Compounds and compositions for treating conditions associated with STING activity
Inventors
Venkatraman, Shankar • Katz, Jason • Roush, William R. • Seidel, Hans Martin
Assignees
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Publication Number
US-12152018-B2
Publication Date
2024-11-26
Expiration Date
Abstract
This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) having formula (I) 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.
Core Innovation
The disclosure relates to compounds of Formula (I), including pharmaceutically acceptable salts, tautomers, hydrates, and cocrystals. The compounds are characterized by a five-membered heteroaryl ring comprising X1 and X2 together with a six-membered aromatic ring, with extensive substituent selection for R1a, R1b, R1c, R2, R3, R5, Q1, Q2, Z, A, W, and the linker LA.
Q1 is defined as a heteroarylene or C6 arylene with specified heteroatom and optional substituent rules, Q2 is Rg, and LA is subject to defined linkage options and a constraint on bonding between O, N, or S(O) atoms unless an N-N bond is further attached to C(O). Ring E is a saturated or partially unsaturated ring of 3-16 ring atoms with 0-3 additional heteroatoms, optionally substituted with oxo, Rc, Rh, and -(Lg)bg-Rh.
The description further constrains Z and A according to (AA) or (BB), including Z as N(H) or N(Rd) and A as H, C1-10 alkyl, or a substituted moiety including (YA1)nA-YA2. The overall framework is presented as STING (TMEM173) antagonists and links the compounds to downstream functional use in inhibiting STING activity.
Claims Coverage
The provided material supports one explicitly identified independent claim directed to a compound of Formula (I). The claim coverage centers on the Formula (I) scaffold and its definitional constraints, with the structural features below capturing the inventive features explicitly stated across the items.
Formula (I) fused heteroaryl and aromatic ring scaffold
A compound of Formula (I), or a pharmaceutically acceptable salt, tautomer, hydrate, or cocrystal thereof, in which X1 and X2 form a five-membered heteroaryl ring with a six-membered aromatic ring.
Extensive substituent definitions on the Formula (I) core
R1a, R1b, R1c, R2, R3, and R5 are independently selected from the defined groups, including H, Rc, Rh, Rd, Rg, and linked forms involving L1 or L2, with Q1 and Q2 selected from the defined heteroarylene/arylene and Rg-containing sets.
Linkage element LA with bonding proviso
Each LA is independently selected from C1-3 alkylene optionally substituted with 1-2 Ra, —O—, —NH—, —NRd—, —S(O)0-2—, and C(O), subject to the proviso that -(LA)a1- cannot contain bond(s) between O, N, or S(O) atoms unless an N-N bond is further attached to C(O).
Z, A, and Ring E structural constraints
Z and A are defined according to (AA) or (BB), including Z as N(H) or N(Rd) and A as H, C1-10 alkyl, or a substituted moiety including (YA1)nA-YA2; Ring E is a saturated or partially unsaturated ring of 3-16 ring atoms with 0-3 additional heteroatoms and optional substitution by oxo, Rc, Rh, and -(Lg)bg-Rh.
The claim coverage is anchored by a Formula (I) compound claim with a fused heteroaryl five-membered ring and aromatic six-membered ring, together with defined substituent families, linkage constraints, and Ring E limitations.
Stated Advantages
Not explicitly described in patent.
Documented Applications
A method of inhibiting STING activity by contacting STING with the claimed compound or by administering a corresponding pharmaceutical composition.
Pharmaceutical compositions for inhibiting STING activity.
Therapeutic use in conditions with excessive STING signaling, including type I interferonopathies such as SAVI and AGS, genetic lupus, systemic lupus erythematosus, rheumatoid arthritis, and cancer.
Treatment methods involving contacting STING and/or administering the compounds or pharmaceutical compositions, including cancer treatment examples and optional combination therapies.
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