COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH STING ACTIVITY
20230365553 · 2023-11-16
Inventors
- Shankar Venkatraman (Lansdale, PA)
- Jason Katz (Newton, MA)
- William R. Roush (Boston, MA, US)
- Hans Martin Seidel (Concord, MA)
Cpc classification
C07D209/40
CHEMISTRY; METALLURGY
C07D409/04
CHEMISTRY; METALLURGY
C07D403/04
CHEMISTRY; METALLURGY
C07D403/10
CHEMISTRY; METALLURGY
C07D401/04
CHEMISTRY; METALLURGY
International classification
C07D403/04
CHEMISTRY; METALLURGY
C07D403/10
CHEMISTRY; METALLURGY
C07D209/40
CHEMISTRY; METALLURGY
Abstract
This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.
Claims
1. A compound of Formula (I): ##STR00448## or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein: Y.sup.1, Y.sup.2, and Y.sup.3 are independently selected from the group consisting of CR.sup.1, C(═O), N, and NR.sup.2; X.sup.1 is selected from the group consisting of O, S, N, NR.sup.2, and CR.sup.1; X.sup.2 is selected from the group consisting of O, S, N, NR.sup.4, and CR.sup.5; each is independently a single bond or a double bond, provided that the five-membered ring comprising X.sup.1 and X.sup.2 is heteroaryl, and that the six-membered ring comprising Y.sup.1, Y.sup.2, and Y.sup.3 is aryl or heteroaryl; each occurrence of R.sup.1 and R.sup.5 is independently selected from the group consisting of: H; R.sup.c; R.sup.h; and -(L.sup.1).sub.b1-R.sup.h; each occurrence of R.sup.2 and R.sup.4 is independently selected from the group consisting of: H; R.sup.d; R.sup.g; and -(L.sup.2).sub.b2-R.sup.g; R.sup.6 is selected from the group consisting of: H; R.sup.d; and R.sup.h; Q.sup.1 is selected from the group consisting of: C.sub.3-12 cycloalkylene or C.sub.3-12 cycloalkenylene, each optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c and R.sup.h; heterocyclylene or heterocycloalkenylene of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h; heteroarylene of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of R.sup.c and R.sup.h; and C.sub.6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of R.sup.c and R.sup.h; each L.sup.A is independently selected from the group consisting of: C.sub.1-3 alkylene optionally substituted with 1-2 R.sup.a1; —O—; —NH—; —NR.sup.d; —S(O).sub.0-2; and C(O); a1 is 0, 1, 2, 3, or 4; Q.sup.2 is selected from the group consisting of: H; R.sup.g; and R.sup.c; W is selected from the group consisting of: H; C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkynyl, each of which is optionally substituted with 1-6 R.sup.a2; monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and monocyclic heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c, provided that when W is heterocyclyl or heterocycloalkenyl, it is attached to the C(═O)NR.sup.6 group via a ring carbon atom; each occurrence of R.sup.a, R.sup.a1, and R.sup.a2 is independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); and cyano; each occurrence of R.sup.c is independently selected from the group consisting of: halo; cyano; C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —S(O).sub.1-2(C.sub.1-4 alkyl); —S(O)(═NH)(C.sub.1-4 alkyl); —NR.sup.eR.sup.f; —OH; —S(O).sub.1-2NR′R″; —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-10 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF.sub.5; each occurrence of R.sup.d is independently selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy; each occurrence of R.sup.e and R.sup.f is independently selected from the group consisting of: H; C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, and R.sup.i; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy; each occurrence of R.sup.g is independently selected from the group consisting of: C.sub.3-12 cycloalkyl or C.sub.3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h; heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h; heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R.sup.c, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h; and C.sub.6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R.sup.c, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h; each occurrence of R.sup.h is independently selected from the group consisting of: C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 R.sup.i; heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R.sup.i; heteroaryl of 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 R.sup.i; and C.sub.6 aryl optionally substituted with 1-4 R.sup.i; each occurrence of R.sup.i is independently selected from the group consisting of: C.sub.1-6 alkyl; C.sub.1-4 haloalkyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; and halo; each occurrence of L.sup.1, L.sup.2, and L.sup.g is selected from the group consisting of: —O—, —NH—, —NR.sup.d, —S(O).sub.0-2, C(O), and C.sub.1-3 alkylene optionally substituted with 1-3 R.sup.a; b1, b2, and bg are each independently 1, 2, or 3; and each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C.sub.1-4 alkyl; provided that when Y.sup.1 and Y.sup.2 are CH; Y.sup.3 is N; W is unsubstituted n-propyl; and Q.sup.1 is unsubstituted phenylene, then: -(L.sup.A).sub.a1-Q.sup.2 is other than —CH.sub.2-morpholinyl, —CH.sub.2—N-methylpiperazinyl, morpholinyl, or N-methylpiperazinyl.
2. The compound of claim 1, wherein Q.sup.3 is heteroarylene of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of R.sup.c and R.sup.h; such as: wherein Q.sup.1 is heteroarylene of 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S, and wherein the heteroarylene is optionally substituted with 1-3 R.sup.c; such as: wherein Q.sup.1 is heteroarylene of 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S, and wherein the heteroarylene is optionally substituted with 1-2 R.sup.c; such as: wherein Q.sup.1 is pyrazolylene which is optionally substituted with 1-2 R.sup.c; such as: wherein Q.sup.1 is ##STR00449## which is optionally substituted with 1-2 R.sup.c (such as unsubstituted), wherein aa represents point of attachment to -(L.sup.A).sub.a1-Q.sup.2.
3. The compound of claim 1, wherein a1 is 0; or wherein a1 is 1, and L.sup.A is C.sub.1-3 alkylene optionally substituted with 1-2 R.sup.a1.
4. The compound of claim 1, wherein Q.sup.2 is R.sup.g.
5. The compound of claim 1, wherein Q.sup.2 is selected from the group consisting of: heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R.sup.c, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h; and C.sub.6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R.sup.c, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h.
6. The compound of claim 1, wherein 1, 2, or 3 of Y.sup.1, Y.sup.2, and Y.sup.3 is an independently selected CR.sup.1, and wherein each R.sup.1 is independently H or R.sup.c.
7. The compound of claim 1, wherein X.sup.1 is NR.sup.2; and X.sup.2 is CR.sup.5, optionally wherein X.sup.1 is NH; and X.sup.2 is CH.
8. The compound of claim 1, wherein W is C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkenyl, each of which is optionally substituted with 1-6 R.sup.a2; such as: wherein W is C.sub.1-10 alkyl, which is optionally substituted with 1-6 R.sup.a2; such as: wherein W is C.sub.1-6, such as C.sub.1, C.sub.2, C.sub.3, or C.sub.4, alkyl, which is optionally substituted with 1-6 R.sup.a2; such as: wherein W is selected from the group consisting of: methyl, ethyl, propyl, isopropyl, and isobutyl, each of which is optionally substituted with 1-3 R.sup.a2.
9. The compound of claim 1, wherein W is selected from the group consisting of: monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and monocyclic heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.
10. The compound of claim 1, wherein W is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; or wherein W is azetidinyl, oxetanyl, pyrrolidinyl, or tetrahydrofuranyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and the ring nitrogen atom when present is optionally substituted with R.sup.d.
11. The compound of claim 1, wherein the compound is a compound of Formula (Ia): ##STR00450## or a pharmaceutically acceptable salt thereof or a tautomer thereof.
12. The compound of claim 11, wherein Y.sup.1, Y.sup.2, and Y.sup.3 are each an independently selected CR.sup.1; and optionally R.sup.2 is H; and optionally R.sup.5 is H, such as: wherein Y.sup.1, Y.sup.2, and Y.sup.3 are each an independently selected CR.sup.1; R.sup.2 is H; and R.sup.5 is H.
13. The compound of claim 11, wherein Q.sup.2 is selected from the group consisting of: heteroaryl of 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 R.sup.c; and C.sub.6-10 aryl optionally substituted with 1-4 R.sup.c.
14. The compound of claim 11, wherein W is C.sub.1-6 (such as C.sub.1, C.sub.2, C.sub.3, or C.sub.4) alkyl, which is optionally substituted with 1-6 R.sup.a2; such as: wherein W is unsubstituted C.sub.1-6 alkyl, such as methyl, ethyl, propyl, isopropyl, or isobutyl, such as methyl or ethyl, such as ethyl.
15. The compound of claim 11, wherein W is monocyclic C.sub.3-8 cycloalkyl (e.g., C.sub.3-6 cycloalkyl) optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c, such as wherein W is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c, such as unsubstituted cyclobutyl, cyclopentyl, or cyclohexyl.
16. The compound of claim 1, wherein the compound is selected from the group consisting of the compounds delineated in Table C1 or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
18. A method for inhibiting STING activity, the method comprising contacting STING with a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof.
19. A method of inducing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof.
20. A method of treatment of disease, disorder, or condition associated with STING, such as a disease, disorder, or condition, in which increased STING signaling, such as excessive STING signaling, contributes to the pathology and/or symptoms and/or progression of the disease, such as cancer, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof.
Description
DETAILED DESCRIPTION
[0074] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.
[0075] Formula I Compounds
[0076] In one aspect, the disclosure features a compound of Formula (I):
##STR00007## [0077] or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein: [0078] Y.sup.1, Y.sup.2, and Y.sup.3 are independently selected from the group consisting of CR.sup.1, C(═O), N, and NR.sup.2; [0079] X.sup.1 is selected from the group consisting of O, S, N, NR.sup.2, and CR.sup.1; [0080] X.sup.2 is selected from the group consisting of O, S, N, NR.sup.4, and CR.sup.5; [0081] each is independently a single bond or a double bond, provided that the five-membered ring comprising X.sup.1 and X.sup.2 is heteroaryl, and that the six-membered ring comprising Y.sup.1, Y.sup.2, and Y.sup.3 is aryl or heteroaryl; [0082] each occurrence of R.sup.1 and R.sup.5 is independently selected from the group consisting of: H; R.sup.c; R.sup.h; and -(L.sup.1).sub.b1-R.sup.h; [0083] each occurrence of R.sup.2 and R.sup.4 is independently selected from the group consisting of: H; R.sup.d; R.sup.g; and -(L.sup.2).sub.b2-R.sup.g; [0084] R.sup.6 is selected from the group consisting of: H; R.sup.d; and R.sup.h; [0085] Q.sup.1 is selected from the group consisting of: [0086] C.sub.3-12 cycloalkylene or C.sub.3-12 cycloalkenylene, each optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h, [0087] heterocyclylene or heterocycloalkenylene of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h, [0088] heteroarylene of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of R.sup.c and R.sup.h; and [0089] C.sub.6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of R.sup.c and R.sup.h; [0090] each L.sup.A is independently selected from the group consisting of: C.sub.1-3 alkylene optionally substituted with 1-2 R.sup.a1; —O—; —NH—; —NR.sup.d; —S(O).sub.0-2; and C(O); [0091] a1 is 0, 1, 2, 3, or 4; [0092] Q.sup.2 is selected from the group consisting of: H; R.sup.g; and R.sup.c; [0093] W is selected from the group consisting of: [0094] H; [0095] C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkynyl, each of which is optionally substituted with 1-6 R.sup.a2; [0096] monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and [0097] monocyclic heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c, provided that when W is heterocyclyl or heterocycloalkenyl, it is attached to the C(═O)NR.sup.6 group via a ring carbon atom; [0098] each occurrence of R.sup.a, R.sup.a1, and R.sup.a2 is independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); and cyano; [0099] each occurrence of R.sup.c is independently selected from the group consisting of: halo; cyano; C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —S(O).sub.1-2(C.sub.1-4 alkyl); —S(O)(═NH)(C.sub.1-4 alkyl); —NR.sup.eR.sup.f; —OH; —S(O).sub.1-2NR′R″; —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-10 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF.sub.5; [0100] each occurrence of R.sup.d is independently selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy; [0101] each occurrence of R.sup.e and R.sup.f is independently selected from the group consisting of: H; C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, and R.sup.i; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy; [0102] each occurrence of R.sup.g is independently selected from the group consisting of: [0103] C.sub.3-12 cycloalkyl or C.sub.3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h; [0104] heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h; [0105] heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R.sup.c, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h; and [0106] C.sub.6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R.sup.c, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h; [0107] each occurrence of R.sup.h is independently selected from the group consisting of: [0108] C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 R.sup.i, [0109] heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R.sup.i, [0110] heteroaryl of 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 R.sup.i; and [0111] C.sub.6 aryl optionally substituted with 1-4 R.sup.i; [0112] each occurrence of R.sup.i is independently selected from the group consisting of: C.sub.1-6 alkyl; C.sub.1-4 haloalkyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; and halo; [0113] each occurrence of L.sup.1, L.sup.2, and L.sup.g is selected from the group consisting of: —O—, —NH—, —NR.sup.d, —S(O).sub.0-2, C(O), and C.sub.1-3 alkylene optionally substituted with 1-3 R.sup.a; [0114] b1, b2, and bg are each independently 1, 2, or 3; and [0115] each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C.sub.1-4 alkyl.
[0116] In some embodiments, it is provided that when Y.sup.1 and Y.sup.2 are CH; Y.sup.3 is N; W is unsubstituted n-propyl; and Q.sup.1 is unsubstituted phenylene, then: -(L.sup.A).sub.a1-Q.sup.2 is other than —CH.sub.2-morpholinyl, —CH.sub.2—N-methylpiperazinyl, morpholinyl, or N-methylpiperazinyl.
The Variable Q.SUP.1
[0117] In some embodiments, Q.sup.1 is heteroarylene of from 5-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroarylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of R.sup.c and R.sup.h.
[0118] In certain embodiments, Q.sup.1 is heteroarylene of from 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S, and wherein the heteroarylene is optionally substituted with from 1-3 substituents independently selected from the group consisting of R.sup.c and R.sup.h.
[0119] In certain embodiments, Q.sup.1 is heteroarylene of from 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S, and wherein the heteroarylene is optionally substituted with from 1-3 R.sup.c.
[0120] In certain of these embodiments, Q.sup.1 is heteroarylene of 5 ring atoms, wherein from 1-3 (e.g., 1 or 2, e.g., 2) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S, and wherein the heteroarylene is optionally substituted with from 1-2 R.sup.c.
[0121] As a non-limiting example of the foregoing embodiments, Q.sup.1 can be pyrazolylene which is optionally substituted with from 1-2 R.sup.c.
[0122] In certain embodiments, Q.sup.1 is
##STR00008##
which is optionally substituted with from 1-2 R.sup.c (e.g., unsubstituted; or substituted with 1 or 2 R.sup.c), wherein aa represents point of attachment to -(L.sup.A).sub.a1-Q.sup.2.
[0123] In certain embodiments, Q.sup.1 is
##STR00009##
each of which is optionally substituted with from 1-2 R.sup.c (e.g., unsubstituted; or substituted with 1 or 2 R.sup.c), wherein aa represents point of attachment to -(L.sup.A).sub.a1-Q.sup.2.
[0124] In certain embodiments, Q.sup.1 is thiophenylene or oxazolylene, each of which is optionally substituted with from 1-2 R.sup.c.
[0125] As a non-limiting example of the foregoing embodiments, Q.sup.1 can be
##STR00010##
each of which is optionally substituted with from 1-2 R.sup.c.
[0126] In some embodiments, Q.sup.1 is heteroarylene of 6 ring atoms, wherein from 1-3 ring atoms are ring nitrogen atoms, and wherein the heteroarylene is optionally substituted with from 1-3 R.sup.c, such as pyridylene optionally substituted with from 1-2 R.sup.c.
[0127] In certain of these embodiments, Q.sup.1 is
##STR00011##
each of which is optionally substituted with from 1-2 R.sup.c, wherein aa is the point of attachment to -(L.sup.A).sub.a1-Q.sup.2.
[0128] In some embodiments, Q.sup.1 is C.sub.6-10 arylene optionally substituted with from 1-4 substituents independently selected from the group consisting of R.sup.c and R.sup.h.
[0129] In certain of these embodiments, Q.sup.1 is phenylene optionally substituted with from 1-4 R.sup.c. As non-limiting examples of the foregoing embodiments, Q.sup.1 can be
##STR00012##
each of which is optionally substituted with from 1-2 R.sup.c (e.g., unsubstituted).
[0130] In some embodiments, Q.sup.1 is selected from the group consisting of: [0131] C.sub.3-12 cycloalkylene or cycloalkenylene, each optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R.sup.c and R.sup.h; and [0132] heterocyclylene or heterocycloalkenylene of from 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h.
[0133] In certain embodiments, Q.sup.1 is C.sub.3-8 cycloalkylene or cycloalkenylene, each optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.c. As non-limiting examples, Q.sup.1 can be
##STR00013##
each of which is optionally substituted with from 1-2 R.sup.c, wherein aa is the point of attachment to -(L.sup.A).sub.a1-Q.sup.2.
[0134] In certain embodiments, Q.sup.1 is heterocyclylene or heterocycloalkenylene of from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.c. As non-limiting examples, Q.sup.1 can be
##STR00014##
each of which is optionally substituted with from 1-2 R.sup.c, wherein aa is the point of attachment to -(L.sup.A).sub.a1-Q.sup.2.
The Variables -(L.sup.A).sub.a1
[0135] In some embodiments, a1 is 0. In some embodiments, a1 is 1. In some embodiments, a1 is 2-4 (e.g., 2, 3, or 4).
[0136] In some embodiments, when L.sup.A is C.sub.1-3 alkylene optionally substituted with from 1-2 R.sup.a1, L.sup.A is CH.sub.2 or CHMe, each of which is optionally substituted with from 1-2 R.sup.a1.
[0137] In some embodiments, L.sup.A is C.sub.1-3 alkylene optionally substituted with from 1-2 R.sub.a1. In certain of these embodiments, L.sup.A is CH.sub.2 or CH(Me), each of which is optionally substituted with from 1-2 R.sup.a1, such as unsubstituted CH.sub.2.
[0138] In some embodiments, L.sup.A is —O—.
The Variable Q.SUP.2
[0139] In some embodiments, Q.sup.2 is R.sup.g.
[0140] In certain embodiments, Q.sup.2 is selected from the group consisting of: [0141] heteroaryl of from 5-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of R.sup.c, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h; and [0142] C.sub.6-10 aryl optionally substituted with from 1-4 substituents independently selected from the group consisting of R.sup.c, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h.
[0143] In certain embodiments, Q.sup.2 is selected from the group consisting of: [0144] heteroaryl of from 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R.sup.cq2; and [0145] C.sub.6-10 aryl optionally substituted with from 1-4 R.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c.
[0146] In certain embodiments, Q.sup.2 is selected from the group consisting of: [0147] heteroaryl of 6 ring atoms, wherein from 1-3 ring atoms are ring nitrogen atoms, and wherein the heteroaryl is optionally substituted with from 1-4 R.sup.cq2; [0148] heteroaryl of 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with from 1-3 R.sup.cq2, such as pyrazolyl
##STR00015##
optionally substituted with from 1-2 R.sup.cq2; and [0149] phenyl optionally substituted with from 1-4 R.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c.
[0150] In certain embodiments, In certain embodiments, Q.sup.2 is selected from the group consisting of: [0151] heteroaryl of 6 ring atoms, wherein from 1-3 ring atoms are ring nitrogen atoms, and wherein the heteroaryl is optionally substituted with from 1-4 R.sup.cq2; and [0152] phenyl optionally substituted with from 1-4 R.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c.
[0153] In certain of these embodiments, Q.sup.2 has the following formula:
##STR00016##
wherein Q.sup.A, Q.sub.B, Q.sub.C, Q.sub.D, and Q.sup.E are each independently selected from the group consisting of CH, CR.sup.cq2, and N, provided that no more than 2 of Q.sup.A-Q.sup.E are N, and no more than 4 of Q.sup.A-Q.sup.E are CR.sup.cq2.
[0154] In certain embodiments Q.sup.A and Q.sup.E are independently CH or CR.sup.cq2, provided that no more than 4 of Q.sup.A-Q.sup.E are CR.sup.cq2.
[0155] In certain of these embodiments, Q.sup.A and Q.sup.E are CH; and Q.sup.B, Q.sup.C, and Q.sup.D are independently CH or CR.sup.cq2.
[0156] In certain embodiments (when Q.sup.2 has the following formula:
##STR00017##
Q.sup.C is CR.sup.cq2; Q.sup.D is CH; and Q.sup.B is CH or CR.sup.cq2, such as CH. For example, Q.sup.2 can be:
##STR00018##
[0157] In certain embodiments (when Q.sup.2 has the following formula:
##STR00019##
Q.sup.C is CH; Q.sup.D is CH; and Q.sup.B is CR.sup.cq2. For example, Q.sup.2 can be
##STR00020##
[0158] In certain embodiments (when Q.sup.2 has the following formula:
##STR00021##
Q.sub.B, Q.sup.C, and Q.sup.D are each CH.
[0159] In certain embodiments (when Q.sup.2 has the following formula:
##STR00022##
Q.sub.2 is selected from the group consisting of: unsubstituted phenyl,
##STR00023##
[0160] In certain embodiments (when Q.sup.2 has the following formula:
##STR00024##
from 1-2 of Q.sup.A-Q.sup.E is N; and each remaining one of Q.sup.A-Q.sup.E is CH or CR.sup.cq2.
[0161] In certain of these embodiments, Q.sup.C is CH or CR.sup.cq2; from 1-2 of Q.sup.A, Q.sup.B, Q.sup.D, and Q.sup.E is N; and each remaining one of Q.sup.A, Q.sup.B, Q.sub.D, and Q.sup.E is CH.
[0162] As non-limiting examples of the foregoing embodiments, Q.sup.2 can be selected from the group consisting of:
##STR00025##
[0163] In some embodiments, Q.sup.2 is selected from the group consisting of: [0164] heteroaryl of from 5-6 (such as 6) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is substituted with R.sup.hq2 and further optionally substituted with from 1-2 R.sup.cq2; and [0165] C.sub.6-10 aryl substituted with R.sup.hq2 and further optionally substituted with from 1-2 R.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c, and R.sup.hq2 is an independently selected R.sup.h.
[0166] In certain of these embodiments, Q.sup.2 is selected from the group consisting of:
##STR00026##
wherein Q.sup.A, Q.sup.B, Q.sup.C, Q.sub.D, and Q.sup.E are each independently selected from the group consisting of CH, CR.sup.cq2, and N, provided that no more than 2 of Q.sup.A-Q.sup.E are N, and no more than 2 of Q.sup.A-Q.sup.E are CR.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c, and R.sup.hq2 is an independently selected R.sup.h.
[0167] In certain of the foregoing embodiments, Q.sup.2 is
##STR00027##
In certain of these embodiments, Q.sup.A, Q.sup.B, Q.sup.D, and Q.sup.E are each CH or CR.sup.cq2, provided that no more than 2 of Q.sup.A-Q.sup.E are R.sup.cq2. For example, each of Q.sup.A, Q.sup.B, Q.sup.D, and Q.sup.E is CH; or one of Q.sup.A, Q.sup.B, Q.sub.D, and Q.sup.E is CR.sup.cq2; and each remaining one of Q.sup.A, Q.sup.B, Q.sup.D, and Q.sup.E is CH.
[0168] In certain embodiments, Q.sup.2 is
##STR00028##
In certain of these embodiments, one of Q.sup.A and Q.sup.B is N; the other one of Q.sup.A and Q.sup.B is CH or CR.sup.cq2; and Q.sup.D and Q.sup.E are independently CH or CR.sup.cq2, provided that no more than 2 of Q.sup.A-Q.sup.E are CR.sup.cq2. For example, Q.sup.A is CH; Q.sup.B is N; Q.sup.E is CH; and Q.sup.D is CH or CR.sup.cq2.
[0169] In certain of the foregoing embodiments, Q.sup.2 is
##STR00029##
In certain of these embodiments, Q.sup.A, Q.sup.B, Q.sup.C, and Q.sup.E are each CH or CR.sup.cq2, provided that no more than 2 of Q.sup.A-Q.sup.E are R.sup.cq2. For example, each of Q.sup.A, Q.sup.B, Q.sup.C, and Q.sup.E is CH; or one of Q.sup.A, Q.sup.B, Q.sup.C, and Q.sup.E is CR.sup.cq2; and each remaining one of Q.sup.A, Q.sup.B, Q.sup.C, and Q.sup.E is CH.
[0170] In certain embodiments, Q.sup.2 is
##STR00030##
In certain of these embodiments, one of Q.sup.A and Q.sup.B is N; the other one of Q.sup.A and Q.sup.B is CH or CR.sup.cq2; and Q.sup.C and Q.sup.E are independently CH or CR.sup.cq2, provided that no more than 2 of Q.sup.A-Q.sup.E are CR.sup.cq2. For example, Q.sup.A is CH; Q.sup.B is N; Q.sup.E is CH; and Q.sup.C is CH or CR.sup.cq2.
[0171] In certain embodiments, R.sup.hq2 is C.sub.3-6 cycloalkyl optionally substituted with from 1-2 R.sup.i (such as C.sub.3, C.sub.4, C.sub.5, or C.sub.6 cycloalkyl optionally substituted with from 1-2 independently selected halo, such as —F).
[0172] In some embodiments, Q.sup.2 is selected from the group consisting of: [0173] C.sub.3-12 cycloalkyl or C.sub.3-12 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R.sup.cq2, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h; [0174] heterocyclyl or heterocycloalkenyl of from 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R.sup.cq2, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h, wherein each R.sup.cq2 is an independently selected R.sup.c.
[0175] In some embodiments, Q.sup.2 is C.sub.3-12 cycloalkyl or C.sub.3-12 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c.
[0176] In certain of these embodiments, Q.sup.2 is C.sub.3-6 (such as C.sub.3, C.sub.4, C.sub.5, or C.sub.6) cycloalkyl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c. As non-limiting examples of the foregoing embodiments, Q.sup.2 can be cyclopropyl or cyclopentyl each of which is optionally substituted with from 1-2 R.sup.cq2
##STR00031##
wherein each R.sup.cq2 is an independently selected R.sup.c.
[0177] In some embodiments, Q.sup.2 is heterocyclyl or heterocycloalkenyl of from 4-8 (such as 4, 5, or 6) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c. As non-limiting examples of the foregoing embodiments, Q.sup.2 can be tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with from 1-2 R.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c.
[0178] In certain embodiments, each R.sup.cq2 is independently selected from the group consisting of: halo; cyano; C.sub.1-6 alkyl which is optionally substituted with from 1-6 independently selected R.sup.a; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; and —C.sub.1-4 thioalkoxy.
[0179] In certain embodiments, each R.sup.cq2 is independently selected from the group consisting of: halo; cyano; C.sub.1-6 alkyl, such as C.sub.1-3 alkyl such as ethyl; C.sub.1-6 alkyl substituted with from 1-6 independently selected R.sup.a; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy, such as —OCF.sub.3 or —OCH.sub.2CF.sub.3; and —C.sub.1-4 thioalkoxy.
[0180] In certain embodiments, each R.sup.cq2 is independently selected from the group consisting of: halo; cyano; C.sub.1-6 alkyl, such as C.sub.1-3 alkyl such as ethyl; C.sub.1-6 alkyl substituted with from 1-6 substituents each independently selected from the group consisting of -halo, C.sub.1-3 alkoxy, and —OH (e.g., —CF.sub.3, —CH.sub.2CF.sub.3, or —CH.sub.2OMe); C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy, such as —OCF.sub.3 or —OCH.sub.2CF.sub.3; and —C.sub.1-4 thioalkoxy.
[0181] In some embodiments, Q.sup.2 is H.
[0182] In some embodiments, Q.sup.2 is R.sup.c.
[0183] In certain embodiments, Q.sup.2 is halo or cyano.
[0184] In certain embodiments, Q.sup.2 is C.sub.1-6 alkyl which is optionally substituted with from 1-6 independently selected R.sup.a. In certain embodiments, Q.sup.2 is C.sub.1-6 alkyl which is optionally substituted with from 1-6 substituents each independently selected from the group consisting of halo, C.sub.1-3 alkoxy, NR.sup.eR.sup.f, and —OH. As non-limiting examples of the foregoing embodiments, Q.sup.2 can be iPr, —CHF.sub.2, —CF.sub.3, —CH.sub.2CH.sub.2OMe, —CH.sub.2OMe, —CH.sub.2CH.sub.2N(Me).sub.2, or —C(OH)(Me).sub.2.
[0185] The Variables Y.sup.1, Y.sup.2, Y.sup.3, X.sup.1, and X.sup.2
[0186] In some embodiments, Y.sup.1 is CR.sup.1. In some embodiments, Y.sup.2 is CR.sup.1. In some embodiments, Y.sup.3 is CR.sup.1.
[0187] In some embodiments, Y.sup.1 is CR.sup.1; Y.sup.2 is CR.sup.1; and Y.sup.3 is CR.sup.1. For example, Y.sup.1 is CH; Y.sup.2 is CH; and Y.sup.3 is CH.
[0188] In some embodiments, one of Y.sup.1-Y.sup.3 is N; and each remaining one of Y.sup.1-Y.sup.3 is CR.sup.1 (e.g., CH).
[0189] In some embodiments, each R.sup.1 is H or R.sup.c. In certain embodiments, each R.sup.1 is H.
[0190] In certain embodiments, from 1-2 (such as 1) occurrence of R.sup.1 is R.sup.c; and each remaining occurrence of R.sup.1 is H. In certain of these embodiments, from 1-2 (such as 1) occurrence of R.sup.1 is halo, such as —F or —Cl; and each remaining occurrence of R.sup.1 is H.
[0191] In some embodiments, X.sup.1 is NR.sup.2. In certain of these embodiments, X.sup.1 is NH.
[0192] In some embodiments, X.sup.2 is CR.sup.5. In certain of these embodiments, X.sup.2 is CH.
[0193] In certain embodiments, X.sup.1 is NR.sup.2; and X.sup.2 is CR.sup.5. In certain of these embodiments, X.sup.1 is NH; and X.sup.2 is CH.
[0194] In certain embodiments, X.sup.1 is NR.sup.2; X.sup.2 is CR.sup.5; and each of Y.sup.1, Y.sup.2, and Y.sup.3 is an independently selected CR.sup.1. In certain of these embodiments, X.sup.1 is NH; and X.sup.2 is CH. In certain of these embodiments, each R.sup.1 is H. In certain embodiments, from 1-2 (such as 1) occurrence of R.sup.1 is R.sup.c; and each remaining occurrence of R.sup.1 is H. For example, from 1-2 (such as 1) occurrence of R.sup.1 is halo, such as —F or —Cl; and each remaining occurrence of R.sup.1 is H.
[0195] The Variable R.sup.6
[0196] In some embodiments, R.sup.6 is H.
[0197] The Variable W
[0198] In some embodiments, W is C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkynyl, each of which is optionally substituted with from 1-6 R.sup.a2.
[0199] In certain embodiments, W is C.sub.1-10 alkyl, which is optionally substituted with from 1-6 R.sup.a2. In certain embodiments, W is C.sub.1-6 (such as C.sub.1, C.sub.2, C.sub.3, or C.sub.4) alkyl, which is optionally substituted with from 1-6 R.sup.a2. As a non-limiting example of the foregoing embodiments, W can be selected from the group consisting of: methyl, ethyl, propyl, isopropyl, and isobutyl, each of which is optionally substituted with from 1-3 R.sup.a2. For example, W can be methyl, ethyl, propyl, isopropyl, or isobutyl, such as methyl or ethyl, such as ethyl.
[0200] In certain embodiments, each R.sup.a2 is independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f, such as —N(C.sub.1-3 alkyl).sub.2 or NHC(O)O(C.sub.1-4 alkyl); C.sub.1-4 alkoxy, such as —OMe; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); and cyano.
[0201] In certain embodiments, W is selected from the group consisting of: methyl, ethyl, propyl, isopropyl, and isobutyl, each of which is substituted with from 1-3 substituents each independently selected from the group consisting of: —OH; -halo, such as —F; —NR.sup.eR.sup.f, such as —N(C.sub.1-3 alkyl).sub.2 or NHC(O)O(C.sub.1-4 alkyl); C.sub.1-4 alkoxy, such as —OMe; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); and cyano. For example, W can be
##STR00032##
[0202] In some embodiments, W is C.sub.2-6 alkenyl or C.sub.2-6 alkynyl, each of which is optionally substituted with from 1-6 R.sup.a2. In certain embodiments, W is C.sub.2-6 alkenyl which is optionally substituted with from 1-6 R.sup.a2. In certain embodiments, W is C.sub.2-6 alkenyl (such as C.sub.3, C.sub.4, or C.sub.5 alkenyl) optionally substituted with from 1-3 substituents each independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f, such as —N(C.sub.1-3 alkyl).sub.2 or NHC(O)O(C.sub.1-4 alkyl); C.sub.1-4 alkoxy, such as —OMe; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); and cyano, such as wherein W is
##STR00033##
[0203] In some embodiments, W is selected from the group consisting of: [0204] monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and [0205] monocyclic heterocyclyl or heterocycloalkenyl of from 3-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.
[0206] In certain embodiments, W is monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c. In certain of these embodiments, W is monocyclic C.sub.3-8 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c. In certain embodiments, W is monocyclic C.sub.3-8 cycloalkyl (e.g., C.sub.3-6 cycloalkyl) optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c. As non-limiting examples of the foregoing embodiments, W can be cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c. For example, W can be unsubstituted cyclobutyl, cyclopentyl, or cyclohexyl.
[0207] In some embodiments, W is monocyclic heterocyclyl or heterocycloalkenyl of from 3-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.
[0208] In certain embodiments, W is monocyclic heterocyclyl of from 4-6 (such as 4, 5, or 6) ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.
[0209] As non-limiting examples of the foregoing embodiments, W can be azetidinyl, oxetanyl, pyrrolidinyl, or tetrahydrofuranyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and the ring nitrogen atom when present is optionally substituted with R.sup.d. For example, W can be
##STR00034##
[0210] In some embodiments, W is H.
[0211] Non-Limiting Combinations
[0212] In some embodiments, the compound is a compound of Formula (Ia):
##STR00035##
[0213] or a pharmaceutically acceptable salt thereof or a tautomer thereof.
[0214] In some embodiments of Formula (Ia), Y.sup.1, Y.sup.2, and Y.sup.3 are each CR.sup.1.
[0215] In some embodiments of Formula (Ia), each R.sup.1 is H.
[0216] In some embodiments of Formula (Ia), one occurrence of R.sup.1 is R.sup.c (such as halo); and each remaining R.sup.1 is H.
[0217] In some embodiments of Formula (Ia), Y.sup.1, Y.sup.2, and Y.sup.3 are each CH.
[0218] In some embodiments of Formula (Ia), a1 is 0.
[0219] In some embodiments of Formula (Ia), a1 is 1.
[0220] In some embodiments of Formula (Ia), L.sup.A is CH.sub.2.
[0221] In some embodiments of Formula (Ia), Q.sup.2 is selected from the group consisting of: [0222] heteroaryl of 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R.sup.cq2; and [0223] C.sub.6-10 aryl optionally substituted with from 1-4 R.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c.
[0224] In certain of these embodiments, Q.sup.2 has the following formula:
##STR00036##
wherein Q.sup.A, Q.sup.B, Q.sup.C, Q.sup.D, and Q.sup.E are each independently selected from the group consisting of CH, CR.sup.cq2, and N, provided that no more than 2 of Q.sup.A-Q.sup.E are N, and no more than 4 of Q.sup.A-Q.sup.E are CR.sup.cq2.
[0225] In certain embodiments Q.sup.A, Q.sup.B, Q.sup.C, Q.sub.D, and Q.sup.E are independently CH or CR.sup.cq2, provided that no more than 4 of Q.sup.A-Q.sup.E are CR.sup.cq2.
[0226] In certain embodiments of Formula (Ia) (when Q.sup.2 is
##STR00037##
Q.sup.A and Q.sup.E are CH; and Q.sup.B, Q.sup.C, and Q.sup.D are independently CH or CR.sup.cq2.
[0227] In certain embodiments of Formula (Ia) (when Q.sup.2 is
##STR00038##
Q.sup.C is CR.sup.cq2; Q.sup.D is CH; and Q.sup.B is CH or CR.sup.cq2, such as CH.
[0228] In certain embodiments of Formula (Ia) (when Q.sup.2 is
##STR00039##
Q.sup.C is CH; Q.sub.D is CH; and Q.sup.B is CR.sup.cq2.
[0229] In certain embodiments of Formula (Ia) (when Q.sup.2 is
##STR00040##
Q.sub.B, Q.sub.C, and Q.sub.D are each CH.
[0230] In certain embodiments of Formula (Ia) (when Q.sup.2 is
##STR00041##
Q.sup.2 is selected from the group consisting of: unsubstituted phenyl,
##STR00042##
[0231] In certain embodiments of Formula (Ia) (when Q.sup.2 is
##STR00043##
from 1-2 of Q.sup.A-Q.sup.E is N; and each remaining one of Q.sup.A-Q.sup.E is CH or CR.sup.cq2.
[0232] In certain of these embodiments, Q.sup.C is CH or CR.sup.cq2; from 1-2 of Q.sup.A, Q.sup.B, Q.sup.D, and Q.sup.E is N; and each remaining one of Q.sub.A, Q.sup.B, Q.sub.D, and Q.sup.E is CH.
[0233] As non-limiting examples of the foregoing embodiments, Q.sup.2 can be selected from the group consisting of:
##STR00044##
[0234] In some embodiments of Formula (Ia), Q.sup.2 is selected from the group consisting of: heteroaryl of from 5-6 (such as 6) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is substituted with R.sup.hq2 and further optionally substituted with from 1-2 R.sub.cq2; and
[0235] C.sub.6-10 aryl substituted with R.sup.hq2 and further optionally substituted with from 1-2 R.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c, and R.sup.hq2 is an independently selected R.sup.h.
[0236] In certain of these embodiments, Q.sup.2 is selected from the group consisting of:
##STR00045##
wherein Q.sup.A, Q.sup.B, Q.sup.C, Q.sub.D, and Q.sup.E are each independently selected from the group consisting of CH, CR.sup.cq2, and N, provided that no more than 2 of Q.sup.A-Q.sup.E are N, and no more than 2 of Q.sup.A-Q.sup.E are CR.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c, and R.sup.hq2 is an independently selected R.sup.h.
[0237] In certain of the foregoing embodiments, Q.sup.2 is
##STR00046##
In certain of these embodiments, Q.sup.A, Q.sup.B, Q.sup.D, and Q.sup.E are each CH or CR.sup.cq2, provided that no more than 2 of Q.sup.A-Q.sup.E are R.sup.cq2. For example, each of Q.sup.A, Q.sup.B, Q.sup.D, and Q.sup.E is CH; or one of Q.sup.A, Q.sup.B, Q.sup.D, and Q.sup.E is CR.sup.cq2; and each remaining one of Q.sup.A, Q.sup.B, Q.sup.D, and Q.sup.E is CH.
[0238] In certain embodiments of Formula (Ia), Q.sup.2 is
##STR00047##
In certain of these embodiments, one of Q.sup.A and Q.sup.B is N; the other one of Q.sup.A and Q.sup.B is CH or CR.sup.cq2; and Q.sup.D and Q.sup.E are independently CH or CR.sup.cq2, provided that no more than 2 of Q.sup.A-Q.sup.E are CR.sup.cq2. For example, Q.sup.A is CH; Q.sup.B is N; Q.sup.E is CH; and Q.sup.D is CH or CR.sup.cq2.
[0239] In certain embodiments of Formula (Ia), Q.sup.2 is
##STR00048##
In certain of these embodiments, Q.sup.A, Q.sup.B, Q.sup.C, and Q.sup.E are each CH or CR.sup.cq2, provided that no more than 2 of Q.sup.A-Q.sup.E are R.sup.cq2. For example, each of Q.sup.A, Q.sup.B, Q.sup.C, and Q.sup.E is CH; or one of Q.sup.A, Q.sup.B, Q.sup.C, and Q.sup.E is CR.sup.cq2; and each remaining one of Q.sup.A, Q.sup.B, Q.sup.C, and Q.sup.E is CH.
[0240] In certain embodiments of Formula (Ia), Q.sup.2 is
##STR00049##
In certain of these embodiments, one of Q.sup.A and Q.sup.B is N; the other one of Q.sup.A and Q.sup.B is CH or CR.sup.cq2; and Q.sup.C and Q.sup.E are independently CH or CR.sup.cq2, provided that no more than 2 of Q.sup.A-Q.sup.E are CR.sup.cq2. For example, Q.sup.A is CH; Q.sup.B is N; Q.sup.E is CH; and Q.sup.C is CH or CR.sup.cq2.
[0241] In some embodiments of Formula (Ia), R.sup.hq2 is C.sub.3-6 cycloalkyl optionally substituted with from 1-2 R.sup.i (such as C.sub.3, C.sub.4, C.sub.5, or C.sub.6 cycloalkyl optionally substituted with from 1-2 independently selected halo, such as —F).
[0242] In some embodiments of Formula (Ia), each R.sup.cq2 is independently selected from the group consisting of: halo; cyano; C.sub.1-6 alkyl, such as C.sub.1-3 alkyl such as ethyl; C.sub.1-6 alkyl substituted with from 1-6 independently selected R.sup.a; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy, such as —OCF.sub.3 or —OCH.sub.2CF.sub.3; and —C.sub.1-4 thioalkoxy.
[0243] In some embodiments of Formula (Ia), each R.sup.cq2 is independently selected from the group consisting of: halo; cyano; C.sub.1-6 alkyl, such as C.sub.1-3 alkyl such as ethyl; C.sub.1-6 alkyl substituted with from 1-6 substituents each independently selected from the group consisting of -halo, C.sub.1-3 alkoxy, and —OH (e.g., —CF.sub.3, —CH.sub.2CF.sub.3, or —CH.sub.2OMe); C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy, such as —OCF.sub.3 or —OCH.sub.2CF.sub.3; and —C.sub.1-4 thioalkoxy.
[0244] In some embodiments of Formula (Ia), R.sup.2 is H; and R.sup.5 is H.
[0245] In some embodiments of Formula (Ia), R.sup.6 is H.
[0246] In some embodiments of Formula (Ia), W is C.sub.1-6 (such as C.sub.1, C.sub.2, C.sub.3, or C.sub.4) alkyl, which is optionally substituted with from 1-6 R.sup.a2. In certain of these embodiments, W is unsubstituted C.sub.1-6 alkyl, such as methyl, ethyl, propyl, isopropyl, or isobutyl, such as methyl or ethyl, such as ethyl.
[0247] In certain embodiments, W is C.sub.1-6 alkyl (such as methyl, ethyl, propyl, isopropyl, or isobutyl) optionally substituted with from 1-3 substituents each independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f, such as —N(C.sub.1-3 alkyl).sub.2 or NHC(O)O(C.sub.1-4 alkyl); C.sub.1-4 alkoxy, such as —OMe; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); and cyano, such as wherein W is
##STR00050##
[0248] In some embodiments of Formula (Ia), W is C.sub.2-6 alkenyl (such as C.sub.3, C.sub.4, or C.sub.5 alkenyl) optionally substituted with from 1-3 substituents each independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f, such as —N(C.sub.1-3 alkyl).sub.2 or NHC(O)O(C.sub.1-4 alkyl); C.sub.1-4 alkoxy, such as —OMe; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); and cyano, such as
##STR00051##
[0249] In some embodiments of Formula (Ia), W is monocyclic C.sub.3-8 cycloalkyl (e.g., C.sub.3-6 cycloalkyl) optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c, such as wherein W is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c, such as unsubstituted cyclobutyl, cyclopentyl, or cyclohexyl.
[0250] In some embodiments of Formula (Ia), W is monocyclic heterocyclyl of from 4-6 (such as 4, 5, or 6) ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.c, such as wherein W is azetidinyl, oxetanyl, pyrrolidinyl, or tetrahydrofuranyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.c, and the ring nitrogen atom when present is optionally substituted with R.sup.d; such as wherein W is
##STR00052##
Compound Provisions
[0251] In some embodiments, the compound is other the compounds disclosed in WO 2003/028724, which is incorporated herein by reference in its entirety.
[0252] In some embodiments, it is provided that when Y.sup.1 and Y.sup.2 are CH; Y.sup.3 is N; W is unsubstituted n-propyl; and Q.sup.1 is unsubstituted phenylene, then: -(L.sup.A).sub.a1-Q.sup.2 is other than —CH.sub.2-morpholinyl, —CH.sub.2—N-methylpiperazinyl, morpholinyl, or N-methylpiperazinyl.
[0253] In some embodiments, when W is unsubstituted n-propyl; and Q.sup.1 is unsubstituted phenylene, then: -(L.sup.A).sub.a1-Q.sup.2 is other than —CH.sub.2-morpholinyl, —CH.sub.2—N-methylpiperazinyl, morpholinyl, or N-methylpiperazinyl.
[0254] In some embodiments, when Q.sup.1 is unsubstituted phenylene, then: -(L.sup.A).sub.a1-Q.sup.2 is other than —CH.sub.2-morpholinyl, —CH.sub.2—N-methylpiperazinyl, morpholinyl, or N-methylpiperazinyl.
[0255] In some embodiments, -(L.sup.A).sub.a1-Q.sup.2 is other than —CH.sub.2-morpholinyl, —CH.sub.2—N-methylpiperazinyl, morpholinyl, or N-methylpiperazinyl.
Non-Limiting Exemplary Compounds
[0256] In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table C1 or a pharmaceutically acceptable salt thereof.
TABLE-US-00001 TABLE C1 Com- pound No. Structure 101
[0257] Pharmaceutical Compositions and Administration
[0258] General
[0259] In some embodiments, a chemical entity (e.g., a compound that inhibits (e.g., antagonizes) STING, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination thereof) is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.
[0260] In some embodiments, the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%-100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22.sup.nd Edition (Pharmaceutical Press, London, U K. 2012).
[0261] Routes of Administration and Composition Components
[0262] In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral).
[0263] Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.
[0264] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
[0265] The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
[0266] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.
[0267] Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia. 2006, 10, 788-795.
[0268] Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methoxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM), lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.
[0269] In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.
[0270] In other embodiments, the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).
[0271] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
[0272] In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.
[0273] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.
[0274] In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient.
[0275] In certain embodiments, solid oral dosage forms can further include one or more components that chemically and/or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and/or transverse colon and/or distal colon and/or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K. J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.
[0276] Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.
[0277] Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric/pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.
[0278] Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).
[0279] Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non-sensitizing.
[0280] In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.
[0281] Dosages
[0282] The dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.
[0283] In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about 0.01 mg/Kg to about 100 mg/Kg; from about 0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0.1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 10 mg/Kg).
[0284] Regimens
[0285] The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).
[0286] In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.
[0287] Methods of Treatment
[0288] In some embodiments, methods for treating a subject having condition, disease or disorder in which increased (e.g., excessive) STING activity (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., immune disorders, cancer) are provided.
[0289] Indications
[0290] In some embodiments, the condition, disease or disorder is cancer. Non-limiting examples of cancer include melanoma, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include breast cancer, colon cancer, rectal cancer, colorectal cancer, kidney or renal cancer, clear cell cancer lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, squamous cell cancer (e.g. epithelial squamous cell cancer), cervical cancer, ovarian cancer, prostate cancer, prostatic neoplasms, liver cancer, bladder cancer, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, gastrointestinal stromal tumor, pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytoma, thecomas, arrhenoblastomas, hepatoma, hematologic malignancies including non-Hodgkins lymphoma (NHL), multiple myeloma, myelodysplasia disorders, myeloproliferative disorders, chronic myelogenous leukemia, and acute hematologic malignancies, endometrial or uterine carcinoma, endometriosis, endometrial stromal sarcoma, fibrosarcomas, choriocarcinoma, salivary gland carcinoma, vulval cancer, thyroid cancer, esophageal carcinomas, hepatic carcinoma, anal carcinoma, penile carcinoma, nasopharyngeal carcinoma, laryngeal carcinomas, Kaposi's sarcoma, mast cell sarcoma, ovarian sarcoma, uterine sarcoma, melanoma, malignant mesothelioma, skin carcinomas, Schwannoma, oligodendroglioma, neuroblastomas, neuroectodermal tumor, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcomas, Ewing Sarcoma, peripheral primitive neuroectodermal tumor, urinary tract carcinomas, thyroid carcinomas, Wilm's tumor, as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome. In some cases, the cancer is melanoma.
[0291] In some embodiments, the condition, disease or disorder is a neurological disorder, which includes disorders that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Non-limiting examples of neurological disorders include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; age-related macular degeneration; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers' disease; alternating hemiplegia; Alzheimer's disease; Vascular dementia; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Anronl-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telegiectasia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; Batten disease; Behcet's disease; Bell's palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger's disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome; causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy; chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing's syndrome; cytomegalic inclusion body disease; cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier's syndrome; Dejerine-Klumke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb's palsy; essential tremor; Fabry's disease; Fahr's syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich's ataxia; fronto-temporal dementia and other “tauopathies”; Gaucher's disease; Gerstmann's syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1-associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (also neurological manifestations of AIDS); holoprosencephaly; Huntington's disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile phytanic acid storage disease; infantile refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh's disease; Lennox-Gustaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; Lissencephaly; locked-in syndrome; Lou Gehrig's disease (i.e., motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; Lyme disease—neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neuron disease; Moyamoya disease; mucopolysaccharidoses; milti-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; p muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O'Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson's disease; paramyotonia congenital; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick's disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; post-polio syndrome; postherpetic neuralgia; postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (types I and II); Rasmussen's encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye's syndrome; Saint Vitus dance; Sandhoff disease; Schilder's disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjögren's syndrome; sleep apnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; Stiff-Person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subcortical arteriosclerotic encephalopathy; Sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; Tic Douloureux; Todd's paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau disease; Wallenberg's syndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome; Wildon's disease; amyotrophe lateral sclerosis and Zellweger syndrome.
[0292] In some embodiments, the condition, disease or disorder is STING-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculopathy with onset in infancy (SAVI)), Aicardi-Goutières Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis. In certain embodiments, the condition, disease or disorder is an autoimmune disease (e.g., a cytosolic DNA-triggered autoinflammatory disease). Non-limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases (IBDs) comprising Crohn disease (CD) and ulcerative colitis (UC), which are chronic inflammatory conditions with polygenic susceptibility. In certain embodiments, the condition is an inflammatory bowel disease. In certain embodiments, the condition is Crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated by one or more alloimmune diseases (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In certain of these embodiments, the condition is alloimmune disease (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis or intestinal mucositis).
[0293] In some embodiments, modulation of the immune system by STING provides for the treatment of diseases, including diseases caused by foreign agents. Exemplary infections by foreign agents which may be treated and/or prevented by the method of the present invention include an infection by a bacterium (e.g., a Gram-positive or Gram-negative bacterium), an infection by a fungus, an infection by a parasite, and an infection by a virus. In one embodiment of the present invention, the infection is a bacterial infection (e.g., infection by E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp., Staphylococcus aureus, Streptococcus spp., or vancomycin-resistant enterococcus), or sepsis. In another embodiment, the infection is a fungal infection (e.g. infection by a mould, a yeast, or a higher fungus). In still another embodiment, the infection is a parasitic infection (e.g., infection by a single-celled or multicellular parasite, including Giardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, and Toxoplasma gondiz). In yet another embodiment, the infection is a viral infection (e.g., infection by a virus associated with AIDS, avian flu, chickenpox, cold sores, common cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, and lower or upper respiratory tract infection (e.g., respiratory syncytial virus)).
[0294] In some embodiments, the condition, disease or disorder is hepatitis B (see, e.g., WO 2015/061294).
[0295] In some embodiments, the condition, disease or disorder is selected from cardiovascular diseases (including e.g., myocardial infarction).
[0296] In some embodiments, the condition, disease or disorder is age-related macular degeneration.
[0297] In some embodiments, the condition, disease or disorder is mucositis, also known as stomatitis, which can occur as a result of chemotherapy or radiation therapy, either alone or in combination as well as damage caused by exposure to radiation outside of the context of radiation therapy.
[0298] In some embodiments, the condition, disease or disorder is uveitis, which is inflammation of the uvea (e.g., anterior uveitis, e.g., iridocyclitis or iritis; intermediate uveitis (also known as pars planitis); posterior uveitis; or chorioretinitis, e.g., pan-uveitis).
[0299] In some embodiments, the condition, disease or disorder is selected from the group consisting of a cancer, a neurological disorder, an autoimmune disease, hepatitis B, uveitis, a cardiovascular disease, age-related macular degeneration, and mucositis.
[0300] Still other examples can include those indications discussed herein and below in contemplated combination therapy regimens.
[0301] Combination Therapy
[0302] This disclosure contemplates both monotherapy regimens as well as combination therapy regimens.
[0303] In some embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and/or one or more therapeutic regimens) in combination with administration of the compounds described herein.
[0304] In certain embodiments, the methods described herein can further include administering one or more additional cancer therapies.
[0305] The one or more additional cancer therapies can include, without limitation, surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine, hepatitis B vaccine, Oncophage, Provenge) and gene therapy, as well as combinations thereof. Immunotherapy, including, without limitation, adoptive cell therapy, the derivation of stem cells and/or dendritic cells, blood transfusions, lavages, and/or other treatments, including, without limitation, freezing a tumor.
[0306] In some embodiments, the one or more additional cancer therapies is chemotherapy, which can include administering one or more additional chemotherapeutic agents.
[0307] In certain embodiments, the additional chemotherapeutic agent is an immunomodulatory moiety, e.g., an immune checkpoint inhibitor. In certain of these embodiments, the immune checkpoint inhibitor targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (DO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155; e.g., CTLA-4 or PD1 or PD-L1). See, e.g., Postow, M. J. Clin. Oncol. 2015, 33, 1.
[0308] In certain of these embodiments, the immune checkpoint inhibitor is selected from the group consisting of: Urelumab, PF-05082566, MEDI6469, TRX518, Varlilumab, CP-870893, Pembrolizumab (PD1), Nivolumab (PD1), Atezolizumab (formerly MPDL3280A) (PDLL), MEDI4736 (PD-L1), Avelumab (PD-L1), PDR001 (PD1), BMS-986016, MGA271, Lirilumab, IPH2201, Emactuzumab, INCB024360, Galunisertib, Ulocuplumab, BKT140, Bavituximab, CC-90002, Bevacizumab, and MNRP1685A, and MGA271.
[0309] In certain embodiments, the additional chemotherapeutic agent is an alkylating agent. Alkylating agents are so named because of their ability to alkylate many nucleophilic functional groups under conditions present in cells, including, but not limited to cancer cells. In a further embodiment, an alkylating agent includes, but is not limited to, Cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin. In an embodiment, alkylating agents can function by impairing cell function by forming covalent bonds with the amino, carboxyl, sulfhydryl, and phosphate groups in biologically important molecules or they can work by modifying a cell's DNA. In a further embodiment an alkylating agent is a synthetic, semisynthetic or derivative.
[0310] In certain embodiments, the additional chemotherapeutic agent is an anti-metabolite. Anti-metabolites masquerade as purines or pyrimidines, the building-blocks of DNA and in general, prevent these substances from becoming incorporated in to DNA during the “S” phase (of the cell cycle), stopping normal development and division. Anti-metabolites can also affect RNA synthesis. In an embodiment, an antimetabolite includes, but is not limited to azathioprine and/or mercaptopurine. In a further embodiment an anti-metabolite is a synthetic, semisynthetic or derivative.
[0311] In certain embodiments, the additional chemotherapeutic agent is a plant alkaloid and/or terpenoid. These alkaloids are derived from plants and block cell division by, in general, preventing microtubule function. In an embodiment, a plant alkaloid and/or terpenoid is a vinca alkaloid, a podophyllotoxin and/or a taxane. Vinca alkaloids, in general, bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules, generally during the M phase of the cell cycle. In an embodiment, a vinca alkaloid is derived, without limitation, from the Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). In an embodiment, a vinca alkaloid includes, without limitation, Vincristine, Vinblastine, Vinorelbine and/or Vindesine. In an embodiment, a taxane includes, but is not limited, to Taxol, Paclitaxel and/or Docetaxel. In a further embodiment a plant alkaloid or terpenoid is a synthetic, semisynthetic or derivative. In a further embodiment, a podophyllotoxin is, without limitation, an etoposide and/or teniposide. In an embodiment, a taxane is, without limitation, docetaxel and/or ortataxel. [021] In an embodiment, a cancer therapeutic is a topoisomerase. Topoisomerases are essential enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by upsetting proper DNA supercoiling. In a further embodiment, a topoisomerase is, without limitation, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In an embodiment a type I topoisomerase inhibitor is, without limitation, a camptothecin. In another embodiment, a camptothecin is, without limitation, exatecan, irinotecan, lurtotecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67) and/or ST 1481. In an embodiment, a type II topoisomerase inhibitor is, without limitation, epipodophyllotoxin. In a further embodiment an epipodophyllotoxin is, without limitation, an amsacrine, etoposid, etoposide phosphate and/or teniposide. In a further embodiment a topoisomerase is a synthetic, semisynthetic or derivative, including those found in nature such as, without limitation, epipodophyllotoxins, substances naturally occurring in the root of American Mayapple (Podophyllum peltatum).
[0312] In certain embodiments, the additional chemotherapeutic agent is a stilbenoid. In a further embodiment, a stilbenoid includes, but is not limited to, Resveratrol, Piceatannol, Pinosylvin, Pterostilbene, Alpha-Viniferin, Ampelopsin A, Ampelopsin E, Diptoindonesin C, Diptoindonesin F, Epsilon-Vinferin, Flexuosol A, Gnetin H, Hemsleyanol D, Hopeaphenol, Trans-Diptoindonesin B, Astringin, Piceid and Diptoindonesin A. In a further embodiment a stilbenoid is a synthetic, semisynthetic or derivative.
[0313] In certain embodiments, the additional chemotherapeutic agent is a cytotoxic antibiotic. In an embodiment, a cytotoxic antibiotic is, without limitation, an actinomycin, an anthracenedione, an anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2-deoxyglucose and/or chlofazimine. In an embodiment, an actinomycin is, without limitation, actinomycin D, bacitracin, colistin (polymyxin E) and/or polymyxin B. In another embodiment, an antracenedione is, without limitation, mitoxantrone and/or pixantrone. In a further embodiment, an anthracycline is, without limitation, bleomycin, doxorubicin (Adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, mitomycin, plicamycin and/or valrubicin. In a further embodiment a cytotoxic antibiotic is a synthetic, semisynthetic or derivative.
[0314] In certain embodiments, the additional chemotherapeutic agent is selected from endostatin, angiogenin, angiostatin, chemokines, angioarrestin, angiostatin (plasminogen fragment), basement-membrane collagen-derived anti-angiogenic factors (tumstatin, canstatin, or arrestin), anti-angiogenic antithrombin III, signal transduction inhibitors, cartilage-derived inhibitor (CDI), CD59 complement fragment, fibronectin fragment, gro-beta, heparinases, heparin hexasaccharide fragment, human chorionic gonadotropin (hCG), interferon alpha/beta/gamma, interferon inducible protein (IP-10), interleukin-12, kringle (plasminogen fragment), metalloproteinase inhibitors (TIMPs), 2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor-4 (PF4), prolactin 16 kD fragment, proliferin-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transforming growth factor-beta (TGF-β), vasculostatin, vasostatin (calreticulin fragment) and the like.
[0315] In certain embodiments, the additional chemotherapeutic agent is selected from abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyureataxanes, ifosfamide, liarozole, lonidamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, onapristone, paclitaxel, prednimustine, procarbazine, RPR109881, stramustine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine.
[0316] In certain embodiments, the additional chemotherapeutic agent is platinum, cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, azathioprine, mercaptopurine, vincristine, vinblastine, vinorelbine, vindesine, etoposide and teniposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, teniposide, 5-fluorouracil, leucovorin, methotrexate, gemcitabine, taxane, leucovorin, mitomycin C, tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide and doxorubicin. Additional agents include inhibitors of mTOR (mammalian target of rapamycin), including but not limited to rapamycin, everolimus, temsirolimus and deforolimus.
[0317] In still other embodiments, the additional chemotherapeutic agent can be selected from those delineated in U.S. Pat. No. 7,927,613, which is incorporated herein by reference in its entirety.
[0318] In some embodiments, the additional therapeutic agent and/or regimen are those that can be used for treating other STING-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculopathy with onset in infancy (SAVI)), Aicardi-Goutières Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis and the like.
[0319] Non-limiting examples of additional therapeutic agents and/or regimens for treating rheumatoid arthritis include non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g, prednisone), disease-modifying antirheumatic drugs (DMARDs; e.g., methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), leflunomide (Arava®), hydroxychloroquine (Plaquenil), PF-06650833, iguratimod, tofacitinib (Xeljanz®), ABBV-599, evobrutinib, and sulfasalazine (Azulfidine®)), and biologics (e.g., abatacept (Orenciag), adalimumab (Humira®), anakinra (Kineret®), certolizumab (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®), infliximab (Remicade®), rituximab (Rituxan®), tocilizumab (Actemra®), vobarilizumab, sarilumab (Kevzara®), secukinumab, ABP 501, CHS-0214, ABC-3373, and tocilizumab (ACTEMRA®)).
[0320] Non-limiting examples of additional therapeutic agents and/or regimens for treating lupus include steroids, topical immunomodulators (e.g., tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel®)), thalidomide (Thalomid®), non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarial drugs (e.g., Hydroxychloroquine (Plaquenil)), corticosteroids (e.g, prednisone) and immunomodulators (e.g., evobrutinib, iberdomide, voclosporin, cenerimod, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), and mycophenolate mofetil) baricitinb, iguratimod, filogotinib, GS-9876, rapamycin, and PF-06650833), and biologics (e.g., belimumab (Benly stag), anifrolumab, prezalumab, MEDI0700, obinutuzumab, vobarilizumab, lulizumab, atacicept, PF-06823859, and lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab, edratide, IFN-α-kinoid, OMS721, RC18, RSLV-132, theralizumab, XmAb5871, and ustekinumab (Stelara®)). For example, non-limiting treatments for systemic lupus erythematosus include non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), antimalarial drugs (e.g., Hydroxychloroquine (Plaquenil)), corticosteroids (e.g, prednisone) and immunomodulators (e.g., iberdomide, voclosporin, azathioprine (Imuran®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral, Sandimmune®, Gengraf®), and mycophenolate mofetil, baricitinb, filogotinib, and PF-06650833), and biologics (e.g., belimumab (Benlysta®), anifrolumab, prezalumab, MEDI0700, vobarilizumab, lulizumab, atacicept, PF-06823859, lupizor, rituximab, BT063, BI655064, BIIB059, aldesleukin (Proleukin®), dapirolizumab, edratide, IFN-α-kinoid, RC18, RSLV-132, theralizumab, XmAb5871, and ustekinumab (Stelara®)). As another example, non-limiting examples of treatments for cutaneous lupus include steroids, immunomodulators (e.g., tacrolimus ointment (Protopic®) and pimecrolimus cream (Elidel®)), GS-9876, filogotinib, and thalidomide (Thalomid®). Agents and regimens for treating drug-induced and/or neonatal lupus can also be administered.
[0321] Non-limiting examples of additional therapeutic agents and/or regimens for treating STING-associated vasculopathy with onset in infancy (SAVI) include JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).
[0322] Non-limiting examples of additional therapeutic agents and/or regimens for treating Aicardi-Goutières Syndrome (AGS) include physiotherapy, treatment for respiratory complications, anticonvulsant therapies for seizures, tube-feeding, nucleoside reverse transcriptase inhibitors (e.g., emtricitabine (e.g., Emtriva®), tenofovir (e.g., Viread®), emtricitabine/tenofovir (e.g., Truvada®), zidovudine, lamivudine, and abacavir), and JAK inhibitors (e.g., tofacitinib, ruxolitinib, filgotinib, and baricitinib).
[0323] Non-limiting examples of additional therapeutic agents and/or regimens for treating IBDs include 6-mercaptopurine, AbGn-168H, ABX464, ABT-494, adalimumab, AJM300, alicaforsen, AMG139, anrukinzumab, apremilast, ATR-107 (PF0530900), autologous CD34-selected peripheral blood stem cells transplant, azathioprine, bertilimumab, BI 655066, BMS-936557, certolizumab pegol (Cimzia®), cobitolimod, corticosteroids (e.g., prednisone, Methylprednisolone, prednisone), CP-690,550, CT-P13, cyclosporine, DIMS0150, E6007, E6011, etrasimod, etrolizumab, fecal microbial transplantation, figlotinib, fingolimod, firategrast (SB-683699) (formerly T-0047), GED0301, GLPG0634, GLPG0974, guselkumab, golimumab, GSK1399686, HMPL-004 (Andrographis paniculata extract), IMU-838, infliximab, Interleukin 2 (IL-2), Janus kinase (JAK) inhibitors, laquinimod, masitinib (AB1010), matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, mirikizumab (LY3074828), natalizumab, NNC 0142-0000-0002, NNC0114-0006, ozanimod, peficitinib (JNJ-54781532), PF-00547659, PF-04236921, PF-06687234, QAX576, RHB-104, rifaximin, risankizumab, RPC1063, SB012, SHP647, sulfasalazine, TD-1473, thalidomide, tildrakizumab (MK 3222), TJ301, TNF-Kinoidg, tofacitinib, tralokinumab, TRK-170, upadacitinib, ustekinumab, UTTR1147A, V565, vatelizumab, VB-201, vedolizumab, and vidofludimus.
[0324] Non-limiting examples of additional therapeutic agents and/or regimens for treating irritable bowel syndrome include alosetron, bile acid sequestrants (e.g., cholestyramine, colestipol, colesevelam), chloride channel activators (e.g., lubiprostone), coated peppermint oil capsules, desipramine, dicyclomine, ebastine, eluxadoline, farnesoid X receptor agonist (e.g., obeticholic acid), fecal microbiota transplantation, fluoxetine, gabapentin, guanylate cyclase-C agonists (e.g., linaclotide, plecanatide), ibodutant, imipramine, JCM-16021, loperamide, lubiprostone, nortriptyline, ondansetron, opioids, paroxetine, pinaverium, polyethylene glycol, pregabalin, probiotics, ramosetron, rifaximin, and tanpanor.
[0325] Non-limiting examples of additional therapeutic agents and/or regimens for treating scleroderma include non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g, prednisone), immunomodulators (e.g., azathioprine, methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral®, Sandimmune®, Gengraf®), antithymocyte globulin, mycophenolate mofetil, intravenous immunoglobulin, rituximab, sirolimus, and alefacept), calcium channel blockers (e.g., nifedipine), alpha blockers, serotonin receptor antagonists, angiotensin II receptor inhibitors, statins, local nitrates, iloprost, phosphodiesterase 5 inhibitors (e.g., sildenafil), bosentan, tetracycline antibiotics, endothelin receptor antagonists, prostanoids, and tyrosine kinase inhibitors (e.g., imatinib, nilotinib and dasatinib).
[0326] Non-limiting examples of additional therapeutic agents and/or regimens for treating Crohn's Disease (CD) include adalimumab, autologous CD34-selected peripheral blood stem cells transplant, 6-mercaptopurine, azathioprine, certolizumab pegol (Cimzia®), corticosteroids (e.g., prednisone), etrolizumab, E6011, fecal microbial transplantation, figlotinib, guselkumab, infliximab, IL-2, JAK inhibitors, matrix metalloproteinase 9 (MMP 9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, natalizumab, ozanimod, RHB-104, rifaximin, risankizumab, SHP647, sulfasalazine, thalidomide, upadacitinib, V565, and vedolizumab.
[0327] Non-limiting examples of additional therapeutic agents and/or regimens for treating UC include AbGn-168H, ABT-494, ABX464, apremilast, PF-00547659, PF-06687234, 6-mercaptopurine, adalimumab, azathioprine, bertilimumab, brazikumab (MEDI2070), cobitolimod, certolizumab pegol (Cimzia®), CP-690,550, corticosteroids (e.g., multimax budesonide, Methylprednisolone), cyclosporine, E6007, etrasimod, etrolizumab, fecal microbial transplantation, figlotinib, guselkumab, golimumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9 (MMP9) inhibitors (e.g., GS-5745), mesalamine, mesalamine, mirikizumab (LY3074828), RPC1063, risankizumab (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, tildrakizumab (MK 3222), tofacitinib, tofacitinib, ustekinumab, UTTR1147A, and vedolizumab.
[0328] Non-limiting examples of additional therapeutic agents and/or regimens for treating autoimmune colitis include corticosteroids (e.g., budesonide, prednisone, prednisolone, Beclometasone dipropionate), diphenoxylate/atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012/0202848), and vedolizumab.
[0329] Non-limiting examples of additional therapeutic agents and/or regimens for treating iatrogenic autoimmune colitis include corticosteroids (e.g., budesonide, prednisone, prednisolone, Beclometasone dipropionate), diphenoxylate/atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012/0202848), and vedolizumab.
[0330] Non-limiting examples of additional therapeutic agents and/or regimens for treating colitis induced by one or more chemotherapeutics agents include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), diphenoxylate/atropine, infliximab, loperamide, mesalamine, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012/0202848), and vedolizumab.
[0331] Non-limiting examples of additional therapeutic agents and/or regimens for treating colitis induced by treatment with adoptive cell therapy include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), diphenoxylate/atropine, infliximab, loperamide, TIP60 inhibitors (see, e.g., U.S. Patent Application Publication No. 2012/0202848), and vedolizumab.
[0332] Non-limiting examples of additional therapeutic agents and/or regimens for treating colitis associated with one or more alloimmune diseases include corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), sulfasalazine, and eicopentaenoic acid.
[0333] Non-limiting examples of additional therapeutic agents and/or regimens for treating radiation enteritis include teduglutide, amifostine, angiotensin-converting enzyme (ACE) inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril), probiotics, selenium supplementation, statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin), sucralfate, and vitamin E.
[0334] Non-limiting examples of additional therapeutic agents and/or regimens for treating collagenous colitis include 6-mercaptopurine, azathaioprine, bismuth sub salicate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.
[0335] Non-limiting examples of additional therapeutic agents and/or regimens for treating lymphocytic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), loperamide, mesalamine, methotrexate, and sulfasalazine.
[0336] Non-limiting examples of additional therapeutic agents and/or regimens for treating microscopic colitis include 6-mercaptopurine, azathioprine, bismuth sub salicylate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), fecal microbial transplantation, loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.
[0337] Non-limiting examples of additional therapeutic agents and/or regimens for treating alloimmune disease include intrauterine platelet transfusions, intravenous immunoglobin, maternal steroids, abatacept, alemtuzumab, alpha1-antitrypsin, AMG592, antithymocyte globulin, baricitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, daclizumab, defibrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.
[0338] Non-limiting examples of additional therapeutic agents and/or regimens for treating multiple sclerosis (MS) include alemtuzumab (Lemtrada®), ALKS 8700, amiloride, ATX-MS-1467, azathioprine, baclofen (Lioresal®), beta interferons (e.g., IFN-β-1a, IFN-β-1b), cladribine, corticosteroids (e.g., methylprednisolone), daclizumab, dimethyl fumarate (Tecfidera®), fingolimod (Gilenya®), fluoxetine, glatiramer acetate (Copaxone®), hydroxychloroquine, ibudilast, idebenone, laquinimod, lipoic acid, losartan, masitinib, MD1003 (biotin), mitoxantrone, montelukast, natalizumab (Tysabri®), NeuroVax™, ocrelizumab, ofatumumab, pioglitazone, and RPC1063.
[0339] Non-limiting examples of additional therapeutic agents and/or regimens for treating graft-vs-host disease include abatacept, alemtuzumab, alpha1-antitrypsin, AMG592, antithymocyte globulin, baricitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, daclizumab, defibrotide, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, itacitinib, LBH589, maraviroc, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, pevonedistat, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.
[0340] Non-limiting examples of additional therapeutic agents and/or regimens for treating acute graft-vs-host disease include alemtuzumab, alpha-1 antitrypsin, antithymocyte globulin, basiliximab, brentuximab, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, daclizumab, defibrotide, denileukin diftitox, ibrutinib, infliximab, itacitinib, LBH589, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, photopheresis, ruxolitinib, sirolimus, tacrolimus, and tocilizumab.
[0341] Non-limiting examples of additional therapeutic agents and/or regimens for treating chronic graft vs. host disease include abatacept, alemtuzumab, AMG592, antithymocyte globulin, basiliximab, bortezomib, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, daclizumab, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, mycophenolate mofetil, pentostatin, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.
[0342] Non-limiting examples of additional therapeutic agents and/or regimens for treating celiac disease include AMG 714, AMY01, Aspergillus niger prolyl endoprotease, BL-7010, CALY-002, GBR 830, Hu-Mik-Beta-1, IMGX003, KumaMax, Larazotide Acetate, Nexvan2®, pancrelipase, TIMP-GLIA, vedolizumab, and ZED1227.
[0343] Non-limiting examples of additional therapeutic agents and/or regimens for treating psoriasis include topical corticosteroids, topical crisaborole/AN2728, topical SNA-120, topical SAN021, topical tapinarof, topical tocafinib, topical IDP-118, topical M518101, topical calcipotriene and betamethasone dipropionate (e.g., MC2-01 cream and Taclonex®), topical P-3073, topical LEO 90100 (Enstilar®), topical betamethasone dipropriate (Sernivo®), halobetasol propionate (Ultravate®), vitamin D analogues (e.g., calcipotriene (Dovonex®) and calcitriol (Vectical®)), anthralin (e.g., Dritho-Scalp® and Dritho-crème®), topical retinoids (e.g., tazarotene (e.g., Tazorac® and Avage®)), calcineurin inhibitors (e.g., tacrolimus (Prograf®) and pimecrolimus (Elidel®)), salicylic acid, coal tar, moisturizers, phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrow band UVB phototherapy, Goeckerman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), retinoids (e.g., acitretin (Soriatane®)), methotrexate (Trexall®, Otrexup®, Rasuvo®, Rheumatrex®), Apo805K1, baricitinib, FP187, KD025, prurisol, VTP-43742, XP23829, ZPL-389, CF101 (piclidenoson), LAS41008, VPD-737 (serlopitant), upadacitinib (ABT-494), aprmilast, tofacitibin, cyclosporine (Neoral®, Sandimmune®, Gengraf®), biologics (e.g., etanercept (Enbrel®), entanercept-szzs (Elrezi®), infliximab (Remicade®), adalimumab (Humira®), adalimumab-adbm (Cyltezo®), ustekinumab (Stelara®), golimumab (Simponi®), apremilast (Otezla®), secukinumab (Cosentyx®), certolixumab pegol, secukinumab, tildrakizumab-asmn, infliximab-dyyb, abatacept, ixekizumab (Taltz®), ABP 710, BCD-057, BI695501, bimekizumab (UCB4940), CHS-1420, GP2017, guselkumab (CNTO 1959), HD203, M923, MSB11022, Mirikizumab (LY3074828), PF-06410293, PF-06438179, risankizumab (BI655066), SB2, SB4, SB5, siliq (brodalumab), namilumab (MT203, tildrakizumab (MK-3222), and ixekizumab (Taltz®)), thioguanine, and hydroxyurea (e.g., Droxia® and Hydrea®).
[0344] Non-limiting examples of additional therapeutic agents and/or regimens for treating cutaneous T-cell lymphoma include phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrow band UVB phototherapy, Goeckerman therapy, psoralen plus ultraviolet A (PUVA) therapy, and excimer laser), extracorporeal photopheresis, radiation therapy (e.g., spot radiation and total skin body electron beam therapy), stem cell transplant, corticosteroids, imiquimod, bexarotene gel, topical bis-chloroethyl-nitrourea, mechlorethamine gel, vorinostat (Zolinza®), romidepsin (Istodax®), pralatrexate (Folotyn®) biologics (e.g., alemtuzumab (Campath®), brentuximab vedotin (SGN-35), mogamulizumab, and IPH4102).
[0345] Non-limiting examples of additional therapeutic agents and/or regimens for treating uveitis include corticosteroids (e.g., intravitreal triamcinolone acetonide injectable suspensions), antibiotics, antiviral s (e.g., acyclovir), dexamethasone, immunomodulators (e.g., tacrolimus, leflunomide, cyclophosphamide (Cytoxan®, Neosar®, Endoxan®), and cyclosporine (Neoral®, Sandimmune®, Gengraf®), chlorambucil, azathioprine, methotrexate, and mycophenolate mofetil), biologics (e.g., infliximab (Remicade®), adalimumab (Humira®), etanercept (Enbrel®), golimumab (Simponi®), certolizumab (Cimzia®), rituximab (Rituxan®), abatacept (Orencia®), basiliximab (Simulect®), anakinra (Kineret®), canakinumab (Ilaris®), gevokixumab (XOMA052), tocilizumab (Actemra®), alemtuzumab (Campath®), efalizumab (Raptiva®), LFG316, sirolimus (Santen®), abatacept, sarilumab (Kevzara®), and daclizumab (Zenapax®)), cytotoxic drugs, surgical implant (e.g., fluocinolone insert), and vitrectomy.
[0346] on-limiting examples of additional therapeutic agents and/or regimens for treating mucositis include AG013, SGX942 (dusquetide), amifostine (Ethyol®), cryotherapy, cepacol lozenges, capsaicin lozenges, mucoadhesives (e.g., MuGard®) oral diphenhydramine (e.g., Benadryl® elixir), oral bioadherents (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, Chamomilla recutita mouthwash, edible grape plant exosome, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periogard®), topical pain relievers (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), pain killers (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble 0-1,3/1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, granules comprising Vaccinium myrtillus extract, Macleaya cordata alkaloids and Echinacea angustifolia extract (e.g., SAMITAL®), and gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)). For example, non-limiting examples of treatments for oral mucositis include AG013, amifostine (Ethyol®), cryotherapy, cepacol lozenges, mucoadhesives (e.g., MuGard®) oral diphenhydramine (e.g., Benadryl® elixir), oral bioadherents (e.g., polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®)), oral lubricants (e.g., Oral Balance®), caphosol, Chamomilla recutita mouthwash, edible grape plant exosome, antiseptic mouthwash (e.g., chlorhexidine gluconate (e.g., Peridex® or Periogard®), topical pain relievers (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., viscous xylocaine 2%), and Ulcerease® (0.6% phenol)), corticosteroids (e.g., prednisone), pain killers (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor; Kepivance®), ATL-104, clonidine lauriad, IZN-6N4, SGX942, rebamipide, nepidermin, soluble β-1,3/1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, and gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)). As another example, non-limiting examples of treatments for esophageal mucositis include xylocaine (e.g., gel viscous Xylocaine 2%). As another example, treatments for intestinal mucositis, treatments to modify intestinal mucositis, and treatments for intestinal mucositis signs and symptoms include gastrointestinal cocktail (an acid reducer such aluminum hydroxide and magnesium hydroxide (e.g., Maalox), an antifungal (e.g., nystatin), and an analgesic (e.g., hurricane liquid)).
[0347] In certain embodiments, the second therapeutic agent or regimen is administered to the subject prior to contacting with or administering the chemical entity (e.g., about one hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, or about 1 week prior, or about 1 month prior).
[0348] In other embodiments, the second therapeutic agent or regimen is administered to the subject at about the same time as contacting with or administering the chemical entity. By way of example, the second therapeutic agent or regimen and the chemical entity are provided to the subject simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the chemical entity are provided to the subject concurrently in separate dosage forms.
[0349] In still other embodiments, the second therapeutic agent or regimen is administered to the subject after contacting with or administering the chemical entity (e.g., about one hour after, or about 6 hours after, or about 12 hours after, or about 24 hours after, or about 48 hours after, or about 1 week after, or about 1 month after).
[0350] Patient Selection
[0351] In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of such treatment (e.g., by way of biopsy, endoscopy, or other conventional method known in the art). In certain embodiments, the STING protein can serve as a biomarker for certain types of cancer, e.g., colon cancer and prostate cancer. In other embodiments, identifying a subject can include assaying the patient's tumor microenvironment for the absence of T-cells and/or presence of exhausted T-cells, e.g., patients having one or more cold tumors. Such patients can include those that are resistant to treatment with checkpoint inhibitors. In certain embodiments, such patients can be treated with a chemical entity herein, e.g., to recruit T-cells into the tumor, and in some cases, further treated with one or more checkpoint inhibitors, e.g., once the T-cells become exhausted.
[0352] In some embodiments, the chemical entities, methods, and compositions described herein can be administered to certain treatment-resistant patient populations (e.g., patients resistant to checkpoint inhibitors; e.g., patients having one or more cold tumors, e.g., tumors lacking T-cells or exhausted T-cells).
[0353] Compound Preparation
[0354] As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and R G M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available. The skilled artisan will also recognize that conditions and reagents described herein that can be interchanged with alternative art-recognized equivalents. For example, in many reactions, triethylamine can be interchanged with other bases, such as non-nucleophilic bases (e.g. diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).
[0355] The skilled artisan will recognize a variety of analytical methods that can be used to characterize the compounds described herein, including, for example, .sup.1H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The foregoing list is a subset of characterization methods available to a skilled artisan and is not intended to be limiting.
[0356] To further illustrate the foregoing, the following non-limiting, exemplary synthetic schemes are included. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled artisan, provided with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples.
EXAMPLES
LCMS Analysis Condition
[0357] LCMS Method A: Kinetex EVO C18 100A, 30*3 mm, 0.5 μL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH.sub.4HCO.sub.3 and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.0 min, hold at 95% MPB for 0.3 min, 95% MPB to 10% in 0.1 min.
[0358] LCMS Method B:)(Bridge Shield RP18, 50*4.6 mm, 0.5 μL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.04% NH3.Math.H2O and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.79 min, 95% MPB to 10% in 0.06 min, then equilibration to 10% MPB for 0.15 min.
[0359] LCMS Method C: Shim-pack XR-ODS, 50*3 mm, 0.3 μL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.05 TFA and Mobile Phase B (MPB): Acetonitrile/0.05% TFA. Elution 5% MPB to 100% in 1.10 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.25 min.
[0360] LCMS Method D: Kinetex 2.6 um EVO C18 100A, 50*3 mm, 0.6 μL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH.sub.4HCO.sub.3 and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 1.20 min, hold at 95% MPB for 0.50 min, 95% MPB to 10% in 0.05 min, then equilibration to 10% MPB for 0.10 min.
[0361] LCMS Method E: EVO C18, 50*3 mm, 0.1 μL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH.sub.4HCO.sub.3 and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.60 min, 95% MPB to 10% in 0.15 min, then equilibration to 10% MPB for 0.25 min.
[0362] LCMS Method F:)(Bridge BEH C18, 50*3 mm, 4.0 μL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/5 mM NH.sub.4HCO.sub.3 and Mobile Phase B (MPB): Acetonitrile. Elution 5% MPB to 95% in 2.00 min, hold at 95% MPB for 0.70 min, 95% MPB to 5% in 0.05 min, then equilibration to 5% MPB for 0.25 min.
[0363] LCMS Method G: HALOC18, 30*3 mm, 0.5 μL injection, 1.5 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.05% TFA and Mobile Phase B (MPB): Acetonitrile/0.05% TFA. Elution 5% MPB to 100% in 1.20 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% in 0.02 min, then equilibration to 5% MPB for 0.18 min.
[0364] LCMS Method H: HPH-C18, 50*3 mm, 3.0 μL injection, 1.2 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.04% NH.sub.4OH and Mobile Phase B (MPB): Acetonitrile. Elution 10% MPB to 95% in 2.00 min, hold at 95% MPB for 0.70 min, 95% MPB to 10% in 0.05 min, then equilibration to 5% MPB for 0.25 min.
[0365] LCMS Method I: HALOC18, 30*3 mm, 0.5 μL injection, 1.5 mL/min flowrate, 30-2000 amu scan range, 254 nm UV detection. Mobile Phase A (MPA): Water/0.1% FA and Mobile Phase B (MPB): Acetonitrile/0.1% FA. Elution 5% MPB to 100% in 1.20 min, hold at 100% MPB for 0.60 min, 100% MPB to 5% in 0.02 min, then equilibration to 5% MPB for 0.18 min.
Method BA
[0366] Instrument: Agilent LCMS system equipped with DAD and ELSD detector [0367] Ion mode: Positive [0368] Column: Waters X-Bridge C18, 50*2.1 mm*5 μm or equivalent [0369] Mobile Phase: A: H.sub.2O (0.04% TFA); B: CH.sub.3CN (0.02% TFA) [0370] Gradient: 4.5 min gradient method, actual method would depend on c log P of compound. [0371] Flow Rate: 0.6 mL/min or 0.8 mL/min [0372] Column Temp: 40° C. or 50° C. [0373] UV: 220 nm
Method BB
[0374] Instrument: Agilent LCMS system equipped with DAD and ELSD detector [0375] Ion mode: Positive [0376] Column: Waters X-Bridge ShieldRP18, 50*2.1 mm*5 μm or equivalent [0377] Mobile Phase: A: H.sub.2O (0.05% NH.sub.3.Math.H.sub.2O) or 10 mM ammonia bicarbonate; B: CH.sub.3CN Gradient: 4.5 min gradient method; actual method would depend on the c log P of the compound. [0378] Flow Rate: 0.6 mL/min or 0.8 mL/min [0379] Column Temp: 40° C. [0380] UV: 220 nm
Prep. HPLC condition
Instrument:
[0381] 1. GILSON 281 and Shimadzu LCMS 2010A [0382] 2. GILSON 215 and Shimadzu LC-20AP [0383] 3. GILSON 215
Mobile Phase:
[0384] A: NH.sub.4OH/H.sub.2O=0.05% v/v; B: ACN [0385] A: FA/H.sub.2O=0.225% v/v; B: ACN
Column
[0386] Xtimate C18 150*25 mm*5 μm; Flow rate: 25 mL/min or 30 mL/min; Monitor wavelength: 220&254 nm; Gradient: actual method would depend on clog P of compound; Detector: MS Trigger or UV
[0387] NMR Method A: NMR was recorded on BRUKER NMR 300.03 Mz, DUL-C-H, ULTRASHIELD™ 300, AVANCE II 300 B-ACS™ 120 or BRUKER NMR 400.13 Mz, BBFO, ULTRASHIELD™ 400, AVANCE III 400, B-ACS™ 120.
Abbreviations
[0388]
TABLE-US-00002 Ac = acetyl Me = methyl ACN = acetonitrile MeOH = methanol AgNO.sub.3 = silver(I) nitrate Na.sub.2CO.sub.3 = sodium carbonate Boc.sub.2O = Di-tert-butyl Na.sub.2SO.sub.4 = sodium sulfate dicarbonate NMR = nuclear magnetic Bu = butyl; Bz = benzoyl resonance Cs.sub.2CO.sub.3 = Cesium Carbonate P(t-Bu)3 Pd G2 = Chloro[(tri- CuI = Copper (I) iodide tert-butylphosphine)-2- DCM = dichloromethane (2-aminobiphenyl)]palladium(II) DMF = N,N- Parallel synthesizer = ZHCHENG dimethylformamide ZWY-113H40 DMSO = dimethyl sulfoxide Pd(CH3CN)2Cl2 = Bis(acetonitrile) DPPA = diphenyl palladium(II)chloride azidophosphate Pd(dppf)Cl.sub.2 .Math. DCM = 1,1′-Bis Dppf = bis(diphenylphosphino) (diphenylphosphino)ferrocene ferrocene palladium dichloride, EDCI = N-(3-dimethyl- dichloromethane complex aminopropyl)-N- Py = pyridine ethylcarbodiimide RT = retention time hydrochloride SnCl.sub.2 = Tin(II) chloride EtOAc = Ethyl acetate Speedvac = Savant SC250EXP FA = formic acid SpeedVac Concentrator H.sub.2O = Water Sphos = dicyclohexyl-[2-(2,6- HOPO = 2-Hydroxypyridine- dimethoxyphenyl)phenyl] N-Oxide phosphane HPLC = high performance T.sub.3P = 2,4,6-tripropyl- liquid chromatography 2,4,6-trioxo-1,3,5,2,4,6- HPLC = high-performance trioxatriphosphorinane liquid chromatography TBAF = Tetrabutylammonium K.sub.2CO.sub.3 = Potassium carbonate fluoride K.sub.3PO.sub.4 = Potassium phosphate TEA = triethylamine LCMS = liquid TFA = trifluoroacetic acid chromatography-mass THF = tetrahydrofuran spectrometry TIPSCl = chlorotriisopropylsilane LC-MS = liquid TMSOK = Potassium chromatography-mass trimethylsilanolate spectrometry XPhos = (2-(2,4,6- HATU = N- triisopropylphenethyl)phenyl) [(Dimethylamino)- dicyclohexylphosphine 1H-1,2,3-triazolo-[4,5-b] Xphos Pd G3 = Methanesulfonato pyridin-1-ylmethylene]-N- (2-dicyclohexylphosphino-2,4,6- methylmethanaminium tri-i-propyl-1,1-biphenyl)(2-amino- hexafluorophosphate N-oxide 1,1-biphenyl-2-yl)palladium(II)
Preparative Examples
Synthesis of Intermediates
Synthesis of Intermediate 1: (N-(5-bromo-1H-indol-3-yl)propionamide and
Intermediate 2: N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)propionamide)
[0389] ##STR00236##
Synthesis of 5-bromo-1H-indole-3-carbonyl Azide
[0390] 5-Bromo-1H-indole-3-carboxylic acid (1.0 g, 4.2 mmol, 1.0 equiv.) was dissolved in THF (10.0 mL), then DPPA (2.3 g, 8.3 mmol, 2.0 equiv.) and TEA (1.8 mL, 12.5 mmol, 3.0 equiv.) were added. The resulting solution was stirred overnight at ambient temperature and then concentrated under vacuum. The residue was diluted with MeOH and the isolated solids were collected by filtration to give 5-bromo-1H-indole-3-carbonyl azide (900 mg) as a white solid. LCMS Method F: [M+H].sup.+=265.
Synthesis of tert-butyl N-(5-bromo-1H-indol-3-yl)carbamate
[0391] 5-Bromo-1H-indole-3-carbonyl azide (900.0 mg, 3.4 mmol, 1.0 equiv.) was dissolved in t-BuOH (6.0 mL). The resulting solution was stirred overnight at 80° C. and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl N-(5-bromo-1H-indol-3-yl)carbamate (910 mg) as a yellow solid. LCMS Method F: [M+H].sup.+=311.
Synthesis of 5-bromo-1H-indol-3-amine Hydrogen Chloride
[0392] tert-Butyl N-(5-bromo-1H-indol-3-yl)carbamate (1.0 g, 3.2 mmol, 1.0 equiv.) was dissolved in HCl (4M in 1,4-dioxane, 20.0 mL). The resulting solution was stirred overnight at ambient temperature and then concentrated under vacuum to give 5-bromo-1H-indol-3-amine hydrogen chloride (500.0 mg) as a green solid. LCMS Method A: [M+H].sup.+=211.
Synthesis of N-(5-bromo-1H-indol-3-yl)propanamide
[0393] 5-Bromo-1H-indol-3-amine hydrogen chloride (5.0 g, 23.7 mmol, 1.0 equiv.) and TEA (13.3 mL, 94.8 mmol, 4.0 equiv.) were dissolved in DCM (50.0 mL) and the solution cooled to 0° C. Then propanoyl chloride (5.2 mL, 59.2 mmol, 2.5 equiv.) was added dropwise, maintaining the internal temperature at 0° C. The reaction mixture was stirred for 16 hours at ambient temperature and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give N-(5-bromo-1H-indol-3-yl)propanamide (3.8 g) as a yellow solid. LCMS Method A: [M+H].sup.+=267.
Synthesis of N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)propionamide
[0394] N-(5-bromo-1H-indol-3-yl)propanamide (500.0 mg, 1.9 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (5.0 mL), then bis(pinacolato)diboron (1.4 g, 5.6 mmol, 3.0 equiv.), AcOK (367.4 mg, 3.7 mmol, 2.0 equiv.) and Pd(dppf)Cl.sub.2 (273.9 mg, 0.4 mmol, 0.2 equiv.) were added under nitrogen. The reaction mixture was heated to 80° C. for 4 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl]propanamide (480 mg) as a pale yellow solid. LCMS Method B: [M+H].sup.+=315.
[0395] The following intermediate was prepared using the same method described for Intermediate 1.
TABLE-US-00003 Intermediate Starting material Used Structure LCMS data Intermediate 3
Synthesis of Intermediate 4 (N-(5-bromo-M-indol-3-yl)cyclobutanecarboxamide)
[0396] ##STR00241##
[0397] 5-Bromo-1H-indol-3-amine hydrogen chloride (250.0 mg, 1.2 mmol, 1.0 equiv.) was dissolved in THF (15.0 mL), then cyclobutene carboxylic acid (118.6 mg, 1.2 mmol, 1.0 equiv.), TEA (0.5 mL, 3.6 mmol, 3.0 equiv.) and T3P (753.8 mg, 2.4 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 5 hours at ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give N-(5-bromo-1H-indol-3-yl)cyclobutanecarboxamide (290 mg) as a pale yellow solid. LCMS Method A: [M+H].sup.+=293.
Synthesis of intermediate 5 (4-bromo-1-(3-ethylphenyl)-1H-pyrazole)
[0398] ##STR00242##
[0399] 3-Ethylphenylboronic acid (500.0 mg, 3.3 mmol, 1.0 equiv.) and 4-bromopyrazole (490.0 mg, 3.3 mmol, 1.0 equiv.) were dissolved in DCM (20.0 mL), then Cu(AcO).sub.2 (1.2 g, 6.7 mmol, 2.0 equiv.) and pyridine (0.3 mL, 4.0 mmol, 1.2 equiv.) were added under nitrogen. The resulting solution was stirred for 16 hours at ambient temperature and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 4-bromo-1-(3-ethylphenyl)pyrazole (450 mg) as a pale yellow solid. LCMS Method A: [M+H].sup.+=251.
[0400] The following intermediates were prepared using the same method described for Intermediate 5.
TABLE-US-00004 Intermediate Starting material Structure LCMS data Intermediate 6
Synthesis of Intermediate 10 (1-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole)
[0401] ##STR00254##
Synthesis of 4-bromo-1-(4-ethylphenyl)-1H-pyrazole
[0402] 4-Ethylphenylboronic acid (10.0 g, 66.7 mmol, 1.0 equiv.) and 4-bromopyrazole (9.8 g, 66.7 mmol, 1.0 equiv.) were dissolved in DCM (300.0 mL), then Cu(OAc).sub.2 (24.2 g, 133.4 mmol, 2.0 equiv.) and pyridine (2.1 mL, 26.7 mmol, 2.0 equiv.) were added under nitrogen. The reaction mixture was stirred overnight at ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give 4-bromo-1-(4-ethylphenyl)pyrazole (9.5 g) as a white solid. LCMS Method F: [M+H].sup.+=251.
Synthesis of 1-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
[0403] 4-Bromo-1-(4-ethylphenyl)pyrazole (9.5 g, 37.8 mmol, 1.0 equiv.) was dissolved in dioxane (200.0 ml), then bis(pinacolato)diboron (9.6 g, 37.8 mmol, 1.0 equiv.), AcOK (7.4 g, 75.7 mmol, 2.0 equiv.) and Pd(dppf)Cl.sub.2 (5.5 g, 7.6 mmol, 0.2 equiv.) were added under nitrogen. The reaction mixture was stirred overnight at 80° C., then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give 1-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.0 g) as a yellow solid. LCMS Method D: [M+H].sup.+=299.
[0404] The following intermediates were prepared using the same method described for Intermediate 10.
TABLE-US-00005 Starting material Intermediate Used Structure LCMS data Intermediate 11
Synthesis of Intermediate 13 (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3-(trifluoromethyl)benzyl)-1H-pyrazole)
[0405] ##STR00261##
Synthesis of 4-bromo-1-(3-(trifluoromethyl)benzyl)-1H-pyrazole
[0406] 4-Bromopyrazole (500.0 mg, 3.4 mmol, 1.0 equiv.) was dissolved in DMF (20.0 mL), then K.sub.2CO.sub.3 (940.3 mg, 6.8 mmol, 2.0 equiv.) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (813.2 mg, 3.4 mmol, 1.0 equiv.) were added. The reaction mixture was heated to 85° C. for 4 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 4-bromo-1-[[3-(trifluoromethyl)phenyl]methyl]pyrazole (480 mg) as a pale yellow solid. LCMS Method A: [M+H].sup.+=305.
Synthesis of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3-(trifluoromethyl)benzyl)-1H-pyrazole
[0407] 4-Bromo-1-[[3-(trifluoromethyl)phenyl]methyl]pyrazole (500.0 mg, 1.6 mmol, 1.0 equiv.) was dissolved in dioxane (6.0 mL), then bis(pinacolato)diboron (1.2 g, 4.9 mmol, 3.0 equiv.), AcOK (482.5 mg, 4.9 mmol, 3.0 equiv.) and Pd(dppf)Cl.sub.2 (239.8 mg, 0.3 mmol, 0.2 equiv.) were added under nitrogen. The resulting solution was heated to 85° C. for 4 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[[3-(trifluoromethyl)phenyl]methyl]pyrazole (510 mg) as a pale yellow solid. LCMS Method A: [M+H].sup.+=353.
Synthesis of Intermediate 14 (2-ethyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine)
[0408] ##STR00262##
Synthesis of 5-(4-bromo-1H-pyrazol-1-yl)-2-ethylpyridine
[0409] 4-Bromopyrazole (1.0 g, 6.8 mmol, 1.0 equiv.) and 5-bromo-2-ethylpyridine (1.3 g, 6.8 mmol, 1.0 equiv.) was dissolved in DMF (5.0 mL), then Ni, N2-dimethylcyclohexane-1,2-diamine (0.3 mL, 2.0 mmol, 0.3 equiv.), K.sub.3PO.sub.4 (2.9 g, 13.6 mmol, 2.0 equiv.) and CuI (388.7 mg, 2.0 mmol, 0.3 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 90° C. for 16 hours and then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give 5-(4-bromopyrazol-1-yl)-2-ethylpyridine (380 mg) as a pale yellow solid. LCMS Method A: [M+H].sup.+=252.
Synthesis of 2-ethyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine
[0410] 5-(4-bromopyrazol-1-yl)-2-ethylpyridine (380.0 mg, 1.5 mmol, 1.0 equiv.) and bis(pinacolato)diboron (1.1 g, 4.5 mmol, 3.0 equiv.) were dissolved in 1,4-dioxane (5.0 mL), then AcOK (295.9 mg, 3.0 mmol, 2.0 equiv.), Pd(dppf)Cl.sub.2 (220.6 mg, 0.3 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 85° C. for 4 hours and then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:4) to give 2-ethyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyridine (300 mg) as a pale yellow solid. LCMS Method A: [M+H].sup.+=230.
Synthesis of Intermediate 15 (4-(4-bromophenyl)-1-isopropyl-1H-pyrazole)
[0411] ##STR00263##
[0412] 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (500.0 mg, 2.1 mmol, 1.0 equiv.) and 4-bromoiodobenzene (898.6 mg, 3.2 mmol, 1.5 equiv.) were dissolved in dioxane (5.0 mL) and water (0.2 mL), then Pd(dppf)Cl.sub.2 (154.9 mg, 0.2 mmol, 0.1 equiv.) and K.sub.2CO.sub.3 (585.3 mg, 4.2 mmol, 2.0 equiv.) were added under nitrogen. The reaction mixture was heated to 80° C. for 3 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:8) to give 4-(4-bromophenyl)-1-isopropylpyrazole (230 mg) as a yellow solid. LCMS Method E: [M+H].sup.+=265.
Synthesis of Intermediate 16 (2-(4-bromo-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyridine)
[0413] ##STR00264##
[0414] 4-bromopyrazole (267.1 mg, 1.8 mmol, 1.0 equiv.) was dissolved in THF (20.0 mL), and the solution cooled to 0° C. Then NaH (60% wt in mineral oil, 242.3 mg, 3.6 mmol, 2.0 equiv.) and 2-fluoro-5-(trifluoromethyl)pyridine (300.0 mg, 1.8 mmol, 1.0 equiv.) were added in portions, maintaining the internal temperature at 0° C. The reaction mixture was stirred for 2 hours at ambient temperature and quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 2-(4-bromopyrazol-1-yl)-5-(trifluoromethyl)pyridine (500 mg) as a pale yellow solid. LCMS Method E: [M+H].sup.+=292.
[0415] The following intermediate was prepared using the same method as described for Intermediate 14 above.
TABLE-US-00006 Starting material Intermediate Used Structure LCMS data Intermediate 20
Synthesis of Intermediate 17 (N-(5-bromo-7-fluoro-1H-indol-3-yl)propionamide)
[0416] ##STR00267##
Step 1: 5-bromo-7-fluoro-3-nitro-1H-indole
[0417] 5-Bromo-7-fluoro-1H-indole (500.0 mg, 2.3 mmol, 1.0 equiv.) was dissolved in ACN (10 mL) and cooled to 0° C., then AgNO.sub.3 (595.3 mg, 3.5 mmol, 1.5 equiv.) and BzCl (0.4 mL, 3.5 mmol, 1.5 equiv.) were added, maintaining the mixture at 0° C. The reaction mixture was stirred for 3 hours at ambient temperature, then quenched by the addition of water. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give 5-bromo-7-fluoro-3-nitro-1H-indole (250 mg) as a brown solid. LCMS Method C: [M+H].sup.+=259.
Step 2: tert-butyl N-(5-bromo-7-fluoro-1H-indol-3-yl)carbamate
[0418] 5-Bromo-7-fluoro-3-nitro-1H-indole (250.0 mg, 1.0 mmol, 1.0 equiv.) and (Boc).sub.2O (252.8 mg, 1.2 mmol, 1.2 equiv.) were dissolved in MeOH (5 mL) and cooled to 0° C., then NaBH.sub.4 (73.0 mg, 1.9 mmol, 2.0 equiv.) and NiCl.sub.2 (250.2 mg, 1.9 mmol, 2.0 equiv.) were added, maintaining the mixture at 0° C. The resulting mixture was stirred for 0.5 hour at 0° C. and then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give tert-butyl N-(5-bromo-7-fluoro-1H-indol-3-yl)carbamate (30.0 mg) as a brown solid. LCMS Method A: [M+H].sup.+=329.
Step 3: 5-bromo-7-fluoro-1H-indol-3-amine
[0419] tert-Butyl (5-bromo-7-fluoro-1H-indol-3-yl)carbamate (780.0 mg, 2.4 mmol, 1.0 equiv.) was dissolved in HCl in 1,4-dioxane (4 M, 8 mL). The resulting solution was stirred for 4 hours at ambient temperature, then concentrated under vacuum. The resulting solid was washed with a mixture of ethyl acetate and petroleum ether (1:2) to give 5-bromo-7-fluoro-1H-indol-3-amine hydrogen chloride (640 mg) as a brown solid. LCMS Method A: [M+H].sup.+=229.
Step 4: N-(5-bromo-7-fluoro-1H-indol-3-yl)propionamide
[0420] 5-Bromo-7-fluoro-1H-indol-3-amine (590.0 mg, 2.6 mmol, 1.0 equiv.) and TEA (1.4 mL, 10.3 mmol, 4.0 equiv.) were dissolved in DCM (10 mL), then propionyl chloride (0.3 mL, 3.1 mmol, 1.2 equiv.) was added. The reaction mixture was stirred for 3 hours at ambient temperature, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:20) to give N-(5-bromo-7-fluoro-1H-indol-3-yl) propionamide (610 mg) as a dark grey solid. LCMS Method A: [M+H].sup.+=285.
Synthesis of Intermediate 22 (5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-amine)
[0421] ##STR00268##
Step 1: tert-butyl N-(5-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate
[0422] tert-Butyl N-[5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl]carbamate (300.0 mg, 1.0 mmol, 1.0 equiv.) was dissolved in 1,4-dioxane (5 mL) and water (0.5 mL), then 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[4-(trifluoromethyl)phenyl]pyrazole (325.0 mg, 1.0 mmol, 1.0 equiv.), Cs.sub.2CO.sub.3 (626.2 mg, 1.9 mmol, 2.0 equiv.) and Pd(dppf)Cl.sub.2 (140.6 mg, 0.2 mmol, 0.2 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 80° C. for 4 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:5) to give tert-butyl N-(5-[1-[4-(trifluoromethyl) phenyl] pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-3-yl) carbamate (400 mg) as a light yellow solid. LCMS Method A: [M+H].sup.+=444.
Step 2: 5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-amine hydrogen chloride
[0423] tert-Butyl N-(5-[1-[4-(trifluoromethyl) phenyl] pyrazol-4-yl]-1H-pyrrolo[3,2-b] pyridin-3-yl) carbamate (410.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in HCl in 1,4-dioxane (4 M, 8 mL). The resulting solution was stirred for 1 hour at ambient temperature, then concentrated under vacuum to give 5-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-3-amine hydrogen chloride (420 mg) as a pale yellow crude solid. LCMS Method A: [M+H].sup.+=344.
[0424] The following intermediates were prepared using the same method described for Intermediate 22.
TABLE-US-00007 Starting Intermediate material A Starting material B Structure LCMS data Intermediate 21
Synthesis of Intermediate 24 (5-(1-(4-(2,2,2-trifluoroethoxy)phenyl)-1H-pyrazol-4-yl)-1H-indol-3-amine)
[0425] ##STR00275##
Step 1: tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)carbamate
[0426] tert-Butyl (5-bromo-1H-indol-3-yl)carbamate (1.8 g, 5.8 mmol, 1.0 equiv.) and bis(pinacolato)diboron (2.6 g, 10.1 mmol, 1.7 equiv.) were dissolved in 1,4-dioxane (40 mL), then KOAc (1.3 g, 13.4 mmol, 2.0 equiv.) and Pd(dppf)Cl.sub.2 (0.5 g, 0.7 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 90° C. for 12 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:3) to give tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)carbamate (800 mg) as a white solid. LCMS Method A: [M+H].sup.+=359.
Step 2: tert-butyl N-(5-[1-[4-(2,2,2-trifluoroethoxy)phenyl]pyrazol-4-yl]-1H-indol-3-yl)carbamate
[0427] tert-Butyl N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl]carbamate (1.1 g, 2.9 mmol, 1.2 equiv.) and 4-bromo-1-[4-(2,2,2-trifluoroethoxy)phenyl]pyrazole (800.0 mg, 2.5 mmol, 1.0 equiv.) were dissolved in 1,4-dioxane (16 mL) and water (2 mL), then Cs.sub.2CO.sub.3 (1.6 g, 4.9 mmol, 2.0 equiv.) and Pd(dppf)Cl.sub.2 (182.3 mg, 0.3 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 90° C. for 8 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:2) to give tert-butyl N-(5-[1-[4-(2,2,2-trifluoroethoxy)phenyl]pyrazol-4-yl]-1H-indol-3-yl)carbamate (800 mg) as a white solid. LCMS Method A: [M+H].sup.+=473.
[0428] Step 3: 5-[1-[4-(2,2,2-trifluoroethoxy)phenyl]pyrazol-4-yl]-1H-indol-3 amine Hydrogen Chloride
[0429] tert-Butyl N-(5-[1-[4-(2,2,2-trifluoroethoxy)phenyl]pyrazol-4-yl]-1H-indol-3-yl)carbamate (500.0 mg, 1.1 mmol, 1.0 equiv.) was dissolved in DCM (10 mL), then HCl in 1,4-dioxane (4M, 5 mL) was added. The reaction mixture was stirred for 4 hours at ambient temperature, then concentrated under vacuum to give 5-[1-[4-(2,2,2-trifluoroethoxy)phenyl]pyrazol-4-yl]-1H-indol-3-amine (300 mg) as a yellow solid. LCMS Method A: [M+H].sup.+=373.
Synthesis of Intermediate 26 (tert-butyl (5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)carbamate)
[0430] ##STR00276##
Step 1: 5-bromo-1H-pyrrolo[3,2-b]pyridine-3-carbonyl Azide
[0431] 5-Bromo-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (1.0 g, 4.1 mmol, 1.0 equiv.) was dissolved in THF (20 mL), then TEA (1.7 mL, 12.4 mmol, 3.0 equiv.) and DPPA (1.7 g, 6.2 mmol, 1.5 equiv.) were added. The reaction mixture was stirred overnight at ambient temperature and concentrated under vacuum to give 5-bromo-1H-pyrrolo[3,2-b]pyridine-3-carbonyl azide (1.1 g) as a white solid. LCMS Method A: [M+H].sup.+=266.
Step 2: tert-butyl N-[5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl]carbamate
[0432] 5-Bromo-1H-pyrrolo[3,2-b]pyridine-3-carbonyl azide (1.0 g, 3.8 mmol, 1.0 equiv.) was dissolved in t-BuOH (20 mL). The reaction mixture was heated to 90° C. for 12 hours, then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give tert-butyl N-[5-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl]carbamate (590 mg) as a white solid. LCMS Method D: [M+H].sup.+=312.
Synthesis of Intermediate 27 (tert-butyl 5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-1H-indol-3-amine)
[0433] ##STR00277##
[0434] tert-butyl N-[5-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-indol-3-yl]carbamate (7 g, 15.82 mmol, 1.0 equiv.) was dissolved in DCM (140 mL), then TFA (35.1 mL, 474.7 mmol, 30 equiv.) was added. The mixture was heated at 30° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to remove solvent to give 5-[1-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]-1H-indol-3-amine (5.0 g, 14.6 mmol, 92% yield) which was used into the next step without further purification.
Example 1: Synthesis of N-(5-(3-(methoxymethyl)phenyl)-1H-indol-3-yl)propionamide (Compound 145)
Synthesis of 5-bromo-3-nitro-1H-indole
[0435] ##STR00278##
[0436] 5-bromo-1H-indole (19.5 g, 99.47 mmol, 1 equiv.) was dissolved in ACN (200 mL) and cooled to 0° C. Then AgNO.sub.3 (18.59 g, 109.41 mmol, 1.1 equiv.) was added portionwise over 3 min, maintaining the temperature at 0° C. After addition, the mixture was stirred at 0° C. for 5 min, and then benzoyl chloride (15.38 g, 109.41 mmol, 12.71 mL, 1.1 equiv.) was added dropwise, maintaining the temperature at 0° C. The resulting mixture was stirred at 30° C. for 16 hours. The reaction mixture was adjusted to pH 8 by dropwise addition of 1 M aqueous Na.sub.2CO.sub.3 1 M solution at 25° C., then the mixture was extracted with EtOAc (150 mL). The combined organic layers were washed with 1 M aqueous Na.sub.2CO.sub.3 solution (300 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give 5-bromo-3-nitro-1H-indole (21 g, 87.14 mmol), which was used in the next step without further purification.
Synthesis of 5-bromo-1H-indol-3-amine
[0437] ##STR00279##
[0438] 5-bromo-3-nitro-1H-indole (20 g, 82.97 mmol, 1 equiv.) was dissolved in HBr/H.sub.2O (200 mL, 40% HBr in water), then SnCl.sub.2 (78.82 g, 414.87 mmol, 5 equiv.) was added in one portion. The mixture was stirred at 30° C. for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 5-bromo-1H-indol-3-amine (13 g, 61.59 mmol), which was used in the next step without further purification.
Synthesis of N-(5-bromo-1H-indol-3-yl)propionamide
[0439] ##STR00280##
[0440] 5-bromo-1H-indol-3-amine (2 g, 9.48 mmol, 1 equiv.) dissolved in DCM (100 mL) and cooled to 0° C. Then TEA (37.90 mmol, 5.28 mL, 4 equiv.) was added, followed by propionoyl chloride (876.8 mg, 9.48 mmol, 876.8 μl, 1 equiv.), maintaining the temperature at 0° C. The mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure give N-(5-bromo-1H-indol-3-yl)propanamide (4 g, 15 mmol), which was used in the next step without further purification.
Synthesis of N-(5-(3-(methoxymethyl)phenyl)-1H-indol-3-yl)propionamide
[0441] ##STR00281##
[0442] N-(5-bromo-1H-indol-3-yl)propionamide (crude, 69.2 mg, 0.26 mmol, 1.0 equiv.) and (3-(methoxymethyl)phenyl)boronic acid (64.7 mg, 0.39 mmol, 1.5 equiv.) were dissolved in 1,4-dioxane (4.0 mL). Then aqueous Cs.sub.2CO.sub.3 (2 M, 0.26 mL, 0.52 mmol, 2.0 equiv.) and Pd(dppf)Cl.sub.2.Math.DCM (9.5 mg, 0.013 mmol, 0.05 equiv.) were added under an atmosphere of nitrogen. The mixture was shaken at 120° C. for 16 hours. 3.0 mL water was added to the reaction mixture and then extracted with EtOAc. The combined organic layers were concentrated by Speedvac and the residue was purified by prep HPLC to give N-(5-(3-(methoxymethyl)phenyl)-1H-indol-3-yl)propionamide (20.9 mg, 67.5 μmol). MS-ESI, 308.9 [M+H.sup.+]. 1-E1 NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.81 (s, 1H), 9.87 (s, 1H), 8.15 (s, 1H), 7.77 (d, 1H), 7.67-7.56 (m, 2H), 7.47-7.35 (m, 3H), 7.25 (d, 1H), 4.49 (s, 2H), 3.34 (s, 3H), 2.41 (q, 2H), 1.13 (t, 3H)
[0443] The compounds in the following table were prepared using the above procedure.
TABLE-US-00008 LC-MS, MS-ESI,- [M + H.sup.+]Met Example Compound hods # # Structure IUPAC Name BA/BB. 2 146
Example 8: Synthesis of N-(5-(1-phenyl-M-pyrazol-4-yl)-1H-indol-3-yl)propionamide (Compound 150)
[0444] ##STR00288##
[0445] N-(5-bromo-1H-indol-3-yl)propionamide (64.1 mg, 0.24 mmol, 1.0 equiv.) and (1-phenyl-1H-pyrazol-4-yl)boronic acid (67.7 mg, 0.36 mmol, 1.5 equiv.) were dissolved in 1,4-dioxane (4.0 mL). Then aqueous K.sub.3PO.sub.4 (2 M, 0.24 mL, 0.48 mmol, 2.0 equiv.) and XPhos Pd G3 (10.2 mg, 0.012 mmol, 0.05 equiv.) were added under an atmosphere of nitrogen. The mixture was shaken at 120° C. for 16 hours. Water (3 mL) was added to the reaction mixture and then extracted with EtOAc. The combined organic layers were concentrated by Speedvac. The residue was purified by prep HPLC to give N-(5-(1-phenyl-1H-pyrazol-4-yl)-1H-indol-3-yl)propionamide (23.6 mg, 71.2 μmol). MS-ESI, 331.1 [M+H.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.78 (d, 1H), 9.75 (s, 1H), 8.83 (s, 1H), 8.14-8.04 (m, 2H), 7.91 (d, 2H), 7.71 (d, 1H), 7.53 (t, 2H), 7.46 (dd, 1H), 7.38-7.29 (m, 2H), 2.42 (q, 2H), 1.14 (t, 3H)
[0446] The compounds in the following table were prepared using the above procedure.
TABLE-US-00009 LC-MS, MS-ESI,- Exam- [M + H.sup.+]Met ple Com- hods # pound # Structure IUPAC Name BA/BB. 9 149
Example 15: Synthesis of N-(5-(4-cyanothiophene-2-yl)-1H-indol-3-yl)propionamide (Compound 136)
[0447] ##STR00295##
[0448] N-(5-bromo-1H-indol-3-yl)propionamide (64.1 mg, 0.24 mmol, 1.0 equiv.) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-3-carbonitrile (84.6 mg, 0.36 mmol, 1.5 equiv.) were dissolved in THF (3.0 mL). Then TMSOK (62.1 mg, 0.48 mmol, 2.0 equiv.) and P(t-Bu).sub.3 Pd G2 (6.14 mg, 0.012 mmol, 0.05 equiv.) were added under an atmosphere of nitrogen. The mixture was shaken at 60° C. for 4 hours. 3 Water (3 mL) was added to the reaction mixture and then extracted with EtOAc. The combined organic layers were collected and concentrated by Speedvac. The residue was purified by prep HPLC to give N-(5-(4-cyanothiophene-2-yl)-1H-indol-3-yl)propionamide (16.8 mg, 56.8 μmol). MS-ESI, 296.6 [M+H.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.96 (br s, 1H), 9.86 (s, 1H), 8.45 (s, 1H), 8.17 (s, 1H), 7.79 (d, 1H), 7.71 (s, 1H), 7.51-7.44 (m, 1H), 7.43-7.35 (m, 1H), 2.41 (q, 2H) 1.13 (t, 3H)
Example 16: Synthesis of N-(5-(5-(morpholinomethyl)thiophen-2-yl)-1H-indol-3-yl)propionamide (Compound 135)
[0449] ##STR00296##
[0450] N-(5-bromo-1H-indol-3-yl)propionamide (64.1 mg, 0.24 mmol, 1.0 equiv.) and 4-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methyl)morpholine (111.1 mg, 0.36 mmol, 1.5 equiv.) were dissolved in 1,4-dioxane (4.0 mL). Then aqueous K.sub.3PO.sub.4 (2 M, 0.24 mL, 0.48 mmol, 2.0 equiv.) and Pd(dppf)Cl2.Math.DCM (8.8 mg, 0.012 mmol, 0.05 equiv.) were added under an atmosphere of nitrogen. The mixture was shaken at 60° C. for 16 hours. Water (3 mL) was added to the reaction mixture and then extracted with EtOAc. The combined organic layers were concentrated by Speedvac. The residue was purified by prep HPLC to give N-(5-(5-(morpholinomethyl)thiophen-2-yl)-1H-indol-3-yl)propionamide (25.3 mg, 68.5 μmol). MS-ESI, 370.1 [M+H.sup.+].
[0451] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.83 (br s, 1H), 9.85 (s, 1H), 8.09 (s, 1H), 7.75 (d, 1H), 7.42-7.37 (m, 1H), 7.35-7.31 (m, 1H), 7.18 (d, 1H), 6.94 (br s, 1H), 3.75-3.53 (m, 6H), 2.50-2.30 (m, 6H), 1.13 (t, 3H)
Example 17: Synthesis of N-(5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)acetamide (Compound 134)
[0452] ##STR00297## ##STR00298##
Synthesis of 4-bromo-1-(4-ethylphenyl)pyrazole
[0453] 1-ethyl-4-iodo-benzene (25 g, 107.73 mmol, 1 equiv.) and 4-bromo-1H-pyrazole (31.67 g, 215.46 mmol, 2.0 equiv.) were dissolved in DMSO (500 mL). Then K.sub.2CO.sub.3 (29.78 g, 215.46 mmol, 2 equiv.), (2S)-pyrrolidine-2-carboxylic acid (2.48 g, 21.55 mmol, 0.2 equiv.) and CuI (2.05 g, 10.77 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The mixture was stirred at 90° C. for 16 hours under an atmosphere of nitrogen. The mixture was poured into 500 mL of H.sub.2O, then extracted with 800 mL of ethyl acetate. The solids were removed by filtration, then the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=0 to 6%) to give 4-bromo-1-(4-ethylphenyl)pyrazole (18.5 g, 73.7 mmol) as a white solid. MS-ESI, 250.9, 252.9 [M+H.sup.+].
Synthesis of 1-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole
[0454] 4-bromo-1-(4-ethylphenyl)pyrazole (18.5 g, 73.7 mmol, 1 equiv.) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (89.57 g, 699.9 mmol, 101.55 mL, 9.5 equiv.) were dissolved in toluene (500 mL), then TEA (174.96 mmol, 24.35 mL, 2.4 equiv.), Pd(CH.sub.3CN).sub.2Cl.sub.2 (907.82 mg, 3.50 mmol, 0.05 equiv.) and SPhos (4.31 g, 10.50 mmol, 0.14 equiv.) were added under an atmosphere of nitrogen. The mixture was heated at 90° C. for 16 hours. The solution was poured into 500 mL of H.sub.2O. The aqueous layer was extracted with ethyl acetate, then the organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtrated, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with petroleum ether/ethyl acetate (0% to 6%) to give 1-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (16.16 g, 54.22 mmol) as a yellow solid. MS-ESI, 299.1 [M+H.sup.+].
Synthesis of N-(5-bromo-M-indol-3-yl)acetamide
[0455] 5-bromo-1H-indol-3-amine (48.3 mg, 0.23 mmol, 1.0 equiv.) and acetic acid (20.7 mg, 0.345 mmol, 1.5 equiv.) were dissolved in DMF (4.0 mL). Then TEA (66.7 μl, 0.46 mmol, 2.0 equiv.), EDCI (44.6 mg, 0.23 mmol, 1 equiv.) and HOPO (25.5 mg, 0.23 mmol, 1 equiv.) were added. The mixture was shaken in a parallel synthesizer at 30° C. for 2 hours. Then 1.0 mL of 2M Na.sub.2CO.sub.3 and 3.0 mL of water were added and the mixture was extracted with EtOAc. The combined organic layers were concentrated by Speedvac. The residue was used directly in the next step without further purification.
Synthesis of N-(5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)acetamide
[0456] N-(5-bromo-1H-indol-3-yl)acetamide (75.6 mg, 0.3 mmol, 1.0 equiv.) and 1-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (134.1 mg, 0.45 mmol, 1.5 equiv.) were dissolved in 1,4-dioxane (4.0 mL). Then K.sub.3PO.sub.4 (2 mol/L, 0.3 mL, 0.6 mmol, 2.0 equiv.) and Xphos Pd G3 (12.7 mg, 0.015 mmol, 0.05 equiv.) were added under an atmosphere. The mixture was shaken in a parallel synthesizer at 120° C. for 16 hours, then concentrated by Speedvac. The residue was purified by prep HPLC to give N-(5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)acetamide (5.92 mg, 17.2 μmol). MS-ESI, 345.2 [M+H.sup.+]. 1-E1 NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.78 (s, 1H), 9.81 (s, 1 H), 8.78 (s, 1H), 8.10-8.02 (m, 2H), 7.81 (d, 2H), 7.68 (d, 1H), 7.49-7.42 (m, 1H), 7.35 (d, 3H), 2.66 (q, 2H), 2.12 (s, 3H), 1.22 (t, 3H)
[0457] The compounds in the following table were prepared using the above procedure.
TABLE-US-00010 LC-MS, MS-ESI,- [M + H.sup.+]. Methods Example Com- IUPAC BA or # pound # Final compound Name BB 18 133
Example 30: Synthesis of N-(5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-hydroxyacetamide (Compound 126)
[0458] ##STR00310##
Synthesis of tert-butyl N-(5-bromo-1H-indol-3-yl)carbamate
[0459] 5-bromo-1H-indol-3-amine (5 g, 9.7 mmol) was dissolved in DCM (100 mL) and cooled to 0° C. Then TEA (96.96 mmol, 13.50 mL, 10 equiv.) was added, followed by the addition of Boc.sub.2O (2.54 g, 11.64 mmol, 1.2 equiv.). The reaction mixture was allowed to warm to ambient temperature. After 16 hours, the mixture was concentrated under vacuum. The residue was dissolved with 200 mL of ethyl acetate, then was washed with 150 mL of H.sub.2O, dried over anhydrous Na.sub.2SO.sub.4, and concentrated under vacuum to give tert-butyl N-(5-bromo-1H-indol-3-yl)carbamate (2.9 g) as a black solid that was used directly without further purification. MS-ESI, 255.1, 257.1 [M-55].
Synthesis of tert-butyl N-[5-[1-(4-ethylphenyl)pyrazol-4-yl]-1H-indol-3-yl]carbamate
[0460] Tert-butyl N-(5-bromo-1H-indol-3-yl)carbamate (crude, 2.9 g, 9.32 mmol, 1 equiv.)
[0461] and 1-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (3.14 g, 10.5 mmol, 1.12 equiv.) were dissolved in H.sub.2O (5 mL) and 1,4-dioxane (50 mL). Then Cs.sub.2CO.sub.3 (7.29 g, 22.37 mmol, 2.4 equiv.) and XPhos Pd G3 (631.08 mg, 745.56 μmol, 0.08 equiv.) were added under an atmosphere of nitrogen. The mixture was heated at 80° C. for 16 hours, then 30 mL H.sub.2O was added. The mixture was extracted with ethyl acetate and the combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, (Petroleum ether/Ethyl acetate=0 to 20%) to give tert-butyl N-[5-[1-(4-ethylphenyl)pyrazol-4-yl]-1H-indol-3-yl]carbamate (1.74 g, 4.32 mmol) as a white solid. MS-ESI, 403.2 [M+H.sup.+].
Synthesis of 5-[1-(4-ethylphenyl)pyrazol-4-yl]-1H-indol-3-amine
[0462] Tert-butyl N-[5-[1-(4-ethylphenyl)pyrazol-4-yl]-1H-indol-3-yl]carbamate (1.74 g, 4.32 mmol, 1 equiv.) was dissolved in DCM (50 mL), then HCl (4 M in 1,4-dioxane, 20 mL) was added. The mixture was stirred at ambient temperature for 2 hours, during which time the solution turned reddish-brown and a solid formed. The mixture was concentrated in vacuum to give 5-[1-(4-ethylphenyl)pyrazol-4-yl]-1H-indol-3-amine (2.1 g) as a light brown solid that was used directly without further purification. MS-ESI, 303.2 [M+H.sup.+].
Synthesis of N-(5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-hydroxyacetamide
[0463] 5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-amine (69.5 mg, 0.23 mmol, 1.0 equiv.) and 2-hydroxyacetic acid (26.2 mg, 0.345 mmol, 1.5 equiv.) were dissolved in DMF (4.0 mL). Then TEA (66.7 μl, 0.46 mmol, 2.0 equiv.), EDCI (44.6 mg, 0.23 mmol, 1 equiv.) and HOPO (25.5 mg, 0.23 mmol, 1 equiv.) were added. The mixture was shaken at 30° C. for 2 hours. The reaction mixture was concentrated by Speedvac. The residue was purified by prep HPLC to give N-(5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-2-hydroxyacetamide (17.0 mg, 47.2 μmol). MS-ESI, 361.2 [M+H.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.88 (s, 1H), 9.48 (s, 1H), 8.83, (s, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.81 (d, 2H), 7.71 (d, 1H), 7.52-7.44 (m, 1H), 7.36 (t, 3H), 5.61 (t, 1H), 4.09 (d, 2H), 2.66 (q, 2H), 1.22 (t, 3H)
[0464] The following compounds were prepared using the above procedure.
TABLE-US-00011 LC-MS, MS-ESI,- [M + H.sup.+] Exam- Com- Methods ple # pound # Structure IUPAC Name BA/BB. 31 115
Example 37: N-(5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)propionamide
[0465] ##STR00317##
[0466] N-(5-bromo-1H-indol-3-yl)propanamide (200.0 mg, 0.7 mmol, 1.0 equiv.) and 1-(4-ethylphenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (223.3 mg, 0.7 mmol, 1.0 equiv.) were dissolved in dioxane (10.0 mL) and water (1.0 mL), then Cs.sub.2CO.sub.3 (731.8 mg, 2.2 mmol, 3.0 equiv.) and XPhos Pd G3 (63.4 mg, 0.08 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture heated overnight at 90° C. and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate and the combined organic layers were concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 5 um, 19*150 mm; mobile phase, Water (10 mM NH.sub.4HCO.sub.3+0.1% NH.sub.4OH) and ACN (42% Phase B up to 62% in 10 min); Detector, uv 254 nm. This resulted in N-[5-[1-(4-ethylphenyl)pyrazol-4-yl]-1H-indol-3-yl]propanamide (16.9 mg) as a white solid. LCMS Method C: [M+H].sup.+=359. .sup.1HNMR (300 MHz, DMSO-d.sub.6): δ 10.76 (s, 1H), 9.73 (s, 1H), 8.76 (s, 1H), 8.06 (d, 2H), 7.80 (d, 2H), 7.71 (d, 1H), 7.46-7.44 (m, 1H), 7.35 (d, 3H), 2.65 (q, 2H), 2.41 (q, 2H), 1.19-1.15 (m, 6H).
[0467] The analogs prepared in the following table were prepared using the same method described for Example 37.
TABLE-US-00012 Example Compound Starting LCMS # # Materials Structure data 38 128 Intermediate 2/ Intermediate 5
Example 56: N-(5-(4-phenylpiperazin-1-yl)-1H-indol-3-yl)propionamide (Compound 131)
[0468] ##STR00336##
Synthesis of N-[5-bromo-1-(triisopropylsilyl)indol-3-yl]propanamide
[0469] N-(5-bromo-1H-indol-3-yl)propanamide (1.0 g, 3.7 mmol, 1.0 equiv.) was dissolved in THF (20.0 mL), and the solution cooled to 0° C. Then NaH (60% wt in mineral oil, 300.0 mg, 7.5 mmol, 2.0 equiv.) and chlorotriisopropylsilane (1.6 mL, 7.5 mmol, 2.0 equiv.) were added dropwise, maintaining the internal temperature at 0° C. The reaction mixture was stirred overnight at ambient temperature under an atmosphere of nitrogen and quenched by the addition of ice-water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:10) to give N-[5-bromo-1-(triisopropylsilyl)indol-3-yl]propanamide (500 mg) as a yellow solid. LCMS Method C: [M+H].sup.+=423.
Synthesis of N-(5-(4-phenylpiperazin-1-yl)-1-(triisopropylsilyl)-1H-indol-3-yl)propionamide
[0470] N-[5-bromo-1-(triisopropylsilyl)indol-3-yl]propanamide (150.0 mg, 0.4 mmol, 1.0 equiv.) and phenylpiperazine (57.5 mg, 0.4 mmol, 1.0 equiv.) were dissolved in 1,4-dioxane (2.0 mL), then RuPhos Pd G3 (29.6 mg, 0.04 mmol, 0.1 equiv.) and t-BuONa (102.1 mg, 1.1 mmol, 3.0 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated overnight at 100° C. and then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and the concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give N-[5-(4-phenylpiperazin-1-yl)-1-(triisopropylsilyl)indol-3-yl]propanamide (150 mg) as a yellow solid. LCMS Method C: [M+H].sup.+=505.
Synthesis of N-(5-(4-phenylpiperazin-1-yl)-1H-indol-3-yl)propionamide
[0471] N-[5-(4-phenylpiperazin-1-yl)-1-(triisopropylsilyl)indol-3-yl]propanamide (130.0 mg, 0.3 mmol, 1.0 equiv.) was dissolved in THF (2.0 mL) and water (2.0 mL), then TBAF (53.9 mg, 0.2 mmol, 0.8 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature and concentrated under vacuum. The residue was purified by Prep-HPLC with following conditions: Column, YMC-Actus Triart C18, 30*250, Sum; mobile phase, Water (10 mM NH.sub.4HCO.sub.3+0.1% NH.sub.4OH) and ACN (30% Phase B up to 50% in 10 min); Detector, UV 254 nm. This resulted in N-[5-(4-phenylpiperazin-1-yl)-1H-indol-3-yl]propanamide (30.7 mg) as a white solid. LCMS Method C: [M+H].sup.+=349. .sup.1HNMR (400 MHz, DMSO-d.sub.6): δ 10.50 (s, 1H), 9.66 (s, 1H), 7.67 (s, 1H), 7.39 (s, 1H), 7.28-7.21 (m, 3H), 7.03 (d, 2H), 6.95-6.93 (m, 1H), 6.84-6.80 (m, 1H), 3.35-3.33 (m, 4H), 3.22-3.20 (m, 4H), 2.39 (q, 2H), 1.13 (t, 3H).
Example 57: N-(5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)tetrahydro-2H-pyran-2-carboxamide (Compound 165)
[0472] ##STR00337##
[0473] 5-(1-(4-Ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-amine hydrogen chloride (168.2 mg, 0.5 mmol, 1.0 equiv.) was dissolved in THF (5 mL), then tetrahydro-2H-pyran-2-carboxylic acid (77.5 mg, 0.6 mmol, 1.2 equiv.), TEA (0.4 mL, 2.5 mmol, 5.0 equiv.) and T.sub.3P (316.1 mg, 1.0 mmol, 2.0 equiv.) were added. The reaction mixture was stirred for 3 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol (10:1) to give material which was further purified by Flash-Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30×150 mm 5 μm; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3+0.1% NH.sub.4OH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 45% B to 75% B in 8 min; 220 nm; RT1: 7.23 min. N-(5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl) tetrahydro-2H-pyran-2-carboxamide (11.4 mg) as a white solid. LCMS Method D: [M+H].sup.+=415. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.88 (s, 1H), 9.32 (s, 1H), 8.83 (s, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.82 (d, 2H), 7.69 (d, 1H), 7.48-7.46 (m, 1H), 7.38-7.35 (m, 3H), 4.11-4.05 (m, 2H), 3.59-3.51 (m, 1H), 2.67 (q, 2H), 1.95-1.88 (m, 2H), 1.69-1.65 (m, 4H), 1.23 (t, 3H).
[0474] The compound in the following table was prepared using the same method described for Example 57.
TABLE-US-00013 Starting LCMS Example materials Structure data 58 (Com- pound 160) Intermediate 22/ cyclobutane- carboxylic acid
Example 59: N-(5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanamide (Compound 166)
[0475] ##STR00339##
[0476] 3,3,3-Trifluoro-2-hydroxypropanoic acid (114.3 mg, 0.8 mmol, 1.2 equiv.) was dissolved in DCM (10 mL), then DIEA (0.4 mL, 2.6 mmol, 4.0 equiv.), HATU (377.2 mg, 1.0 mmol, 1.5 equiv.) and 5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-amine hydrogen chloride (224.1 mg, 0.7 mmol, 1.0 equiv.) were added. The reaction mixture was stirred for 4 hours at ambient temperature, then quenched by the addition of water. The resulting solution was extracted with DCM, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Flash-Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mM NH.sub.4HCO.sub.3+0.1% NH.sub.4OH), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 45% B to 75% B in 8 min; 254 nm; RT1: 7.23 min. This resulted in N-(5-(1-(4-ethylphenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanamide (12.9 mg) as a yellow solid. LCMS Method D: [M+H].sup.+=429. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.09 (s, 1H), 10.07 (s, 1H), 8.82 (s, 1H), 8.10 (s, 1H), 8.04 (s, 1H), 7.82 (d, 2H), 7.77 (d, 1H), 7.52-7.49 (m, 1H), 7.42-7.36 (m, 3H), 7.30 (d, 1H), 4.88-4.85 (m, 1H), 2.67 (q, 2H), 1.24 (t, 3H).
[0477] The following compounds were prepared using the same method described for Example 59.
TABLE-US-00014 Starting LCMS Example materials Structure data Example 60 (Compound 162) Intermediate 24/ (S)-2- hydroxypropanoic acid
Example 62: N-[5-[1-(4-ethylphenyl)pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-3-yl]propanamide (Compound 164)
[0478] ##STR00342##
[0479] 5-[1-(4-Ethylphenyl)pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-3-amine hydrogen chloride (224.0 mg, 0.7 mmol, 1.0 equiv.) and TEA (0.14 mL, 1.0 mmol, 1.5 equiv.) were dissolved in DCM (15 mL), then propionoyl chloride (0.1 mL, 0.7 mmol, 1.0 equiv.) was added. The resulting solution was stirred for 1 hour at ambient temperature, and then concentrated under vacuum. The residue was further purified by Prep-HPLC with the following conditions: Column,)(Bridge Prep OBD C18 Column, 30*150 mm, 5 μm; mobile phase, Water (10 mM NH.sub.4HCO.sub.3+0.1% NH.sub.4OH) and ACN (30% Phase B up to 60% in 7 min); Detector, UV 254 nm. This resulted in N-[5-[1-(4-ethylphenyl)pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-3-yl]propanamide (84.3 mg) as an off-white solid. LCMS Method I: [M+H].sup.+=360. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.98 (s, 1H), 9.64 (s, 1H), 9.00 (s, 1H), 8.38 (s, 1H), 8.01 (s, 1H), 7.83-7.77 (m, 3H), 7.59 (d, 1H), 7.39-7.36 (m, 2H), 2.67 (q, 2H), 2.49 (q, 2H), 1.23 (t, 3H), 1.13 (t, 3H).
Example 63: 3-hydroxy-N-(5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)cyclobutanecarboxamide (Compound 242)
[0480] ##STR00343##
[0481] 5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-1H-indol-3-amine (80.0 mg, 0.23 mmol, 1.0 equiv.) and 3-hydroxycyclobutanecarboxylic acid (32.5 mg, 0.28 mmol, 1.2 equiv.) were dissolved in DMF (4 mL). Then HATU (96.1 mg, 0.25 mmol, 1.1 equiv.) and TEA (230 μl, 1.66 mmol, 7.2 equiv.) were added. The mixture was heated at 30° C. for 16 hours. The solvent was concentrated under vacuum and the residue was purified by prep HPLC to give 3-hydroxy-N-(5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)cyclobutanecarboxamide. MS-ESI, 441.1 [M+H.sup.+].
[0482] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.82 (s, 1H), 9.73 (s, 1H), 8.99 (s, 1H), 8.22-8.07 (m, 4H), 7.90 (d, J=8.5 Hz, 2H), 7.75 (d, J=2.3 Hz, 1H), 7.48 (dd, J=8.4, 1.4 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 5.16 (d, J=6.8 Hz, 1H), 4.11-3.92 (m, 1H), 2.82-2.71 (m, 1H), 2.43-2.34 (m, 2H), 2.14-2.04 (m, 2H).
[0483] The following compounds were prepared using the same method described for Example 63.
TABLE-US-00015 LC-MS, Example Compound MS-ESI, # # Structure IUPAC Name [M + H+]. 64 262
Example 134 Synthesis of 4-methoxy-N-(5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)butanamide (Compound 177)
[0484] ##STR00414##
[0485] 5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-1H-indol-3-amine (80.0 mg, 0.23 mmol, 1.0 equiv.) and 4-methoxybutanoic acid (33.0 mg, 0.28 mmol, 1.2 equiv.) was dissolved in ACN (4 mL). Then T3P (50% in EtOAc, 210 μl, 0.36 mmol, 1.6 equiv.) and DIEA (200 μl, 1.21 mmol, 5.3 equiv.) were added. The mixture was heated at 80° C. for 16 hours. The solvent was concentrated under vacuum and the residue was purified by prep HPLC to give 4-methoxy-N-(5-(1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-1H-indol-3-yl)butanamide. MS-ESI, 443.1 [M+H.sup.+].
[0486] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.82 (d, J=2.0 Hz, 1H), 9.81 (s, 1H), 8.99 (s, 1H), 8.21-8.10 (m, 4H), 7.90 (d, J=8.6 Hz, 2H), 7.72 (d, J=2.3 Hz, 1H), 7.48 (dd, J=8.4, 1.6 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 3.41-3.39 (m, 2H), 3.26 (s, 3H), 2.48-2.42 (m, 2H), 1.92-1.80 (m, 2H).
[0487] The following compounds were prepared using the same method described for Example 134.
TABLE-US-00016 LC-MS, Example Compound MS-ESI,- # # Structure IUPAC Name [M + H+]. 135 260
Biological Assays
[0488] STING pathway activation by the compounds described herein was measured using THP 1-Dual™ cells (KO-IFNAR2).
[0489] THP1-Dual™ KO-IFNAR2 Cells (obtained from invivogen) were maintained in RPMI, 10% FCS, 5 ml P/S, 2 mM L-glut, 10 mM Hepes, and 1 mM sodium pyruvate. Compounds were spotted in empty 384 well tissue culture plates (Greiner 781182) by Echo for a final concentration of 0.0017-100 μM. Cells were plated into the TC plates at 40 μL per well, 2×10E6 cells/mL. For activation with STING ligand, 2′3′cGAMP (MW 718.38, obtained from Invivogen), was prepared in Optimem media.
[0490] The following solutions were prepared for each 1×384 plate: [0491] Solution A: 2 mL Optimem with one of the following stimuli: [0492] 60 μL of 10 mM 2′3′cGAMP.fwdarw.150 μM stock [0493] Solution B: 2 mL Optimem with 60 μL Lipofectamine 2000.fwdarw.Incubate 5 min at RT
[0494] 2 mL of solution A and 2 ml Solution B was mixed and incubated for 20 min at room temperature (RT). 20 μL of transfection solution (A+B) was added on top of the plated cells, with a final 2′3′cGAMP concentration of 15 μM. The plates were then centrifuged immediately at 340 g for 1 minute, after which they were incubated at 37° C., 5% CO.sub.2, >98% humidity for 24h. Luciferase reporter activity was then measured. EC.sub.50 values were calculated by using standard methods known in the art.
[0495] Luciferase reporter assay: 10 μL of supernatant from the assay was transferred to white 384-plate with flat bottom and squared wells. One pouch of QUANTI-Luc™ Plus was dissolved in 25 mL of water. 100 μL of QLC Stabilizer per 25 mL of QUANTI-Luc™ Plus solution was added. 50 μL of QUANTI-Luc™ Plus/QLC solution per well was then added. Luminescence was measured on a Platereader (e.g., Spectramax I3X (Molecular Devices GF3637001)).
[0496] Luciferase reporter activity was then measured. EC.sub.50 values were calculated by using standard methods known in the art.
[0497] Table BA shows the activity of compounds in STING reporter assay: <0.008 μM=“++++++”; >0.008 and <0.04 μM=“+++++”; ≥0.04 and <0.2 μM=“++++”; ≥0.2 and <1 μM=“+++”; ≥1 and <5 μM=“++”; ≥5 and <100 μM=“+”.
TABLE-US-00017 TABLE BA hSTING Compound # EC.sub.50 101 +++ 102 +++ 103 +++ 104 +++ 105 +++ 106 ++++ 107 +++ 108 +++ 109 +++ 110 ++++ 111 +++ 112 +++ 113 ++++ 114 +++ 115 ++++ 116 + 117 ++ 118 ++ 119 +++ 120 ++ 121 +++ 122 +++ 123 ++++ 124 ++++ 125 + 126 +++ 127 +++ 128 +++ 129 + 130 +++ 131 + 132 +++ 133 ++++ 134 ++++ 135 + 136 ++ 137 + 138 + 139 +++ 140 + 141 + 142 ++ 143 ++ 144 + 145 + 146 ++ 147 + 148 + 149 +++ 150 +++ 151 ++++ 164 + 165 +++ 166 ++ 167 ++++ 168 +++ 169 +++ 170 ++ 171 ++ 172 ++++ 173 +++ 174 +++ 175 +++ 176 +++ 177 ++++ 178 +++ 179 +++ 180 +++ 181 + 182 + 183 ++ 184 + 185 + 186 +++ 187 +++ 188 ++ 189 + 190 + 191 +++ 192 +++ 193 ++ 194 ++ 195 +++ 196 ++ 197 +++ 198 ++ 199 ++ 200 ++ 201 ++ 202 +++ 203 + 204 ++ 205 ++ 206 +++ 207 +++ 208 ++ 209 + 210 + 211 ++ 212 +++ 213 +++ 214 +++ 215 ++ 216 ++ 217 +++ 218 ++ 219 ++ 220 + 221 ++ 222 ++ 223 ++ 224 ++ 225 ++ 226 ++ 227 ++ 228 ++ 229 ++ 230 + 231 ++ 232 +++ 233 +++ 234 ++ 235 ++ 236 +++ 237 +++ 238 ++ 239 +++ 240 +++ 241 +++ 242 +++ 243 +++ 242 +++ 245 ++++ 246 + 247 +++ 248 ++ 249 ++ 250 + 251 + 252 ++ 253 +++ 254 + 255 + 256 ++ 257 +++ 258 ++++ 259 +++ 260 + 261 ++ 262 +++ 263 +++ 264 ++ 265 +++ 266 +++ 267 +++ 268 +++ 269 ++ 270 +++ 271 +++ 272 ++ 273 ++ 274 +++ 275 ++ 276 +++ 277 + 278 +++ 279 +++ 280 +++ 281 ++ 282 ++ 283 +++
Numbered Clauses
[0498] The compounds, compositions, methods, and other subject matter described herein are further described in the following numbered clauses:
[0499] 1. A compound of Formula (I):
##STR00423## [0500] or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein: [0501] Y.sup.1, Y.sup.2, and Y.sup.3 are independently selected from the group consisting of CR.sup.1, C(═O), N, and NR.sup.2; [0502] X.sup.4 is selected from the group consisting of O, S, N, NR.sup.2, and CR.sup.1; [0503] X.sup.2 is selected from the group consisting of O, S, N, NR.sup.4, and CR.sup.5; [0504] each is independently a single bond or a double bond, provided that the five-membered ring comprising X.sup.1 and X.sup.2 is heteroaryl, and that the six-membered ring comprising Y.sup.1, Y.sup.2, and Y.sup.3 is aryl or heteroaryl; [0505] each occurrence of R.sup.1 and R.sup.5 is independently selected from the group consisting of: H; R.sup.c; R.sup.h; and -(L.sup.1).sub.b1-R.sup.h; [0506] each occurrence of R.sup.2 and R.sup.4 is independently selected from the group consisting of: H; R.sup.d; R.sup.g; and -(L.sup.2).sub.b2-R.sup.g; [0507] R.sup.6 is selected from the group consisting of: H; R.sup.d; and R.sup.h; [0508] Q.sup.4 is selected from the group consisting of: [0509] C.sub.3-12 cycloalkylene or C.sub.3-12 cycloalkenylene, each optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c and R.sup.h; [0510] heterocyclylene or heterocycloalkenylene of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h; [0511] heteroarylene of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroarylene is optionally substituted with 1-4 substituents independently selected from the group consisting of R.sup.c and R.sup.h; and [0512] C.sub.6-10 arylene optionally substituted with 1-4 substituents independently selected from the group consisting of R.sup.c and R.sup.h; [0513] each L.sup.A is independently selected from the group consisting of: C.sub.1-3 alkylene optionally substituted with 1-2 R.sup.a1; —O—; —NH—; —NR.sup.d; —S(O).sub.0-2; and C(O); [0514] a1 is 0, 1, 2, 3, or 4; [0515] Q.sup.2 is selected from the group consisting of: H; R.sup.g; and R.sup.c; [0516] W is selected from the group consisting of: [0517] H; [0518] C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkynyl, each of which is optionally substituted with 1-6 R.sup.a2; [0519] monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and [0520] monocyclic heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c, provided that when W is heterocyclyl or heterocycloalkenyl, it is attached to the C(═O)NR.sup.6 group via a ring carbon atom; [0521] each occurrence of R.sup.a, R.sup.a1, and R.sup.a2 is independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); —C(═O)OH; —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); and cyano; [0522] each occurrence of R.sup.c is independently selected from the group consisting of: halo; cyano; C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —S(O).sub.1-2(C.sub.1-4 alkyl); —S(O)(═NH)(C.sub.1-4 alkyl); —NR.sup.eR.sup.f; —OH; —S(O).sub.1-2NR′R″; —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-10 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; —C(═O)NR′R″; and —SF.sub.5; [0523] each occurrence of R.sup.d is independently selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy; [0524] each occurrence of R.sup.e and R.sup.f is independently selected from the group consisting of: H; C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of NR′R″, —OH, and R′; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CONR′R″; —S(O).sub.1-2NR′R″; —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy; [0525] each occurrence of R.sup.g is independently selected from the group consisting of: [0526] C.sub.3-12 cycloalkyl or C.sub.3-12 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h; [0527] heterocyclyl or heterocycloalkenyl of 3-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h; [0528] heteroaryl of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of R.sup.c, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h; and [0529] C.sub.6-10 aryl optionally substituted with 1-4 substituents independently selected from the group consisting of R.sup.c, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h; [0530] each occurrence of R.sup.h is independently selected from the group consisting of: [0531] C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 R.sup.i; [0532] heterocyclyl or heterocycloalkenyl of 3-8 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 R.sup.i; [0533] heteroaryl of 5-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with 1-4 R.sup.i; and [0534] C.sub.6 aryl optionally substituted with 1-4 R.sup.i; [0535] each occurrence of R.sup.i is independently selected from the group consisting of: C.sub.1-6 alkyl; C.sub.1-4 haloalkyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; and halo; [0536] each occurrence of L.sup.1, L.sup.2, and L.sup.g is selected from the group consisting of: —O—, —NH—, —NR.sup.d, —S(O).sub.0-2, C(O), and C.sub.1-3 alkylene optionally substituted with 1-3 R.sup.a; [0537] b1, b2, and bg are each independently 1, 2, or 3; and [0538] each occurrence of R′ and R″ is independently selected from the group consisting of: H; —OH; and C.sub.1-4 alkyl; [0539] provided that when Y.sup.1 and Y.sup.2 are CH; Y.sup.3 is N; W is unsubstituted n-propyl; and Q.sup.1 is unsubstituted phenylene, then: -(L.sup.A).sub.a1-Q.sup.2 is other than —CH.sub.2-morpholinyl, —CH.sub.2—N-methylpiperazinyl, morpholinyl, or N-methylpiperazinyl.
[0540] 2. The compound of clause 1, wherein Q.sup.1 is heteroarylene of 5-12 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroarylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of R.sup.c and R.sup.h.
[0541] 3. The compound of clauses 1 or 2, wherein Q.sup.1 is heteroarylene of from 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S, and wherein the heteroarylene is optionally substituted with from 1-3 substituents independently selected from the group consisting of R.sup.c and R.sup.h.
[0542] 4. The compound of any one of clauses 1-3, wherein Q.sup.1 is heteroarylene of from 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S, and wherein the heteroarylene is optionally substituted with from 1-3 R.sup.c.
[0543] 5. The compound of any one of clauses 1-4, wherein Q.sup.1 is heteroarylene of 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S, and wherein the heteroarylene is optionally substituted with from 1-2 R.sup.c.
[0544] 6. The compound of any one of clauses 1-5, wherein Q.sup.1 is pyrazolylene which is optionally substituted with from 1-2 R.sup.c.
[0545] 7. The compound of any one of clauses 1-6, wherein Q.sup.1 is
##STR00424##
which is optionally substituted with from 1-2 R.sup.c (e.g., unsubstituted), wherein aa represents point of attachment to -(L.sup.A).sub.a1-Q.sup.2.
[0546] 8. The compound of any one of clauses 1-6, wherein Q.sup.1 is
##STR00425##
each of which is optionally substituted with from 1-2 R.sup.c (e.g., unsubstituted), wherein aa represents point of attachment to -(L.sup.A).sub.a1-Q.sup.2.
[0547] 9. The compound of any one of clauses 1-5, wherein Q.sup.1 is thiophenylene or oxazolylene, each of which is optionally substituted with from 1-2 R.sup.c.
[0548] 10. The compound of clause 9, wherein Q.sup.1 is
##STR00426##
each of which is optionally substituted with from 1-2 R.sup.c.
[0549] 11. The compound of any one of clauses 1-3, wherein Q.sup.1 is heteroarylene of 6 ring atoms, wherein from 1-3 ring atoms are ring nitrogen atoms, and wherein the heteroarylene is optionally substituted with from 1-3 R.sup.c, such as pyridylene optionally substituted with from 1-2 R.sup.c (such as:
##STR00427##
each of which is optionally substituted with from 1-2 R.sup.c, wherein aa is the point of attachment to -(L.sup.A).sub.a1-Q.sup.2.
[0550] 12. The compound of clause 1, wherein Q.sup.1 is C.sub.6-10 arylene optionally substituted with from 1-4 substituents independently selected from the group consisting of R.sup.c and R.sup.h.
[0551] 13. The compound of clauses 1 or 12, wherein Q.sup.1 is phenylene optionally substituted with from 1-4 R.sup.c, such as:
##STR00428##
each of which is optionally substituted with from 1-2 R.sup.c (e.g., unsubstituted).
[0552] 14. The compound of clause 1, wherein Q.sup.1 is selected from the group consisting of: [0553] C.sub.3-12 cycloalkylene or cycloalkenylene, each optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R.sup.c and R.sup.h; and [0554] heterocyclylene or heterocycloalkenylene of 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R.sup.c, and R.sup.h.
[0555] 15. The compound of clauses 1 or 14, wherein Q.sup.1 is selected from the group consisting of: [0556] C.sub.3-8 cycloalkylene or cycloalkenylene, each optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.c, such as
##STR00429##
each of which is optionally substituted with from 1-2 R.sup.c, wherein aa is the point of attachment to -(L.sup.A).sub.a1-Q.sup.2; and [0557] heterocyclylene or heterocycloalkenylene of from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclylene or heterocycloalkenylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.c, such as
##STR00430##
each of which is optionally substituted with from 1-2 R.sup.c, wherein aa is the point of attachment to -(L.sup.A).sub.a1-Q.sup.2.
[0558] 16. The compound of any one of clauses 1-15, wherein a1 is 0.
[0559] 17. The compound of any one of clauses 1-15, wherein a1 is 1.
[0560] 18. The compound of any one of clauses 1-15 or 17, wherein L.sup.A is C.sub.1-3 alkylene optionally substituted with from 1-2 R.sup.a1.
[0561] 19. The compound of clause 18, wherein L.sup.A is CH.sub.2 or CH(Me), each of which is optionally substituted with from 1-2 R.sup.a1, such as unsubstituted CH.sub.2.
[0562] 20. The compound of any one of clauses 1-15 or 17-19, wherein L.sup.A is —O—.
[0563] 21. The compound of any one of clauses 1-20, wherein Q.sup.2 is R.sup.g.
[0564] 22. The compound of any one of clauses 1-21, wherein Q.sup.2 is selected from the group consisting of: [0565] heteroaryl of from 5-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of R.sup.c, le, and -(L.sup.g).sub.bg-R.sup.h; and [0566] C.sub.6-10 aryl optionally substituted with from 1-4 substituents independently selected from the group consisting of R.sup.c, le, and -(L.sup.g).sub.bg-R.sup.h, wherein each R.sup.c is an independently selected R.sup.c.
[0567] 23. The compound of any one of clauses 1-22, wherein Q.sup.2 is selected from the group consisting of: [0568] heteroaryl of from 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R.sup.cq2; and [0569] C.sub.6-10 aryl optionally substituted with from 1-4 R.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c.
[0570] 24. The compound of any one of clauses 1-23, wherein Q.sup.2 is selected from the group consisting of: [0571] heteroaryl of 6 ring atoms, wherein from 1-3 ring atoms are ring nitrogen atoms, and wherein the heteroaryl is optionally substituted with from 1-4 R.sup.cq2; [0572] heteroaryl of 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with from 1-3 R.sup.cq2, such as pyrazolyl
##STR00431##
optionally substituted with from 1-2 R.sup.cq2; and
[0573] phenyl optionally substituted with from 1-4 R.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c.
[0574] 25. The compound of clause 24, wherein Q.sup.2 has the following formula:
##STR00432##
wherein Q.sup.A, Q.sup.B, Q.sup.C, Q.sup.D, and Q.sup.E are each independently selected from the group consisting of CH, CR.sup.cq2, and N, provided that no more than 2 of Q.sup.A-Q.sup.E are N, and no more than 4 of Q.sup.A-Q.sup.E are CR.sup.cq2.
[0575] 26. The compound of clause 25, wherein Q.sup.A, Q.sup.B, Q.sup.C, Q.sup.D, and Q.sup.E are independently CH or CR.sup.cq2, provided that no more than 4 of Q.sup.A-Q.sup.E are CR.sup.cq2.
[0576] 27. The compound of clauses 25 or 26, wherein Q.sup.A and Q.sup.E are CH; and Q.sup.B, Q.sup.C, and Q.sup.D are independently CH or CR.sup.cq2.
[0577] 28. The compound of clause 27, wherein Q.sup.C is CR.sup.cq2; Q.sup.D is CH; and Q.sup.B is CH or CR.sup.cq2, such as CH.
[0578] 29. The compound of clause 27, wherein Q.sup.C is CH; Q.sup.B is CH; and Q.sup.B is CR.sup.cq2.
[0579] 30. The compound of clause 27, wherein Q.sup.B, Q.sup.C, and Q.sup.D are each CH.
[0580] 31. The compound of clause 25, wherein Q.sup.2 is selected from the group consisting of: unsubstituted phenyl,
##STR00433##
[0581] 32. The compound of clause 25, wherein from 1-2 of Q.sup.A-Q.sup.E is N; and each remaining one of Q.sup.A-Q.sup.E is CH or CR.sup.cq2.
[0582] 33. The compound of clause 32, wherein Q.sup.C is CH or CR.sup.cq2; from 1-2 of Q.sup.A, Q.sup.B, Q.sup.D, and Q.sup.E is N; and each remaining one of Q.sup.A, Q.sup.B, Q.sub.D, and Q.sup.E is CH.
[0583] 34. The compound of clauses 32 or 33, wherein Q.sup.2 is selected from the group consisting of:
##STR00434##
[0584] 35. The compound of any one of clauses 1-22, wherein Q.sup.2 is selected from the group consisting of: [0585] heteroaryl of from 5-6 (such as 6) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is substituted with R.sup.hq2 and further optionally substituted with from 1-2 R.sup.cq2; and [0586] C.sub.6-10 aryl substituted with R.sup.hq2 and further optionally substituted with from 1-2 R.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c, and R.sup.hq2 is an independently selected R.sup.h.
[0587] 36. The compound of any one of clauses 1-22 or 35, wherein Q.sup.2 is selected from the group consisting of:
##STR00435##
wherein Q.sup.A, Q.sup.B, Q.sup.C, Q.sup.D, and Q.sup.E are each independently selected from the group consisting of CH, CR.sup.cq2, and N, provided that no more than 2 of Q.sup.A-Q.sup.E are N, and no more than 2 of Q.sup.A-Q.sup.E are CR.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c, and R.sup.hq2 is an independently selected R.sup.h.
[0588] 37. The compound of clause 36, wherein R.sup.hq2 is C.sub.3-6 cycloalkyl optionally substituted with from 1-2 R.sup.i (such as C.sub.3, C.sub.4, C.sub.5, or C.sub.6 cycloalkyl optionally substituted with from 1-2 independently selected halo, such as —F).
[0589] 38. The compound of any one of clauses 1-21, wherein Q.sup.2 is selected from the group consisting of: [0590] C.sub.3-12 cycloalkyl or C.sub.3-12 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R.sup.cq2, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h; [0591] heterocyclyl or heterocycloalkenyl of from 3-12 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R.sup.cq2, R.sup.h, and -(L.sup.g).sub.bg-R.sup.h, wherein each R.sup.cq2 is an independently selected R.sup.c.
[0592] 39. The compound of any one of clauses 1-21 or 38, wherein Q.sup.2 is C.sub.3-12 cycloalkyl or C.sub.3-12 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c.
[0593] 40. The compound of any one of clauses 1-21 or 38-39, Q.sup.2 is C.sub.3-6 (such as C.sub.3, C.sub.4, C.sub.5, or C.sub.6) cycloalkyl, which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.cq2, such as cyclopropyl or cyclopentyl each of which is optionally substituted with from 1-2 R.sup.cq2
##STR00436##
wherein each R.sup.cq2 is an independently selected R.sup.c.
[0594] 41. The compound of any one of clauses 1-21 or 38, wherein Q.sup.2 is heterocyclyl or heterocycloalkenyl of from 4-8 (such as 4, 5, or 6) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.cq2, such as wherein Q.sup.2 is tetrahydropyranyl, pyrrolidinyl, morpholinyl, piperidinyl, or piperazinyl, each of which is optionally substituted with from 1-2 R.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c.
[0595] 42. The compound of any one of clauses 22-41, wherein each R.sup.cq2 is independently selected from the group consisting of: halo; cyano; C.sub.1-6 alkyl which is optionally substituted with from 1-6 independently selected R.sup.a; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; and —C.sub.1-4 thioalkoxy.
[0596] 43. The compound of any one of clauses 22-42, wherein each R.sup.cq2 is independently selected from the group consisting of: halo; cyano; C.sub.1-6 alkyl, such as C.sub.1-3 alkyl such as ethyl; C.sub.1-6 alkyl substituted with from 1-6 independently selected R.sup.a; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy, such as —OCF.sub.3 or —OCH.sub.2CF.sub.3; and —C.sub.1-4 thioalkoxy.
[0597] 44. The compound of any one of clauses 22-43, wherein each R.sup.cq2 is independently selected from the group consisting of: halo; cyano; C.sub.1-6 alkyl, such as C.sub.1-3 alkyl such as ethyl; C.sub.1-6 alkyl substituted with from 1-6 substituents each independently selected from the group consisting of -halo, C.sub.1-3 alkoxy, and —OH (e.g., —CF.sub.3, —CH.sub.2CF.sub.3, or —CH.sub.2OMe); C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy, such as —OCF.sub.3 or —OCH.sub.2CF.sub.3; and —C.sub.1-4 thioalkoxy.
[0598] 45. The compound of any one of clauses 1-20, wherein Q.sup.2 is H.
[0599] 46. The compound of any one of clauses 1-20, wherein Q.sup.2 is R.sup.c.
[0600] 47. The compound of clause 46, wherein Q.sup.2 is halo or cyano.
[0601] 48. The compound of clause 46, wherein Q.sup.2 is C.sub.1-6 alkyl which is optionally substituted with from 1-6 independently selected R.sup.a.
[0602] 49. The compound of clauses 46 or 48, wherein Q.sup.2 is C.sub.1-6 alkyl which is optionally substituted with from 1-6 substituents each independently selected from the group consisting of halo, C.sub.1-3 alkoxy, NR.sup.eR.sup.f, and —OH, such as wherein Q.sup.2 is iPr, —CHF.sub.2, —CF.sub.3, —CH.sub.2CH.sub.2OMe, —CH.sub.2OMe, —CH.sub.2CH.sub.2N(Me).sub.2, or —C(OH)(Me).sub.2.
[0603] 50. The compound of any one of clauses 1-49, wherein Y.sup.1 is CR.sup.1.
[0604] 51. The compound of any one of clauses 1-50, wherein Y.sup.2 is CR.sup.1.
[0605] 52. The compound of any one of clauses 1-51, wherein Y.sup.3 is CR.sup.1.
[0606] 53. The compound of any one of clauses 1-52, wherein each R.sup.1 is H or R.sup.c.
[0607] 54. The compound of any one of clauses 1-53, wherein each R.sup.1 is H.
[0608] 55. The compound of any one of clauses 1-53, wherein from 1-2 (such as 1) occurrence of R.sup.1 is R.sup.c; and each remaining occurrence of R.sup.1 is H.
[0609] 56. The compound of any one of clauses 1-53 or 55, wherein from 1-2 (such as 1) occurrence of R.sup.1 is halo, such as —F or —Cl; and each remaining occurrence of R.sup.1 is H.
[0610] 57. The compound of any one of clauses 1-56, wherein X.sup.1 is NR.sup.2.
[0611] 58. The compound of any one of clauses 1-57, wherein X.sup.1 is NH.
[0612] 59. The compound of any one of clauses 1-58, wherein X.sup.2 is CR.sup.5.
[0613] 60. The compound of any one of clauses 1-59, wherein X.sup.2 is CH.
[0614] 61. The compound of any one of clauses 1-56, wherein X.sup.1 is NR.sup.2; and X.sup.2 is CR.sup.5.
[0615] 62. The compound of any one of clauses 1-56 or 61, wherein X.sup.1 is NH; and X.sup.2 is CH.
[0616] 63. The compound of any one of clauses 1-62, wherein R.sup.6 is H.
[0617] 64. The compound of any one of clauses 1-63, wherein W is C.sub.1-10 alkyl, C.sub.2-10 alkenyl, or C.sub.2-10 alkenyl, each of which is optionally substituted with from 1-6 R.sup.a2.
[0618] 65. The compound of any one of clauses 1-64, wherein W is C.sub.1-10 alkyl, which is optionally substituted with from 1-6 R.sup.a2.
[0619] 66. The compound of any one of clauses 1-65, wherein W is C.sub.1-6 (such as C.sub.1, C.sub.2, C.sub.3, or C.sub.4) alkyl, which is optionally substituted with from 1-6 R.sup.a2.
[0620] 67. The compound of clause 66, wherein W is selected from the group consisting of: methyl, ethyl, propyl, isopropyl, and isobutyl, each of which is optionally substituted with from 1-3 R.sup.a2.
[0621] 68. The compound of clauses 66 or 67, wherein W is methyl, ethyl, propyl, isopropyl, or isobutyl, such as methyl or ethyl, such as ethyl.
[0622] 69. The compound of any one of clauses 1-68, wherein each R.sup.a2 is independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f, such as —N(C.sub.1-3 alkyl).sub.2 or NHC(O)O(C.sub.1-4 alkyl); C.sub.1-4 alkoxy, such as —OMe; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); and cyano.
[0623] 70. The compound of any one of clauses 1-67 or 69, wherein W is selected from the group consisting of: methyl, ethyl, propyl, isopropyl, and isobutyl, each of which is substituted with from 1-3 substituents each independently selected from the group consisting of: —OH; -halo, such as —F; —NR.sup.eR.sup.f, such as —N(C.sub.1-3 alkyl).sub.2 or NHC(O)O(C.sub.1-4 alkyl); C.sub.1-4 alkoxy, such as —OMe; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); and cyano, such as wherein W is
##STR00437##
[0624] 71. The compound of any one of clauses 1-64, wherein W is C.sub.2-6 alkenyl or C.sub.2-6 alkynyl, each of which is optionally substituted with from 1-6 R.sup.a2.
[0625] 72. The compound of any one of clauses 1-64 or 71, wherein W is C.sub.2-6 alkenyl which is optionally substituted with from 1-6 R.sup.a2.
[0626] 73. The compound of any one of clauses 1-64 or 72, wherein W is C.sub.2-6 alkenyl (such as C.sub.3, C.sub.4, or C.sub.5 alkenyl) optionally substituted with from 1-3 substituents each independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f, such as —N(C.sub.1-3 alkyl).sub.2 or NHC(O)O(C.sub.1-4 alkyl); C.sub.1-4 alkoxy, such as —OMe; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); and cyano, such as wherein W is
##STR00438##
[0627] 74. The compound of any one of clauses 1-63, wherein W is selected from the group consisting of: [0628] monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and [0629] monocyclic heterocyclyl or heterocycloalkenyl of from 3-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.
[0630] 75. The compound of any one of clauses 1-63 or 74, wherein W is monocyclic C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.
[0631] 76. The compound of any one of clauses 1-63 or 74-75, wherein W is monocyclic C.sub.3-8 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.
[0632] 77. The compound of clause 76, wherein W is monocyclic C.sub.3-8 cycloalkyl (e.g., C.sub.3-6 cycloalkyl) optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.
[0633] 78. The compound of clause 77, wherein W is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c, such as unsubstituted cyclobutyl, cyclopentyl, or cyclohexyl.
[0634] 79. The compound of any one of clauses 1-63 or 74, wherein W is monocyclic heterocyclyl or heterocycloalkenyl of from 3-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.
[0635] 80. The compound of clause 79, wherein W is monocyclic heterocyclyl of from 4-6 (such as 4, 5, or 6) ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.c.
[0636] 81. The compound of clause 80, wherein W is azetidinyl, oxetanyl, pyrrolidinyl, or tetrahydrofuranyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.c; and the ring nitrogen atom when present is optionally substituted with R.sup.d.
[0637] 82. The compound of clause 81, wherein W is
##STR00439##
[0638] 83. The compound of any one of clauses 1-63, wherein W is H.
[0639] 84. The compound of clause 1, wherein the compound is a compound of Formula (Ia):
##STR00440##
[0640] or a pharmaceutically acceptable salt thereof or a tautomer thereof.
[0641] 85. The compound of clause 84, wherein Y.sup.1, Y.sup.2, and Y.sup.3 are each CR.sup.1.
[0642] 86. The compound of clauses 84 or 85, wherein each R.sup.1 is H.
[0643] 87. The compound of clauses 84 or 85, wherein one occurrence of R.sup.3 is R.sup.c (such as halo); and each remaining R.sup.1 is H.
[0644] 88. The compound of clause 84, wherein Y.sup.1, Y.sup.2, and Y.sup.3 are each CH.
[0645] 89. The compound of any one of clauses 84-88, wherein a1 is 0.
[0646] 90. The compound of any one of clauses 84-88, wherein a1 is 1.
[0647] 91. The compound of any one of clauses 84-88 or 90, wherein L.sup.A is CH.sub.2.
[0648] 92. The compound of any one of clauses 84-91, wherein Q.sup.2 is selected from the group consisting of: [0649] heteroaryl of from 5-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R.sup.cq2; and [0650] C.sub.6-10 aryl optionally substituted with from 1-4 R.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c.
[0651] 93. The compound of clause 92, wherein Q.sup.2 has the following formula:
##STR00441##
wherein Q.sup.A, Q.sup.B, Q.sup.C, Q.sup.D, and Q.sup.E are each independently selected from the group consisting of CH, CR.sup.cq2, and N, provided that no more than 2 of Q.sup.A-Q.sup.E are N, and no more than 4 of Q.sup.A-Q.sup.E are CR.sup.cq2.
[0652] 94. The compound of clause 93, wherein Q.sup.A, Q.sub.B, Q.sub.C, Q.sub.D, and Q.sup.E are independently CH or CR.sup.cq2, provided that no more than 4 of Q.sup.A-Q.sup.E are CR.sup.cq2.
[0653] 95. The compound of clauses 93 or 94, wherein Q.sup.A and Q.sup.E are CH; and Q.sup.B, Q.sup.C, and Q.sup.D are independently CH or CR.sup.cq2.
[0654] 96. The compound of clause 95, wherein Q.sup.C is CR.sup.cq2; Q.sup.D is CH; and Q.sup.B is CH or CR.sup.cq2, such as CH.
[0655] 97. The compound of clause 95, wherein Q.sup.C is CH; Q.sup.B is CH; and Q.sup.B is CR.sup.cq2.
[0656] 98. The compound of clause 95, wherein Q.sup.B, Q.sup.C, and Q.sup.D are each CH.
[0657] 99. The compound of clause 93, wherein Q.sup.2 is selected from the group consisting of: unsubstituted phenyl,
##STR00442##
[0658] 100. The compound of clause 93, wherein from 1-2 of Q.sup.A-Q.sup.E is N; and each remaining one of Q.sup.A-Q.sup.E is CH or CR.sup.cq2.
[0659] 101. The compound of clause 100, wherein Q.sup.C is CH or CR.sup.cq2; from 1-2 of Q.sup.A, Q.sup.B, Q.sup.D, and Q.sup.E is N; and each remaining one of Q.sup.A, Q.sup.B, Q.sub.D, and Q.sup.E is CH.
[0660] 102. The compound of clauses 100 or 101, wherein Q.sup.2 is selected from the group consisting of:
##STR00443##
[0661] 103. The compound of any one of clauses 84-91, wherein Q.sup.2 is selected from the group consisting of: [0662] heteroaryl of from 5-6 (such as 6) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heteroaryl is substituted with R.sup.hq2 and further optionally substituted with from 1-2 R.sup.cq2; and [0663] C.sub.6-10 aryl substituted with R.sup.hq2 and further optionally substituted with from 1-2 R.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c, and R.sup.hq2 is an independently selected R.sup.h.
[0664] 104. The compound of clause 103, wherein Q.sup.2 is selected from the group consisting of:
##STR00444##
wherein Q.sup.A, Q.sub.B, Q.sub.C, Q.sub.D, and Q.sup.E are each independently selected from the group consisting of CH, CR.sup.cq2, and N, provided that no more than 2 of Q.sup.A-Q.sup.E are N, and no more than 2 of Q.sup.A-Q.sup.E are CR.sup.cq2, wherein each R.sup.cq2 is an independently selected R.sup.c, and R.sup.hq2 is an independently selected R.sup.h.
[0665] 105. The compound of clause 104, wherein R.sup.hq2 is C.sub.3-6 cycloalkyl optionally substituted with from 1-2 R.sup.i (such as C.sub.3, C.sub.4, C.sub.5, or C.sub.6 cycloalkyl optionally substituted with from 1-2 independently selected halo, such as —F).
[0666] 106. The compound of any one of clauses 92-105, wherein each R.sup.cq2 is independently selected from the group consisting of: halo; cyano; C.sub.1-6 alkyl, such as C.sub.1-3 alkyl such as ethyl; C.sub.1-6 alkyl substituted with from 1-6 independently selected R.sup.a; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy, such as —OCF.sub.3 or —OCH.sub.2CF.sub.3; and —C.sub.1-4 thioalkoxy.
[0667] 107. The compound of clause 106, wherein each R.sup.cq2 is independently selected from the group consisting of: halo; cyano; C.sub.1-6 alkyl, such as C.sub.1-3 alkyl such as ethyl; C.sub.1-6 alkyl substituted with from 1-6 substituents each independently selected from the group consisting of -halo, C.sub.1-3 alkoxy, and —OH (e.g., —CF.sub.3, —CH.sub.2CF.sub.3, or —CH.sub.2OMe); C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy, such as —OCF.sub.3 or —OCH.sub.2CF.sub.3; and —C.sub.1-4 thioalkoxy.
[0668] 108. The compound of any one of clauses 84-107, wherein R.sup.2 is H; and R.sup.5 is H.
[0669] 109. The compound of any one of clauses 84-108, wherein R.sup.6 is H.
[0670] 110. The compound of any one of clauses 84-109, wherein W is C.sub.1-6 (such as C.sub.1, C.sub.2, C.sub.3, or C.sub.4) alkyl, which is optionally substituted with from 1-6 R.sup.a2.
[0671] 111. The compound of clause 110, wherein W is unsubstituted C.sub.1-6 alkyl, such as methyl, ethyl, propyl, isopropyl, or isobutyl, such as methyl or ethyl, such as ethyl.
[0672] 112. The compound of clause 110, wherein W is C.sub.1-6 alkyl (such as methyl, ethyl, propyl, isopropyl, or isobutyl) optionally substituted with from 1-3 substituents each independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f, such as —N(C.sub.1-3 alkyl).sub.2 or NHC(O)O(C.sub.1-4 alkyl); C.sub.1-4 alkoxy, such as —OMe; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); and cyano, such as wherein W is
##STR00445##
[0673] 113. The compound of any one of clauses 84-109, wherein W is C.sub.2-6 alkenyl (such as C.sub.3, C.sub.4, or C.sub.5 alkenyl) optionally substituted with from 1-3 substituents each independently selected from the group consisting of: —OH; -halo; —NR.sup.eR.sup.f, such as —N(C.sub.1-3 alkyl).sub.2 or NHC(O)O(C.sub.1-4 alkyl); C.sub.1-4 alkoxy, such as —OMe; C.sub.1-4 haloalkoxy; —C(═O)O(C.sub.1-4 alkyl); —C(═O)(C.sub.1-4 alkyl); and cyano, such as
##STR00446##
[0674] 114. The compound of any one of clauses 84-109, wherein W is monocyclic C.sub.3-8 cycloalkyl (e.g., C.sub.3-6 cycloalkyl) optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c, such as wherein W is cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and R.sup.c, such as unsubstituted cyclobutyl, cyclopentyl, or cyclohexyl.
[0675] 115. The compound of any one of clauses 84-109, wherein W is monocyclic heterocyclyl of from 4-6 (such as 4, 5, or 6) ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), O, and S(O).sub.0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.c, such as wherein W is azetidinyl, oxetanyl, pyrrolidinyl, or tetrahydrofuranyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R.sup.c, and the ring nitrogen atom when present is optionally substituted with R.sup.d; such as wherein W is
##STR00447##
[0676] 116. The compound of clause 1, wherein the compound is selected from the group consisting of compounds delineated in Table C1, and a pharmaceutically acceptable salt thereof.
[0677] 117. A pharmaceutical composition comprising a compound of clauses 1-116 and one or more pharmaceutically acceptable excipients.
[0678] 118. A method for inhibiting STING activity, the method comprising contacting STING with a compound or a pharmaceutically acceptable salt thereof as defined in any one of clauses 1-116; or a pharmaceutical composition as defined in clause 117.
[0679] 119. The method of clause 118, wherein the inhibiting comprises antagonizing STING.
[0680] 120. The method of any one of clauses 118-119, which is carried out in vitro.
[0681] 121. The method of clause 120, wherein the method comprises contacting a sample comprising one or more cells comprising STING with the compound.
[0682] 122. The method of clause 120 or 121, wherein the one or more cells are one or more cancer cells.
[0683] 123. The method of clause 121 or 122, wherein the sample further comprises one or more cancer cells, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.
[0684] 124. The method of clause 118 or 119, which is carried out in vivo.
[0685] 125. The method of clause 124, wherein the method comprises administering the compound to a subject having a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease.
[0686] 126. The method of clause 125, wherein the subject is a human.
[0687] 127. The method of clause 126, wherein the disease is cancer.
[0688] 128. The method of clause 127, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.
[0689] 129. The method of clause 127 or 128, wherein the cancer is a refractory cancer.
[0690] 130. The method of clause 125, wherein the compound is administered in combination with one or more additional cancer therapies.
[0691] 131. The method of clause 130, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.
[0692] 132. The method of clause 131, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.
[0693] 133. The method of clause 132, wherein the one or more additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g., azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti-helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48 CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).
[0694] 134. The method of any one of clauses 125-133, wherein the compound is administered intratumorally.
[0695] 135. A method of treating cancer, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of clauses 1-116, or a pharmaceutical composition as defined in clause 117.
[0696] 136. The method of clause 135, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.
[0697] 137. The method of clause 135 or 136, wherein the cancer is a refractory cancer.
[0698] 138. The method of clause 135, wherein the compound is administered in combination with one or more additional cancer therapies.
[0699] 139. The method of clause 138, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.
[0700] 140. The method of clause 139, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.
[0701] 141. The method of clause 139, wherein the one or more additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g., azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti-helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48 CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).
[0702] 142. The method of any one of clauses 135-141, wherein the compound is administered intratumorally.
[0703] 143. A method of inducing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound as defined in any one of clauses 1-116, or a pharmaceutical composition as defined in clause 117.
[0704] 144. The method of clause 143, wherein the subject has cancer.
[0705] 145. The method of clause 144, wherein the subject has undergone and/or is undergoing and/or will undergo one or more cancer therapies.
[0706] 146. The method of clause 144, wherein the cancer selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.
[0707] 147. The method of clause any one of clauses 144-146, wherein the cancer is a refractory cancer.
[0708] 148. The method of clause 143, wherein the immune response is an innate immune response.
[0709] 149. The method of clause 148, wherein the at least one or more cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.
[0710] 150. The method of clause 149, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.
[0711] 151. The method of clause 150, wherein the one or more additional chemotherapeutic agents is selected from alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g., azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti-helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).
[0712] 152. A method of treatment of a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of clauses 1-116, or a pharmaceutical composition as defined in clause 117.
[0713] 153. A method of treatment comprising administering to a subject having a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease an effective amount of a compound as defined in any one of clauses 1-116, or a pharmaceutical composition as defined in clause 117.
[0714] 154. A method of treatment comprising administering to a subject a compound as defined in any one of clauses 1-116, or a pharmaceutical composition as defined in clause 117, wherein the compound or composition is administered in an amount effective to treat a disease in which increased (e.g., excessive) STING signaling contributes to the pathology and/or symptoms and/or progression of the disease, thereby treating the disease.
[0715] 155. The method of any one of clauses 152-154, wherein the disease is cancer.
[0716] 156. The method of clause 155, wherein the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial carcinoma, bladder cancer, non-small cell lung cancer, small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumors, gastroesophageal carcinoma, colorectal cancer, pancreatic cancer, kidney cancer, hepatocellular cancer, malignant mesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasma cell neoplasms, Wilm's tumor, or hepatocellular carcinoma.
[0717] 157. The method of clause 155 or 156, wherein the cancer is a refractory cancer.
[0718] 158. The method of any one of clauses 155-157, wherein the compound is administered in combination with one or more additional cancer therapies.
[0719] 159. The method of clause 158, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.
[0720] 160. The method of clause 159, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.
[0721] 161. The method of clause 160, wherein the one or more additional chemotherapeutic agents is selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g., azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or Vindesine Taxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, such as irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., a lutenizing hormone releasing hormone agonist; e.g., leuprolidine, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab, Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin, Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab, Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomab tiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab, Tocilizumab, Tositumomab and/or Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombotic agent; a growth inhibitory agent; an anti-helminthic agent; and an immune checkpoint inhibitor that targets an immune checkpoint receptor selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).
[0722] 162. The method of any one of clauses 152-161, wherein the compound is administered intratumorally.
[0723] 163. A method of treatment of a disease, disorder, or condition associated with STING, comprising administering to a subject in need of such treatment an effective amount of a compound as defined in any one of clauses 1-116, or a pharmaceutical composition as defined in clause 117.
[0724] 164. The method of clause 163, wherein the disease, disorder, or condition is selected from type I interferonopathies, Aicardi-Goutières Syndrome (AGS), genetic forms of lupus, inflammation-associated disorders, and rheumatoid arthritis.
[0725] 165. The method of clause 164, wherein the disease, disorder, or condition is a type I interferonopathy (e.g., STING-associated vasculopathy with onset in infancy (SAVI)).
[0726] 166. The method of clause 165, wherein the type I interferonopathy is STING-associated vasculopathy with onset in infancy (SAVI)).
[0727] 167. The method of clause 164, wherein the disease, disorder, or condition is Aicardi-Goutières Syndrome (AGS).
[0728] 168. The method of clause 164, wherein the disease, disorder, or condition is a genetic form of lupus.
[0729] 169. The method of clause 164, wherein the disease, disorder, or condition is inflammation-associated disorder.
[0730] 170. The method of clause 169, wherein the inflammation-associated disorder is systemic lupus erythematosus.
[0731] 171. The method of any one of clauses 118-170, wherein the method further comprises identifying the subject.
[0732] 172. A combination comprising a compounds defined in any one of clauses 1 to 116 or a pharmaceutically acceptable salt or tautomer thereof, and one or more therapeutically active agents.
[0733] 173. A compound defined in any one of clauses 1 to 116 or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 117, for use as a medicament.
[0734] 174. A compound defined in any one of clauses 1 to 116 or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 117, for use in the treatment of a disease, condition or disorder modulated by STING inhibition.
[0735] 175. A compound defined in any one of clauses 1 to 116 or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition defined in clause 117, for use in the treatment of a disease mentioned in any one of clauses 118 to 171.
[0736] 176. Use of a compound defined in any one of clauses 1 to 116 or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 117, in the manufacture of a medicament for the treatment of a disease mentioned in in any one of clauses 118 to 171.