S, SO 2 , and NR 4 ;
R 4 is selected from the group H, C 1-4 alkyl and C 1-4 haloalkyl;
each R 5 , R 6 , R 8′ and R 8 is independently selected from the group consisting of hydrogen, halo, COOH, hydroxy, OC 1-4 alkyl, C 1-4 alkyl and C 1-4 haloalkyl;
R 9 is COOR 13 , —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, —B(OR 13′ ) 2 , —PO(OR 13 ″) 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, C 1-4 alkyl and C 1-4 haloalkyl;
R 10 is selected from the group consisting of hydrogen, C 1-4 alkyl, —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl, —C(O)HET and —C(O)C 1-4 alkyl; wherein the C 1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups; wherein the —C(O)C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 , HET, —O—C 1-4 alkyl and C 6-10 aryl; wherein the —O—C 1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 and C 6-10 aryl; wherein the C 6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 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 C 1 -4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, halo, hydroxy and oxo groups;
R 11 is selected from hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
R 12 is selected from the group consisting of hydrogen, C 1-4 alkyl, —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl, —C(O)HET and —C(O)C 1-4 alkyl; wherein the C 1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups; wherein the —C(O)C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 , HET, —O—C 1-4 alkyl and C 6-10 aryl; wherein the —O—C 1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 and C 6-10 aryl; wherein the C 6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl and halo groups; and
each of R 13 , R 13′ , and R 13 ″, independently, is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl and HET,
wherein at least one of R 1 , R 2 , R 5 and R 9 optionally comprises an imaging agent.
28 . 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;
R 1 and R 2 are each independently selected from the group consisting of: hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, HET and —NR 10 R 12 , wherein each C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and hydroxy, and each C 6-10 aryl and HET are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C 1-4 alkyl and C 1-4 haloalkyl;
or R 1 and R 2 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 R 10 groups;
each R 3 and R 7 is independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
X is selected from the group consisting of CH 2 , O, S, SO 2 , and NR 4 ;
R 4 is selected from the group H, C 1-4 alkyl and C 1-4 haloalkyl;
each R 5 , R 6 , R 8′ and R 8 is independently selected from the group consisting of hydrogen, halo, COOH, hydroxy, OC 1-4 alkyl, C 1-4 alkyl and C 1-4 haloalkyl;
R 9 is COOR 13 , —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, —B(OR 13′ ) 2 , —PO(OR 13 ″) 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, C 1-4 alkyl and C 1-4 haloalkyl;
R 10 is selected from the group consisting of hydrogen, C 1-4 alkyl, —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl, —C(O)HET and —C(O)C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups; wherein the —C(O)C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 , HET, —O—C 1-4 alkyl and C 6-10 aryl; wherein the —O—C 1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 and C 6-10 aryl; wherein the C 6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 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 C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, halo, hydroxy and oxo groups;
R 11 is selected from hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
R 12 is selected from the group consisting of hydrogen, C 1-4 alkyl, —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl, —C(O)HET and —C(O)C 1-4 alkyl; wherein the C 1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups; wherein the —C(O)C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 , HET, —O—C 1-4 alkyl and C 6-10 aryl; wherein the —O—C 1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 and C 6-10 aryl; wherein the C 6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl and halo groups; and
each of R 13 , R 13′ , and R 13 ″, independently, is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl and HET,
wherein at least one of R 1 , R 2 , R 5 and R 9 optionally comprises an imaging agent.
29 . 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;
R 1 and R 2 are each independently selected from the group consisting of: hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, HET and —NR 10 R 12 , wherein each C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and hydroxy, and each C 6-10 aryl and HET are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C 1-4 alkyl and C 1-4 haloalkyl;
or R 1 and R 2 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 R 1 ″ groups;
each R 3 and R 7 is independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
X is selected from the group consisting of CH 2 , O, S, SO 2 , and NR 4 ;
R 4 is selected from the group H, C 1-4 alkyl and C 1-4 haloalkyl;
each R 5 , R 6 , R 8′ and R 8 is independently selected from the group consisting of hydrogen, halo, COOH, hydroxy, OC 1-4 alkyl, C 1-4 alkyl and C 1-4 haloalkyl;
R 9 is COOR 13 , —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, —B(OR 13′ ) 2 , —PO(OR 13″ ) 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, C 1-4 alkyl and C 1-4 haloalkyl;
R 10 is selected from the group consisting of hydrogen, C 1-4 alkyl, —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl, —C(O)HET and —C(O)C 1-4 alkyl; wherein the C 1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups; wherein the —C(O)C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 , HET, —O—C 1-4 alkyl and C 6-10 aryl; wherein the —O—C 1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 and C 6-10 aryl; wherein the C 6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 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 C 1 -4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, halo, hydroxy and oxo groups;
R 11 is selected from hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
R 12 is selected from the group consisting of hydrogen, C 1-4 alkyl, —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl, —C(O)HET and —C(O)C 1-4 alkyl; wherein the C 1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups; wherein the —C(O)C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 , HET, —O—C 1-4 alkyl and C 6-10 aryl; wherein the —O—C 1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 and C 6-10 aryl; wherein the C 6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl and halo groups; and
each of R 13 , R 13′ , and R 13″ , independently, is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl and HET,
wherein at least one of R 1 , R 2 , R 5 and R 9 optionally comprises an imaging agent.
30 . 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;
R 1 and R 2 are each independently selected from the group consisting of: hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, HET and —NR 10 R 12 , wherein each C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and hydroxy, and each C 6-10 aryl and HET are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C 1-4 alkyl and C 1-4 haloalkyl;
or R 1 and R 2 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 R 10 groups;
each R 3 and R 7 is independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
X is selected from the group consisting of CH 2 , O, S, SO 2 , and NR 4 ;
R 4 is selected from the group H, C 1-4 alkyl and C 1-4 haloalkyl;
each R 5 , R 6 , R 8′ and R 8 is independently selected from the group consisting of hydrogen, halo, COOH, hydroxy, OC 1-4 alkyl, C 1-4 alkyl and C 1-4 haloalkyl;
R 9 is COOR 13 , —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, —B(OR 13′ ) 2 , —PO(OR 13 ″) 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, C 1-4 alkyl and C 1-4 haloalkyl;
R 10 is selected from the group consisting of hydrogen, C 1-4 alkyl, —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl, —C(O)HET and —C(O)C 1-4 alkyl; wherein the C 1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups; wherein the —C(O)C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 , HET, —O—C 1-4 alkyl and C 6-10 aryl; wherein the —O—C 1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 and C 6-10 aryl; wherein the C 6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 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 C 1 -4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, halo, hydroxy and oxo groups;
R 11 is selected from hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
R 12 is selected from the group consisting of hydrogen, C 1-4 alkyl, —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl, —C(O)HET and —C(O)C 1-4 alkyl; wherein the C 1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups; wherein the —C(O)C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 , HET, —O—C 1-4 alkyl and C 6-10 aryl; wherein the —O—C 1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 and C 6-10 aryl; wherein the C 6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl and halo groups; and
each of R 13 , R 13′ , and R 13 ″, independently, is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl and HET,
wherein at least one of R 1 , R 2 , R 5 and R 9 optionally comprises an imaging agent.
31 . 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;
R 1 and R 2 are each independently selected from the group consisting of: hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, HET and —NR 10 R 12 , wherein each C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo and hydroxy, and each C 6-10 aryl and HET are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of oxo, halo, hydroxy, C 1-4 alkyl and C 1-4 haloalkyl;
or R 1 and R 2 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 R 10 groups;
each R 3 and R 7 is independently selected from the group consisting of hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
X is selected from the group consisting of CH 2 , O, S, SO 2 , and NR 4 ;
R 4 is selected from the group H, C 1-4 alkyl and C 1-4 haloalkyl;
each R 5 , R 6 , R 8′ and R 8 is independently selected from the group consisting of hydrogen, halo, COOH, hydroxy, OC 1-4 alkyl, C 1-4 alkyl and C 1-4 haloalkyl;
R 9 is COOR 13 , —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, —B(OR 13′ ) 2 , —PO(OR 13″ ) 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, C 1-4 alkyl and C 1-4 haloalkyl;
R 10 is selected from the group consisting of hydrogen, C 1-4 alkyl, —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl, —C(O)HET and —C(O)C 1-4 alkyl; wherein the C 1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups; wherein the —C(O)C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 , HET, —O—C 1-4 alkyl and C 6-10 aryl; wherein the —O—C 1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 and C 6-10 aryl; wherein the C 6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 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 C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —O—C 1-4 haloalkyl, halo, hydroxy and oxo groups;
R 11 is selected from hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
R 12 is selected from the group consisting of hydrogen, C 1-4 alkyl, —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl, —C(O)HET and —C(O)C 1-4 alkyl; wherein the C 1-4 alkyl is optionally substituted with 1, 2, or 3 halo groups; wherein the —C(O)C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 , HET, —O—C 1-4 alkyl and C 6-10 aryl; wherein the —O—C 1-4 alkyl may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, oxo, —N(R 11 ) 2 and C 6-10 aryl; wherein the C 6-10 aryl may be optionally substituted with 1, 2, or 3 halo groups and wherein the —C(O)C 6-10 aryl, —C(O)C 6-10 cycloalkyl and —C(O)HET may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, —O—C 1-4 alkyl, —OC 1-4 haloalkyl and halo groups; and
each of R 13 , R 13′ , and R 13″ , independently, is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl and HET,
wherein at least one of R 1 , R 2 , R 5 and R 9 optionally comprises an imaging agent.
32 . The compound according to claims 1 - 31 , wherein at least one of R 1 , R 2 , R 5 and R 9 comprises an imaging agent.
33 . The compound according to claim 32 , wherein the said imaging agent is selected from a group consisting of a PET imaging agent, a SPECT imaging agent, and a computed tomography imaging agent.
34 . The compound according to claim 32 , wherein the said imaging agent is selected from a group consisting of a paramagnetic ion, an x-ray imaging agent, a fluorophore and a radioisotope.
35 . The compound according to claims 1 - 31 , wherein at least one of R 1 , R 2 , R 5 and R 9 contains a radioisotope.
36 . The compound according to claim 35 , wherein the said radioisotope is 18 F.
37 . The compound according to claims 1 - 31 , wherein at least one of R 1 , R 2 , R 5 and R 9 contains a PET imaging agent.
38 . The compound according to claim 37 , wherein the said PET imaging agent comprises 18 F.
39 . A pharmaceutical composition comprising a compound according to claims 1 - 38 and a pharmaceutically acceptable carrier.
40 . A method of treating an immunoregulatory abnormality in a subject in need thereof, the method comprising administering to said patient a compound according to claims 1 - 38 in an amount effective for treating said immunoregulatory abnormality.Join the waitlist — get patent alerts
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