http://rdf.ncbi.nlm.nih.gov/pubchem/patent/AR-120153-A1

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filingDate 2020-10-02-04:00^^<http://www.w3.org/2001/XMLSchema#date>
inventor http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_e4941ba9247240c788774c13b92156c1
http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_60f7da0c295c32d0c21d3b1811d6ce66
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publicationDate 2022-02-02-04:00^^<http://www.w3.org/2001/XMLSchema#date>
publicationNumber AR-120153-A1
titleOfInvention COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF CONDITIONS RELATED TO THE ACTIVITY OF STING
abstract This disclosure features chemical entities (eg, a compound or a pharmaceutically acceptable salt and/or hydrate and/or co-crystal and/or drug combination of the compound) that inhibit (eg, antagonize) the gene stimulator of interferon (STING). Such chemical entities are useful, e.g. e.g., to treat 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 the progression of the condition, disease, or disorder (eg, cancer) in a subject (eg, a human). This disclosure further presents compositions containing these, as well as methods of using and preparing them. Claim 1: A compound of formula (1) or a pharmaceutically acceptable salt thereof or a tautomer thereof, characterized in that: X¹ is selected from the group consisting of O, S, N, NR² and CR⁵; X² is selected from the group consisting of O, S, N, NR⁴ and CR⁵; each ⁻ ⁻ ⁻ ⁻ ⁻ is independently a single bond or a double bond, provided that the five-membered ring comprising X¹ and X² is heteroaryl; and the 6-membered ring of formula (2) is aromatic; QA is defined according to (A) or (B) below: (A) Q is selected from the group consisting of: NH and N(C₁₋₆ alkyl) where C₁₋₆ alkyl is optionally substituted with 1-2 Rᵃ independently selected; and A is: (I) -(YA¹)ₙ-YA², where: n is 0 or 1; YA¹ is C₁₋₆ alkylene, which is optionally substituted with 1-6 substituents each independently selected from the group consisting of: oxo; Rᵃ; C₆₋₁₀ aryl optionally substituted with 1-4 independently selected C₁₋₄ alkyl; and heteroaryl of 5-10 ring atoms, where 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rᵈ), O and S(O) ₀₋₂ and wherein the heteroaryl ring is optionally substituted with independently selected 1-4 C₁₋₄ alkyl; or YA¹ is -YA³-YA⁴-YA⁵ connecting to Q through YA³ where: YA³ is a C₁₋₃ alkylene optionally substituted with 1-2 substituents each independently selected from the group consisting of oxo and Rᵃ; YA⁴ is -O-, -NH-, -N(C₁₋₆ alkyl)- or -S-; and YA⁵ is a bond or C₁₋₃ alkylene optionally substituted with 1-2 independently selected Rᵃ; and YA² is: (a) C₃₋₂₀ cycloalkyl or C₃₋₂₀ cycloalkenyl, each of which is optionally substituted with 1-4 Rᵇ, (b) C₆₋₂₀ aryl which is optionally substituted with 1-4 Rᶜ; (c) heteroaryl of 5 to 20 ring atoms, where 1 - 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rᵈ), O and S(O )₀₋₂ and wherein the heteroaryl ring is optionally substituted with 1-4 independently selected Rᶜ; or (d) heterocyclyl or heterocycloalkenyl of 3-16 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rᵈ), O and S(O)₀₋₂ and where the heterocyclyl or heterocycloalkenyl ring is optionally substituted with 1-4 independently selected Rᵇ, or (II) -Z¹-Z²-Z³, where: Z¹ is C₁₋₃ alkylene, which is optionally substituted with 1 - 4 Rᵃ; Z² is -N(H)-, -N(Rᵈ)-, -O- or -S-; and Z³ is C₂₋₇ alkylene, which is optionally substituted with 1-4 Rᵃ; or (III) C₁₋₁₀ alkyl, which is optionally substituted with 1-6 independently selected Rᵃ, or (B) Q and A together form: a compound of formula (3); and E is a ring of 3-16 ring atoms, where 0-3 ring atoms are heteroatoms (in addition to the nitrogen atom already present), each independently selected from the group consisting of N, N(H ), N(Rᵈ), O and S(O)₀₋₂ and where the ring is optionally substituted with 1 - 4 independently selected Rᵇ, each of R¹ᵃ, R¹ᵇ, R¹ᶜ and R¹ᵈ is independently selected from the group consisting of H ; halo; cyan; C₁₋₆ alkyl optionally substituted with 1-2 Rᵃ; C₂₋₆ alkenyl; C₂₋₆ alkynyl; C₁₋₄ haloalkyl; C₁₋₄ alkoxy; C₁₋₄ haloalkoxy; -L³-L⁴-Rⁱ; -S(O)₁₋₂(C₁₋₄ alkyl); -S(O)(=NH)(C₁₋₄ alkyl); SF₅; -NRᵉRᶠ; -OH; oxo; -S(O)₁₋₂(NR'R''); thioalkoxy -C₁₋₄; NO₂; -C(=O)(C₁₋₄ alkyl); -C(=O)O(C₁₋₄ alkyl); -C(=O)OH; and -C(=O)N(R')(R''); o R¹ᵃ and R¹ᵇ, R¹ᵇ and R¹ᶜ or R¹ᶜ and R¹ᵈ, together with the connecting atoms, form a ring of 3 - 10 ring atoms, where 0 - 2 ring atoms are heteroatoms each selected independently of the group that consists of N, N(H), N(Rᵈ), O and S(O)₀₋₂; and wherein the ring is optionally substituted with 1-4 substituents each independently selected from the group consisting of C₁₋₆ alkyl, halo, C₁₋₆ haloalkyl, -OH, NRᵉRᶠ, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy, each occurrence R² is independently selected from the group consisting of: (I) C₁₋₆ alkyl, which is optionally substituted with 1-2 independently selected Rᵃ; (II) C₃₋₆ cycloalkyl or C₃₋₆ cycloalkenyl; (III) heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rᵈ), O, and S(O)₀₋₂; (IV) C₆₋₁₀ aryl; (V) heteroaryl of 5-10 ring atoms, where 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rᵈ), O, and S( O)₀₋₂; (VI) -C(O)(C₁₋₄ alkyl); (VII) -C(O)O(C₁₋₄ alkyl); (VIII) -CON(R')(R''); (IX) -S(O)₁₋₂(NR'R''); (X) -S(O)₁₋₂(C₁₋₄ alkyl); (XI)-OH; (XII) C₁₋₄ alkoxy; and (XIII)H; R⁴ is selected from the group consisting of H and independently selected C₁₋₆ alkyl optionally substituted with 1-3 Rᵃ; R⁵ is selected from the group consisting of H; halo; -OH; -C₁₋₄ alkyl; haloalkyl -C₁₋₄; C₁₋₄ alkoxy; C₁₋₄ haloalkoxy; -C(=O)O(C₁₋₄ alkyl); -C(=O)(C₁₋₄ alkyl); -C(=O)OH; -CON(R’)(R’’); -S(O)₁₋₂(NR'R''); -S(O)₁₋₂(C₁₋₄ alkyl); cyano and C₃₋₆ cycloalkyl or C₃₋₆ cycloalkenyl, each optionally substituted with independently selected 1-4 C₁₋₄ alkyl; R⁶ is selected from the group consisting of H; C₁₋₆ alkyl optionally substituted with 1-3 independently selected Rᵃ; -OH; C₁₋₄ alkoxy; C(=O)H; C(=O)(C₁₋₄ alkyl); C₆₋₁₀ aryl optionally substituted with 1-4 independently selected C₁₋₄ 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(Rᵈ), O and S(O)₀ ₋₂ and wherein the heteroaryl ring is optionally substituted with independently selected 1-4 C₁₋₄ alkyl; each occurrence of Rᵃ is independently selected from the group consisting of: -OH; -F; -Cl; -Br; -NRᵉRᶠ; C₁₋₄ alkoxy; C₁₋₄ haloalkoxy; -C(=O)O(C₁₋₄ alkyl); -C(=O)(C₁₋₄ alkyl); -C(=O)OH; -CON(R’)(R’’); -S(O)₁₋₂(NR'R''); -S(O)₁₋₂(C₁₋₄ alkyl); cyano and C₃₋₆ cycloalkyl or C₃₋₆ cycloalkenyl, each optionally substituted with 1-4 independently selected C₁₋₄ alkyl; each occurrence of Rᵇ is independently selected from the group consisting of: independently selected C₁₋₁₀ alkyl optionally substituted with 1-6 Rᵃ; C₁₋₄ haloalkyl; -OH; oxo; -F; -Cl; -Br; -NRᵉRᶠ; C₁₋₄ alkoxy; C₁₋₄ haloalkoxy; -C(=O)(C₁₋₁₀ alkyl); -C(=O)O(C₁₋₄ alkyl); -C(=O)OH; -C(=O)N(R')(R''); -S(O)₁₋₂(NR'R''); -S(O)₁₋₂(C₁₋₄ alkyl); cyan; and -L¹-L²-Rʰ; each occurrence of Rᶜ is independently selected from the group consisting of: halo; cyan; C₁₋₁₀ alkyl, which is optionally substituted with 1-6 independently selected Rᵃ; C₂₋₆ alkenyl; C₂₋₆ alkynyl; C₁₋₄ alkoxy optionally substituted with 1-2 independently selected Rᵃ; C₁₋₄ haloalkoxy; -S(O)₁₋₂(C₁₋₄ alkyl); -NRᵉRᶠ; -OH; -S(O)₁₋₂(NR'R''); -C₁₋₄-thioalkoxy or -C₁₋₄-thiohaloalkoxy; -NO₂; -SF₅; -C(=O)(C₁₋₁₀ alkyl); -C(=O)O(C₁₋₄ alkyl); -C(=O)OH; -C(=O)N(R')(R''); and -L¹-L²-Rʰ; Rᵈ is selected from the group consisting of: C₁₋₆ alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; C₃₋₆ cycloalkyl or C₃₋₆ cycloalkenyl, each optionally substituted with 1-3 substituents each independently selected from the group consisting of halo and OH; -C(O)(C₁₋₄ alkyl); -C(O)O(C₁₋₄ alkyl); -CON(R’)(R’’); -S(O)₁₋₂(NR'R''); -S(O)₁₋₂(C₁₋₄ alkyl); -OH; and C₁₋₄ alkoxy; each occurrence of Rᵉ and Rᶠ is independently selected from the group consisting of: H; C₁₋₆ alkyl; C₁₋₆ haloalkyl; C₃₋₆ cycloalkyl or C₃₋₆ cycloalkenyl; -C(O)(C₁₋₄ alkyl); -C(O)O(C₁₋₄ alkyl); -CON(R’)(R’’); -S(O)₁₋₂(NR'R''); -S(O)₁₋₂(C₁₋₄ alkyl); -OH; and C₁₋₄ alkoxy; o Rᵉ and Rᶠ together with the nitrogen atom to which each is attached form a ring of 3 - 8 ring atoms, where the ring has: (a) 1 - 7 carbon ring atoms, each of which is substituted with 1-2 substituents independently selected from the group consisting of H and C₁₋₃ alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to Rᵉ and Rᶠ), each independently selected from the group consisting of N(Rᵈ), NH, O and S; -L¹ is a bond or C₁₋₃ alkylene; -L² is -O-, -N(H)-, -N(C₁₋₃ alkyl)-, -S(O)₀₋₂-, or a bond; Rʰ is selected from the group consisting of: C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C₁₋₄ alkyl optionally substituted with 1-2 Rᵃ independently selected; C₁₋₄ haloalkyl; cyan; C₁₋₄ alkoxy; and C₁₋₄ haloalkoxy; heterocyclyl or heterocycloalkenyl, wherein heterocyclyl or 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(Rᵈ), O and S(O)₀₋₂, where heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C₁₋₄ alkyl optionally substituted with 1-2 Rᵃ independently selected; C₁₋₄ haloalkyl; cyan; C₁₋₄ alkoxy; and C₁₋₄ haloalkoxy; heteroaryl of 5-10 ring atoms, where 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rᵈ), O and S(O)₀₋ ₂ and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C₁₋₄ alkyl optionally substituted with 1-2 Rᵃ independently selected; C₁₋₄ haloalkyl; cyan; C₁₋₄ alkoxy; and C₁₋₄ haloalkoxy; and C₆₋₁₀ aryl, which is optionally substituted with 1-4 independently selected substituents from the group consisting of halo, C₁₋₄ alkyl optionally substituted with 1-2 independently selected Rᵃ; C₁₋₄ haloalkyl; cyan; C₁₋₄ alkoxy; and C₁₋₄ haloalkoxy; -L³ is a bond or C₁₋₃ alkylene; -L⁴ is -O-, -N(H)-, -N(C₁₋₃ alkyl)-, -S(O)₀₋₂-, or a bond; Rⁱ is selected from the group consisting of: C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halo; C₁₋₄ alkyl optionally substituted with 1-2 Rᵃ independently selected; C₁₋₄ haloalkyl; cyan; C₁₋₄ alkoxy; and C₁₋₄ haloalkoxy; heterocyclyl or heterocycloalkenyl, wherein heterocyclyl or 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(Rᵈ), O and S(O)₀₋₂, where heterocyclyl or heterocycloalkenyl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halo, C₁₋₄ alkyl optionally substituted with 1-2 Rᵃ independently selected; C₁₋₄ haloalkyl; cyan; C₁₋₄ alkoxy; and C₁₋₄ haloalkoxy; heteroaryl of 5-10 ring atoms, where 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rᵈ), O and S(O)₀₋ ₂ and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, C₁₋₄ alkyl optionally substituted with 1-2 Rᵃ independently selected; C₁₋₄ haloalkyl; cyan; C₁₋₄ alkoxy; and C₁₋₄ haloalkoxy; and C₆₋₁₀ aryl, which is optionally substituted with 1-4 independently selected substituents from the group consisting of halo, C₁₋₄ alkyl optionally substituted with 1-2 independently selected Rᵃ; C₁₋₄ haloalkyl; cyan; C₁₋₄ alkoxy; and C₁₋₄ haloalkoxy; and each occurrence of R' and R'' is independently selected from the group consisting of: H, C₁₋₄ alkyl, C₆₋₁₀ aryl optionally substituted with 1-2 substituents selected from the group consisting of halo, C₁₋₄ alkyl and C₁₋₄ haloalkyl and heteroaryl of 5-10 ring atoms, where 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rᵈ), O and S (O)₀₋₂ and wherein the heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halo, -OH, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ , C₁₋₄ alkyl and C₁₋₄ haloalkyl; o R’ and R’’ together with the nitrogen atom to which each is attached form a ring of 3 - 8 ring atoms, where the ring has: (a) 1 - 7 carbon ring atoms, each one of which is substituted with 1-2 substituents independently selected from the group consisting of H and C₁₋₃ alkyl; and (b) 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R' and R''), each independently selected from the group consisting of N(H), N(C₁₋₆ alkyl) , O and S.
priorityDate 2019-10-03-04:00^^<http://www.w3.org/2001/XMLSchema#date>
type http://data.epo.org/linked-data/def/patent/Publication

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isDiscussedBy http://rdf.ncbi.nlm.nih.gov/pubchem/substance/SID457444288

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