COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH STING ACTIVITY
20230002320 · 2023-01-05
Inventors
- Hans Martin Seidel (Concord, MA)
- William R. Roush (Boston, MA, US)
- Jason Katz (Newton, MA)
- Shankar Venkatraman (Lansdale, PA)
Cpc classification
C07D405/12
CHEMISTRY; METALLURGY
C07D409/10
CHEMISTRY; METALLURGY
C07D413/04
CHEMISTRY; METALLURGY
C07D409/04
CHEMISTRY; METALLURGY
C07D209/40
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
C07D417/12
CHEMISTRY; METALLURGY
C07D405/04
CHEMISTRY; METALLURGY
C07D405/10
CHEMISTRY; METALLURGY
C07D401/10
CHEMISTRY; METALLURGY
C07D403/04
CHEMISTRY; METALLURGY
C07D403/10
CHEMISTRY; METALLURGY
A61P37/06
HUMAN NECESSITIES
C07D401/04
CHEMISTRY; METALLURGY
C07D417/04
CHEMISTRY; METALLURGY
International classification
C07D209/40
CHEMISTRY; METALLURGY
C07D401/10
CHEMISTRY; METALLURGY
C07D403/10
CHEMISTRY; METALLURGY
C07D405/10
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 prodrug, and/or tautomer, 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. Formula (I).
##STR00001##
Claims
1. A compound of Formula I: ##STR00488## or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein: X.sup.1 is selected from the group consisting of O, S, N, NR.sup.2, and CR.sup.5; 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 the 6-membered ring ##STR00489## is aromatic; one of R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is selected from the group consisting of: R* and —OR*; and each of the three remaining R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is an independently selected R**; wherein: R* is selected from the group consisting of: C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each optionally substituted with 1-4 independently selected R.sup.g; heterocyclyl or heterocycloalkenyl, wherein each of the heterocyclyl and heterocycloalkenyl has 3-16 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, wherein each of the heterocyclyl and heterocycloalkenyl is optionally substituted with 1-4 independently selected R.sup.g; heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g; and C.sub.6-10 aryl, which is optionally substituted with 1-4 independently selected R.sup.g; and each R** is independently selected from the group consisting of: H; halo; cyano; C.sub.1-6 alkyl optionally substituted with 1-2 R.sup.a; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; C.sub.1-4 haloalkyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; -L.sup.3-L.sup.4-R*; —S(O).sub.1-2(C.sub.1-4 alkyl); —S(O)(═NH)(C.sub.1-4 alkyl); SF.sub.5; —NR.sup.e1R.sup.f1; —OH; —S(O).sub.1-2(NR′R″); —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-4 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; and —C(═O)N(R′)(R″); W is selected from the group consisting of C(═O); C(═S); S(O).sub.1-2; C(═NR.sup.d); C(═NH); C(═C—NO.sub.2); S(═O)═N(R.sup.d); and S(═O)═NH; Q-A is defined according to (A) or (B) below: ##STR00490## Q is selected from the group consisting of: NH and N(C.sub.1-6 alkyl), wherein the C.sub.1-6 alkyl is optionally substituted with 1-2 independently selected R.sup.a; and A is: (i) —(Y.sup.A1).sub.n—Y.sup.A2, wherein: n is 0 or 1; Y.sup.A1 is C.sub.1-6 alkylene, which is optionally substituted with 1-6 independently selected R.sup.a; and Y.sup.A2 is (a) C.sub.3-20 cycloalkyl or C.sub.3-20 cycloalkenyl, each of which is optionally substituted with 1-4 R.sup.b, (b) C.sub.6-20 aryl, which is optionally substituted with 1-4 R.sup.c; (c) heteroaryl of 5-20 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 ring is optionally substituted with 1-4 independently selected R.sup.c; or (d) heterocyclyl or heterocycloalkenyl, each of 3-16 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 each of the heterocyclyl and heterocycloalkenyl ring is optionally substituted with 1-4 independently selected R.sup.b, or (ii) C.sub.1-10 alkyl, which is optionally substituted with 1-6 independently selected R.sup.a, or Q and A, taken together, form: ##STR00491## and E is a ring of 3-16 ring atoms, wherein aside from the nitrogen atom present, 0-3 additional 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 ring is optionally substituted with 1-4 independently selected R.sup.b, each occurrence of R.sup.2 is independently selected from the group consisting of: (i) C.sub.1-6 alkyl, which is optionally substituted with 1-2 independently selected R.sup.a; (ii) C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, wherein the cycloalkyl or cycloalkenyl is optionally substituted with 1-4 independently selected R.sup.b; (iii) heterocyclyl or heterocycloalkenyl, each of 3-10 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 is optionally substituted with 1-4 independently selected R.sup.b; (iv) C.sub.6-10 aryl, which is optionally substituted with 1-4 independently selected R.sup.b; (v) heteroaryl of 5-10 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 independently selected R.sup.b; (vi) —C(O)(C.sub.1-4 alkyl), which is optionally substituted with 1-2 independently selected R.sup.a; (vii) —C(O)(C.sub.6-10 aryl), which is optionally substituted with 1-2 independently selected R.sup.c; (viii) —C(O)(heteroaryl), wherein the heteroaryl has 5-10 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 1-2 independently selected R.sup.c; (vii) —C(O)O(C.sub.1-4 alkyl); (viii) —CON(R′)(R″); (ix) —S(O).sub.1-2(NR′R″); (x) —S(O).sub.1-2(C.sub.1-4 alkyl), which is optionally substituted with 1-2 independently selected R.sup.a; (xiii) —S(O).sub.1-2(C.sub.6-10 aryl), which is optionally substituted with 1-2 independently selected R.sup.c; (xiv) —S(O).sub.1-2(heteroaryl), wherein the heteroaryl has 5-10 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 1-2 independently selected R.sup.c; (xi) —OH; (xii) C.sub.1-4 alkoxy; and (xiii) H; R.sup.4 is selected from the group consisting of H and C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a; R.sup.5 is selected from the group consisting of H; halo; —OH; —C.sub.1-4 alkyl; —C.sub.1-4 haloalkyl; 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; —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); cyano, and C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected C.sub.1-4 alkyl; R.sup.6 is selected from the group consisting of H; C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a; —OH; C.sub.1-4 alkoxy; C(═O)H; C(═O)(C.sub.1-4 alkyl); C.sub.6-10 aryl optionally substituted with 1-4 independently selected C.sub.1-4 alkyl; and heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected C.sub.1-4 alkyl; each occurrence of R.sup.a is independently selected from the group consisting of: —OH; —F; —Cl; —Br; —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; —CON(R′R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); cyano; C.sub.6-10 aryl; heteroaryl of 5-10 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; heterocyclyl or heterocycloalkenyl, each of 3-10 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 C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected C.sub.1-4 alkyl; each occurrence of R.sup.a1 is independently selected from the group consisting of: —OH; —F; —Cl; —Br; —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; —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); cyano; C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected C.sub.1-4 alkyl; C.sub.6-10 aryl optionally substituted with 1-4 independently selected C.sub.1-4 alkyl; and heteroaryl of 5-10 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 wherein the heteroaryl ring is optionally substituted with 1-4 independently selected C.sub.1-4 alkyl; each occurrence of R.sup.b is independently selected from the group consisting of: C.sub.1-10 alkyl optionally substituted with 1-6 independently selected R.sup.a; C.sub.1-4 haloalkyl; —OH; oxo; —F; —Cl; —Br; —NR.sup.e1R.sup.f1; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —C(═O)(C.sub.1-10 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; —C(═O)N(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); cyano; and -L.sup.1-L.sup.2-R.sup.h; 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); —NR.sup.e1R.sup.f1; —OH; —S(O).sub.1-2(NR′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)N(R′)(R″); and -L.sup.1-L.sup.2-R.sup.h; R.sup.d is selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CON(R′)(R″); —S(O).sub.1-2(NR′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; C.sub.1-6 haloalkyl; C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy; or R.sup.e and R.sup.f together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C.sub.1-3 alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R.sup.e and R), which are each independently selected from the group consisting of N(R.sup.d), NH, O, and S; each occurrence of R.sup.e1 and R.sup.f1 is independently selected from the group consisting of: H; C.sub.1-6 alkyl; C.sub.1-6 haloalkyl; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CON(R′)(R″); —S(O).sub.1-2(NR′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: halo; cyano; C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1; C.sub.1-4 haloalkyl; C.sub.1-6 alkoxy optionally substituted with 1-2 independently selected Rai; C.sub.1-4 haloalkoxy; C.sub.3-8 cycloalkyl optionally substituted with C.sub.1-6 alkyl or cyano; C.sub.6-10 aryl; S(O).sub.1-2(C.sub.1-4 alkyl); —NR.sup.eR.sup.f; —OH; oxo; —S(O).sub.1-2(NR′R″); —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-4 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; —Si(C.sub.1-4 alkyl).sub.4; and —C(═O)N(R′)(R″); -L.sup.1 is a bond or C.sub.1-3 alkylene; -L.sup.2 is —O—, —N(H)—, —S(O).sub.0-2—, or a bond; R.sup.h is selected from the group consisting of: C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl (in certain embodiments, it is provided that when R.sup.h is C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected C.sub.1-4 alkyl, -L.sup.1 is a bond, or -L.sup.2 is —O—, —N(H)—, or —S—); heterocyclyl or heterocycloalkenyl, wherein each of the heterocyclyl and heterocycloalkenyl has 3-16 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, wherein each of the heterocyclyl and heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; and C.sub.6-10 aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; -L.sup.3 is —C.sub.1-3 alkylene or a bond; -L.sup.4 is —O—, —N(H)—, —S(O).sub.0-2—, or a bond; each occurrence of R′ and R″ is independently selected from the group consisting of: H, —OH, C.sub.1-4 alkyl, C.sub.6-10 aryl optionally substituted with 1-2 substituents selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl, and heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, —OH, NH.sub.2, NH(C.sub.1-4 alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; or R′ and R″ together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C.sub.1-3 alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R′ and R″), which are each independently selected from the group consisting of N(H), N(C.sub.1-6 alkyl), O, and S; and with the proviso that the compound is not ##STR00492##
2. The compound of claim 1, wherein X.sup.1 is NR.sup.2, such as: wherein X.sup.1 is NH.
3. The compound of claim 1 or 2, wherein X.sup.2 is CR.sup.5, such as: wherein X.sup.2 is CH.
4. The compound of any one of claims 1-3, wherein the ##STR00493## moiety is ##STR00494## wherein one of R.sup.1a and R.sup.1b is R*, such as: wherein the ##STR00495## moiety is ##STR00496##
5. The compound of any one of claims 1-3, wherein the compound is a compound of Formula (I-a1), (I-a2), (I-a3), or (I-a4): ##STR00497## such as: wherein the compound is a compound of Formula (I-a2-1), (I-a1-1), or (I-a3-1): ##STR00498## and optionally R.sup.2 is H; and R.sup.5 is H.
6. The compound of any one of claims 1-5, wherein R* is selected from the group consisting of: heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g; and C.sub.6-10 aryl, which is optionally substituted with 1-4 independently selected R.sup.g.
7. The compound of any one of claims 1-6, wherein R* is heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g; such as: wherein R* is heteroaryl of 5 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g; or wherein R* is heteroaryl of 6 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g.
8. The compound of any one of claims 1-7, wherein R* is C.sub.6-10 aryl, which is optionally substituted with 1-4 independently selected R.sup.g.
9. The compound of any one of claims 1-8, wherein each occurrence of R** is independently selected from the group consisting of: H; halo, such as F; cyano; C.sub.1-6 alkyl optionally substituted with 1-2 R.sup.a; C.sub.1-4 haloalkyl, such as CF.sub.3; C.sub.1-4 alkoxy; —NR.sup.e1R.sup.f1; —OH; —S(O).sub.1-2(NR′R″); —NO.sub.2; —C(═O)(C.sub.1-4 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; and —C(═O)N(R′)(R″).
10. The compound of any one of claims 1-9, wherein W is selected from the group consisting of: C(═O); S(O).sub.2; C(═NR.sup.d); C(═NH); C(═C—NO.sub.2); S(O)N(R.sup.d); and S(O)NH, such as: wherein W is C(═O).
11. The compound of any one of claims 1-10, wherein Q-A is defined according to (A), optionally wherein Q is NH.
12. The compound of any one of claims 1-11, wherein A is —(Y.sup.A1).sub.nY.sup.A2.
13. The compound of any one of claims 1-12, wherein Y.sup.A2 is C.sub.6-10 aryl, which is optionally substituted with 1-3 R.sup.c; or wherein Y.sup.A2 is heteroaryl of 5-14 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), 0, and S(O).sub.0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected R.sup.c; or wherein Y.sup.A2 is C.sub.3-20 cycloalkyl or C.sub.3-20 cycloalkenyl, each of which is optionally substituted with 1-4 R.sup.b; or wherein Y.sup.A2 is heterocyclyl or heterocycloalkenyl, each of 3-16 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 each of the heterocyclyl and heterocycloalkenyl ring is optionally substituted with 1-3 independently selected R.sup.b.
14. The compound of any one of claims 1-10, wherein Q-A is as defined according to (B); and E is a ring of 5-8 ring atoms, wherein 0-3 ring atoms are heteroatoms (in addition to the ring nitrogen atom that is present), 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 ring is optionally substituted with 1-4 independently selected R.sup.b, such as: wherein E is ##STR00499## wherein R.sup.b is C.sub.1-6 alkyl.
15. The compound of claim 1, wherein the compound is a compound of Formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), or (I-9): ##STR00500## wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH; n1 is 0, 1, or 2; each of R.sup.cA and R.sup.cB is an independently selected R.sup.c; and R.sup.7 is H or C.sub.1-4 alkyl; ##STR00501## wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH; n1 is 0, 1, or 2; each of R.sup.cA and R.sup.cB is an independently selected R.sup.c; and R.sup.7 is H or C.sub.1-4 alkyl; ##STR00502## wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH; one of Q.sup.1 and Q.sup.2 is N; the other one of Q.sup.1 and Q.sup.2 is CH; n1 is 0, 1, or 2; each of R.sup.cA and R.sup.cB is an independently selected R.sup.c; and R.sup.7 is H or C.sub.1-4 alkyl; ##STR00503## wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH; one of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 is N; each of the remaining of Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4 is CH; n1 is 0, 1, or 2; and each of R.sup.cA and R.sup.cB is an independently selected R.sup.c; and R.sup.7 is H or C.sub.1-4 alkyl; ##STR00504## wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH; B.sup.1 is selected from the group consisting of: (a) bicyclic or tricyclic heteroaryl of 7-14 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), 0, and S(O).sub.0-2, and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected R.sup.c; and (b) C.sub.7-10 bicyclic aryl, which is optionally substituted with 1-3 R.sup.c; and R.sup.7 is H or C.sub.1-4 alkyl; ##STR00505## wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH; n2 is 0, 1, or 2; each of R.sup.bA and R.sup.bB is an independently selected R.sup.b; and R.sup.7 is H or C.sub.1-4 alkyl; ##STR00506## wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH; n2 is 0, 1, or 2; each of R.sup.bA and R.sup.bB is an independently selected R.sup.b; and R.sup.7 is H or C.sub.1-4 alkyl; ##STR00507## wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH; B.sup.2 is: bicyclic, tricyclic, or polycyclic C.sub.7-20 cycloalkyl or C.sub.7-20 cycloalkenyl, each optionally substituted with 1-2 R.sup.b; and R.sup.7 is H or C.sub.1-4 alkyl; ##STR00508## wherein E is a ring of 3-16 ring atoms, wherein aside from the nitrogen atom present, 0-3 additional 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 ring is optionally substituted with 1-4 independently selected R.sup.b, optionally X.sup.1 is NH; and X.sup.2 is CH in Formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), or (I-9); optionally W.sup.A is O in Formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), or (I-8); optionally R.sup.cA is 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); —NR.sup.eR.sup.f; —C.sub.1-4 thioalkoxy; —C(═O)(C.sub.1-10 alkyl); —C(═O)(OH); —C(═O)O(C.sub.1-4 alkyl); and -L.sup.1-L.sup.2-R.sup.h in Formula (I-1), (I-2), (I-3), or (I-4); optionally R.sup.bA is selected from the group consisting of C.sub.1-10 alkyl which is substituted with 1-6 independently selected R.sup.a; —F; —Cl; -L.sup.1-L.sup.2-R.sup.h; C.sub.1-4 alkoxy; and C.sub.1-4 haloalkoxy in Formula (I-6) or (I-7); and optionally one of R.sup.1a and R.sup.1b, such as R.sup.1b, is R*; the other of R.sup.1a and R.sup.1b, such as R.sup.1a, is R**, such as H or —F; and each of R.sup.c and R.sup.1d is H.
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 claims 1-16 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 any one of claims 1-16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 17.
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 any one of claims 1-16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 17.
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 any one of claims 1-16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 17.
Description
DETAILED DESCRIPTION
[0062] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or prodrug, and/or tautomer, 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.
[0063] Formula I Compounds
[0064] In one aspect, compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are featured:
##STR00008##
[0065] or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:
[0066] X.sup.1 is selected from the group consisting of O, S, N, NR.sup.2, and CR.sup.5;
[0067] X.sup.2 is selected from the group consisting of O, S, N, NR.sup.4, and CR.sup.5;
[0068] 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
[0069] the 6-membered ring
##STR00009##
is aromatic;
[0070] one of R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is selected from the group consisting of R* and —OR*;
[0071] and each of the three remaining R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is an independently selected R**; wherein:
[0072] R* is selected from the group consisting of: [0073] C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each optionally substituted with 1-4 independently selected R.sup.g; [0074] heterocyclyl or heterocycloalkenyl, wherein each of the heterocyclyl and heterocycloalkenyl has 3-16 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, wherein each of the heterocyclyl and heterocycloalkenyl is optionally substituted with 1-4 independently selected R.sup.g; [0075] heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g; and [0076] C.sub.6-10 aryl, which is optionally substituted with 1-4 independently selected R.sup.g; and
[0077] each R** is independently selected from the group consisting of:
[0078] H; halo; cyano; C.sub.1-6 alkyl optionally substituted with 1-2 R.sup.a; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; C.sub.1-4 haloalkyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; -L.sup.3-L.sup.4-R*; —S(O).sub.1-2(C.sub.1-4 alkyl); —S(O)(═NH)(C.sub.1-4 alkyl); SF.sub.5; —NR.sup.e1R.sup.f1; —OH; —S(O).sub.1-2(NR′R″); —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-4 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; and —C(═O)N(R′)(R″);
[0079] W is selected from the group consisting of:
[0080] (i) C(═O);
[0081] (ii) C(═S);
[0082] (iii) S(O).sub.1-2;
[0083] (iv) C(═NR.sup.d) or C(═NH);
[0084] (vi) C(═C—NO.sub.2); and
[0085] (vii) S(O)N(R.sup.d) or S(O)NH;
[0086] Q-A is defined according to (A) or (B) below:
##STR00010##
[0087] Q is selected from the group consisting of: NH and N(C.sub.1-6 alkyl) wherein the C.sub.1-6 alkyl is optionally substituted with 1-2 independently selected R.sup.a; and
[0088] A is:
[0089] (i) —(Y.sup.A1).sub.n—Y.sup.A2, wherein: [0090] n is 0 or 1; [0091] Y.sup.A1 is C.sub.1-6 alkylene, which is optionally substituted with 1-6 independently selected R.sup.a; and [0092] Y.sup.A2 is: [0093] (a) C.sub.3-20 cycloalkyl or C.sub.3-20 cycloalkenyl, each of which is optionally substituted with 1-4 R.sup.b, [0094] (b) C.sub.6-20 aryl, which is optionally substituted with 1-4 R.sup.c; [0095] (c) heteroaryl of 5-20 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 ring is optionally substituted with 1-4 independently selected R.sup.c; or [0096] (d) heterocyclyl or heterocycloalkenyl, each of 3-16 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 each of the heterocyclyl and heterocycloalkenyl ring is optionally substituted with 1-4 independently selected R.sup.b, or
[0097] (ii) C.sub.1-10 alkyl, which is optionally substituted with 1-6 independently selected R.sup.a, or
[0098] Q and A, taken together, form:
##STR00011##
and
[0099] E is a ring of 3-16 ring atoms, wherein aside from the nitrogen atom present, 0-3 additional 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 ring is optionally substituted with 1-4 independently selected R.sup.b, [0100] each occurrence of R.sup.2 is independently selected from the group consisting of: [0101] (i) C.sub.1-6 alkyl, which is optionally substituted with 1-2 independently selected R.sup.a; [0102] (ii) C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, wherein the cycloalkyl or cycloalkenyl is optionally substituted with 1-4 independently selected R.sup.b; [0103] (iii) heterocyclyl or heterocycloalkenyl, each of 3-10 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 is optionally substituted with 1-4 independently selected R.sup.b; [0104] (iv) C.sub.6-10 aryl, which is optionally substituted with 1-4 independently selected R.sup.b; [0105] (v) heteroaryl of 5-10 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 independently selected R.sup.b; [0106] (vi) —C(O)(C.sub.1-4 alkyl), which is optionally substituted with 1-2 independently selected R.sup.a; [0107] (vii) —C(O)(C.sub.6-10 aryl), which is optionally substituted with 1-2 independently selected R.sup.c; [0108] (viii) —C(O)(heteroaryl), wherein the heteroaryl has 5-10 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 1-2 independently selected R.sup.c; [0109] (ix) —C(O)O(C.sub.1-4 alkyl); [0110] (x) —CON(R′)(R″); [0111] (xi) —S(O).sub.1-2(NR′R″); [0112] (xii) —S(O).sub.1-2(C.sub.1-4 alkyl), which is optionally substituted with 1-2 independently selected R.sup.a; [0113] (xiii) —S(O).sub.1-2(C.sub.6-10 aryl), which is optionally substituted with 1-2 independently selected R.sup.c; [0114] (xiv) —S(O).sub.1-2(heteroaryl), wherein the heteroaryl has 5-10 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 1-2 independently selected R.sup.c; [0115] (xv) —OH; [0116] (xvi) C.sub.1-4 alkoxy; and [0117] (xvii) H;
[0118] R.sup.4 is selected from the group consisting of H and C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a;
[0119] R.sup.5 is selected from the group consisting of H; halo; —OH; —C.sub.1-4 alkyl; —C.sub.1-4 haloalkyl; 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; —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); cyano, and C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected C.sub.1-4 alkyl;
[0120] R.sup.6 is selected from the group consisting of H; C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a; —OH; C.sub.1-4 alkoxy; C(═O)H; C(═O)(C.sub.1-4 alkyl); C.sub.6-10 aryl optionally substituted with 1-4 independently selected C.sub.1-4 alkyl; and heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected C.sub.1-4 alkyl;
[0121] each occurrence of R.sup.a is independently selected from the group consisting of: —OH; —F; —Cl; —Br; —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; —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); cyano; C.sub.6-10 aryl; heteroaryl of 5-10 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; heterocyclyl or heterocycloalkenyl, each of 3-10 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 C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected C.sub.1-4 alkyl;
[0122] each occurrence of R.sup.at is independently selected from the group consisting of: —OH; —F; —Cl; —Br; —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; —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); cyano; C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected C.sub.1-4 alkyl; C.sub.6-10 aryl optionally substituted with 1-4 independently selected C.sub.1-4 alkyl; and heteroaryl of 5-10 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 wherein the heteroaryl ring is optionally substituted with 1-4 independently selected C.sub.1-4 alkyl;
[0123] each occurrence of R.sup.b is independently selected from the group consisting of: C.sub.1-10 alkyl optionally substituted with 1-6 independently selected R.sup.a; C.sub.1-4 haloalkyl; —OH; oxo; —F; —Cl; —Br; —NR.sup.e1R.sup.f1; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —C(═O)(C.sub.1-10 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; —C(═O)N(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); cyano; and -L.sup.1-L.sup.2-R.sup.h;
[0124] each occurrence of R.sup.c is independently selected from the group consisting of:
[0125] 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); —NR.sup.e1R.sup.f1; —OH; —S(O).sub.1-2(NR′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)N(R′)(R″); and -L.sup.1-L.sup.2-R.sup.h;
[0126] R.sup.d is selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy;
[0127] each occurrence of R.sup.e and R.sup.f is independently selected from the group consisting of: H; C.sub.1-6 alkyl; C.sub.1-6 haloalkyl; C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy; or R.sup.e and R.sup.f together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C.sub.1-3 alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R.sup.e and R), which are each independently selected from the group consisting of N(R.sup.d), NH, O, and S;
[0128] each occurrence of R.sup.e1 and R.sup.f1 is independently selected from the group consisting of: H; C.sub.1-6 alkyl; C.sub.1-6 haloalkyl; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy;
[0129] each occurrence of R.sup.g is independently selected from the group consisting of: halo; cyano; C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1; C.sub.1-4 haloalkyl; C.sub.1-6 alkoxy optionally substituted with 1-2 independently selected R.sup.a1; C.sub.1-4 haloalkoxy; C.sub.3-8 cycloalkyl optionally substituted with C.sub.1-6 alkyl or cyano; C.sub.6-10 aryl; S(O).sub.1-2(C.sub.1-4 alkyl); —NR.sup.e1R.sup.f1; —OH; oxo; —S(O).sub.1-2(NR′R″); —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-4 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; —Si(C.sub.1-4 alkyl).sub.4; and —C(═O)N(R′)(R″);
[0130] -L.sup.1 is a bond or C.sub.1-3 alkylene;
[0131] -L.sup.2 is —O—, —N(H)—, —S(O).sub.0-2—, or a bond;
[0132] R.sup.h is selected from the group consisting of: [0133] C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl (in certain embodiments, it is provided that when R.sup.h is C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected C.sub.1-4 alkyl, -L.sup.1 is a bond, or -L.sup.2 is —O—, —N(H)—, or —S—); [0134] heterocyclyl or heterocycloalkenyl, wherein each of the heterocyclyl and heterocycloalkenyl has 3-16 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, wherein each of the heterocyclyl and heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; [0135] heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; and [0136] C.sub.6-10 aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl;
[0137] -L.sup.3 is —C.sub.1-3 alkylene or a bond;
[0138] -L.sup.4 is —O—, —N(H)—, —S(O).sub.0-2—, or a bond;
[0139] each occurrence of R′ and R″ is independently selected from the group consisting of: H, —OH, C.sub.1-4 alkyl, C.sub.6-10 aryl optionally substituted with 1-2 substituents selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl, and heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, —OH, NH.sub.2, NH(C.sub.1-4 alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; or R′ and R″ together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C.sub.1-3 alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R′ and R″), which are each independently selected from the group consisting of N(H), N(C.sub.1-6 alkyl), O, and S; and
[0140] with the proviso that the compound is not
##STR00012##
[0141] In one aspect, compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are featured:
##STR00013##
[0142] or a pharmaceutically acceptable salt thereof or a tautomer thereof,
[0143] wherein:
[0144] X.sup.1 is selected from the group consisting of O, S, N, NR.sup.2, and CR.sup.5;
[0145] X.sup.2 is selected from the group consisting of O, S, N, NR.sup.4, and CR.sup.5;
[0146] 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
[0147] the 6-membered ring is aromatic:
##STR00014##
[0148] one of R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is selected from the group consisting of R* and —OR*;
[0149] and each of the three remaining R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is an independently selected R**;
[0150] wherein:
[0151] R* is selected from the group consisting of: [0152] C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each optionally substituted with 1-4 independently selected R.sup.g; [0153] heterocyclyl or heterocycloalkenyl, wherein each of the heterocyclyl and heterocycloalkenyl has 3-16 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, wherein each of the heterocyclyl and heterocycloalkenyl is optionally substituted with 1-4 independently selected R.sup.g; [0154] heteroaryl of 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), 0, and S(O).sub.0-2 and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected R.sup.g; and [0155] C.sub.6-10 aryl, which is optionally substituted with 1-4 independently selected R.sup.g; and
[0156] each R** is independently selected from the group consisting of:
[0157] H; halo; cyano; C.sub.1-6 alkyl optionally substituted with 1-2 R.sup.a; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; C.sub.1-4 haloalkyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; -L.sup.3-L.sup.4-R*; —S(O).sub.1-2(C.sub.1-4 alkyl); —S(O)(═NH)(C.sub.1-4 alkyl); SF.sub.5; —NR.sup.e1R.sup.f1; —OH; —S(O).sub.1-2(NR′R″); —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-4 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; and —C(═O)N(R′)(R″);
[0158] W is selected from the group consisting of:
[0159] (i) C(═O);
[0160] (ii) C(═S);
[0161] (iii) S(O).sub.1-2;
[0162] (iv) C(═NR.sup.d) or C(═NH);
[0163] (vi) C(═C—NO.sub.2); and
[0164] (vii) S(O)N(R.sup.d) or S(O)NH;
[0165] Q-A is defined according to (A) or (B) below:
##STR00015##
[0166] Q is selected from the group consisting of: NH and N(C.sub.1-6 alkyl) wherein the C.sub.1-6 alkyl is optionally substituted with 1-2 independently selected R.sup.a; and
[0167] A is:
[0168] (i) —(Y.sup.A1).sub.n—Y.sup.A2, wherein: [0169] n is 0 or 1; [0170] Y.sup.A1 is C.sub.1-6 alkylene, which is optionally substituted with 1-6 independently selected R.sup.a; and [0171] Y.sup.A2 is: [0172] (a) C.sub.3-20 cycloalkyl or C.sub.3-20 cycloalkenyl, each of which is optionally substituted with 1-4 R.sup.b, [0173] (b) C.sub.6-20 aryl, which is optionally substituted with 1-4 R.sup.c; [0174] (c) heteroaryl of 5-20 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 ring is optionally substituted with 1-4 independently selected R.sup.c; or [0175] (d) heterocyclyl or heterocycloalkenyl, each of 3-16 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 each of the heterocyclyl and heterocycloalkenyl ring is optionally substituted with 1-4 independently selected R.sup.b, OR
[0176] (ii) C.sub.1-10 alkyl, which is optionally substituted with 1-6 independently selected R.sup.a, OR
##STR00016##
[0177] Q and A, taken together, form:
##STR00017##
and
[0178] E is a ring of 3-16 ring atoms, wherein aside from the nitrogen atom present, 0-3 additional 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 ring is optionally substituted with 1-4 independently selected R.sup.b,
[0179] each occurrence of R.sup.2 is independently selected from the group consisting of: [0180] (i) C.sub.1-6 alkyl, which is optionally substituted with 1-2 independently selected R.sup.a; [0181] (ii) C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl; [0182] (iii) heterocyclyl or heterocycloalkenyl, each of 3-10 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; [0183] (iv) C.sub.6-10 aryl; [0184] (v) heteroaryl of 5-10 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; [0185] (vi) —C(O)(C.sub.1-4 alkyl); [0186] (vii) —C(O)O(C.sub.1-4 alkyl); [0187] (viii) —CON(R′)(R″); [0188] (ix) —S(O).sub.1-2(NR′R″); [0189] (x) —S(O).sub.1-2(C.sub.1-4 alkyl); [0190] (xi) —OH; [0191] (xii) C.sub.1-4 alkoxy; and [0192] (xiii) H;
[0193] R.sup.4 is selected from the group consisting of H and C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a;
[0194] R.sup.5 is selected from the group consisting of H; halo; —OH; —C.sub.1-4 alkyl; —C.sub.1-4 haloalkyl; 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; —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); cyano, and C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected C.sub.1-4 alkyl;
[0195] R.sup.6 is selected from the group consisting of H; C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a; —OH; C.sub.1-4 alkoxy; C(═O)H; C(═O)(C.sub.1-4 alkyl); C.sub.6-10 aryl optionally substituted with 1-4 independently selected C.sub.1-4 alkyl; and heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected C.sub.1-4 alkyl;
[0196] each occurrence of R.sup.a is independently selected from the group consisting of: —OH; —F; —Cl; —Br; —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; —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); cyano, and C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected C.sub.1-4 alkyl;
[0197] each occurrence of R.sup.a1 is independently selected from the group consisting of: —OH; —F; —Cl; —Br; —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; —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); cyano, C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected C.sub.1-4 alkyl, C.sub.6-10 aryl optionally substituted with 1-4 independently selected C.sub.1-4 alkyl, and heteroaryl of 5-10 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 wherein the heteroaryl ring is optionally substituted with 1-4 independently selected C.sub.1-4 alkyl;
[0198] each occurrence of R.sup.b is independently selected from the group consisting of: C.sub.1-10 alkyl optionally substituted with 1-6 independently selected R.sup.a; C.sub.1-4 haloalkyl; —OH; oxo; —F; —Cl; —Br; —NR.sup.e1R.sup.f1; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —C(═O)(C.sub.1-10 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; —C(═O)N(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); cyano; and -L.sup.1-L.sup.2-R.sup.h;
[0199] each occurrence of R.sup.c is independently selected from the group consisting of:
[0200] 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); —NR.sup.e1R.sup.f1; —OH; —S(O).sub.1-2(NR′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)N(R′)(R″); and -L.sup.1-L.sup.2-R.sup.h;
[0201] R.sup.d is selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy;
[0202] each occurrence of R.sup.e and R.sup.f is independently selected from the group consisting of: H; C.sub.1-6 alkyl; C.sub.1-6 haloalkyl; C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy; or R.sup.e and R.sup.f together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C.sub.1-3 alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R.sup.e and R), which are each independently selected from the group consisting of N(R.sup.d), NH, O, and S;
[0203] each occurrence of R.sup.e1 and R.sup.f1 is independently selected from the group consisting of: H; C.sub.1-6 alkyl; C.sub.1-6 haloalkyl; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy;
[0204] each occurrence of R.sup.g is independently selected from the group consisting of: halo; cyano; C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1; C.sub.1-4 haloalkyl; C.sub.1-6 alkoxy optionally substituted with 1-2 independently selected R.sup.a1; C.sub.1-4 haloalkoxy; S(O).sub.1-2(C.sub.1-4 alkyl); —NR.sup.e1R.sup.f1; —OH; oxo; —S(O).sub.1-2(NR′R″); —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-4 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; and —C(═O)N(R′)(R″);
[0205] -L.sup.1 is a bond or C.sub.1-3 alkylene;
[0206] -L.sup.2 is —O—, —N(H)—, —S(O).sub.0-2—, or a bond;
[0207] R.sup.h is selected from the group consisting of: [0208] C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl (in certain embodiments, it is provided that when R.sup.h is C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected C.sub.1-4 alkyl, -L.sup.1 is a bond, or -L.sup.2 is —O—, —N(H)—, or —S—); [0209] heterocyclyl or heterocycloalkenyl, wherein each of the heterocyclyl and heterocycloalkenyl has 3-16 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, wherein each of the heterocyclyl and heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; [0210] heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; and [0211] C.sub.6-10 aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl;
[0212] -L.sup.3 is —C.sub.1-3 alkylene or a bond;
[0213] -L.sup.4 is —O—, —N(H)—, —S(O).sub.0-2—, or a bond; and
[0214] each occurrence of R′ and R″ is independently selected from the group consisting of: H, —OH, C.sub.1-4 alkyl, C.sub.6-10 aryl optionally substituted with 1-2 substituents selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl, and heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, —OH, NH.sub.2, NH(C.sub.1-4 alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; or R′ and R″ together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C.sub.1-3 alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R′ and R″), which are each independently selected from the group consisting of N(H), N(C.sub.1-6 alkyl), O, and S.
[0215] In some embodiments, it is provided that the compound is not
##STR00018##
(e.g., with the proviso that the compound is not
##STR00019##
[0216] Embodiments can include any one or more of the features delineated below and/or in the claims.
[0217] The Variables X.sup.1 and X.sup.2
[0218] In some embodiments, X.sup.1 is NR.sup.2. In certain of these embodiments, X.sup.1 is NH.
[0219] In some embodiments, X.sup.2 is CR.sup.5. In certain of these embodiments, X.sup.2 is CH. In other embodiments, R.sup.5 is other than H.
[0220] In certain embodiments, X.sup.1 is NR.sup.2; and X.sup.2 is CR.sup.5.
[0221] In certain embodiments, X.sup.1 is NH; and X.sup.2 is CH.
[0222] The
##STR00020##
Moiety
[0223] In some embodiments, the R
##STR00021##
moiety is
##STR00022##
wherein one of R.sup.1a and R.sup.1b is R*.
[0224] In some embodiments, the
##STR00023##
moiety is
##STR00024##
wherein the asterisk denotes point of attachment to X.sup.1.
[0225] In some embodiments, the
##STR00025##
moiety is
##STR00026##
[0226] In some embodiments, the
##STR00027##
moiety is
##STR00028##
[0227] Non-Limiting Combinations of X.sup.1, X.sup.2, and the
##STR00029##
Moiety
[0228] In some embodiments, the compound is a compound of Formula (I-a):
##STR00030##
[0229] In certain embodiments of Formula (I-a), the compound has formula the compound has formula (I-a1):
##STR00031##
[0230] In certain embodiments of Formula (I-a), the compound has formula (I-a2):
##STR00032##
[0231] In certain embodiments of Formula (I-a), (when the compound has formula (I-a2)) the compound has formula (I-a2-1):
##STR00033##
[0232] In certain embodiments of Formula (I-a), the compound has formula (I-a3):
##STR00034##
[0233] In certain embodiments of Formula (I-a), the compound has formula (I-a4):
##STR00035##
[0234] In certain embodiments of Formula (I-a) (when the compound has formula (I-a1) or (I-a3)), the compound has formula (I-a1-1) or (I-a3-1):
##STR00036##
[0235] In certain embodiments of Formula (I-a) (e.g., when the compound has Formula (I-a1), (I-a2), (I-a2-1), (I-a3), (I-a3-1), or (I-a4)), R.sup.2 is H; and R.sup.5 is H.
[0236] In certain embodiments of Formula (I-a) (e.g., when the compound has Formula (I-a1), (I-a2), (I-a2-1), (I-a3), (I-a3-1), or (I-a4)), R.sup.2 is selected from the group consisting of: heterocyclyl or heterocycloalkenyl, each of 3-10 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 heteroaryl of 5-10 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 R.sup.5 is H.
[0237] The Variables R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1dIn some embodiments, one of R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is selected from the group consisting of R* and —OR*; and each of the three remaining R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is an independently selected R**.
[0238] In some embodiments, one of R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is selected from the group consisting of R*; and each of the three remaining R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is an independently selected R**.
[0239] In some embodiments, R* is selected from the group consisting of: [0240] heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g; and [0241] C.sub.6-10 aryl, which is optionally substituted with 1-4 independently selected R.sup.g.
[0242] In certain embodiments, R* is heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g. In certain of these embodiments, R* is heteroaryl of 5 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g.
[0243] As a non-limiting example of the foregoing, R* is
##STR00037##
wherein
[0244] each is independently a single bond or a double bond, provided that the five-membered ring comprising Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4 is heteroaryl;
[0245] Z.sup.1 is selected from N and CH;
[0246] Z.sup.2 is selected from N, O, and CH;
[0247] Z.sup.3 is selected from C(R.sup.g), N(R.sup.g), N(R.sup.d), and N;
[0248] Z.sup.4 is selected from N, NH, S, CH, N(R.sup.g), N(R.sup.d), and O; and
[0249] the asterisk denotes point of attachment to the six-membered ring of the bicyclic ring portion of Formula I.
[0250] In certain of the foregoing R* embodiments, each occurrence of R.sup.g is independently selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl; C.sub.6-10 aryl; —OH; —C(═O)(C.sub.1-4 alkyl); C.sub.1-4 alkoxy; or cyano); halo; C.sub.6-10 aryl; and cyano.
[0251] In certain of the foregoing R* embodiments, each occurrence of R.sup.g is C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected C.sub.3-6 cycloalkyl or C.sub.6-10 aryl).
[0252] In certain of the foregoing R* embodiments, each occurrence of R.sup.g is independently selected from the group consisting of: methyl, ethyl, isopropyl, hydroxyethyl, difluoromethyl, benzyl,
##STR00038##
phenyl, cyano, —Cl, —C(O)CH.sub.3, and cyclobutyl.
[0253] In certain of the foregoing R* embodiments, each occurrence of R.sup.d is C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH.
[0254] In certain embodiments, R* is heteroaryl of 6 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g. As a non-limiting example of the foregoing, R* is heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are N atoms (e.g., pyridyl (e.g., 3-pyridyl or 4-pyridyl) and wherein the heteroaryl ring is optionally substituted with 1-4 C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected —OH, —F, or C.sub.1-4 alkoxy); halo (e.g., F or Cl); or —NR.sup.eR.sup.f (e.g., —NH.sub.2 or —NHMe). As a further non-limiting example of the foregoing, R* is heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are N atoms and wherein the heteroaryl ring is optionally substituted with 1-4 C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected —OH, —F, or C.sub.1-4 alkoxy) and —NR.sup.eR.sup.f (e.g., —NH.sub.2).
[0255] In certain embodiments, R* is heteroaryl of 9 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g. As a non-limiting example of the foregoing, R* is selected from the group consisting of:
##STR00039##
and each optionally substituted with 1-4 substituents selected from oxo or fluoro. For example, R* is selected from the group consisting of:
##STR00040##
[0256] In certain other embodiments, R* is C.sub.6-10 aryl, which is optionally substituted with 1-4 independently selected R.sup.g. As a non-limiting example of the foregoing, R* is phenyl, which is optionally substituted with 1-4 independently selected halo (e.g., F or Cl); —OH; cyano; —C(═O)N(R′)(R″) (e.g., —C(═O)NMe.sub.2); S(O).sub.1-2(C.sub.1-4 alkyl) (e.g., —SO.sub.2Et); —C(═O)(C.sub.1-4 alkyl) (e.g., —C(═O)Me); —Si(C.sub.1-4 alkyl).sub.4 (e.g., —Si(CH.sub.3).sub.4); C.sub.3-8 cycloalkyl optionally substituted with cyano; C.sub.1-4 haloalkoxy (e.g., —OCHF.sub.2 or —OCF.sub.3); C.sub.1-6 alkoxy (e.g., methoxy); or C.sub.1-6 alkyl optionally substituted with 1-2 independently selected Rai (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 —OH, C.sub.1-4 alkoxy, cyano, —C(═O)O(C.sub.1-4 alkyl), or —NR.sup.eR.sup.f). As a further non-limiting example of the foregoing, R* is phenyl, which is optionally substituted with 1-4 independently selected halo (e.g., F or Cl) or C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 —OH).
[0257] Non-limiting examples of R* include:
##STR00041##
[0258] Further non-limiting examples of R* include:
##STR00042##
[0259] In some embodiments, each occurrence of R** is selected from the group consisting of: H; halo (e.g., F); cyano; C.sub.1-6 alkyl optionally substituted with 1-2 R.sup.a; C.sub.1-4 haloalkyl (e.g., CF.sub.3); C.sub.1-4 alkoxy; —NR.sup.e1R.sup.f1; —OH; —S(O).sub.1-2(NR′R″); —NO.sub.2; —C(═O)(C.sub.1-4 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; and —C(═O)N(R′)(R″).
[0260] For example, each occurrence of R** is H or F:
The Variable W
[0261] In some embodiments, W is selected from the group consisting of:
[0262] (i) C(═O);
[0263] (iii) S(O).sub.2;
[0264] (iv) C(═NR.sup.d) or C(═NH);
[0265] (vi) C(═C—NO.sub.2); and
[0266] (vii) S(O)N(R.sup.d) or S(O)NH.
[0267] In certain embodiments, W is selected from the group consisting of C(═O) and S(O).sub.2 (e.g., W is C(═O)).
The Variables R.sup.2, R.sup.5, and R.sup.6
[0268] In some embodiments, R.sup.2 is H.
[0269] In some embodiments, R.sup.2 is selected from the group consisting of: heterocyclyl or heterocycloalkenyl, each of 3-10 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 heteroaryl of 5-10 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.
[0270] In some embodiments, R.sup.5 is H or halo. In certain embodiments, R.sup.5 is H.
[0271] In some embodiments, R.sup.6 is H.
The Variables Q-A
[0272] In some embodiments, Q-A is defined according to (A).
[0273] In some embodiments, Q is NH. In some other embodiments, Q is N(C.sub.1-3 alkyl) (e.g., NMe or NEt).
[0274] In some embodiments, A is —(Y.sup.A1).sub.n—Y.sup.A2. In certain of these embodiments, n is 0.
[0275] In certain other embodiments (when A is —(Y.sup.A1).sub.n—Y.sup.A2), n is 1. In certain of these embodiments, Y.sup.A1 is C.sub.1-6 alkylene, which is optionally substituted with 1-4 R.sup.a.
[0276] In certain of these embodiments, Y.sup.A1 is —CH.sub.2—, —CH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2CH.sub.2—, —CH(CF.sub.3)—, —CH.sub.2CH(OH)—,
##STR00043##
(e.g., Y.sup.A1 is CH.sub.2). As a non-limiting example of the foregoing embodiments, Y.sup.A1 can be —CH.sub.2— or —CH.sub.2CH.sub.2—.
[0277] In certain embodiments, Y.sup.A2 is C.sub.6-10 aryl, which is optionally substituted with 1-3 R.sup.c.
[0278] In certain of these embodiments, Y.sup.A2 is C.sub.6 aryl, which is optionally substituted with 1-3 R.sup.c.
[0279] In certain embodiments, Y.sup.A2 is C.sub.6 aryl, which is substituted with 1-3 R.sup.c.
[0280] In certain embodiments, Y.sup.A2 is phenyl substituted with 1-3 R.sup.c, wherein one R.sup.c is at the ring carbon para to the point of attachment to Y.sup.A1.
[0281] In certain embodiments, Y.sup.A2 is phenyl substituted with 1-3 R.sup.c, wherein 1-2 R.sup.c is at the ring carbons meta to the point of attachment to Y.sup.A1.
[0282] In certain embodiments (when Y.sup.A2 is C.sub.6-10 aryl, which is optionally substituted with 1-3 R.sup.c), each occurrence of R.sup.c is selected from the group consisting of: [0283] halo (e.g., F or Cl); [0284] C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a (e.g., CF.sub.3); and [0285] -L.sup.1-L.sup.2-R.sup.h.
[0286] In certain of these embodiments (when each occurrence of R.sup.c is selected from the group consisting of: (a) halo (e.g., F or Cl); (c) C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a (e.g., CF.sub.3); and (s) -L.sup.1-L.sup.2-R.sup.h), L.sup.1 is a bond; L.sup.2 is a bond or —N(H)—; and R.sup.h is selected from the group consisting of: [0287] C.sub.4-6 cycloalkyl or C.sub.4-6 cycloalkenyl, each optionally substituted with from 1 substituent selected from the group consisting of halo (e.g., F), C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; [0288] phenyl, which is optionally substituted with from 1 substituent selected from the group consisting of halo (e.g., F), C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; and [0289] heterocyclyl or heterocycloalkenyl, wherein each of the heterocyclyl and heterocycloalkenyl has 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), and O, wherein each of the heterocyclyl and heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl (e.g.,
##STR00044##
[0290] In certain embodiments, Y.sup.A2 is C.sub.7-10 bicyclic aryl, which is optionally substituted with 1-3 R.sup.e (e.g., Y.sup.A2 is naphthyl (e.g.,
##STR00045##
indanyl (e.g.,
##STR00046##
tetrahydronapthyl, or
##STR00047##
each of which is optionally substituted with 1-3 R.sup.c).
[0291] In certain embodiments, Y.sup.A2 is heteroaryl of 5-14 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 ring is optionally substituted with 1-4 independently selected R.sup.c.
[0292] In certain of the foregoing embodiments, Y.sup.A2 is heteroaryl of 6 ring atoms (e.g., pyridyl or pyrimidinyl (e.g., pyridyl)), wherein 1-2 (e.g., 1) ring atoms are ring nitrogen atoms, and wherein the heteroaryl ring is optionally substituted with 1-3 (e.g., 1-2) independently selected R.sup.c.
[0293] In certain of the foregoing embodiments, Y.sup.A2 is heteroaryl of 6 ring atoms (e.g., pyridyl or pyrimidinyl (e.g., pyridyl)), Y.sup.A2 is substituted with 1-3 independently selected R.sup.c; and one occurrence of R.sup.c is at the ring carbon atom para to the point of attachment to Y.sup.A1 (e.g.,
##STR00048##
[0294] In certain of the foregoing embodiments, Y.sup.A2 is heteroaryl of 6 ring atoms (e.g., pyridyl or pyrimidinyl (e.g., pyridyl)), Y.sup.A2 is substituted with 1-3 independently selected R.sup.c; and one occurrence of R.sup.c is at the ring carbon atom meta to the point of attachment to Y.sup.A1.
[0295] In certain of the foregoing embodiments, Y.sup.A2 is heteroaryl of 6 ring atoms (e.g., pyridyl or pyrimidinyl (e.g., pyridyl)), wherein 1-2 (e.g., 1) ring atoms are ring nitrogen atoms, and wherein the heteroaryl ring is optionally substituted with 1-3 (e.g., 1-2) independently selected R.sup.c. In certain of these embodiments, when the heteroaryl ring is substituted with 2 or 3 independently selected R.sup.c, one occurrence of R.sup.c is at the position para to the point of attachment of Y.sup.A2 to Y.sup.A1 and at least one occurrence of R.sup.c is at the position meta to the point of attachment of Y.sup.A2 to Y.sup.A1.
[0296] In certain embodiments, Y.sup.A2 is bicyclic or tricyclic heteroaryl of 7-14 (e.g., 9-12 (e.g., 9, 10, 11, or 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 ring is optionally substituted with 1-4 independently selected R.sup.c.
[0297] In certain of these embodiments, Y.sup.A2 is bicyclic heteroaryl of 9-10 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 ring is optionally substituted with 1-4 independently selected R.sup.c.
[0298] As a non-limiting example of the foregoing embodiments, Y.sup.A2 can be bicyclic heteroaryl of 10 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 (e.g.,
##STR00049##
and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected R.sup.c.
[0299] In certain of the foregoing embodiments (wherein Y.sup.A2 is aryl or heteroaryl as described supra), 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); —NR.sup.eR.sup.f; —C.sub.1-4 thioalkoxy; —C(═O)(C.sub.1-10 alkyl); —C(═O)(OH); —C(═O)O(C.sub.1-4 alkyl); and -L.sup.1-L.sup.2-R.sup.h.
[0300] In certain embodiments, each occurrence of R.sup.c is selected from the group consisting of halo (e.g., F) and -L.sup.1-L.sup.2-R.sup.h. In certain of these embodiments, L.sup.1 is a bond; L.sup.2 is —O—, —N(H)—, or a bond; and R.sup.h is selected from the group consisting of: [0301] C.sub.4-6 cycloalkyl or C.sub.4-6 cycloalkenyl, each optionally substituted with 1-2 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; and [0302] heterocyclyl or heterocycloalkenyl, wherein each of the heterocyclyl and heterocycloalkenyl has 3-16 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), and O, wherein each of the heterocyclyl and heterocycloalkenyl is optionally substituted with 1-2 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl.
[0303] As a non-limiting example of the foregoing, R.sup.h is selected from cyclobutyl, cyclohexyl, and piperidine; wherein R.sup.h is optionally substituted with 1-2 F.
[0304] In certain embodiments, one occurrence of R.sup.c is halo (e.g., F or Cl (e.g., Cl)).
[0305] In certain embodiments, one occurrence of R.sup.c is C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a.
[0306] In certain embodiments, one occurrence of R.sup.c is unsubstituted C.sub.1-10 alkyl (e.g., C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, or C.sub.7-10). As a non-limiting example, one occurrence of R.sup.c can be ethyl, propyl (e.g., n-propyl), butyl (e.g., n-butyl, iso-butyl, sec-butyl, tert-butyl), or octyl (e.g., n-octyl).
[0307] In certain embodiments (when one occurrence of R.sup.c is C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a), the occurrence of R.sup.c is C.sub.1-10 alkyl which is substituted with 1-6 independently selected R.sup.a. In certain of these embodiments, each occurrence of R.sup.a is independently selected from halo, OH, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy. As a non-limiting example, each occurrence of R.sup.a is halo (e.g., F). In certain embodiments (e.g., when one occurrence of R.sup.c is C.sub.1-10 alkyl which is substituted with 1-6 independently selected R.sup.a), the occurrence of R.sup.c is CF.sub.3.
[0308] In certain embodiments, one occurrence of R.sup.c is -L.sup.1-L.sup.2-R.sup.h. In certain of these embodiments, L.sup.1 is a bond and/or L.sup.2 is a bond.
[0309] In certain embodiments (when one occurrence of R.sup.c is -L.sup.1-L.sup.2-R.sup.h), R.sup.h is C.sub.6-10 aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl.
[0310] In certain embodiments (when one occurrence of R.sup.c is -L.sup.1-L.sup.2-R.sup.h), R.sup.h is C.sub.6 aryl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl (e.g.,
##STR00050##
[0311] In certain embodiments (when one occurrence of R.sup.c is -L.sup.1-L.sup.2-R.sup.h), R.sup.h is heterocyclyl or heterocycloalkenyl, wherein each of the heterocyclyl and heterocycloalkenyl has 3-10 (e.g., 5-6) ring atoms, wherein 1-3 (e.g., 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, wherein each of the heterocyclyl and heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl. As a non-limiting example of the foregoing embodiments, R.sup.h can be
##STR00051##
[0312] In certain embodiments (when one occurrence of R.sup.e is -L.sup.1-L.sup.2-R.sup.h), R.sup.h is C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl. In certain of these embodiments, R.sup.h is C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl. As non-limiting examples, R.sup.h can be selected from the group consisting of:
##STR00052##
[0313] In any one of more of the foregoing embodiments of R.sup.c, each of the remaining occurrences of R.sup.c is C.sub.1-6 alkyl or halo.
[0314] In certain embodiments, Y.sup.A2 is C.sub.3-20 cycloalkyl or C.sub.3-20 cycloalkenyl, each of which is optionally substituted with 1-4 R.sup.b. In certain of these embodiments, Y.sup.A2 is C.sub.3-10 cycloalkyl (e.g., monocyclic C.sub.3-10 cycloalkyl), which is optionally substituted with 1-4 R.sup.b.
[0315] In certain embodiments, Y.sup.A2 is C.sub.3-6 (e.g., C.sub.3, C.sub.5, or C.sub.6) cycloalkyl or C.sub.3-6 (e.g., C.sub.3, C.sub.5, or C.sub.6) cycloalkenyl, each of which is substituted with 1-4 (e.g., 1-2) R.sup.b (e.g., Y.sup.A2 is cyclopropyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with 1-2 R.sup.b).
[0316] In certain embodiments, Y.sup.A2 is C.sub.5-6 (e.g., C.sub.6) cycloalkyl or C.sub.5-6 (e.g., C.sub.6) cycloalkenyl, each of which is substituted with 1-4 (e.g., 1-2) R.sup.b (e.g., Y.sup.A2 is cyclopentyl or cyclohexyl, each of which is optionally substituted with 1-2 R.sup.b).
[0317] In certain embodiments, Y.sup.A2 is cyclohexyl which is optionally substituted with 1-2 R.sup.b.
[0318] In certain embodiments (when Y.sup.A2 is cyclohexyl which is optionally substituted with 1-2 R.sup.b), one occurrence of R.sup.b is at the ring carbon atom para to the point of attachment to Y.sup.A1; or one occurrence of R.sup.b is at the ring carbon atom meta to the point of attachment to Y.sup.A1.
[0319] In certain embodiments, Y.sup.A2 is cyclopentyl which is optionally substituted with 1-2 R.sup.b.
[0320] In certain embodiments, Y.sup.A2 is bicyclic, tricyclic, or polycyclic (e.g., bicyclic or polycyclic) C.sub.7-20 cycloalkyl or C.sub.7-20 cycloalkenyl, each optionally substituted with 1-2 R.sup.b.
[0321] In certain of these embodiments, Y.sup.A2 is selected from the group consisting of: spiro[5.5]undecanyl (e.g.,
##STR00053##
bicyclo[2.2.1]hept-2-enyl (e.g.,
##STR00054##
bicyclo[2.2.1]heptanyl (e.g.,
##STR00055##
spiro[2.5]octanyl (e.g.,
##STR00056##
and adamantly (e.g.
##STR00057##
As a non-limiting example, Y.sup.A2 is
##STR00058##
[0322] In certain embodiments (when Y.sup.A2 is C.sub.3-20 cycloalkyl or C.sub.3-20 cycloalkenyl, each of which is optionally substituted with 1-4 R.sup.b), each occurrence of R.sup.b is independently selected from the group consisting of: C.sub.1-10 alkyl optionally substituted with 1-2 independently selected R.sup.a; C.sub.1-4 haloalkyl; —OH; oxo; —F; —Cl; —NR.sup.e1R.sup.f1; C.sub.1-4 alkoxy; —C(═O)(C.sub.1-10 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)N(R′)(R″); —S(O).sub.2(NR′R″); cyano; and —R.sup.h. In certain of these embodiments, each occurrence of R.sup.b is independently selected from the group consisting of: C.sub.1-4 alkyl; C.sub.1-4 haloalkyl (e.g., CF.sub.3); —F; —NR.sup.e1R.sup.f1; C.sub.1-4 alkoxy; and —R.sup.h. In certain of the foregoing embodiments, —R.sup.h is C.sub.6-10 aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl (e.g., phenyl optionally substituted with 1-2 F).
[0323] In certain embodiments, Y.sup.A2 is heterocyclyl or heterocycloalkenyl, each of 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), 0, and S(O).sub.0-2, and wherein each of the heterocyclyl and heterocycloalkenyl ring is optionally substituted with 1-3 independently selected R.sup.b. In certain of these embodiments, Y.sup.A2 is heterocyclyl or heterocycloalkenyl, each of 4-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), and O, and wherein each of the heterocyclyl and heterocycloalkenyl ring is optionally substituted with 1-3 independently selected R.sup.b. As a non-limiting example of the foregoing, Y.sup.A2 is heterocyclyl or heterocycloalkenyl, each of 4-6 ring atoms, wherein 1 ring atom is N(R.sup.d).
[0324] In certain embodiments (when Y.sup.A2 is heterocyclyl or heterocycloalkenyl, each of 3-16 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 each of the heterocyclyl and heterocycloalkenyl ring is optionally substituted with 1-3 independently selected R.sup.b), R.sup.d is selected from the group consisting of C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; and C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH.
[0325] In certain embodiments (when Y.sup.A2 is heterocyclyl or heterocycloalkenyl, each of 3-16 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 each of the heterocyclyl and heterocycloalkenyl ring is optionally substituted with 1-3 independently selected R.sup.b), each occurrence of R.sup.b substituent of Y.sup.A2 is independently selected from the group consisting of: C.sub.1-10 alkyl optionally substituted with 1-6 independently selected R.sup.a; C.sub.1-4 haloalkyl; —F; —Cl; —Br; cyano; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —C(═O)(C.sub.1-10 alkyl); —C(═O)O(C.sub.1-4 alkyl); —S(O).sub.1-2(C.sub.1-4 alkyl); oxo; cyano; and -L.sup.1-L.sup.2-R.sup.h.
[0326] In certain of these embodiments, one occurrence of R.sup.b substituent of Y.sup.A2 is C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a.
[0327] In certain of these embodiments, one occurrence of R.sup.b substituent of Y.sup.A2 is unsubstituted C.sub.1-10 alkyl (e.g., C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, or C.sub.7-10). As a non-limiting example of the foregoing embodiments, one occurrence of R.sup.b substituent of Y.sup.A2 can be ethyl, propyl (e.g., n-propyl), butyl (e.g., n-butyl; or sec-butyl; or tert-butyl; or iso-butyl), or octyl (e.g., n-octyl).
[0328] In certain embodiments (when Y.sup.A2 is heterocyclyl or heterocycloalkenyl, each of 3-16 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 each of the heterocyclyl and heterocycloalkenyl ring is optionally substituted with 1-3 independently selected R.sup.b), one occurrence of R.sup.b substituent of Y.sup.A2 is C.sub.1-10 alkyl which is substituted with 1-6 independently selected R.sup.a. In certain of these embodiments, each occurrence of R.sup.a is independently selected from halo, OH, C.sub.1-4 alkoxy, and C.sub.1-4haloalkoxy. For example, one or more occurrences of R.sup.a can be an independently selected halo (which can be the same or different halo); e.g., fluoro, and R.sup.b can be CF.sub.3 or —CF.sub.2CH.sub.3.
[0329] In certain embodiments (when Y.sup.A2 is heterocyclyl or heterocycloalkenyl, each of 3-16 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 each of the heterocyclyl and heterocycloalkenyl ring is optionally substituted with 1-3 independently selected R.sup.b), one occurrence of R.sup.b substituent of Y.sup.A2 is -L.sup.1-L.sup.2-R.sup.h (e.g., —R.sup.h or —CH.sub.2—R.sup.h such as benzyl).
[0330] In certain embodiments (when Y.sup.A2 is heterocyclyl or heterocycloalkenyl, each of 3-16 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 each of the heterocyclyl and heterocycloalkenyl ring is optionally substituted with 1-3 independently selected R.sup.b), one occurrence of R.sup.b substituent of Y.sup.A2 is C.sub.1-4 alkoxy or C.sub.1-4 haloalkoxy (e.g.,
##STR00059##
[0331] In certain embodiments (when Y.sup.A2 is heterocyclyl or heterocycloalkenyl, each of 3-16 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 each of the heterocyclyl and heterocycloalkenyl ring is optionally substituted with 1-3 independently selected R.sup.b), one occurrence of R.sup.b is —F or —Cl (e.g., —F).
[0332] In certain embodiments, Y.sup.A2 is
##STR00060##
n1 is 0, 1, or 2; and each of R.sup.cA and R.sup.cB is an independently selected R.sup.c.
[0333] In certain embodiments, Y.sup.A2 is
##STR00061##
n1 is 0, 1, or 2; and each of R.sup.cA and R.sup.cB is an independently selected R.sup.c.
[0334] In certain embodiments, Y.sup.A2 is
##STR00062##
one of Q.sup.1 and Q.sup.2 is N; the other one of Q.sup.1 and Q.sup.2 is CH; n1 is 0, 1, or 2; and each of R.sup.cA and R.sup.cB is an independently selected R.sup.c.
[0335] In certain embodiments, Y.sup.A2 is
##STR00063##
one of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 is N; each of the remaining of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 is CH; n1 is 0, 1, or 2; and each of R.sup.cA and R.sup.cB is an independently selected R.sup.c.
[0336] In certain embodiments (when Y.sup.A2 is
##STR00064##
R.sup.cA is 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); —NR.sup.eR.sup.f; —C.sub.1-4 thioalkoxy; —C(═O)(C.sub.1-10 alkyl); —C(═O)(OH); —C(═O)O(C.sub.1-4 alkyl); and -L.sup.1-L.sup.2-R.sup.h.
[0337] In certain embodiments (when Y.sup.A2 is
##STR00065##
R.sup.cA is halo (e.g., F) or unsubstituted C.sub.1-10 alkyl (e.g., C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, or C.sub.7-10), such as ethyl, propyl (e.g., n-propyl), butyl (e.g., n-butyl, iso-butyl, sec-butyl, tert-butyl), or octyl (e.g., n-octyl).
[0338] In certain embodiments (when Y.sup.A2 is
##STR00066##
R.sup.cA is C.sub.1-10 alkyl which is substituted with 1-6 independently selected R.sup.a (e.g., each occurrence of R.sup.a is independently selected from halo, OH, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy). In certain of these embodiments, R.sup.cA is C.sub.1-10 alkyl which is substituted with 1-6 independently selected halo (e.g., R.sup.cA is CF.sub.3).
[0339] In certain embodiments (when Y.sup.A2 is
##STR00067##
R.sup.cA is -L.sup.1-L.sup.2-R.sup.h.
[0340] In certain of these embodiments, -L.sup.1 is a bond. In certain embodiments (when R.sup.cA is -L.sup.1-L.sup.2-R.sup.h), -L.sup.2 is a bond.
[0341] In certain embodiments (when R.sup.cA is -L.sup.1-L.sup.2-R.sup.h), R.sup.h is C.sub.6-10 aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl, such as C.sub.6 aryl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo (e.g., F), C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl (e.g.,
##STR00068##
[0342] In certain embodiments (when R.sup.cA is -L.sup.1-L.sup.2-R.sup.h), R.sup.h is heterocyclyl or heterocycloalkenyl, wherein each of the heterocyclyl and heterocycloalkenyl has 3-10 (e.g., 5-6) ring atoms, wherein 1-3 (e.g., 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, wherein each of the heterocyclyl and heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl, such as
##STR00069##
[0343] In certain embodiments (when R.sup.cA is -L.sup.1-L.sup.2-R.sup.h), R.sup.h is C.sub.3-8 (e.g., C.sub.3-6) cycloalkyl or C.sub.3-8 (e.g., C.sub.3-6) cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl (e.g., R.sup.h is cyclohexyl or 3,3-difluorocyclobutyl (e.g., R.sup.h is cyclohexyl)).
[0344] In certain embodiments (when Y.sup.A2 is
##STR00070##
n1 is 0.
[0345] In certain embodiments (when Y.sup.A2 is
##STR00071##
n1 is 1 or 2 (e.g., 1). In certain of these embodiments, each occurrence of R.sup.cB is independently halo or C.sub.1-3 alkyl (e.g., halo).
[0346] In certain embodiments, Y.sup.A2 is
##STR00072##
n2 is 0, 1, or 2; and each of R.sup.bA and R.sup.bB is an independently selected R.sup.b.
[0347] In certain embodiments, Y.sup.A2 is
##STR00073##
n2 is 0, 1, or 2; and each of R.sup.bA and R.sup.bB is an independently selected R.sup.b.
[0348] In certain embodiments (when Y.sup.A2 is
##STR00074##
R.sup.bA is C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a.
[0349] In certain embodiments (when Y.sup.A2 is
##STR00075##
R.sup.bA is unsubstituted C.sub.1-10 alkyl (e.g., C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, or C.sub.7-10), such as ethyl, propyl (e.g., n-propyl), butyl (e.g., n-butyl; or sec-butyl; or tert-butyl; or iso-butyl), or octyl (e.g., n-octyl).
[0350] In certain embodiments (when Y.sup.A2 is
##STR00076##
R.sup.bA is C.sub.1-10 alkyl which is substituted with 1-6 independently selected R.sup.a (e.g., each R.sup.a is selected from the group consisting of halo, OH, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy) (e.g., R.sup.bA is CF.sub.3 or —CF.sub.2CH.sub.3).
[0351] In certain embodiments (when Y.sup.A2 is
##STR00077##
R.SUP.bA .is —F or —Cl.
[0352] In certain embodiments (when Y.sup.A2 is
##STR00078##
R.sup.bA is -L.sup.1-L.sup.2-R.sup.h (e.g., —R.sup.h (e.g., phenyl or 3,5-difluorophenyl) or —CH.sub.2—R.sup.h such as benzyl).
[0353] In certain embodiments (when Y.sup.A2 is
##STR00079##
R.sup.bA is C.sub.1-4 alkoxy or C.sub.1-4 haloalkoxy (e.g.,
##STR00080##
[0354] In certain embodiments (when Y.sup.A2 is
##STR00081##
n2 is 0.
[0355] In certain other embodiments, n2 is 1 or 2. In certain of these embodiments, each occurrence R.sup.bB is selected from the group consisting of —F, —Cl, and C.sub.1-3 alkyl.
[0356] Non-limiting examples of A include:
##STR00082##
[0357] Further non-limiting examples of A include:
##STR00083##
[0358] Further non-limiting examples of A include:
##STR00084##
[0359] Further non-limiting examples of A include:
##STR00085##
[0360] In some embodiments, Q-A is as defined according to (B).
[0361] In certain embodiments, E is a saturated or partially unsaturated ring of 3-16 ring atoms, wherein 0-3 ring atoms are heteroatoms (in addition to the nitrogen atom that is present), each independently selected from the group consisting of N, N(H), N(R.sup.d), 0, and S(O).sub.0-2, and wherein the carbon portion of the ring is optionally substituted with 1-4 independently selected R.sup.b.
[0362] In certain embodiments, E a ring of 5-8 ring atoms, wherein aside from the nitrogen atom present, 0-3 additional 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 ring is optionally substituted with 1-4 independently selected R.sup.b (e.g., E is piperidinyl which is optionally substituted with 1-2 independently selected R.sup.b (e.g., E is
##STR00086##
wherein R.sup.b is C.sub.1-6 alkyl)). As a non-limiting example, E is
##STR00087##
[0363] Non-Limiting Combinations
[0364] In certain embodiments, the compound has the following formula:
##STR00088##
[0365] wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH (e.g., O); n1 is 0, 1, or 2; each of R.sup.cA and R.sup.cB is an independently selected R.sup.c; and R.sup.7 is H or C.sub.1-4 alkyl.
[0366] In certain embodiments, the compound has the following formula:
##STR00089##
[0367] wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH (e.g., O); n1 is 0, 1, or 2; each of R.sup.cA and R.sup.cB is an independently selected R.sup.c; and R.sup.7 is H or C.sub.1-4 alkyl.
[0368] In certain embodiments, the compound has the following formula:
##STR00090##
[0369] wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH (e.g., O); one of Q.sup.1 and Q.sup.2 is N; the other one of Q.sup.1 and Q.sup.2 is CH; n1 is 0, 1, or 2; each of R.sup.cA and R.sup.cB is an independently selected R.sup.c; and R.sup.7 is H or C.sub.1-4 alkyl.
[0370] In certain embodiments, the compound has the following formula:
##STR00091##
[0371] wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH (e.g., O); one of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 is N; each of the remaining of Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4 is CH; n1 is 0, 1, or 2; and each of R.sup.cA and R″ is an independently selected R.sup.c; and R.sup.7 is H or C.sub.1-4 alkyl.
[0372] In certain embodiments, the compound has the following formula:
##STR00092##
wherein
[0373] W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH (e.g., O);
[0374] B.sup.1 is selected from the group consisting of:
[0375] (a) bicyclic or tricyclic heteroaryl of 7-14 (e.g., 9-12 (e.g., 9, 10, 11, or 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 ring is optionally substituted with 1-4 independently selected R.sup.c; and
[0376] (b) C.sub.7-10 bicyclic aryl, which is optionally substituted with 1-3 R.sup.c;
[0377] and R.sup.7 is H or C.sub.1-4 alkyl.
[0378] In certain embodiments of Formula (I-5), B1 is bicyclic or tricyclic heteroaryl of 9-10 (e.g., 10) 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 ring is optionally substituted with 1-4 independently selected R.sup.c.
[0379] As a non-limiting example of the foregoing embodiments, B1 can be
##STR00093##
[0380] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4), R.sup.cA is 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); —NR.sup.eR.sup.f; —C.sub.1-4 thioalkoxy; —C(═O)(C.sub.1-10 alkyl); —C(═O)(OH); —C(═O)O(C.sub.1-4 alkyl); and -L.sup.1-L.sup.2-R.sup.h.
[0381] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4), R.sup.cA is unsubstituted C.sub.1-10 alkyl (e.g., C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, or C.sub.7-10), such as ethyl, propyl (e.g., n-propyl), butyl (e.g., n-butyl, iso-butyl, sec-butyl, tert-butyl), or octyl (e.g., n-octyl).
[0382] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4), R.sup.cA is C.sub.1-10 alkyl which is substituted with 1-6 independently selected R.sup.a (e.g., each occurrence of R.sup.a is independently selected from halo, OH, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy). In certain of these embodiments, R.sup.cA is C.sub.1-10 alkyl which is substituted with 1-6 independently selected halo (e.g., R.sup.cA is CF.sub.3).
[0383] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4), R.sup.cA is halo (e.g., F or Cl (e.g., F)).
[0384] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4), R.sup.cA is -L.sup.1-L.sup.2-R.sup.h. In certain of these embodiments, -L.sup.1 is a bond. In certain embodiments (when R.sup.cA is -L.sup.1-L.sup.2-R.sup.h), -L.sup.2 is a —N(H) or bond (e.g., a bond).
[0385] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4) (when R.sup.cA is -L.sup.1-L.sup.2-R.sup.h), R.sup.h is C.sub.6-10 aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl, such as C.sub.6 aryl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl (e.g.,
##STR00094##
[0386] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4) (when R.sup.cA is -L.sup.1-L.sup.2-R.sup.h), R.sup.h is heterocyclyl or heterocycloalkenyl, wherein each of the heterocyclyl and heterocycloalkenyl has 3-10 (e.g., 5-6) ring atoms, wherein 1-3 (e.g., 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, wherein each of the heterocyclyl and heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl, such as
##STR00095##
[0387] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4) (when R.sup.cA is -L.sup.1-L.sup.2-R.sup.h), R.sup.h is C.sub.3-8 (e.g., C.sub.3-6) cycloalkyl or C.sub.3-8 (e.g., C.sub.3-6) cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl (e.g., R.sup.h is cyclohexyl).
[0388] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), and (I-4), n1 is 0.
[0389] In certain other embodiments, n1 is 1 or 2 (e.g., 1). In certain of these embodiments, each occurrence of R.sup.cB is independently halo or C.sub.1-3 alkyl (e.g., halo).
[0390] In certain embodiments of the compound of Formula (I-1),
[0391] X.sup.2 is CH; X.sup.1 is NH; R.sup.1d is H;
[0392] one of R.sup.1a, R.sup.1b, and R.sup.1c is
##STR00096##
wherein [0393] each is independently a single bond or a double bond, provided that the five-membered ring comprising Z.sup.1, Z.sup.2, and Z.sup.3 is heteroaryl; [0394] Z.sup.1 is selected from N and CH; [0395] Z.sup.2 is selected from N, O, and CH; [0396] Z.sup.3 is selected from C(R.sup.g), N(R.sup.g), N(R.sup.d), and N; [0397] each occurrence of R.sup.g is C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl; —F; —Cl; or C.sub.6-10 aryl). [0398] the asterisk denotes point of attachment to the six-membered ring of the bicyclic ring portion of Formula I; [0399] and the other of R.sup.1a, R.sup.1b, and R.sup.1c are each R**.
[0400] In certain embodiments, the compound has the following formula:
##STR00097##
[0401] wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH (e.g., O); n2 is 0, 1, or 2; each of R.sup.bA and R.sup.bB is an independently selected R.sup.b; and R.sup.7 is H or C.sub.1-4 alkyl.
[0402] In certain embodiments, the compound has the following formula:
##STR00098##
[0403] wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH (e.g., O); n2 is 0, 1, or 2; each of R.sup.bA and R.sup.bB is an independently selected R.sup.b; and R.sup.7 is H or C.sub.1-4 alkyl.
[0404] In certain embodiments, the compound has the following formula:
##STR00099##
[0405] wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH (e.g., O); B.sup.2 is: bicyclic, tricyclic, or polycyclic C.sub.7-20 cycloalkyl or C.sub.7-20 cycloalkenyl, each optionally substituted with 1-2 R.sup.b, and
[0406] R.sup.7 is H or C.sub.1-4 alkyl.
[0407] In certain embodiments of Formula (I-8), B.sup.2 is selected from the group consisting of: spiro[5.5]undecanyl (e.g.,
##STR00100##
bicyclo[2.2.1]hept-2-enyl (e.g.,
##STR00101##
bicyclo[2.2.1]heptanyl (e.g.,
##STR00102##
spiro[2.5]octanyl (e.g.,
##STR00103##
and adamantly (e.g.,
##STR00104##
For example, B.sup.2 is
##STR00105##
[0408] In certain embodiments of any one or more of Formulae (I-6) and (I-7), R.sup.bA is C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a.
[0409] In certain of these embodiments, R.sup.bA is unsubstituted C.sub.1-10 alkyl (e.g., C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, or C.sub.7-10), such as ethyl, propyl (e.g., n-propyl), butyl (e.g., n-butyl; or sec-butyl; or tert-butyl; or iso-butyl), or octyl (e.g., n-octyl).
[0410] In certain other embodiments, R.sup.bA is C.sub.1-10 alkyl which is substituted with 1-6 independently selected R.sup.a (e.g., each R.sup.a is selected from the group consisting of halo, OH, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy) (e.g., R.sup.bA is CF.sub.3).
[0411] In certain embodiments of any one or more of Formulae (I-6) and (I-7), R.sup.bA is —F or —Cl.
[0412] In certain embodiments of any one or more of Formulae (I-6) and (I-7), R.sup.bA is -L.sup.1-L.sup.2-R.sup.h (e.g., —R.sup.h (e.g., phenyl or 3,5-difluorophenyl) or —CH.sub.2—R.sup.h such as benzyl).
[0413] In certain embodiments of any one or more of Formulae (I-6) and (I-7), R.sup.bA is C.sub.1-4 alkoxy or C.sub.1-4 haloalkoxy (e.g.,
##STR00106##
[0414] In certain embodiments of any one or more of Formulae (I-6) and (I-7), n2 is 0.
[0415] In certain other embodiments, n2 is 1 or 2. In certain of these embodiments, each occurrence R.sup.bB is selected from the group consisting of —F, —Cl, and C.sub.1-3 alkyl.
[0416] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), and (I-8), n is 0.
[0417] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), and (I-8), n is 1. In certain of these embodiments, Y.sup.A1 is C.sub.1-6 alkylene, which is optionally substituted with 1-2 R.sup.a. In certain of these embodiments, Y.sup.A1 is —CH.sub.2—, —CH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2CH.sub.2—, —CH(CF.sub.3)—, —CH.sub.2CH(OH)—,
##STR00107##
(e.g., CH.SUB.2.),
[0418] ##STR00108##
(e.g., Y.sup.A1 is —CH.sub.2— or —CH.sub.2CH.sub.2—).
[0419] In certain embodiments, the compound has the following formula:
##STR00109##
[0420] wherein:
[0421] E is a ring of 3-16 ring atoms, wherein aside from the nitrogen atom present, 0-3 additional 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 ring is optionally substituted with 1-4 independently selected R.sup.b.
[0422] In certain of these embodiments, E is a saturated or partially unsaturated ring of 3-16 ring atoms, wherein 0-3 ring atoms are heteroatoms (in addition to the nitrogen atom that is present), 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 carbon portion of the ring is optionally substituted with 1-4 independently selected R.sup.b.
[0423] In certain embodiments of Formula (I-9), E is a ring of 5-8 ring atoms, herein aside from the nitrogen atom present, 0-3 additional 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 ring is optionally substituted with 1-4 independently selected R.sup.b (e.g., E is piperidinyl which is optionally substituted with 1-2 independently selected R.sup.b (e.g., E is
##STR00110##
wherein R.sup.b is C.sub.1-6 alkyl)).
[0424] In some embodiments of any one or more of Formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), and (I-9), one of R.sup.1a and R.sup.1b is R*, the other of R.sup.1a and R.sup.1b is R** (e.g., H or F); and each of R.sup.1c and R.sup.1d is H.
[0425] In some embodiments of any one or more of Formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), and (I-9), one of R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is R*, one of R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is R** (e.g., H or F); and the remaining two of R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d are each H.
[0426] In some embodiments of any one or more of Formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), and (I-9), (when one of R.sup.1a and R.sup.1b is R*, the other of R.sup.1a and R.sup.1b is R** (e.g., H or F); and each of R.sup.1c and R.sup.1d is H), R* is
##STR00111##
wherein [0427] each is independently a single bond or a double bond, provided that the five-membered ring comprising Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4 is heteroaryl; [0428] Z.sup.1 is selected from N and CH; [0429] Z.sup.2 is selected from N, O, and CH; [0430] Z.sup.3 is selected from C(R.sup.g), N(R.sup.g), N(R.sup.d), and N; [0431] Z.sup.4 is selected from N, NH, S, CH, N(R.sup.d), and O; and [0432] the asterisk denotes point of attachment to the six-membered ring of the bicyclic ring portion of Formula I.
[0433] In some embodiments of any one or more of Formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), and (I-9), (when R* is
##STR00112##
as defined immediately above), each occurrence of R.sup.g is C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl; or C.sub.6-10 aryl). In some of these embodiments, X.sup.1 is NH and X.sup.2 is CH. In some further of these embodiments,
[0434] In some embodiments of any one or more of Formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), and (I-9), (when R* is
##STR00113##
as defined immediately above), each occurrence of R.sup.g is independently selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl; C.sub.6-10 aryl; —OH; —C(═O)(C.sub.1-4 alkyl); C.sub.1-4 alkoxy; or cyano); halo; C.sub.6-10 aryl; and cyano.
[0435] In some embodiments of any one or more of Formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), and (I-9), (when R* is
##STR00114##
as defined immediately above), R.sup.d is C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH.
[0436] In some embodiments of any one or more of Formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), and (I-9), (when one of R.sup.1a and R.sup.1b is R*, the other of R.sup.1a and R.sup.1b is R** (e.g., H or F); and each of R.sup.1c and R.sup.1d is H), R* is heteroaryl of 6 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g. In certain of these embodiments, R* is heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are N atoms and wherein the heteroaryl ring is optionally substituted with 1-4 C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected —OH, —F, or C.sub.1-4 alkoxy) and —NR.sup.eR.sup.f (e.g., —NH.sub.2). In certain other of these embodiments, R* is heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are N atoms (e.g., pyridyl (e.g., 3-pyridyl or 4-pyridyl) and wherein the heteroaryl ring is optionally substituted with 1-4 C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected —OH, —F, or C.sub.1-4 alkoxy); halo (e.g., F or Cl); or —NR.sup.eR.sup.f (e.g., —NH.sub.2 or —NHMe).
[0437] In some embodiments of any one or more of Formulas (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), and (I-9), (when one of R.sup.1a and R.sup.1b is R*, the other of R.sup.1a and R.sup.1b is R** (e.g., H or F); and each of R.sup.1c and R.sup.1d is H), R* is C.sub.6-10 aryl, which is optionally substituted with 1-4 independently selected R.sup.g. In certain of these embodiments, R* is phenyl, which is optionally substituted with 1-4 independently selected halo (e.g., F or Cl) or C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 —OH). In certain of these embodiments, R* is phenyl, which is optionally substituted with 1-4 independently selected halo (e.g., F or Cl); —OH; cyano; —C(═O)N(R′)(R″) (e.g., —C(═O)NMe.sub.2); S(O).sub.1-2(C.sub.1-4 alkyl) (e.g., —SO.sub.2Et); —C(═O)(C.sub.1-4 alkyl) (e.g., —C(═O)Me); —Si(C.sub.1-4 alkyl).sub.4 (e.g., —Si(CH.sub.3).sub.4); C.sub.3-8 cycloalkyl optionally substituted with cyano; C.sub.1-4 haloalkoxy (e.g., —OCHF.sub.2 or —OCF.sub.3); C.sub.1-6 alkoxy (e.g., methoxy); or C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 —OH, C.sub.1-4 alkoxy, cyano, —C(═O)O(C.sub.1-4 alkyl), or —NR.sup.eR.sup.f).
[0438] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), and (I-9), the
##STR00115##
moiety is
##STR00116##
[0439] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), and (I-9), the
##STR00117##
moiety is
##STR00118##
[0440] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), and (I-9), the
##STR00119##
moiety is
##STR00120##
[0441] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5, (I-6), (I-7), (I-8), and (I-9), the
##STR00121##
moiety is
##STR00122##
[0442] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), and (I-9), R.sup.2 is H.
[0443] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), and (I-9), R.sup.2 is selected from the group consisting of: heterocyclyl or heterocycloalkenyl, each of 3-10 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 heteroaryl of 5-10 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.
[0444] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), and (I-9), R.sup.5 is H.
[0445] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), and (I-8), R.sup.7 is H.
[0446] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), and (I-9), each R** is independently selected from the group consisting of: H; halo; cyano; C.sub.1-6 alkyl optionally substituted with 1-2 R.sup.a; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; C.sub.1-4 haloalkyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; -L.sup.3-L.sup.4-R.sup.i; —S(O).sub.1-2(C.sub.1-4 alkyl); —S(O)(═NH)(C.sub.1-4 alkyl); —S(O).sub.1-2(NR′R″); —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-4 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; and —C(═O)N(R′)(R″).
[0447] In certain embodiments of any one or more of Formulae (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), and (I-9), R.sup.6 is H.
[0448] Non-Limiting Exemplary Compounds
[0449] In certain embodiments, the compound is selected from the group consisting of the compound delineated in Table C.sub.1 below.
TABLE-US-00001 TABLE C1 Com- pound No. Structure 101
[0450] In some embodiments, the compound is the following compound:
##STR00281##
and pharmaceutically acceptable salts thereof.
[0451] Pharmaceutical Compositions and Administration
[0452] General
[0453] 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.
[0454] 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%.
[0455] 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).
[0456] Routes of Administration and Composition Components
[0457] 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).
[0458] 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.
[0459] 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.
[0460] 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.
[0461] 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.
[0462] 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.
[0463] 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, methyloxybenzoate, 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.
[0464] 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.
[0465] 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).
[0466] 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.
[0467] 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.
[0468] 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.
[0469] 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.
[0470] 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.
[0471] Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.
[0472] 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.
[0473] 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.)).
[0474] 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.
[0475] 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, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.
[0476] Dosages
[0477] 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.
[0478] 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 0.001 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kg to about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about 0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg; from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about 0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0.1 mg/Kg to about 200 mg/Kg; from about 0.1 mg/Kg to about 150 mg/Kg; from about 0.1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 50 mg/Kg; from about 0.1 mg/Kg to about 10 mg/Kg; from about 0.1 mg/Kg to about 5 mg/Kg; from about 0.1 mg/Kg to about 1 mg/Kg; from about 0.1 mg/Kg to about 0.5 mg/Kg).
[0479] Regimens
[0480] 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).
[0481] 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, 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 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.
[0482] Methods of Treatment
[0483] 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.
[0484] Indications
[0485] 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.
[0486] 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 cancer 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.
[0487] In some embodiments, the condition, disease or disorder is STING-associated conditions, e.g., type I interferonopathies (e.g., STING-associated vasculopathywith onset in infancy (SAVI)), Aicardi-Goutiéres 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).
[0488] 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).
[0489] 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)).
[0490] In some embodiments, the condition, disease or disorder is hepatitis B (see, e.g., WO 2015/061294).
[0491] In some embodiments, the condition, disease or disorder is selected from cardiovascular diseases (including e.g., myocardial infarction).
[0492] In some embodiments, the condition, disease or disorder is age-related macular degeneration.
[0493] In some embodiments, the condition, disease or disorder is mucositis, also known as stomatitits, 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.
[0494] 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).
[0495] 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, uvetitis, a cardiovascular disease, age-related macular degeneration, and mucositis.
[0496] Still other examples can include those indications discussed herein and below in contemplated combination therapy regimens.
[0497] Combination Therapy
[0498] This disclosure contemplates both monotherapy regimens as well as combination therapy regimens.
[0499] 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.
[0500] In certain embodiments, the methods described herein can further include administering one or more additional cancer therapies.
[0501] 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.
[0502] In some embodiments, the one or more additional cancer therapies is chemotherapy, which can include administering one or more additional chemotherapeutic agents.
[0503] 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 (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 orPDI or PD-L1). See, e.g., Postow, M. J. Clin. Oncol. 2015, 33, 1.
[0504] 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) (PDL1), 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.
[0505] 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.
[0506] 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.
[0507] 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 terpernoid 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).
[0508] 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.
[0509] 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.
[0510] 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 5 (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-3), vasculostatin, vasostatin (calreticulin fragment) and the like.
[0511] 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.
[0512] 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.
[0513] 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.
[0514] 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 vasculopathywith onset in infancy (SAVI)), Aicardi-Goutiéres Syndrome (AGS), genetic forms of lupus, and inflammation-associated disorders such as systemic lupus erythematosus, and rheumatoid arthritis and the like.
[0515] 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 (Orencia®), 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®)).
[0516] 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 (Benlysta®), anifrolumab, prezalumab, MEDIO700, 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, MEDIO700, 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.
[0517] 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).
[0518] Non-limiting examples of additional therapeutic agents and/or regimens for treating Aicardi-Goutiéres 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).
[0519] 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-Kinoid®, tofacitinib, tralokinumab, TRK-170, upadacitinib, ustekinumab, UTTR1147A, V565, vatelizumab, VB-201, vedolizumab, and vidofludimus.
[0520] Non-limiting examples of additional therapeutic agents and/or regimens for treating irritable bowel syndrome include alosetron, bile acid sequesterants (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.
[0521] 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).
[0522] 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.
[0523] 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.
[0524] 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.
[0525] 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.
[0526] 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.
[0527] 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.
[0528] 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.
[0529] 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.
[0530] Non-limiting examples of additional therapeutic agents and/or regimens for treating collagenous colitis include 6-mercaptopurine, azathaioprine, bismuth subsalicate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.
[0531] Non-limiting examples of additional therapeutic agents and/or regimens for treating lyphocytic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), loperamide, mesalamine, methotrexate, and sulfasalazine.
[0532] Non-limiting examples of additional therapeutic agents and/or regimens for treating microscopic colitis include 6-mercaptopurine, azathioprine, bismuth subsalicylate, Boswellia serrata extract, cholestyramine, colestipol, corticosteroids (e.g., budesonide, prednisone, prednisolone, beclometasone dipropionate), fecal microbial transplantation, loperamide, mesalamine, methotrexate, probiotics, and sulfasalazine.
[0533] 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, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, 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.
[0534] 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, MDD1003 (biotin), mitoxantrone, montelukast, natalizumab (Tysabri®), NeuroVax™, ocrelizumab, ofatumumab, pioglitazone, and RPC1063.
[0535] Non-limiting examples of additional therapeutic agents and/or regimens for treating graft-vs-host disease include abatacept, alemtuzumab, alpha1-antitrypsin, AMG592, antithymocyte globulin, barcitinib, basiliximab, bortezomib, brentuximab, cannabidiol, corticosteroids (e.g., methylprednisone, prednisone), cyclosporine, dacilzumab, defribrotide, 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.
[0536] 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, dacilzumab, defribrotide, denileukin diftitox, ibrutinib, infliximab, itacitinib, LBH589, mycophenolate mofetil, natalizumab, neihulizumab, pentostatin, photopheresis, ruxolitinib, sirolimus, tacrolimus, and tocilizumab.
[0537] 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, dacilzumab, denileukin diftitox, glasdegib, ibrutinib, IL-2, imatinib, infliximab, mycophenolate mofetil, pentostatin, photobiomodulation, photopheresis, ruxolitinib, sirolimus, sonidegib, tacrolimus, tocilizumab, and vismodegib.
[0538] 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.
[0539] Non-limiting examples of additional therapeutic agents and/or regimens for treating psoriasis include topical corticosteroids, topical crisaborole/AN2728, topical SNA-120, topical SANO21, 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-creme®), 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®).
[0540] 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).
[0541] Non-limiting examples of additional therapeutic agents and/or regimens for treating uveitis include corticosteroids (e.g., intravitreal triamcinolone acetonide injectable suspensions), antibiotics, antivirals (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.
[0542] Non-limiting examples of additional therapeutic agents and/or regimens for treating mucositis include AG013, SGX942 (dusquetide), amifostine (Ethyol®), cryotherapy, cepacol lonzenges, capsaicin lozenges, mucoadhesives (e.g., MuGard®) oral diphenhydramine (e.g., Benadry® 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, 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 lonzenges, mucoadhesives (e.g., MuGard®) oral diphenhydramine (e.g., Benadry® 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)).
[0543] 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).
[0544] 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.
[0545] 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).
[0546] Patient Selection
[0547] 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.
[0548] 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).
[0549] Compound Preparation
[0550] 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 RGM. 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).
[0551] The skilled artisan will recognize a variety of analytical methods that can be used to characterize the compounds described herein, including, for example, 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.
[0552] 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.
[0553] The following abbreviations have the indicated meanings: [0554] ACN=acetonitrile [0555] AcOH=acetic acid [0556] DCM=dichloromethane [0557] Dioxane=1,4-dioxane [0558] EtOAc=Ethyl acetate [0559] DMF=N,N-dimethylformamide [0560] DMSO=dimethyl sulfoxide [0561] Et=ethyl [0562] EtOH=ethanol [0563] FA=formic acid [0564] HPLC=high-performance liquid chromatography [0565] LC-MS=liquid chromatography-mass spectrometry [0566] Me=methyl [0567] MeOH=methanol [0568] n-Bu=n-butyl [0569] NMR=nuclear magnetic resonance [0570] Pd-132=bis(di-tert-butyl(4-dimethylamino phenyl) phosphine) dichloroPalladium(II) [0571] Pd(dppf)Cl.sub.2=dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium [0572] Pd(dppf)Cl.sub.2.DCM=1,1′-Bis(diphenylphosphino) ferrocene palladium dichloride, dichloromethane complex [0573] Pd(PPh3).sub.4=tetrakis(triphenylphosphine)Palladium(0) [0574] Ph=phenyl [0575] HPLC=high performance liquid chromatography [0576] RT=room temperature [0577] Speedvac=Savant SC250EXP SpeedVac Concentrator [0578] t-Bu=tert-butyl [0579] TEA=triethylamine [0580] TFA=trifluoroacetic acid [0581] THE=tetrahydrofuran [0582] Ti(i-PrO).sub.4=tetraisopropyl titanate [0583] TLC=thin layer chromatography [0584] XPhos Pd G3=Methanesulfonato(2-dicyclohexylphosphino-2,4,6-tri-i-propyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II)
EXAMPLES
Materials and Methods
[0585] The progress of reactions was often monitored by TLC or LC-MS. The identity of the products was often confirmed by LC-MS. The LC-MS was recorded using one of the following methods.
Method A: Titank C18, 50×3 mm, 3 um column, 0.3 uL injection, 1.5 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: Water+5mMNH.sub.4HCO.sub.3 and Mobile Phase B: Acetonitrile. 10% MPB to 95.0% in 1.39 min, hold at 95% MPB for 0.8 min, 95% MPB to 10% in 0.03 min, then equilibration to 10% MPB for 0.27 min.
Method B: XBridge C18, 50×3 mm, 2.8 um column, 0.2 uL injection, 1.2 mL/min flow rate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: Water+5mMNH.sub.4HCO.sub.3 and Mobile Phase B: Acetonitrile. 10% MPB to 95.0% in 1.99 min, hold at 95% MPB for 0.6 min, 95% MPB to 10% in 0.20 min, then equilibration to 10% MPB for 0.2 min.
Method C: Shim-pack XR-ODS, 50×3 mm, 2.2 um column, 2 uL injection, 1.2 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: Water/0.05% TFA and Mobile Phase B: Acetonitrile/0.05% TFA. 5% MPB to 100.0% in 1.09 min, hold at 100% MPB for 0.6 min, 100% MPB to 5% in 0.02 min, then equilibration to 5% MPB for 0.38 min.
Method D: Poroshell HPH-C18, 50*3 mm, 2.7 μL injection, 1.2 mL/min flowrate, 90-900 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 1.99 min, hold at 95% MPB for 0.6 min, 95% MPB to 10% in 0.03 min, then equilibration to 10% MPB for 0.17 min.
Method E: Titank C18, 50*3.0 mm, 3.0 μL injection, 1.5 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 30% MPB to 70% in 2.24 min, 70% MPB to 95% in 0.75 min, hold at 95% MPB for 0.5 min, 95% MPB to 10% in 0.05 min, then equilibration to 10% MPB for 0.35 min.
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.
Method F: HALO, 30*3 mm, 0.5 uL injection, 1.5 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: Water/5 mM NH4HCO3 and Mobile Phase B: Acetonitrile. 5% MPB to 100% in 0.90 min, hold at 100% MPB for 0.2 min, 100% MPB to 5% in 0.01 min, then equilibration to 5% MPB for 0.19 min.
Method G: HALO C18, 30*3 mm, 1 uL injection, 1.5 mL/min flowrate, 90-900 amu scan range, 254 nm UV detection. Mobile phase A: Water+0.05% TFA and Mobile Phase B: Acetonitrile+0.05% TFA. 5% MPB to 100% in 1.19 min, hold at 100% MPB for 0.6 min, 100% MPB to 5% in 0.03 min, then equilibration to 5% MPB for 0.17 min.
Method H
[0586] Instrument: Agilent LCMS system equipped with DAD and ELSD detector
Ion mode: Positive
Column: Waters X-Bridge C18, 50*2.1 mm*5 m or equivalent
Mobile Phase: A: H.sub.2O (0.04% TFA); B: CH.sub.3CN (0.02% TFA)
Gradient: 4.5 min gradient method, actual method would depend on clogP of compound.
Flow Rate: 0.6 mL/min or 0.8 mL/min
Column Temp: 40° C. or 50° C.
UV: 220 nm
Method I
[0587] Instrument: Agilent LCMS system equipped with DAD and ELSD detector
Ion mode: Positive
Column: Waters X-Bridge ShieldRP18, 50*2.1 mm*5 m or equivalent
Mobile Phase: A: H.sub.2O (0.05% NH.sub.3.H.sub.2O) or 10 mM ammonia bicarbonate; B: CH.sub.3CN
Gradient: 4.5 min gradient method; actual method would depend on the clogP of the compound.
Flow Rate: 0.6 mL/min or 0.8 mL/min
Column Temp: 40° C.
UV: 220 nm
[0588] Preparative HPLC was used in the purification of a number of examples 9-80. The parameters used are described below.
Instrument:
1. GILSON 281 and Shimadzu LCMS 2010A
2. GILSON 215 and Shimadzu LC-20AP
3. GILSON 215
Mobile Phase:
[0589] A: NH.sub.4OH/H.sub.2O=0.05% v/v; B: ACN
A: FA/H.sub.2O=0.225% v/v; B: ACN
Column
[0590] 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
EXAMPLES
[0591] Scheme A below depicts the general cross-coupling method used to prepare compounds of Formula I. A haloindole (e.g., bromoindole) is treated with a catalyst (e.g., a palladium or rhodium catalyst), an organometal (e.g., boronic acid, boronate ester, organozinc halide, organomagnesium halide, or organolithium), and an optional base (e.g., potassium carbonate) in a solvent (e.g., 1,4-dioxane or acetonitrile) with optional heating to generate the compound of Formula I.
##STR00282##
Example 1: Preparation of Compound 101
[0592] ##STR00283##
Synthesis of 5-bromo-1H-indole-3-carbonyl azide
[0593] ##STR00284##
[0594] 5-Bromo-1H-indole-3-carboxylic acid (1.0 g, 5.1 mmol, 1.0 equiv) was dissolved in THE (20.0 mL). DPPA (1.4 g, 5.1 mmol, 1.0 equiv) and TEA (0.5 g, 5.1 mmol, 1.0 equiv) were added and stirred for 18 hrs at room temperature and solvent was removed under reduced pressure. The crude product was used in the next step directly without further purification.
Synthesis of tert-butyl (5-bromo-1H-indol-3-yl)carbamate
[0595] ##STR00285##
[0596] 5-Bromo-1H-indole-3-carbonyl azide (600.0 mg, 1.3 mmol, 1.0 equiv) was dissolved in t-BuOH (20.0 mL). The resulting mixture was stirred overnight at 90° C. and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to afford tert-butyl (5-bromo-1H-indol-3-yl)carbamate (400.0 mg, 69.0%) as an off-white solid. LC-MS Method A, MS-ESI: 311 [M+H.sup.+].
Synthesis of 5-bromo-1H-indol-3-amine
[0597] ##STR00286##
[0598] Tert-butyl (5-bromo-1H-indol-3-yl)carbamate (400.0 mg, 5.6 mmol, 1.0 equiv) was dissolved in dioxane (5.0 mL). Subsequently, HCl in 1,4-dioxane (4N, 5.0 mL) was added at RT. The resulting mixture was stirred for 2 hrs at RT and concentrated under vacuum. 5-Bromo-1H-indol-3-amine (400.0 mg, crude) was obtained and used without any further purification. LC-MS Method A, MS-ESI: 211 [M+H.sup.+].
Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)urea
[0599] ##STR00287##
[0600] 5-Bromo-1H-indol-3-amine (400.0 mg, 0.9 mmol, 1.0 equiv) dissolved in THE (10.0 ml), TEA (391.8 mg, 1.9 mmol, 2.0 equiv), and 1-isocyanato-4-(trifluoromethyl)benzene (377.3 mg, 0.9 mmol, 1.0 equiv) were combined and stirred for 3 hrs at RT and concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with PE/EtOAc (2:1) to afford 1-(5-bromo-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)urea (500.0 mg, 66.6%) as brown oil. LC-MS Method B, MS-ESI: 398 [M+H.sup.+].
Synthesis of 1-(5-phenyl-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)urea
[0601] ##STR00288##
[0602] 1-(5-Bromo-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)urea (500.0 mg, 1.3 mmol, 1.0 equiv) was dissolved in dioxane (20.0 mL) and H.sub.2O (2.0 mL). Phenylboronic acid (183.7 mg, 1.5 mmol, 1.2 equiv), K.sub.2CO.sub.3 (520.6 mg, 3.8 mmol, 3.0 equiv), and Pd(dppf)Cl.sub.2 (91.9 mg, 0.1 mmol, 0.1 equiv) were added under N2. The resulting mixture was stirred for 2 hrs at 90° C. under nitrogen atmosphere and concentrated. The residue was purified by silica gel column chromatography and eluted with PE/EtOAc (1:1) and further purified by Prep-HPLC with the following conditions (2 #SHIMADZU (HPLC-01)): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase A Water (10 MMOL/L NH.sub.4HCO.sub.3) and mobile phase B: ACN (50% PhaseB up to 66% in 7 min); Detector, UV 210/254 nm. This resulted in 1-(5-phenyl-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)urea (50.0 mg, 10.07%) as a white solid. LC-MS Method C, MS-ESI: 396.2 [M+H.sup.+]
Example 2: Preparation of Compound 156
[0603] ##STR00289##
[0604] Compound 156 was synthesized 1-(5-bromo-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)urea and 3-hydroxymethyl phenyl boronate by the method described in step 5 for Compound 101. LC-MS Method C, MS-ESI: 426.1 [M+H.sup.+]
Example 3: Preparation of Compound 104
[0605] ##STR00290##
[0606] Compound 104 was synthesized 1-(5-bromo-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)urea and 3-hydroxymethyl phenyl boronate by the method described in step 5 for Compound 101. LC-MS Method C, MS-ESI: 428.1 [M+H.sup.+]
Example 4: Preparation of Compound 154
[0607] ##STR00291##
[0608] Compound 154 was synthesized by method described similar to Compound 101. In step 4, 1-isocyanato-3-Fluoro-4-(trifluoromethyl)benzene was utilized as the isocyanate. In step 5 1(1-isopropyl-1H-pyrazol-4-yl)boronic acid was utilized as the boronic acid. LC-MS Method C, MS-ESI: 446.2 [M+H.sup.+]
Example 5: Preparation of Compound 153
[0609] ##STR00292##
[0610] Compound 153 was synthesized by the method described similar to Compound 101. In step 5, 1(1-isopropyl-1H-pyrazol-4-yl)boronic acid was utilized in place of phenylboronic acid. LC-MS Method C, MS-ESI: 428.1 [M+H.sup.+]
Example 6: Preparation of Compound 155
[0611] ##STR00293##
[0612] Compound 155 was synthesized by the method described similar to Compound 101. In step 4, 2-cyclohexyl-5-isocyanatopyridine) was utilized as the isocyanate. In step 5 1(1-isopropyl-1H-pyrazol-4-yl)boronic acid was utilized as the boronic acid. LC-MS Method C, MS-ESI. 443.2 [M+H.sup.+]
Example 7: Preparation of Compound 155
[0613] ##STR00294##
Synthesis of 5-(cyclohex-1-en-1-yl)-2-nitropyridine
[0614] ##STR00295##
[0615] 5-Bromo-2-nitropyridine (1.0 g, 4.9 mmol, 1.0 equiv.) was dissolved in toluene (10 mL). Then Cs.sub.2CO.sub.3 (4.8 mg, 14.8 mmol, 3.0 equiv.), Pd(dppf)Cl.sub.2 (1.1 g, 1.5 mmol, 0.3 equiv.) and 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 g, 6.4 mmol, 1.3 equiv.) were added and the reaction mixture was stirred for 16 h at 80° C. Then the reaction mixture was colled to ambient temperature, washed with water (3×20 mL), and extracted with 3×20 mL of EtOAc. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography over silica gel, eluting with EtOAc/petroleum ether (1:2) to give 5-(Cyclohex-1-en-1-yl)-2-nitropyridine (500 mg) as a white solid. LCMS Method D: [M+H].sup.+=205.
Synthesis of 5-cyclohexylpyridin-2-amine
[0616] ##STR00296##
[0617] 5-(Cyclohex-1-en-1-yl)-2-nitropyridine (500 mg, 2.5 mmol, 1.0 equiv.) was dissolved in MeOH (10 mL). Pd/C (10% wt, 176.0 mg) was added and the reaction mixture was placed under an atmosphere of hydrogen. After 10 h, the reaction mixture was filtered through Celite and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography over silica gel, eluting with dichloromethane/methanol (10:1) to give 5-cyclohexylpyridin-2-amine (300 mg) as a yellow solid. LCMS Method D: [M+H].sup.+=177.
Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-(5-cyclohexylpyridin-2-yl) urea
[0618] ##STR00297##
[0619] 5-Cyclohexylpyridin-2-amine (300 mg, 1.7 mmol, 1.0 equiv.) was dissolved in toluene (5 mL), then 5-bromo-1H-indole-3-carboxylic acid (409 mg, 1.7 mmol, 1.0 equiv.), DPPA (703 mg, 2.6 mmol, 1.5 equiv.) and TEA (516.7 mg, 5.1 mmol, 3.0 equiv.) were added and the reaction mixture was heated to 100° C. After 5 h, the reaction mixture was cooled to ambient temperature, then washed with H.sub.2O (3×20 mL) and extracted with EtOAc (3×20 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1:1) to give 1-(5-Bromo-1H-indol-3-yl)-3-(5-cyclohexylpyridin-2-yl) urea (200 mg) as a brown solid. LCMS Method D: [M+H].sup.+=414.
Synthesis of 1-(5-cyclohexylpyridin-2-yl)-3-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)urea
[0620] ##STR00298##
[0621] 1-(5-Bromo-1H-indol-3-yl)-3-(5-cyclohexylpyridin-2-yl) urea (200 mg, 0.5 mmol, 1.0 equiv.) was dissolved in dioxane (5 mL), then 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (228 mg, 1.0 mmol, 2.0 equiv.), XPhos Pd G3 (82 mg, 0.1 mmol, 0.2 equiv.) and K.sub.3PO.sub.4 (308 mg, 1.5 mmol, 3.0 equiv.) were added. The reaction mixture was heated to 100° C. for 6 h. After cooling to ambient temperature, the reaction mixture was washed with H.sub.2O (3×20 mL) and then extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1:1). The resulting solids was further purified by Prep-HPLC with the following conditions: Column: Sunfire prep C18 column, 30*150, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 45 B to 75 B in 7 min; 254/210 nm; RT1:6.42.
[0622] 1-(5-Cyclohexylpyridin-2-yl)-3-(5-(1-isopropyl-1H-pyrazol-4-yl)-1H-indol-3-yl)urea (Compound 155; 33.4 mg, 15.6%) was obtained as an off-white solid. LCMS Method E: [M+H].sup.+=443. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.75 (s, 1H), 10.55 (br s, 1H), 9.42 (br s, 1H), 8.22 (d, 1H), 8.14 (s, 1H), 7.81 (s, 1H), 7.67-7.63 (m, 2H), 7.52 (d, 1H), 7.42-7.40 (m, 2H), 7.35 (s, 1H), 4.53-4.51 (m, 1H), 1.84-1.73 (m, 5H), 1.48 (d, 6H), 1.43-1.37 (m, 4H), 1.25-1.22 (m, 2H).
Example 8: Preparation of Compound 212
[0623] ##STR00299##
Synthesis of 1-(5-bromo-6-fluoro-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)urea
[0624] ##STR00300##
[0625] 5-Bromo-6-fluoro-1H-indole-3-carboxylic acid (1.0 g, 3.8 mmol, 1.0 equiv) was dissolved in CH.sub.2Cl.sub.2 (30 mL), TEA (1.1 g, 11.6 mmol, 3.0 equiv), HATU (2.2 g, 5.8 mmol, 1.5 equiv) and P-trifluoromethylaniline (0.6 g, 3.8 mmol, 1.0 equiv) were added and the resulting mixture was stirred for 6 hr at RT. The resulting solution was quenched by the addition of water, extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1:1) to give 1-(5-bromo-6-fluoro-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl) urea (815 mg) as a yellow solid. LCMS Method F: [M+H].sup.+=416.
2. Synthesis of 1-(5-(1-(difluoromethyl)-1H-pyrazol-4-yl)-6-fluoro-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)urea
[0626] ##STR00301##
[0627] 3-(5-Bromo-6-fluoro-1H-indol-3-yl)-1-[4-(trifluoromethyl)phenyl]urea (250.0 mg, 0.6 mmol, 1.0 equiv) was dissolved in dioxane/H.sub.2O (10/1 mL), K.sub.3PO.sub.4 (382.5 mg, 1.8 mmol, 3.0 equiv), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (293.2 mg, 1.2 mmol, 2 equiv) and Xphos Pd G3 (101.6 mg, 0.1 mmol, 0.2 equiv) were added under nitrogen. The reaction mixture was heated to 100° C. for 6 hr. After cooling to ambient temperature, the reaction mixture was washed with brine, and then extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (1:1). The resulting solids was further purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C18, 30*250.5 um; Mobile Phase A: Water (10 MMOL/L NH.sub.4HCO.sub.3+0.1% NH.sub.3.H.sub.2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 50 B to 70 B in 7 min; 210/254 nm; RT1:6.58. 1-(5-(1-(difluoromethyl)-1H-pyrazol-4-yl)-6-fluoro-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)urea (50 mg, 18.4%) was obtained as a white solid. LCMS Method G: [M+H].sup.+=454.
[0628] 1H NMR (400 MHz, DMSO-d.sub.6) δ 10.93 (d, J=1.6 Hz, 1H), 9.06 (s, 1H), 8.66 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.16 (s, 1H), 7.87 (s, 1H), 7.82 (d, J=7.2 Hz, 1H), 7.72-7.68 (m, 2H), 7.63-7.61 (m, 2H), 7.52 (d, J=2.4 Hz, 1H), 7.27 (d, J=11.6 Hz, 1H).
Examples 9-80 were analyzed using LC-MS methods H and I.
Example 9: Preparation of Compound 302
[0629] ##STR00302##
Procedure:
[0630] 1-(5-bromo-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)urea (185 mg, 0.23 mmol, 1.0 equiv) and (4-(trans-4-propylcyclohexyl)phenyl)boronic acid (84.9 mg, 0.35 mmol, 1.5 equiv.) were dissolved in Dioxane (2.5 mL). Then aqueous Cs.sub.2CO.sub.3 (0.69 mmol, 2.0 M, 0.35 mL, 3.0 equiv.) and Pd-132 (0.05 equiv.) were added under N2 atmosphere. The mixture was stirred at 100° C. for 16 hours. 1.0 mL water was added to the reaction mixture and extracted with EtOAc. The organic layer was concentrated by Speedvac. The residue was purified by prep HPLC to give 1-(5-(4-(trans-4-propylcyclohexyl)phenyl)-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)urea (20.8 mg, 40.0 μmol). MS-ESI, 520.3 [M+H.sup.+].
[0631] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.83 (s, 1H) 9.02 (s, 1H) 8.71 (s, 1H) 7.76 (s, 1H) 7.67-7.71 (m, 2H) 7.61-7.65 (m, 2H) 7.54-7.59 (m, 3H) 7.41 (s, 2H) 7.30 (d, 2H) 1.84 (br d, 4H) 1.41-1.54 (m, 3H) 1.28-1.38 (m, 3H) 1.17-1.24 (m, 2H) 0.99-1.12 (m, 2H) 0.89 (t, 3H)
TABLE-US-00002 TABLE 1 The compounds in Table 1 were prepared using the above procedure. LC-MS, MS-ESI, Example Compound -- # # Structure IUPAC Name [M + H.sup.+]. 10 156
Example 43: Preparation of Compound 223
[0632] ##STR00336##
[0633] 1-(5-bromo-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)urea (185 mg, 0.23 mmol, 1.0 equiv.) and (4-isopropylphenyl)boronic acid (56.6 mg, 0.35 mmol, 1.5 equiv.) were dissolved in Dioxane (2.5 mL). Then aqueous K.sub.3PO.sub.4 (0.69 mmol, 0.35 mL, 2.0 M, 3.0 equiv.) and Pd(dppf)Cl.sub.2 DCM (0.05 equiv.) under N2 atmosphere. The mixture was stirred at 145° C. for 2 hours. 1.0 mL water was added to the reaction mixture and extracted with EtOAc. The organic layer was concentrated by Speedvac. The residue was purified by prep HPLC to give 1-(5-(4-isopropylphenyl)-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)urea (26.0 mg, 59.0 μmol). MS-ESI, 438.2 [M+H.sup.+].
[0634] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.77-10.94 (m, 1H) 8.94-9.10 (m, 1H) 8.64-8.78 (m, 1H) 7.77 (s, 1H) 7.68-7.72 (m, 1H) 7.64 (s, 1H) 7.60-7.62 (m, 1H) 7.56-7.59 (m, 1H) 7.55 (d, 1H) 7.41 (s, 1H) 7.33 (br d, 2H) 2.93 (dt, 7.00 Hz, 3H) 1.12-1.32 (m, 6H) 0.83-0.91 (m, 1H)
TABLE-US-00003 TABLE2 The compounds in Table 2 were prepared using the above procedure. LC-MS, MS-ESI, Example Compound -- # # Structure IUPAC Name [M + H.sup.+]. 44 271
Example 68: Preparation of Compound 214
[0635] ##STR00361##
Procedure:
[0636] 1-(5-bromo-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)urea (185.0 mg, 0.23 mmol, 1.0 equiv.) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (71.8 mg, 0.35 mmol, 1.5 equiv.) were dissolved in Dioxane (2.5 mL). Then aqueous K.sub.3PO.sub.4 (2 M, 0.35 mL, 0.69 mmol, 3.0 equiv.) and XPhos Pd G3 (0.05 equiv.) under N2 atmosphere. The mixture was stirred at 100° C. for 16 hours. 1.0 mL water was added to reaction mixture and extracted with EtOAc. The organic layer was concentrated by Speedvac. The residue was purified by prep HPLC to give 1-(5-(1-methyl-1H-pyrazol-3-yl)-1H-indol-3-yl)-3-(4-(trifluoromethyl)phenyl)urea (29.0 mg, 72.6 μmol). MS-ESI, 400.2 [M+H.sup.+].
[0637] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm 10.78 (s, 1H) 9.05 (s, 1H) 8.78 (s, 1H) 8.03 (s, 1H) 7.68-7.72 (m, 3H) 7.61-7.66 (m, 2H) 7.52-7.57 (m, 2H) 7.34 (d, 1H) 6.60 (d, 1H) 3.73-4.02 (m, 3H).
TABLE-US-00004 TABLE 3 The compounds in Table 3 were prepared using the above procedure. LC-MS, MS-ESI, Example Compound -- # # Structure IUPAC Name [M + H.sup.+]. 69 291
[0638] Examples are listed in the table below, which can be prepared according to methods similar to those described above. LC-MS was performed on the compounds using the following column and settings: Shim-pack XR-ODS, C18, 3×50 mm, 2.5 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 5-100% (1.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA) and water (0.05% TFA), with 2.0 minute as total run time.
TABLE-US-00005 Compound LC-MS No. Structure [M + H].sup.+ 127
Biological Assays
[0639] STING pathway activation by the compounds described herein was measured using THP1-Dual™ cells (KO-IFNAR2).
[0640] 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.
[0641] The following solutions were prepared for each 1×384 plate: [0642] Solution A: 2 mL Optimem with one of the following stimuli: [0643] 60 uL of 10 mM 2′3′ cGAMP ->150 μM stock [0644] Solution B: 2 mL Optimem with 60 μL Lipofectamine 2000->Incubate 5 min at RT
[0645] 2 mL of solution A and 2 ml Solution B was mixed and incubated for 20 min at room temperature (RT). 20 uL 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 24 h. Luciferase reporter activity was then measured. EC.sub.50 values were calculated by using standard methods known in the art.
[0646] 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)).
[0647] Luciferase reporter activity was then measured. EC.sub.50 values were calculated by using standard methods known in the art.
[0648] 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 is measured on a Platereader (e.g., Spectramax I3X (Molecular Devices GF3637001)).
[0649] Luciferase reporter activity was then measured. EC.sub.50 values were calculated by using standard methods known in the art.
[0650] Table BA shows the activity of compounds in STING reporter assay: <0.008 μM=“++++++”; ≥01008 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-00006 TABLE BA Compound hSTING: No. EC50 (μM) 101 +++ 104 ++++ 127 +++ 156 +++ 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 +++ 272 +++ 273 +++ 274 ++ 275 +++ 276 ++ 277 +++ 278 ++ 279 +++ 280 +++ 281 ++ 282 ++ 283 +++ 284 ++ 285 +++ 286 ++ 287 +++ 288 +++ 289 +++ 290 + 293 ++++ 294 +++ 295 ++++ 296 ++++ 297 +++ 298 +++ 300 ++++ 301 +++
Numbered Clauses
[0651] The compounds, compositions, methods, and other subject matter described herein are further described in the following numbered clauses:
[0652] 1. A compound of Formula I:
##STR00418##
[0653] or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein:
[0654] X.sup.1 is selected from the group consisting of O, S, N, NR.sup.2, and CR.sup.5;
[0655] X.sup.2 is selected from the group consisting of O, S, N, NR.sup.4, and CR.sup.5;
[0656] 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
[0657] the 6-membered ring
##STR00419##
is aromatic;
[0658] one of R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is selected from the group consisting of R* and —OR*;
[0659] and each of the three remaining R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is an independently selected R**; wherein:
[0660] R* is selected from the group consisting of [0661] C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each optionally substituted with 1-4 independently selected R.sup.g; [0662] heterocyclyl or heterocycloalkenyl, wherein each of the heterocyclyl and heterocycloalkenyl has 3-16 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, wherein each of the heterocyclyl and heterocycloalkenyl is optionally substituted with 1-4 independently selected R.sup.g; [0663] heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g; and [0664] C.sub.6-10 aryl, which is optionally substituted with 1-4 independently selected R.sup.g; and
[0665] each R** is independently selected from the group consisting of: H; halo; cyano; C.sub.1-6 alkyl optionally substituted with 1-2 R.sup.a; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; C.sub.1-4 haloalkyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; -L.sup.3-L.sup.4-R*; —S(O).sub.1-2(C.sub.1-4 alkyl); —S(O)(═NH)(C.sub.1-4 alkyl); SF.sub.5; —NR.sup.e1R.sup.f1; —OH; —S(O).sub.1-2(NR′R″); —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-4 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; and —C(═O)N(R′)(R″);
[0666] W is selected from the group consisting of:
[0667] (i) C(═O);
[0668] (ii) C(═S);
[0669] (iii) S(O).sub.1-2;
[0670] (iv) C(═NR.sup.d) or C(═NH);
[0671] (vi) C(═C—NO.sub.2); and
[0672] (vii) S(═O)═N(R.sup.d) or S(═O)═NH;
[0673] Q-A is defined according to (A) or (B) below:
##STR00420##
[0674] Q is selected from the group consisting of: NH and N(C.sub.1-6 alkyl) wherein the C.sub.1-6 alkyl is optionally substituted with 1-2 independently selected R.sup.a; and
[0675] A is:
[0676] (i) —(Y.sup.A1).sub.n—Y.sup.A2, wherein: [0677] n is 0 or 1; [0678] Y.sup.A1 is C.sub.1-6 alkylene, which is optionally substituted with 1-6 independently selected R.sup.a; and [0679] Y.sup.A2 is [0680] (a) C.sub.3-20 cycloalkyl or C.sub.3-20 cycloalkenyl, each of which is optionally substituted with 1-4 R.sup.b, [0681] (b) C.sub.6-20 aryl, which is optionally substituted with 1-4 R.sup.c; [0682] (c) heteroaryl of 5-20 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 ring is optionally substituted with 1-4 independently selected R.sup.c; or [0683] (d) heterocyclyl or heterocycloalkenyl, each of 3-16 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 each of the heterocyclyl and heterocycloalkenyl ring is optionally substituted with 1-4 independently selected R.sup.b, or
[0684] (ii) C.sub.1-10 alkyl, which is optionally substituted with 1-6 independently selected R.sup.a, or
[0685] Q and A, taken together, form:
##STR00421##
and
[0686] E is a ring of 3-16 ring atoms, wherein aside from the nitrogen atom present, 0-3 additional 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 ring is optionally substituted with 1-4 independently selected R.sup.b,
[0687] each occurrence of R.sup.2 is independently selected from the group consisting of:
[0688] (i) C.sub.1-6 alkyl, which is optionally substituted with 1-2 independently selected R.sup.a;
[0689] (ii) C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, wherein the cycloalkyl or cycloalkenyl is optionally substituted with 1-4 independently selected R.sup.b;
[0690] (iii) heterocyclyl or heterocycloalkenyl, each of 3-10 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 is optionally substituted with 1-4 independently selected R.sup.b;
[0691] (iv) C.sub.6-10 aryl, which is optionally substituted with 1-4 independently selected R.sup.b;
[0692] (v) heteroaryl of 5-10 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 independently selected R.sup.b;
[0693] (vi) —C(O)(C.sub.1-4 alkyl), which is optionally substituted with 1-2 independently selected R.sup.a;
[0694] (vii) —C(O)(C.sub.6-10 aryl), which is optionally substituted with 1-2 independently selected R.sup.c;
[0695] (viii) —C(O)(heteroaryl), wherein the heteroaryl has 5-10 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 1-2 independently selected R.sup.c;
[0696] (vii) —C(O)O(C.sub.1-4 alkyl);
[0697] (viii) —CON(R′)(R″);
[0698] (ix) —S(O).sub.1-2(NR′R″);
[0699] (x) —S(O).sub.1-2(C.sub.1-4 alkyl), which is optionally substituted with 1-2 independently selected R.sup.a;
[0700] (xiii) —S(O).sub.1-2(C.sub.6-10 aryl), which is optionally substituted with 1-2 independently selected R.sup.c;
[0701] (xiv) —S(O).sub.1-2(heteroaryl), wherein the heteroaryl has 5-10 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 1-2 independently selected R.sup.c;
[0702] (xi) —OH;
[0703] (xii) C.sub.1-4 alkoxy; and
[0704] (xiii) H;
[0705] R.sup.4 is selected from the group consisting of H and C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a;
[0706] R.sup.5 is selected from the group consisting of H; halo; —OH; —C.sub.1-4 alkyl; —C.sub.1-4 haloalkyl; 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; —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); cyano, and C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected C.sub.1-4 alkyl;
[0707] R.sup.6 is selected from the group consisting of H; C.sub.1-6 alkyl optionally substituted with 1-3 independently selected R.sup.a; —OH; C.sub.1-4 alkoxy; C(═O)H; C(═O)(C.sub.1-4 alkyl); C.sub.6-10 aryl optionally substituted with 1-4 independently selected C.sub.1-4 alkyl; and heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected C.sub.1-4 alkyl;
[0708] each occurrence of R.sup.a is independently selected from the group consisting of: —OH; —F; —Cl; —Br; —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; —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); cyano; C.sub.6-10 aryl; heteroaryl of 5-10 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; heterocyclyl or heterocycloalkenyl, each of 3-10 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 C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected C.sub.1-4 alkyl;
[0709] each occurrence of R.sup.a1 is independently selected from the group consisting of: —OH; —F; —Cl; —Br; —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; —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); cyano; C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-4 independently selected C.sub.1-4 alkyl; C.sub.6-10 aryl optionally substituted with 1-4 independently selected C.sub.1-4 alkyl; and heteroaryl of 5-10 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 wherein the heteroaryl ring is optionally substituted with 1-4 independently selected C.sub.1-4 alkyl;
[0710] each occurrence of R.sup.b is independently selected from the group consisting of: C.sub.1-10 alkyl optionally substituted with 1-6 independently selected R.sup.a; C.sub.1-4 haloalkyl; —OH; oxo; —F; —Cl; —Br; —NR.sup.e1R.sup.f1; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —C(═O)(C.sub.1-10 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; —C(═O)N(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); cyano; and -L.sup.1-L.sup.2-R.sup.h;
[0711] 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); —NR.sup.e1R.sup.f1; —OH; —S(O).sub.1-2(NR′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)N(R′)(R″); and -L.sup.1-L.sup.2-R.sup.h;
[0712] R.sup.d is selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy;
[0713] each occurrence of R.sup.e and R.sup.f is independently selected from the group consisting of: H; C.sub.1-6 alkyl; C.sub.1-6 haloalkyl; C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy; or R.sup.e and R.sup.f together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C.sub.1-3 alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R.sup.e and R.sup.f), which are each independently selected from the group consisting of N(R.sup.d), NH, O, and S;
[0714] each occurrence of R.sup.e1 and R.sup.f1 is independently selected from the group consisting of: H; C.sub.1-6 alkyl; C.sub.1-6 haloalkyl; —C(O)(C.sub.1-4 alkyl); —C(O)O(C.sub.1-4 alkyl); —CON(R′)(R″); —S(O).sub.1-2(NR′R″); —S(O).sub.1-2(C.sub.1-4 alkyl); —OH; and C.sub.1-4 alkoxy;
[0715] each occurrence of R.sup.g is independently selected from the group consisting of: halo; cyano; C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1; C.sub.1-4 haloalkyl; C.sub.1-6 alkoxy optionally substituted with 1-2 independently selected R.sup.a1; C.sub.1-4 haloalkoxy; C.sub.3-8 cycloalkyl optionally substituted with C.sub.1-6 alkyl or cyano; C.sub.6-10 aryl; S(O).sub.1-2(C.sub.1-4 alkyl); —NR.sup.eR.sup.f; —OH; oxo; —S(O).sub.1-2(NR′R″); —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-4 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; —Si(C.sub.1-4 alkyl).sub.4; and —C(═O)N(R′)(R″);
[0716] -L.sup.1 is a bond or C.sub.1-3 alkylene;
[0717] -L.sup.2 is —O—, —N(H)—, —S(O).sub.0-2—, or a bond;
[0718] R.sup.h is selected from the group consisting of: [0719] C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl (in certain embodiments, it is provided that when R.sup.h is C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-4 substituents independently selected C.sub.1-4 alkyl, -L.sup.1 is a bond, or -L.sup.2 is —O—, —N(H)—, or —S—); [0720] heterocyclyl or heterocycloalkenyl, wherein each of the heterocyclyl and heterocycloalkenyl has 3-16 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, wherein each of the heterocyclyl and heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; [0721] heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; and [0722] C.sub.6-10 aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl;
[0723] -L.sup.3 is —C.sub.1-3 alkylene or a bond;
[0724] -L.sup.4 is —O—, —N(H)—, —S(O).sub.0-2—, or a bond;
[0725] each occurrence of R′ and R″ is independently selected from the group consisting of: H, —OH, C.sub.1-4 alkyl, C.sub.6-10 aryl optionally substituted with 1-2 substituents selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl, and heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, —OH, NH.sub.2, NH(C.sub.1-4 alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; or R′ and R″ together with the nitrogen atom to which each is attached forms a ring of 3-8 ring atoms, wherein the ring has: (a) 1-7 ring carbon atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C.sub.1-3 alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R′ and R″), which are each independently selected from the group consisting of N(H), N(C.sub.1-6 alkyl), O, and S; and
[0726] with the proviso that the compound is not
##STR00422##
[0727] 2. The compound of clause 1, wherein X.sup.1 is NR.sup.2.
[0728] 3. The compound of any one of clauses 1-2, wherein X is NH.
[0729] 4. The compound of any one of clauses 1-3, wherein X.sup.2 is CR.sup.5.
[0730] 5. The compound of any one of clauses 1-4, wherein X.sup.2 is CH.
[0731] 6. The compound of any one of clauses 1-2 and 4, wherein X is NR.sup.2; and X.sup.2 is CR.sup.5.
[0732] 7. The compound of any one of clauses 1-6, wherein X.sup.1 is NH; and X.sup.2 is CH.
[0733] 8. The compound of any one of clauses 1-7, wherein the
##STR00423##
moiety is
##STR00424##
wherein one of R.sup.1a and R.sup.1b is R*.
[0734] 9. The compound of any one of clauses 1-7, wherein the
##STR00425##
moiety is
##STR00426##
wherein the asterisk denotes point of attachment to X.sup.1.
[0735] 10. The compound of any one of clauses 1-2, wherein the compound has formula (I-a1):
##STR00427##
11. The compound of any one of clauses 1-2, wherein the compound has formula (I-a2):
##STR00428##
[0736] 12. The compound of any one of clauses 1-2, wherein the compound has formula (I-a2-1):
##STR00429##
[0737] 13. The compound of any one of clauses 1-2, wherein the compound has formula (I-a3):
##STR00430##
14. The compound of any one of clauses 1-2, wherein the compound has formula (I-a4):
##STR00431##
[0738] 15. The compound of any one of clauses 1-2, wherein the compound has formula (I-a1-1) or (I-a3-1):
##STR00432##
[0739] 16. The compound of any one of clauses 9-15, wherein R.sup.2 is H; and R.sup.5 is H.
[0740] 17. The compound of any one of clauses 1-16, wherein R* is selected from the group consisting of: [0741] heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g; and [0742] C.sub.6-10 aryl, which is optionally substituted with 1-4 independently selected R.sup.g.
[0743] 18. The compound of any one of clauses 1-17, wherein R* is heteroaryl of 5-10 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g.
[0744] 19. The compound of any one of clauses 1-18, wherein R* is heteroaryl of 5 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g.
[0745] 20. The compound of any one of clauses 1-19, wherein R* is
##STR00433##
wherein
[0746] each is independently a single bond or a double bond, provided that the five-membered ring comprising Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4 is heteroaryl;
[0747] Z.sup.1 is selected from N and CH;
[0748] Z.sup.2 is selected from N, O, and CH;
[0749] Z.sup.3 is selected from C(R.sup.g), N(R.sup.g), N(R.sup.d), and N;
[0750] Z.sup.4 is selected from N, NH, S, CH, N(R.sup.g), N(R.sup.d), and O; and
[0751] the asterisk denotes point of attachment to the six-membered ring of the bicyclic ring portion of Formula I.
[0752] 21. The compound of clause 20, wherein each occurrence of R.sup.g is C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl; or C.sub.6-10 aryl); or
[0753] wherein each occurrence of R.sup.g is independently selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl; C.sub.6-10 aryl; —OH; —C(═O)(C.sub.1-4 alkyl); C.sub.1-4 alkoxy; or cyano); halo; C.sub.6-10 aryl; and cyano.
[0754] 22. The compound of any one of clauses 19-21, wherein each occurrence of R.sup.d is C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH.
[0755] 23. The compound of any one of clauses 1-18, wherein R* is heteroaryl of 6 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g.
[0756] 24. The compound of any one of clauses 1-18 and 23, wherein R* is heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are N atoms and wherein the heteroaryl ring is optionally substituted with 1-4 C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected —OH, —F, or C.sub.1-4 alkoxy) and —NR.sup.eR.sup.f (e.g., —NH.sub.2); or
[0757] wherein R* is heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are N atoms (e.g., pyridyl (e.g., 3-pyridyl or 4-pyridyl) and wherein the heteroaryl ring is optionally substituted with 1-4 C.sub.1-6 alkyl optionally substituted with 1-2 independently selected Rai (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected —OH, —F, or C.sub.1-4 alkoxy); halo (e.g., F or Cl); or —NR.sup.eR.sup.f (e.g., —NH.sub.2 or —NHMe).
[0758] 25. The compound of any one of clauses 1-17, wherein R* is C.sub.6-10 aryl, which is optionally substituted with 1-4 independently selected R.sup.g.
[0759] 26. The compound of any one of clauses 1-17 and 25, wherein R* is phenyl, which is optionally substituted with 1-4 independently selected halo (e.g., F or Cl) or C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 —OH); or
[0760] wherein R* is phenyl, which is optionally substituted with 1-4 independently selected halo (e.g., F or Cl); —OH; cyano; —C(═O)N(R′)(R″) (e.g., —C(═O)NMe.sub.2); S(O).sub.1-2(C.sub.1-4 alkyl) (e.g., —SO.sub.2Et); —C(═O)(C.sub.1-4 alkyl) (e.g., —C(═O)Me); —Si(C.sub.1-4 alkyl).sub.4 (e.g., —Si(CH.sub.3).sub.4); C.sub.3-8 cycloalkyl optionally substituted with cyano; C.sub.1-4 haloalkoxy (e.g., —OCHF.sub.2 or —OCF.sub.3); C.sub.1-6 alkoxy (e.g., methoxy); or C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 —OH, C.sub.1-4 alkoxy, cyano, —C(═O)O(C.sub.1-4 alkyl), or —NR.sup.eR.sup.f).
[0761] 27. The compound of any one of clauses 1-7, 9-11, 13, and 17-26, wherein each occurrence of R** is selected from the group consisting of: H; halo (e.g., F); cyano; C.sub.1-6 alkyl optionally substituted with 1-2 R.sup.a; C.sub.1-4 haloalkyl (e.g., CF.sub.3); C.sub.1-4 alkoxy; —NR.sup.e1R.sup.f1; —OH; —S(O).sub.1-2(NR′R″); —NO.sub.2; —C(═O)(C.sub.1-4 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; and —C(═O)N(R′)(R″).
[0762] 28. The compound of any one of clauses 1-7, 9-11, 13, and 17-27, wherein each occurrence of R** is H or F:
[0763] 29. The compound of any one of clauses 1-28, wherein W is selected from the group consisting of: C(═O); S(O).sub.2; C(═NR.sup.d) or C(═NH); C(═C—NO.sub.2); and S(O)N(R.sup.d) or S(O)NH.
[0764] 30. The compound of any one of clauses 1-29, wherein W is selected from the group consisting of C(═O) and S(O).sub.2 (e.g., W is C(═O)).
[0765] 31. The compound of any one of clauses 1-30, wherein Q-A is defined according to (A).
[0766] 32. The compound of any one of clauses 1-31, wherein Q is NH.
[0767] 33. The compound of any one of clauses 1-32, wherein Q is N(C.sub.1-3 alkyl) (e.g., NMe or NEt).
[0768] 34. The compound of any one of clauses 1-33, wherein A is —(Y.sup.A1).sub.n—Y.sup.A2.
[0769] 35. The compound of any one of clauses 1-34, wherein n is 0.
[0770] 36. The compound of any one of clauses 1-34, wherein n is 1.
[0771] 37. The compound of any one of clauses 1-34 and 36, wherein Y.sup.A1 is C.sub.1-6 alkylene, which is optionally substituted with 1-4 R.sup.a.
[0772] 38. The compound of any one of clauses 1-34 and 36-37, wherein Y.sup.A1 is —CH.sub.2—, —CH.sub.2CH.sub.2—, —CH.sub.2CH.sub.2CH.sub.2—, —CH(CF.sub.3)—, —CH.sub.2CH(OH)—,
##STR00434##
(e.g., Y.sup.A1 is CH.sub.2).
[0773] 39. The compound of any one of clauses 1-34 and 36-38, wherein Y.sup.A1 is —CH.sub.2— or —CH.sub.2CH.sub.2—.
[0774] 40. The compound of any one of clauses 1-39 wherein Y.sup.A2 is C.sub.6-10 aryl, which is optionally substituted with 1-3 R.sup.c.
[0775] 41. The compound of any one of clauses 1-40, wherein Y.sup.A2 is C.sub.6 aryl, which is optionally substituted with 1-3 R.sup.c.
[0776] 42. The compound of any one of clauses 1-41, wherein Y.sup.A2 is C.sub.6 aryl, which is substituted with 1-3 R.sup.c.
[0777] 43. The compound of any one of clauses 1-42, wherein Y.sup.A2 is phenyl substituted with 1-3 R.sup.c, wherein one R.sup.c is at the ring carbon para to the point of attachment to Y.sup.A1.
[0778] 44. The compound of any one of clauses 1-42, wherein Y.sup.A2 is phenyl substituted with 1-3 R.sup.c, wherein 1-2 R.sup.c is at the ring carbons meta to the point of attachment to Y.sup.A1.
[0779] 45. The compound of any one of clauses 40-44, wherein each occurrence of R.sup.c is selected from the group consisting of:
[0780] (a) halo (e.g., F or Cl);
[0781] (c) C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a (e.g., CF.sub.3); and
[0782] (s) -L.sup.1-L.sup.2-R.sup.h.
[0783] 46. The compound of clause 45, wherein L.sup.1 is a bond; L.sup.2 is a bond or —N(H)—; and R.sup.h is selected from the group consisting of: [0784] C.sub.4-6 cycloalkyl or C.sub.4-6 cycloalkenyl, each optionally substituted with from 1 substituent selected from the group consisting of halo (e.g., F), C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; [0785] phenyl, which is optionally substituted with from 1 substituent selected from the group consisting of halo (e.g., F), C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; and [0786] heterocyclyl or heterocycloalkenyl, wherein each of the heterocyclyl and heterocycloalkenyl has 5-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), and O, wherein each of the heterocyclyl and heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl (e.g.,
##STR00435##
[0787] 47. The compound of any one of clauses 1-39, wherein Y.sup.A2 is C.sub.7-10 bicyclic aryl, which is optionally substituted with 1-3 R.sup.c (e.g., Y.sup.A2 is naphthyl (e.g.,
##STR00436##
indanyl (e.g.,
##STR00437##
tetrahydronaphthyl, or
##STR00438##
each of which is optionally substituted with 1-3 R.sup.c).
[0788] 48. The compound of any one of clauses 1-39, wherein Y.sup.A2 is heteroaryl of 5-14 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 ring is optionally substituted with 1-4 independently selected R.sup.c.
[0789] 49. The compound of any one of clauses 1-39 and 48, wherein Y.sup.A2 is heteroaryl of 6 ring atoms (e.g., pyridyl or pyrimidinyl (e.g., pyridyl)), wherein 1-2 (e.g., 1) ring atoms are ring nitrogen atoms, and wherein the heteroaryl ring is optionally substituted with 1-3 (e.g., 1-2) independently selected R.sup.c.
[0790] 50. The compound of clause 49, wherein one occurrence of R.sup.c is at the position para to the point of attachment of Y.sup.A2 to Y.sup.A1.
[0791] 51. The compound of clause 49, wherein when the heteroaryl ring is substituted with 2 or 3 independently selected R.sup.c, one occurrence of R.sup.c is at the position para to the point of attachment of Y.sup.A2 to Y.sup.A1 and at least one occurrence of R.sup.c is at the position meta to the point of attachment of Y.sup.A2 to Y.sup.A1.
[0792] 52. The compound of any one of clauses 48-51, wherein each occurrence of R.sup.c is selected from the group consisting of halo (e.g., F) and -L.sup.1-L.sup.2-R.sup.h.
[0793] 53. The compound of clause 52, wherein L.sup.1 is a bond; L.sup.2 is —O—, —N(H)—, or a bond; and R.sup.h is selected from the group consisting of: [0794] C.sub.4-6 cycloalkyl or C.sub.4-6 cycloalkenyl, each optionally substituted with 1-2 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl; and [0795] heterocyclyl or heterocycloalkenyl, wherein each of the heterocyclyl and heterocycloalkenyl has 3-16 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), and O, wherein each of the heterocyclyl and heterocycloalkenyl is optionally substituted with 1-2 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl.
[0796] 54. The compound of any one of clauses 52-53, wherein R.sup.h is selected from cyclobutyl, cyclohexyl, and piperidine; wherein R.sup.h is optionally substituted with 1-2 F.
[0797] 55. The compound of any one of clauses 1-39 and 48, wherein Y.sup.A2 is bicyclic or tricyclic heteroaryl of 7-14 (e.g., 9-12 (e.g., 9, 10, 11, or 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 ring is optionally substituted with 1-4 independently selected R.sup.c.
[0798] 56. The compound of clause 55, wherein Y.sup.A2 is bicyclic heteroaryl of 9-10 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 ring is optionally substituted with 1-4 independently selected R.sup.c.
[0799] 57. The compound of any one of clauses 55-56, wherein Y.sup.A2 is bicyclic heteroaryl of 10 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 (e.g.,
##STR00439##
and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected R.sup.c.
[0800] 58. The compound of any one of clauses 1-39, wherein Y.sup.A2 is C.sub.3-20 cycloalkyl or C.sub.3-20 cycloalkenyl, each of which is optionally substituted with 1-4 R.sup.b.
[0801] 59. The compound of any one of clauses 1-39 and 58, wherein Y.sup.A2 is monocyclic C.sub.3-10 cycloalkyl or C.sub.3-10 cycloalkenyl, each of which is optionally substituted with 1-4 R.sup.b.
[0802] 60. The compound of any one of clauses 1-39 and 58-59, wherein Y.sup.A2 is C.sub.5-6 (e.g., C.sub.6) cycloalkyl or C.sub.5-6 (e.g., C.sub.6) cycloalkenyl, each of which is substituted with 1-4 (e.g., 1-2) R.sup.b (e.g., Y.sup.A2 is cyclopentyl or cyclohexyl, each of which is optionally substituted with 1-2 R.sup.b).
[0803] 61. The compound of clause 60, wherein Y.sup.A2 is cyclohexyl which is optionally substituted with 1-2 R.sup.b. 62. The compound of clause 61, wherein one occurrence of R.sup.b is at the ring carbon atom para to the point of attachment to Y.sup.A1; or one occurrence of R.sup.b is at the ring carbon atom meta to the point of attachment to Y.sup.A1.
[0804] 63. The compound of clause 60, wherein Y.sup.A2 is cyclopentyl which is optionally substituted with 1-2 R.sup.b.
[0805] 64. The compound of clause 58, wherein Y.sup.A2 is bicyclic or polycyclic C.sub.7-20 cycloalkyl or C.sub.7-20 cycloalkenyl, each optionally substituted with 1-2 R.sup.b.
[0806] 65. The compound of clause 64, wherein Y.sup.A2 is selected from the group consisting of: spiro[5.5]undecanyl (e.g.,
##STR00440##
bicyclo[2.2.1]hept-2-enyl (e.g.,
##STR00441##
bicyclo[2.2.1]heptanyl (e.g.,
##STR00442##
spiro[2.5]octanyl (e.g.,
##STR00443##
and adamantyl (e.g.,
##STR00444##
[0807] 66. The compound of any one of clauses 64-65, wherein Y.sup.A2 is
##STR00445##
67. The compound of any one of clauses 58-66, wherein each occurrence of R.sup.b is independently selected from the group consisting of: C.sub.1-10 alkyl optionally substituted with 1-2 independently selected R.sup.a; C.sub.1-4 haloalkyl; —OH; oxo; —F; —Cl; —NR.sup.e1R.sup.f1; C.sub.1-4 alkoxy; —C(═O)(C.sub.1-10 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)N(R′)(R″); —S(O).sub.2(NR′R″); cyano; and —R.sup.h.
[0808] 68. The compound of any one of clauses 58-67, wherein each occurrence of R.sup.b is independently selected from the group consisting of: C.sub.1-4 alkyl; C.sub.1-4 haloalkyl (e.g., CF.sub.3); —F; —NR.sup.e1R.sup.f1; C.sub.1-4 alkoxy; and —R.sup.h.
[0809] 69. The compound of any one of clauses 67-68, wherein —R.sup.h is C.sub.6-10 aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl (e.g., phenyl optionally substituted with 1-2 F).
[0810] 70. The compound of any one of clauses 1-39, wherein Y.sup.A2 is heterocyclyl or heterocycloalkenyl, each of 3-16 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 each of the heterocyclyl and heterocycloalkenyl ring is optionally substituted with 1-3 independently selected R.sup.b.
[0811] 71. The compound of any one of clauses 1-39 and 70, wherein Y.sup.A2 is heterocyclyl or heterocycloalkenyl, each of 4-6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R.sup.d), and O, and wherein each of the heterocyclyl and heterocycloalkenyl ring is optionally substituted with 1-3 independently selected R.sup.b.
[0812] 72. The compound of any one of clauses 1-39 and 70-71, wherein Y.sup.A2 is heterocyclyl or heterocycloalkenyl, each of 4-6 ring atoms, wherein 1 ring atom is N(R.sup.d).
[0813] 73. The compound of any one of clauses 70-72, wherein R.sup.d is selected from the group consisting of C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; and C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl, each optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH.
[0814] 74. The compound of any one of clauses 70-73, wherein each occurrence of R.sup.b substituent of Y.sup.A2 is independently selected from the group consisting of: C.sub.1-10 alkyl optionally substituted with 1-6 independently selected R.sup.a; C.sub.1-4 haloalkyl; —F; —Cl; —Br; cyano; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; —C(═O)(C.sub.1-10 alkyl); —C(═O)O(C.sub.1-4 alkyl); —S(O).sub.1-2(C.sub.1-4 alkyl); oxo; cyano; and -L.sup.1-L.sup.2-R.sup.h.
[0815] 75. The compound of any one of clauses 70-74, wherein one occurrence of R.sup.b substituent of Y.sup.A2 is C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a.
[0816] 76. The compound of any one of clauses 70-75, wherein one occurrence of R.sup.b substituent of Y.sup.A2 is unsubstituted C.sub.1-10 alkyl (e.g., C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, or C.sub.7-10).
[0817] 77. The compound any one of clauses 70-76, wherein one occurrence of R.sup.b substituent of Y.sup.A2 is ethyl, propyl (e.g., n-propyl), butyl (e.g., n-butyl; or sec-butyl; or tert-butyl; or iso-butyl), or octyl (e.g., n-octyl).
[0818] 78. The compound any one of clauses 70-76, wherein one occurrence of R.sup.b substituent of Y.sup.A2 is C.sub.1-10 alkyl which is substituted with 1-6 independently selected R.sup.a (e.g., R.sup.b is CF.sub.3 or —CF.sub.2CH.sub.3).
[0819] 79. The compound of any one of clauses 74, 75, and 78, wherein each occurrence of R.sup.a is independently selected from halo, OH, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy.
[0820] 80. The compound of any one of clauses 70-73, wherein one occurrence of R.sup.b substituent of Y.sup.A2 is -L.sup.1-L.sup.2-R.sup.h (e.g., —R.sup.h or —CH.sub.2—R.sup.h such as benzyl); or wherein one occurrence of R.sup.b substituent of Y.sup.A2 is C.sub.1-4 alkoxy or C.sub.1-4 haloalkoxy (e.g.,
##STR00446##
[0821] 81. The compound of any one of clauses 70-73 and 80, wherein one occurrence of R.sup.b is —F or —Cl (e.g., —F).
[0822] 82. The compound of any one of clauses 1-39, wherein Y.sup.A2 is
##STR00447##
n1 is 0, 1, or 2; and each of R.sup.cA and R.sup.cB is an independently selected R.sup.c.
[0823] 83. The compound of any one of clauses 1-39, wherein Y.sup.A2 is
##STR00448##
n1 is 0, 1, or 2; and each of R.sup.cA and R.sup.cB is an independently selected R.sup.c.
[0824] 84. The compound of any one of clauses 1-39, wherein Y.sup.A2 is
##STR00449##
one of Q.sup.1 and Q.sup.2 is N; the other one of Q.sup.1 and Q.sup.2 is CH; n1 is 0, 1, or 2; and each of R.sup.cA and R.sup.cB is an independently selected R.sup.c.
[0825] 85. The compound of any one of clauses 1-39, wherein Y.sup.A2 is
##STR00450##
one of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 is N; each of the remaining of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 is CH; n1 is 0, 1, or 2; and each of R.sup.cA and R.sup.cB is an independently selected R.sup.c.
[0826] 86. The compound of any one of clauses 82-85, wherein R.sup.cA is 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); —NR.sup.eR.sup.f; —C.sub.1-4 thioalkoxy; —C(═O)(C.sub.1-10 alkyl); —C(═O)(OH); —C(═O)O(C.sub.1-4 alkyl); and -L.sup.1-L.sup.2-R.sup.h.
[0827] 87. The compound of any one of clauses 82-86, wherein R.sup.cA is halo (e.g., F) or unsubstituted C.sub.1-10 alkyl (e.g., C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, or C.sub.7-10), such as ethyl, propyl (e.g., n-propyl), butyl (e.g., n-butyl, iso-butyl, sec-butyl, tert-butyl), or octyl (e.g., n-octyl).
[0828] 88. The compound of any one of clauses 82-86, wherein R.sup.cA is C.sub.1-10 alkyl which is substituted with 1-6 independently selected R.sup.a (e.g., each occurrence of R.sup.a is independently selected from halo, OH, C.sub.1-4 alkoxy, and C.sub.1-4haloalkoxy).
[0829] 89. The compound of any one of clauses 82-86, wherein R.sup.cA is C.sub.1-10 alkyl which is substituted with 1-6 independently selected halo (e.g., R.sup.cA is CF.sub.3).
[0830] 90. The compound of any one of clauses 82-86, wherein R.sup.cA is -L.sup.1-L.sup.2-R.sup.h.
[0831] 91. The compound of clause 90, wherein -L.sup.1 is a bond.
[0832] 92. The compound of any one of clauses 90-91, wherein -L.sup.2 is a bond.
[0833] 93. The compound of any one of clauses 90-92, wherein R.sup.h is C.sub.6-10 aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl,
[0834] such as C.sub.6 aryl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo (e.g., F), C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl (e.g.,
##STR00451##
[0835] 94. The compound of any one of clauses 90-92, wherein R.sup.h is heterocyclyl or heterocycloalkenyl, wherein each of the heterocyclyl and heterocycloalkenyl has 3-10 (e.g., 5-6) ring atoms, wherein 1-3 (e.g., 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, wherein each of the heterocyclyl and heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl, such as
##STR00452##
[0836] 95. The compound of any one of clauses 90-92, wherein R.sup.h is C.sub.3-8 (e.g., C.sub.3-6) cycloalkyl or C.sub.3-8 (e.g., C.sub.3-6) cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl (e.g., R.sup.h is cyclohexyl or 3,3-difluorocyclobutyl).
[0837] 96. The compound of any one of clauses 82-95, wherein n1 is 0.
[0838] 97. The compound of any one of clauses 82-95, wherein n1 is 1 or 2 (e.g., 1).
[0839] 98. The compound of any one of clauses 82-95 and 97, wherein each occurrence of R.sup.cB is independently halo or C.sub.1-3 alkyl (e.g., halo).
[0840] 99. The compound of any one of clauses 1-39, wherein Y.sup.A2 is
##STR00453##
n2 is 0, 1, or 2; and each of R.sup.bA and R.sup.bB is an independently selected R.sup.b.
[0841] 100. The compound of any one of clauses 1-39, wherein Y.sup.A2 is
##STR00454##
n2 is 0, 1, or 2; and each of R.sup.bA and R.sup.bB is an independently selected R.sup.b.
[0842] 101. The compound of any one of clauses 99-100, wherein R.sup.bA is C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a.
[0843] 102. The compound of any one of clauses 99-100, wherein R.sup.bA is unsubstituted C.sub.1-10 alkyl (e.g., C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, or C.sub.7-10), such as ethyl, propyl (e.g., n-propyl), butyl (e.g., n-butyl; or sec-butyl; or tert-butyl; or iso-butyl), or octyl (e.g., n-octyl).
[0844] 103. The compound of any one of clauses 99-100, wherein R.sup.bA is C.sub.1-10 alkyl which is substituted with 1-6 independently selected R.sup.a (e.g., each R.sup.a is selected from the group consisting of halo, OH, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy) (e.g., R.sup.bA is CF.sub.3 or —CF.sub.2CH.sub.3).
[0845] 104. The compound of any one of clauses 99-100, wherein R.sup.bA is —F or —Cl.
[0846] 105. The compound of any one of clauses 99-100, wherein R.sup.bA is -L.sup.1-L.sup.2-R.sup.h(e.g., —R.sup.h (e.g., phenyl or 3,5-difluorophenyl) or —CH.sub.2—R.sup.h such as benzyl); or R.sup.BA is C.sub.1-4 alkoxy or C.sub.1-4 haloalkoxy (e.g.,
##STR00455##
[0847] 106. The compound of any one of clauses 99-105, wherein n2 is 0.
[0848] 107. The compound of any one of clauses 99-105, wherein n2 is 1 or 2; and/or wherein each occurrence R.sup.bB is selected from the group consisting of —F, —Cl, and C.sub.1-3 alkyl.
[0849] 108. The compound of any one of clauses 1-29, wherein Q-A is as defined according to (B); and E is a ring of 5-8 ring atoms, wherein 0-3 ring atoms are heteroatoms (in addition to the ring nitrogen atom that is present), 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 ring is optionally substituted with 1-4 independently selected R.sup.b (e.g., E is piperidinyl which is optionally substituted with 1-2 independently selected R.sup.b (e.g., E is
##STR00456##
wherein R.sup.b is C.sub.1-6 alkyl)).
[0850] 109. The compound of clause 1, wherein the compound has the following formula:
##STR00457##
[0851] wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH (e.g., O); n1 is 0, 1, or 2; each of R.sup.cA and R.sup.cB is an independently selected R.sup.c; and R.sup.7 is H or C.sub.1-4 alkyl.
[0852] 110. The compound of clause 1, wherein the compound has the following formula:
##STR00458##
[0853] wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH (e.g., O); n1 is 0, 1, or 2; each of R.sup.cA and R.sup.cB is an independently selected R.sup.c; and R.sup.7 is H or C.sub.1-4 alkyl.
[0854] 111. The compound of clause 1, wherein the compound has the following formula:
##STR00459##
[0855] wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH (e.g., O); one of Q.sup.1 and Q.sup.2 is N; the other one of Q.sup.1 and Q.sup.2 is CH; n1 is 0, 1, or 2; each of R.sup.cA and R.sup.cB is an independently selected R.sup.c; and R.sup.7 is H or C.sub.1-4 alkyl.
[0856] 112. The compound of clause 1, wherein the compound has the following formula:
##STR00460##
[0857] wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH (e.g., O); one of Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 is N; each of the remaining of Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4 is CH; n1 is 0, 1, or 2; and each of R.sup.cA and R.sup.cB is an independently selected R.sup.c; and R.sup.7 is H or C.sub.1-4 alkyl.
[0858] 113. The compound of clause 1, wherein the compound has the following formula:
##STR00461##
[0859] wherein
[0860] W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH (e.g., O);
[0861] B.sup.1 is selected from the group consisting of:
[0862] (a) bicyclic or tricyclic heteroaryl of 7-14 (e.g., 9-12 (e.g., 9, 10, 11, or 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 ring is optionally substituted with 1-4 independently selected R.sup.c; and
[0863] (b) C.sub.7-10 bicyclic aryl, which is optionally substituted with 1-3 R.sup.c;
[0864] and R.sup.7 is H or C.sub.1-4 alkyl.
[0865] 114. The compound of clause 113, wherein B.sup.1 is bicyclic or tricyclic heteroaryl of 9-10 (e.g., 10) 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 ring is optionally substituted with 1-4 independently selected R.sup.c.
[0866] 115. The compound of clause 113, wherein B.sup.1 is
##STR00462##
[0867] 116. The compound of any one of clauses 109-115, wherein one of R.sup.1a and R.sup.1b is R*, the other of R.sup.1a and R.sup.1b is R** (e.g., H or F); and each of R.sup.1c and R.sup.1d is H.
[0868] 117. The compound of clause 116, wherein R* is
##STR00463##
wherein
[0869] each is independently a single bond or a double bond, provided that the five-membered ring comprising Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4 is heteroaryl;
[0870] Z.sup.1 is selected from N and CH;
[0871] Z.sup.2 is selected from N, O, and CH;
[0872] Z.sup.3 is selected from C(R.sup.g), N(R.sup.g), N(R.sup.d), and N;
[0873] Z.sup.4 is selected from N, NH, S, CH, N(R.sup.d), and O; and
[0874] the asterisk denotes point of attachment to the six-membered ring of the bicyclic ring portion of Formula I.
[0875] 118. The compound of clause 117, wherein each occurrence of R.sup.g is C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl; or C.sub.6-10 aryl); or
[0876] wherein each occurrence of R.sup.g is independently selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl; C.sub.6-10 aryl; —OH; —C(═O)(C.sub.1-4 alkyl); C.sub.1-4 alkoxy; or cyano); halo; C.sub.6-10 aryl; and cyano.
[0877] 119. The compound of any one of clauses 117-118, wherein R.sup.d is C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH.
[0878] 120. The compound of clause 116, wherein R* is heteroaryl of 6 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g.
[0879] 121. The compound of any one of clauses 116 and 120, wherein R* is heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are N atoms and wherein the heteroaryl ring is optionally substituted with 1-4 C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected —OH, —F, or C.sub.1-4 alkoxy) and —NR.sup.eR.sup.f (e.g., —NH.sub.2); or
[0880] wherein R* is heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are N atoms (e.g., pyridyl (e.g., 3-pyridyl or 4-pyridyl) and wherein the heteroaryl ring is optionally substituted with 1-4 C.sub.1-6 alkyl optionally substituted with 1-2 independently selected Rai (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected —OH, —F, or C.sub.1-4 alkoxy); halo (e.g., F or Cl); or —NR.sup.eR.sup.f (e.g., —NH.sub.2 or —NHMe).
[0881] 122. The compound of clause 116, wherein R* is C.sub.6-10 aryl, which is optionally substituted with 1-4 independently selected R.sup.g.
[0882] 123. The compound of any one of clauses 116 and 122, wherein R* is phenyl, which is optionally substituted with 1-4 independently selected halo (e.g., F or Cl) or C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 —OH); or
[0883] R* is phenyl, which is optionally substituted with 1-4 independently selected halo (e.g., F or Cl); —OH; cyano; —C(═O)N(R′)(R″) (e.g., —C(═O)NMe.sub.2); S(O).sub.1-2(C.sub.1-4 alkyl) (e.g., —SO.sub.2Et); —C(═O)(C.sub.1-4 alkyl) (e.g., —C(═O)Me); —Si(C.sub.1-4 alkyl).sub.4 (e.g., —Si(CH.sub.3).sub.4); C.sub.3-8 cycloalkyl optionally substituted with cyano; C.sub.1-4 haloalkoxy (e.g., —OCHF.sub.2 or —OCF.sub.3); C.sub.1-6 alkoxy (e.g., methoxy); or C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 —OH, C.sub.1-4 alkoxy, cyano, —C(═O)O(C.sub.1-4 alkyl), or —NR.sup.eR.sup.f).
[0884] 124. The compound of any one of clauses 109-112 and 116-123, wherein R.sup.cA is 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); —NR.sup.eR.sup.f; —C.sub.1-4 thioalkoxy; —C(═O)(C.sub.1-10 alkyl); —C(═O)(OH); —C(═O)O(C.sub.1-4 alkyl); and -L.sup.1-L.sup.2-R.sup.h.
[0885] 125. The compound of any one of clauses 109-112 and 116-124, wherein R.sup.cA is unsubstituted C.sub.1-10 alkyl (e.g., C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, or C.sub.7-10), such as ethyl, propyl (e.g., n-propyl), butyl (e.g., n-butyl, iso-butyl, sec-butyl, tert-butyl), or octyl (e.g., n-octyl).
[0886] 126. The compound of any one of clauses 109-112 and 116-124, wherein R.sup.cA is C.sub.1-10 alkyl which is substituted with 1-6 independently selected R.sup.a (e.g., each occurrence of R.sup.a is independently selected from halo, OH, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy).
[0887] 127. The compound of clause 126, wherein R.sup.cA is C.sub.1-10 alkyl which is substituted with 1-6 independently selected halo (e.g., R.sup.cA is CF.sub.3).
[0888] 128. The compound of any one of clauses 109-112 and 116-124, wherein R.sup.cA is halo (e.g., F or Cl (e.g., F)).
[0889] 129. The compound of clause 124, wherein R.sup.cA is -L.sup.1-L.sup.2-R.sup.h.
[0890] 130. The compound of clause 129, wherein -L.sup.1 is a bond.
[0891] 131. The compound of any one of clauses 129-130, wherein -L.sup.2 is —N(H)— or a bond (e.g., a bond).
[0892] 132. The compound of any one of clauses 129-130, wherein R.sup.h is C.sub.6-10 aryl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl,
[0893] such as C.sub.6 aryl, which is optionally substituted with 1-2 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, or C.sub.1-4 haloalkyl (e.g.,
##STR00464##
[0894] 133. The compound of any one of clauses 129-130, wherein R.sup.h is heterocyclyl or heterocycloalkenyl, wherein each of the heterocyclyl and heterocycloalkenyl has 3-10 (e.g., 5-6) ring atoms, wherein 1-3 (e.g., 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, wherein each of the heterocyclyl and heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl, such as
##STR00465##
[0895] 134. The compound of any one of clauses 129-130, wherein R.sup.h is C.sub.3-8 (e.g., C.sub.3-6) cycloalkyl or C.sub.3-8 (e.g., C.sub.3-6) cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C.sub.1-4 alkyl, and C.sub.1-4 haloalkyl (e.g., R.sup.h is cyclohexyl or cyclobutyl optionally substituted with 1-2 F).
[0896] 135. The compound of any one of clauses 109-134, wherein n1 is 0.
[0897] 136. The compound of any one of clauses 109-134, wherein n1 is 1 or 2 (e.g., 1).
[0898] 137. The compound of any one of clauses 109-134 and 136, wherein each occurrence of R.sup.cB is independently halo or C.sub.1-3 alkyl (e.g., halo).
[0899] 138. The compound of clause 1, wherein the compound has the following formula:
##STR00466##
[0900] wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH (e.g., O); n2 is 0, 1, or 2; each of R.sup.bA and R.sup.bB is an independently selected R.sup.b; and R.sup.7 is H or C.sub.1-4 alkyl.
[0901] 139. The compound of clause 1, wherein the compound has the following formula:
##STR00467##
[0902] wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH (e.g., O); n2 is 0, 1, or 2; each of R.sup.bA and R.sup.bB is an independently selected R.sup.b; and R.sup.7 is H or C.sub.1-4 alkyl.
[0903] 140. The compound of clause 1, wherein the compound has the following formula:
##STR00468##
[0904] wherein W.sup.A is O, S, CHNO.sub.2, NR.sup.d, or NH (e.g., O); B.sup.2 is: bicyclic, tricyclic, or polycyclic C.sub.7-20 cycloalkyl or C.sub.7-20 cycloalkenyl, each optionally substituted with 1-2 R.sup.b, and
[0905] R.sup.7 is H or C.sub.1-4 alkyl.
[0906] 141. The compound of clause 140, wherein B.sup.2 is selected from the group consisting of: spiro[5.5]undecanyl (e.g.,
##STR00469##
bicyclo[2.2.1]hept-2-enyl (e.g.,
##STR00470##
bicyclo[2.2.1]heptanyl (e.g.,
##STR00471##
spiro[2.5]octanyl (e.g.,
##STR00472##
and adamantly (e.g.,
##STR00473##
[0907] 142. The compound of clause 141, wherein B.sup.2 is
##STR00474##
[0908] 143. The compound of any one of clauses 138-142, wherein one of R.sup.1a and R.sup.1b is R*, the other of R.sup.1a and R.sup.1b is R** (e.g., H or F); and each of R.sup.1c and R.sup.1d is H.
[0909] 144. The compound of clause 143, wherein R* is
##STR00475##
wherein
[0910] each is independently a single bond or a double bond, provided that the five-membered ring comprising Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4 is heteroaryl;
[0911] Z.sup.1 is selected from N and CH;
[0912] Z.sup.2 is selected from N, O, and CH;
[0913] Z.sup.3 is selected from C(R.sup.g), N(R.sup.g), N(R.sup.d), and N;
[0914] Z.sup.4 is selected from N, NH, S, CH, N(R.sup.g), N(R.sup.d), and O; and
[0915] the asterisk denotes point of attachment to the six-membered ring of the bicyclic ring portion of Formula I.
[0916] 145. The compound of clause 144, wherein each occurrence of R.sup.g is C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected C.sub.3-6 cycloalkyl or C.sub.6-10 aryl); or
[0917] wherein each occurrence of R.sup.g is independently selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl; C.sub.6-10 aryl; —OH; —C(═O)(C.sub.1-4 alkyl); C.sub.1-4 alkoxy; or cyano); halo; C.sub.6-10 aryl; and cyano.
[0918] 146. The compound of clause 144, wherein each occurrence of R.sup.d is C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH.
[0919] 147. The compound of clause 143, wherein R* is heteroaryl of 6 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g.
[0920] 148. The compound of any one of clauses 143 and 147, wherein R* is heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are N atoms and wherein the heteroaryl ring is optionally substituted with 1-4 C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected —OH, —F, or C.sub.1-4 alkoxy) and —NR.sup.eR.sup.f (e.g., —NH.sub.2); or
[0921] wherein R* is heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are N atoms (e.g., pyridyl (e.g., 3-pyridyl or 4-pyridyl) and wherein the heteroaryl ring is optionally substituted with 1-4 C.sub.1-6 alkyl optionally substituted with 1-2 independently selected Rai (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected —OH, —F, or C.sub.1-4 alkoxy); halo (e.g., F or Cl); or —NR.sup.eR.sup.f (e.g., —NH.sub.2 or —NHMe).
[0922] 149. The compound of clause 143, wherein R* is C.sub.6-10 aryl, which is optionally substituted with 1-4 independently selected R.sup.g.
[0923] 150. The compound of any one of clauses 143 and 149, wherein R* is phenyl, which is optionally substituted with 1-4 independently selected halo (e.g., F or Cl) or C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 —OH); or
[0924] wherein R* is phenyl, which is optionally substituted with 1-4 independently selected halo (e.g., F or Cl); —OH; cyano; —C(═O)N(R′)(R″) (e.g., —C(═O)NMe.sub.2); S(O).sub.1-2(C.sub.1-4 alkyl) (e.g., —SO.sub.2Et); —C(═O)(C.sub.1-4 alkyl) (e.g., —C(═O)Me); —Si(C.sub.1-4 alkyl).sub.4 (e.g., —Si(CH.sub.3).sub.4); C.sub.3-8 cycloalkyl optionally substituted with cyano; C.sub.1-4 haloalkoxy (e.g., —OCHF.sub.2 or —OCF.sub.3); C.sub.1-6 alkoxy (e.g., methoxy); or C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 —OH, C.sub.1-4 alkoxy, cyano, —C(═O)O(C.sub.1-4 alkyl), or —NR.sup.eR.sup.f).
[0925] 151. The compound of any one of clauses 138-150, wherein R.sup.bA is C.sub.1-10 alkyl which is optionally substituted with 1-6 independently selected R.sup.a.
[0926] 152. The compound of clause 151, wherein R.sup.bA is unsubstituted C.sub.1-10 alkyl (e.g., C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, or C.sub.7-10), such as ethyl, propyl (e.g., n-propyl), butyl (e.g., n-butyl; or sec-butyl; or tert-butyl; or iso-butyl), or octyl (e.g., n-octyl).
[0927] 153. The compound of clause 151, wherein R.sup.bA is C.sub.1-10 alkyl which is substituted with 1-6 independently selected R.sup.a (e.g., each R.sup.a is selected from the group consisting of halo, OH, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy) (e.g., R.sup.bA is CF.sub.3).
[0928] 154. The compound of any one of clauses 138-150, wherein R.sup.bA is —F or —Cl.
[0929] 155. The compound of any one of clauses 138-150, wherein R.sup.bA is -L1-L.sup.2-R.sup.h(e.g., —R.sup.h (e.g., phenyl or 3,5-difluorophenyl) or —CH.sub.2—R.sup.h such as benzyl); or wherein one occurrence of R.sup.b substituent of Y.sup.A2 is C.sub.1-4 alkoxy or C.sub.1-4 haloalkoxy (e.g.,
##STR00476##
[0930] 156. The compound of any one of clauses 138-155, wherein n2 is 0.
[0931] 157. The compound of any one of clauses 138-155, wherein n2 is 1 or 2.
[0932] 158. The compound of clause 138-155 and 157, wherein each occurrence R.sup.bB is selected from the group consisting of —F, —Cl, and C.sub.1-3 alkyl.
[0933] 159. The compound of any one of clauses 109-158, wherein n is 0.
[0934] 160. The compound of any one of clauses 109-158, wherein n is 1.
[0935] 161. The compound of clause 160, wherein Y.sup.A1 is C.sub.1-6 alkylene, which is optionally substituted with 1-2 R.sup.a.
[0936] 162. The compound of any one of clauses 160-161, wherein Y.sup.A1 is —CH.sub.2—, —CH.sub.2CH.sub.2— —CH.sub.2CH.sub.2CH.sub.2— —CH(CF.sub.3)—, —CH.sub.2CH(OH)—,
##STR00477##
(e.g., CH.SUB.2.),
[0937] ##STR00478##
(e.g., Y.sup.A1 is —CH.sub.2— or —CH.sub.2CH.sub.2—).
[0938] 163. The compound of clause 1, wherein the compound has the following formula:
##STR00479##
[0939] wherein:
[0940] E is a ring of 3-16 ring atoms, wherein aside from the nitrogen atom present, 0-3 additional 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 ring is optionally substituted with 1-4 independently selected R.sup.b.
[0941] 164. The compound of clause 163, wherein E is a ring of 5-8 ring atoms, herein aside from the nitrogen atom present, 0-3 additional 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 ring is optionally substituted with 1-4 independently selected R.sup.b (e.g., E is piperidinyl which is optionally substituted with 1-2 independently selected R.sup.b (e.g., E is
##STR00480##
wherein R.sup.b is C.sub.1-6 alkyl)).
[0942] 165. The compound of any one of clauses 138-142 and 163-164, wherein one of R.sup.1a and R.sup.1b is R*, the other of R.sup.1a and R.sup.1b is R** (e.g., H or F); and each of R.sup.1c and R.sup.1d is H.
[0943] 166. The compound of clause 165, wherein R* is
##STR00481##
wherein
[0944] each is independently a single bond or a double bond, provided that the five-membered ring comprising Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4 is heteroaryl;
[0945] Z.sup.1 is selected from N and CH;
[0946] Z.sup.2 is selected from N, O, and CH;
[0947] Z.sup.3 is selected from C(R.sup.g), N(R.sup.g), N(R.sup.d), and N;
[0948] Z.sup.4 is selected from N, NH, S, CH, S, N(R.sup.g), N(R.sup.d), and O; and
[0949] the asterisk denotes point of attachment to the six-membered ring of the bicyclic ring portion of Formula I.
[0950] 167. The compound of clause 166, wherein each occurrence of R.sup.g is C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected C.sub.3-6 cycloalkyl or C.sub.6-10 aryl); or
[0951] wherein each occurrence of R.sup.g is independently selected from the group consisting of: C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected C.sub.3-6 cycloalkyl or C.sub.3-6 cycloalkenyl; C.sub.6-10 aryl; —OH; —C(═O)(C.sub.1-4 alkyl); C.sub.1-4 alkoxy; or cyano); halo; C.sub.6-10 aryl; and cyano.
[0952] 168. The compound of any one of clauses 166-167, wherein each occurrence of R.sup.d is C.sub.1-6 alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH.
[0953] 169. The compound of clause 165, wherein R* is heteroaryl of 6 ring atoms, wherein 1-4 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 ring is optionally substituted with 1-4 independently selected R.sup.g.
[0954] 170. The compound of any one of clauses 165 and 169, wherein R* is heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are N atoms and wherein the heteroaryl ring is optionally substituted with 1-4 C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected —OH, —F, or C.sub.1-4 alkoxy) and —NR.sup.eR.sup.f (e.g., —NH.sub.2); or
[0955] wherein R* is heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are N atoms (e.g., pyridyl (e.g., 3-pyridyl or 4-pyridyl) and wherein the heteroaryl ring is optionally substituted with 1-4 C.sub.1-6 alkyl optionally substituted with 1-2 independently selected Rai (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 independently selected —OH, —F, or C.sub.1-4 alkoxy); halo (e.g., F or Cl); or —NR.sup.eR.sup.f (e.g., —NH.sub.2 or —NHMe).
[0956] 171. The compound of any one of clauses 165 and 169, wherein R* is C.sub.6-10 aryl, which is optionally substituted with 1-4 independently selected R.sup.g.
[0957] 172. The compound of any one of clauses 165, 169, and 171, wherein R* is phenyl, which is optionally substituted with 1-4 independently selected halo (e.g., F or Cl) or C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 —OH); or
[0958] wherein R* is phenyl, which is optionally substituted with 1-4 independently selected halo (e.g., F or Cl); —OH; cyano; —C(═O)N(R′)(R″) (e.g., —C(═O)NMe.sub.2); S(O).sub.1-2(C.sub.1-4 alkyl) (e.g., —SO.sub.2Et); —C(═O)(C.sub.1-4 alkyl) (e.g., —C(═O)Me); —Si(C.sub.1-4 alkyl).sub.4 (e.g., —Si(CH.sub.3).sub.4); C.sub.3-8 cycloalkyl optionally substituted with cyano; C.sub.1-4 haloalkoxy (e.g., —OCHF.sub.2 or —OCF.sub.3); C.sub.1-6 alkoxy (e.g., methoxy); or C.sub.1-6 alkyl optionally substituted with 1-2 independently selected R.sup.a1 (e.g., C.sub.1-6 alkyl optionally substituted with 1-2 —OH, C.sub.1-4 alkoxy, cyano, —C(═O)O(C.sub.1-4 alkyl), or —NR.sup.eR.sup.f).
[0959] 173. The compound of any one of clauses 109-142 and 151-164 wherein the
##STR00482##
moiety is
##STR00483##
[0960] 174. The compound of any one of clauses 109-142 and 151-164, wherein the
##STR00484##
moiety is
##STR00485##
[0961] 175. The compound of any one of clauses 109-142 and 151-164, wherein the
##STR00486##
moiety is
##STR00487##
[0962] 176. The compound of any one of clauses 109-175, wherein R.sup.2 is H.
[0963] 177. The compound of any one of clauses 109-176, wherein R.sup.5 is H.
[0964] 178. The compound of any one of clauses 109-177, wherein each R** is independently selected from the group consisting of: H; halo; cyano; C.sub.1-6 alkyl optionally substituted with 1-2 R.sup.a; C.sub.2-6 alkenyl; C.sub.2-6 alkynyl; C.sub.1-4 haloalkyl; C.sub.1-4 alkoxy; C.sub.1-4 haloalkoxy; -L.sup.3-L.sup.4-R*; —S(O).sub.1-2(C.sub.1-4 alkyl); —S(O)(═NH)(C.sub.1-4 alkyl); —S(O).sub.1-2(NR′R″); —C.sub.1-4 thioalkoxy; —NO.sub.2; —C(═O)(C.sub.1-4 alkyl); —C(═O)O(C.sub.1-4 alkyl); —C(═O)OH; and —C(═O)N(R′)(R″).
[0965] 179. The compound of any one of clauses 109-178, wherein R.sup.7 is H.
[0966] 180. The compound of any one of clauses 1-179, wherein R.sup.6 is H.
[0967] 181. The compound of clause 1, wherein the compound is selected from the group consisting of the compounds delineated in Table C1, or a pharmaceutically acceptable salt thereof.
[0968] 182. A pharmaceutical composition comprising a compound of clauses 1-181 and one or more pharmaceutically acceptable excipients.
[0969] 183. A method for inhibiting STING activity, the method comprising contacting STING with a compound as defined in any one of clauses 1-181.
[0970] 184. The method of clause 183, wherein the inhibiting comprises antagonizing STING.
[0971] 185. The method of any one of clauses 183-184, which is carried out in vitro.
[0972] 186. The method of clause 185, wherein the method comprises contacting a sample comprising one or more cells comprising STING with the compound.
[0973] 187. The method of clause 185 or 186, wherein the one or more cells are one or more cancer cells.
[0974] 188. The method of clause 186 or 187 wherein the sample further comprises one or more cancer cells (e.g., 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).
[0975] 189. The method of clause 183, which is carried out in vivo.
[0976] 190. The method of clause 189, 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.
[0977] 191. The method of clause 190, wherein the subject is a human.
[0978] 192. The method of clause 190, wherein the disease is cancer.
[0979] 193. The method of clause 192, 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.
[0980] 194. The method of clause 192 or 193, wherein the cancer is a refractory cancer.
[0981] 195. The method of clause 190, wherein the compound is administered in combination with one or more additional cancer therapies.
[0982] 196. The method of clause 195, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.
[0983] 197. The method of clause 196, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.
[0984] 198. The method of clause 197, 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).
[0985] 199. The method of any one of clauses 190-198, wherein the compound is administered intratumorally.
[0986] 200. 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 1-181, or a pharmaceutical composition as defined in clause 182.
[0987] 201. The method of clause 200, 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.
[0988] 202. The method of clause 200 or 201, wherein the cancer is a refractory cancer.
[0989] 203. The method of clause 200, wherein the compound is administered in combination with one or more additional cancer therapies.
[0990] 204. The method of clause 203, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.
[0991] 205. The method of clause 204, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.
[0992] 206. The method of clause 205, 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).
[0993] 207. The method of any one of clauses 200-206, wherein the compound is administered intratumorally.
[0994] 208. 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 1-181, or a pharmaceutical composition as defined in clause 182.
[0995] 209. The method of clause 208, wherein the subject has cancer.
[0996] 210. The method of clause 209, wherein the subject has undergone and/or is undergoing and/or will undergo one or more cancer therapies.
[0997] 211. The method of clause 209, 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.
[0998] 212. The method of clause 211, wherein the cancer is a refractory cancer.
[0999] 213. The method of clause 208, wherein the immune response is an innate immune response.
[1000] 214. The method of clause 213, wherein the at least one or more cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.
[1001] 215. The method of clause 214, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.
[1002] 216. The method of clause 215, 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).
[1003] 217. 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 1-181, or a pharmaceutical composition as defined in clause 182.
[1004] 218. 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 1-181, or a pharmaceutical composition as defined in clause 182.
[1005] 219. A method of treatment comprising administering to a subject a compound as defined in any one of clauses 1-181, or a pharmaceutical composition as defined in clause 182, 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.
[1006] 220. The method of any one of clauses 217-219, wherein the disease is cancer.
[1007] 221. The method of clause 220, 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.
[1008] 222. The method of clause 220 or 221, wherein the cancer is a refractory cancer.
[1009] 223. The method of any one of clauses 220-222, wherein the compound is administered in combination with one or more additional cancer therapies.
[1010] 224. The method of clause 223, wherein the one or more additional cancer therapies comprises surgery, radiotherapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.
[1011] 225. The method of clause 224, wherein chemotherapy comprises administering one or more additional chemotherapeutic agents.
[1012] 226. The method of clause 225, 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).
[1013] 227. The method of any one of clauses 217-226, wherein the compound is administered intratumorally.
[1014] 228. 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 1-181, or a pharmaceutical composition as defined in clause 182.
[1015] 229. The method of clause 228, wherein the disease, disorder, or condition is selected from type I interferonopathies, Aicardi-Goutiéres Syndrome (AGS), genetic forms of lupus, inflammation-associated disorders, and rheumatoid arthritis.
[1016] 230. The method of clause 229, wherein the disease, disorder, or condition is a type I interferonopathy (e.g., STING-associated vasculopathywith onset in infancy (SAVI)).
[1017] 231. The method of clause 230, wherein the type I interferonopathy is STING-associated vasculopathy with onset in infancy (SAVI)).
[1018] 232. The method of clause 230, wherein the disease, disorder, or condition is Aicardi-Goutiéres Syndrome (AGS).
[1019] 233. The method of clause 229, wherein the disease, disorder, or condition is a genetic form of lupus.
[1020] 234. The method of clause 229, wherein the disease, disorder, or condition is inflammation-associated disorder.
[1021] 235. The method of clause 234, wherein the inflammation-associated disorder is systemic lupus erythematosus.
[1022] 236. The method of any one of clauses 190-235, wherein the method further comprises identifying the subject.
[1023] 237. A combination comprising a compounds defined in any one of clauses 1 to 181 or a pharmaceutically acceptable salt or tautomer thereof, and one or more therapeutically active agents.
[1024] 238. A compound defined in any one of clauses 1 to 181 or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 182, for use as a medicament.
[1025] 239. A compound defined in any one of clauses 1 to 181 or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 182, for use in the treatment of a disease, condition or disorder modulated by STING inhibition.
[1026] 240. A compound defined in any one of clauses 1 to 181 or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition defined in clause 182, for use in the treatment of a disease mentioned in any one of clauses 183 to 236.
[1027] 241. Use of a compound defined in any one of clauses 1 to 181 or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition defined in clause 182, in the manufacture of a medicament for the treatment of a disease mentioned in in any one of clauses 183 to 236.