US2022048936A1PendingUtilityA1
Novel sting agonists
Est. expiryOct 29, 2038(~12.3 yrs left)· nominal 20-yr term from priority
Inventors:David DillerAxel MetzgerDavid E. KaelinSteven PagetChia-Yu HuangBrian F. McguinnessAudrey HospitalWilliam Ronald Solvibile
A61P 31/22C07F 9/6587A61P 35/00A61K 45/06C07F 9/65746
61
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Claims
Abstract
The present invention provides compounds of Formula I′: wherein W, X, Y, Z, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug ester or solvate form thereof, wherein all of the variables are as defined herein. These compounds are effective at modulating the STING protein and thus can be used as medicaments for treating or preventing disorders affected by the agonism of STING.
Claims
exact text as granted — not AI-modified1 .- 17 . (canceled)
18 . A method of treating a disorder, disease, syndrome, or condition, wherein said disorder, disease, syndrome, or condition is affected by the agonism of STING, comprising administering to a subject in need thereof a therapeutically effective amount of the compound, or pharmaceutically acceptable salt of a compound of Formula I′ having the structure:
or a pharmaceutically acceptable salt thereof, wherein:
W is absent or independently selected from O, S or —NR 6 ;
X is CH 2 , O or S;
Y is absent or independently selected from O, S or —NR 7 ;
Q 1 and Q 2 are each independently O or S;
is a 5- to 6-membered monocyclic heteroaryl or a 7- to 12-membered bicyclic heteroaryl; both of which are optionally substituted with R 10 and R 11 and wherein the 7- to 12-membered bicyclic heteroaryl contains at least two N atoms;
Z is independently selected from C 1 -C 6 alkyl, halo-C 1 -C 6 -alkyl and C 3 -C 6 cycloalkyl;
Z 1 is independently selected from C 1 -C 6 alkyl, halo-C 1 -C 6 -alkyl and C 3 -C 6 cycloalkyl;
Z 2 is independently selected from C 1 -C 4 alkyl and halo-C 1 -C 4 -alkyl;
R 1 is a 5- to 6-membered monocyclic heteroaryl or a 7- to 10-membered bicyclic heteroaryl;
both of which are optionally substituted with R 12 and R 13 and wherein the 7- to 10-membered bicyclic heteroaryl contains at least two N atoms;
R 2 is independently selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, —NR 8 R 9 , C 3 -C 4 cycloalkyl and OH;
R 3 is independently selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, and OH;
or R 2 and R 3 can be taken together with the carbon to which they are attached to form a C 3 -C 4 cycloalkyl ring;
R 4 is selected from OH, SH, C 1 -C 6 alkoxy-carbonyl-oxy-C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-carbonyl-oxy-C 1 -C 6 alkylthio, and BH 3 ;
R 5 is selected from OH, SH, C 1 -C 6 alkoxy-carbonyl-oxy-C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-carbonyl-oxy-C 1 -C 6 alkylthio, and BH 3 ;
R 6 is independently selected from H, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 3 -C 6 cycloalkyl and C 1 -C 4 alkoxy;
R 7 is independently selected from H, C 1 -C 4 alkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, C 3 -C 6 cycloalkyl and C 1 -C 4 alkoxy;
R 8 is independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 -alkyl, —C(═O)R 15 and —SO 2 R 15 ;
R 9 is independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and halo-C 1 -C 4 -alkyl;
R 10 is independently selected from H, ═O, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, —NR 14 R 15 , —NR 14 C(═O)R 15 , —C(═O)NR 14 R 15 , a C 6 -C 10 aryl, a 5- to 10-membered heteroaryl, a 4- to 6-membered heterocycloalkyl, a C 3 -C 6 cycloalkyl, SR 18 and OH; wherein the C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, C 6 -C 10 aryl, the 5- to 10-membered heteroaryl and the C 3 -C 6 cycloalkyl are each optionally substituted with OH, 1 to 3 halo, CN, —NR 14 R 15 , —C(═O)NR 14 R 15 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl and halo-C 1 -C 4 alkoxy;
R 11 is independently selected from H, ═O, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, —NR 14 R 15 , —NR 14 C(═O)R 15 , —C(═O)NR 14 R 15 , a C 6 -C 10 aryl, a 5- to 10-membered heteroaryl, a 4- to 6-membered heterocycloalkyl, a C 3 -C 6 cycloalkyl, SR 18 and OH; wherein the C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, C 6 -C 10 aryl, the 5- to 10-membered heteroaryl and the C 3 -C 6 cycloalkyl are optionally substituted with OH, 1 to 3 halo, CN, —NR 14 R 15 , —C(═O)NR 14 R 15 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl and halo-C 1 -C 4 alkoxy;
R 12 is independently selected from H, ═O, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, —NR 16 R 17 , —NR 16 C(═O)R 17 , a C 6 -C 10 aryl, a 5- to 10-membered heteroaryl and OH;
R 13 is independently selected from H, ═O, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, —NR 16 R 17 , —NR 16 C(═O)R 17 , a C 6 -C 10 aryl, a 5- to 10-membered heteroaryl and OH;
R 14 , at each occurrence, is independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 -alkyl, —C(═O)R 18 and —SO 2 R 15 ;
R 15 , at each occurrence, is independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 -alkyl, a C 6 -C 10 aryl and a 5- to 10-membered heteroaryl;
R 16 , at each occurrence, is independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 -alkyl, —C(═O)R 17 and —SO 2 R 17 ;
R 17 , at each occurrence, is independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 -alkyl, a C 6 -C 10 aryl, and a 5- to 10-membered heteroaryl; and
R 18 is selected from H and C 1 -C 4 alkyl.
19 . (canceled)
20 . (canceled)
21 . The method of claim 18 , wherein said disorder, disease, syndrome, or condition is a viral infection.
22 . (canceled)
23 . (canceled)
24 . The method according to claim 18 additionally comprising combination with radiation therapy.
25 . The method of claim 18 wherein said disorder, disease, syndrome, or condition is colon adenocarcinoma or colorectal carcinoma.
26 . The method of claim 21 , wherein the viral infection is Herpes simplex virus 1.
27 . The method of claim 18 wherein, in said compound of Formula I′:
W is O;
X is O;
Y is O;
Q 1 and Q 2 are each independently O or S;
is a 5- to 6-membered monocyclic heteroaryl or a 7- to 12-membered bicyclic heteroaryl; both of which are optionally substituted with R 10 and R 11 and wherein the 7- to 12-membered bicyclic heteroaryl contains at least two N atoms;
Z is independently selected from C 1 -C 6 alkyl, halo-C 1 -C 6 -alkyl and C 3 -C 6 cycloalkyl;
Z 1 is independently selected from —CH 2 — and —CH(CH 3 )—;
Z 2 is —CH 2 —;
R 1 is a purine or azapurine ring, optionally substituted with R 12 and R 13 ;
R 2 is independently selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, —NR 8 R 9 , C 3 -C 4 cycloalkyl and OH;
R 3 is independently selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, and OH;
or R 2 and R 3 can be taken together with the carbon to which they are attached to form a C 3 -C 4 cycloalkyl ring;
R 4 is selected from OH, SH, C 1 -C 6 alkoxy-carbonyl-oxy-C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-carbonyl-oxy-C 1 -C 6 alkylthio, and BH 3 ;
R 5 is selected from OH, SH, C 1 -C 6 alkoxy-carbonyl-oxy-C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-carbonyl-oxy-C 1 -C 6 alkylthio, and BH 3 ;
R 8 is independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 -alkyl, —C(═O)R 18 and —SO 2 R 15 ;
R 9 is independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and halo-C 1 -C 4 -alkyl;
R 10 is independently selected from H, ═O, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, —NR 14 R 15 , —NR 14 C(═O)R 15 , —C(═O)NR 14 R 15 , a C 6 -C 10 aryl, a 5- to 10-membered heteroaryl, a 4- to 6-membered heterocycloalkyl, a C 3 -C 6 cycloalkyl, SR 18 and OH; wherein the C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, C 6 -C 10 aryl, the 5- to 10-membered heteroaryl and the C 3 -C 6 cycloalkyl are each optionally substituted with OH, 1 to 3 halo, CN, —NR 14 R 15 , —C(═O)NR 14 R 15 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl and halo-C 1 -C 4 alkoxy;
R 11 is independently selected from H, ═O, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, —NR 14 R 15 , —NR 14 C(═O)R 15 , —C(═O)NR 14 R 15 , a C 6 -C 10 aryl, a 5- to 10-membered heteroaryl, a 4- to 6-membered heterocycloalkyl, a C 3 -C 6 cycloalkyl, SR 18 and OH; wherein the C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, C 6 -C 10 aryl, the 5- to 10-membered heteroaryl and the C 3 -C 6 cycloalkyl are optionally substituted with OH, 1 to 3 halo, CN, —NR 14 R 15 , —C(═O)NR 14 R 15 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl and halo-C 1 -C 4 alkoxy;
R 12 is independently selected from H, ═O, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, —NR 16 R 17 , —NR 16 C(═O)R 17 , a C 6 -C 10 aryl, a 5- to 10-membered heteroaryl and OH;
R 13 is independently selected from H, ═O, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, —NR 16 R 17 , —NR 16 C(═O)R 17 , a C 6 -C 10 aryl, a 5- to 10-membered heteroaryl and OH;
R 14 , at each occurrence, is independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 -alkyl, —C(═O)R 15 and —SO 2 R 15 ;
R 15 , at each occurrence, is independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 -alkyl, a C 6 -C 10 aryl and a 5- to 10-membered heteroaryl;
R 16 , at each occurrence, is independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 -alkyl, —C(═O)R 17 and —SO 2 R 17 ;
R 17 , at each occurrence, is independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 -alkyl, a C 6 -C 10 aryl, and a 5- to 10-membered heteroaryl; and
R 18 is selected from H and C 1 -C 4 alkyl.
28 . The method of claim 27 wherein said compound of formula I′ has the structure:
wherein:
V is CH or N;
Q 1 and Q 2 are each independently O or S;
is a 5- to 6-membered monocyclic heteroaryl or a 7- to 12-membered bicyclic heteroaryl; both of which are optionally substituted with R 10 and R 11 and wherein the 7- to 12-membered bicyclic heteroaryl contains at least two N atoms;
Z is selected from C 1 -C 6 alkyl, halo-C 1 -C 6 -alkyl and C 3 -C 6 cycloalkyl;
R 2 is selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, —NR 8 R 9 , C 3 -C 4 cycloalkyl and OH;
R 3 is selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, and OH;
or R 2 and R 3 can be taken together with the carbon to which they are attached to form a C 3 -C 4 cycloalkyl ring;
R 4 is selected from OH, SH, C 1 -C 6 alkoxy-carbonyloxy-C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-carbonyloxy-C 1 -C 6 alkylthio, and BH 3 ;
R 5 is selected from OH, SH, C 1 -C 6 alkoxy-carbonyloxy-C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-carbonyloxy-C 1 -C 6 alkylthio, and BH 3 ;
R 8 is selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 -alkyl, —C(═O)R 15 and —SO 2 R 15 ;
R 9 is selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and halo-C 1 -C 4 -alkyl;
R 10 is selected from H, ═O, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, —NR 14 R 15 , —NR 14 C(═O)R 15 , —C(═O)NR 14 R 15 , a C 6 -C 10 aryl, a 5- to 10-membered heteroaryl, a 4- to 6-membered heterocycloalkyl, a C 3 -C 6 cycloalkyl, SR 18 and OH; wherein the C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, C 6 -C 10 aryl, the 5- to 10-membered heteroaryl and the C 3 -C 6 cycloalkyl are each optionally substituted with OH, 1 to 3 halo, CN, —NR 14 R 15 , —C(═O)NR 14 R 15 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl and halo-C 1 -C 4 alkoxy;
R 11 is selected from H, ═O, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, —NR 14 R 15 , —NR 14 C(═O)R 15 , —C(═O)NR 14 R 15 , a C 6 -C 10 aryl, a 5- to 10-membered heteroaryl, a 4- to 6-membered heterocycloalkyl, a C 3 -C 6 cycloalkyl, SR 18 and OH; wherein the C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, C 6 -C 10 aryl, the 5- to 10-membered heteroaryl and the C 3 -C 6 cycloalkyl are optionally substituted with OH, 1 to 3 halo, CN, —NR 14 R 15 , —C(═O)NR 14 R 15 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl and halo-C 1 -C 4 alkoxy;
R 12 is selected from H and NH 2 ;
R 14 , at each occurrence, is independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 -alkyl, —C(═O)R 18 and —SO 2 R 15 ;
R 15 , at each occurrence, is independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 -alkyl, a C 6 -C 10 aryl and a 5- to 10-membered heteroaryl; and
R 18 is selected from H and C 1 -C 4 alkyl.
29 . The method of claim 27 wherein said compound of formula I′ has the structure:
wherein:
Q 1 and Q 2 are each independently O or S;
is selected from
all of which are optionally substituted with R 10 and R 11 ;
Z is selected from C 1 -C 6 alkyl, halo-C 1 -C 6 -alkyl and C 3 -C 6 cycloalkyl;
R 2 is selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, —NR 8 R 9 , C 3 -C 4 cycloalkyl and OH;
R 3 is selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, and OH;
or R 2 and R 3 can be taken together with the carbon to which they are attached to form a C 3 -C 4 cycloalkyl ring;
R 4 is selected from OH, SH, C 1 -C 6 alkoxy-carbonyloxy-C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-carbonyloxy-C 1 -C 6 alkylthio, and BH 3 ;
R 5 is selected from OH, SH, C 1 -C 6 alkoxy-carbonyloxy-C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-carbonyloxy-C 1 -C 6 alkylthio, and BH 3 ;
R 8 is selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 -alkyl, —C(═O)R 15 and —SO 2 R 15 ;
R 9 is selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and halo-C 1 -C 4 -alkyl;
R 10 is selected from H, ═O, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, —NR 14 R 15 , —NR 14 C(═O)R 15 , —C(═O)NR 14 R 15 , a C 6 -C 10 aryl, a 5- to 10-membered heteroaryl, a 4- to 6-membered heterocycloalkyl, a C 3 -C 6 cycloalkyl, SR 18 and OH; wherein the C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, C 6 -C 10 aryl, the 5- to 10-membered heteroaryl and the C 3 -C 6 cycloalkyl are each optionally substituted with OH, 1 to 3 halo, CN, —NR 14 R 15 , —C(═O)NR 14 R 15 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl and halo-C 1 -C 4 alkoxy;
R 11 is selected from H, ═O, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, CN, —NR 14 R 15 , —NR 14 C(═O)R 15 , —C(═O)NR 14 R 15 , a C 6 -C 10 aryl, a 5- to 10-membered heteroaryl, a 4- to 6-membered heterocycloalkyl, a C 3 -C 6 cycloalkyl, SR 18 and OH; wherein the C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl, halo-C 1 -C 4 alkoxy, C 6 -C 10 aryl, the 5- to 10-membered heteroaryl and the C 3 -C 6 cycloalkyl are optionally substituted with OH, 1 to 3 halo, CN, —NR 14 R 15 , —C(═O)NR 14 R 15 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 alkyl and halo-C 1 -C 4 alkoxy;
R 12 is selected from H and NH 2 ;
R 14 , at each occurrence, is independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 -alkyl, —C(═O)R 15 and —SO 2 R 15 ;
R 15 , at each occurrence, is independently selected from H, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo-C 1 -C 4 -alkyl, a C 6 -C 10 aryl and a 5- to 10-membered heteroaryl; and
R 18 is selected from H and C 1 -C 4 alkyl.
30 . The method of claim 18 wherein said compound of formula I′, or pharmaceutically acceptable salt thereof, is selected from any one of the following compounds:
31 . The method of claim 18 wherein said compound of formula I′ isCited by (0)
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