Bicyclic carboxamides and methods of use thereof
Inventors
Bravo, Yalda • Chen, Austin Chih-Yu • DING, Jinyue • Gomez, Robert • Lam, Heather • NAGAMIZO, Joe Fred • Oballa, Renata Marcella • POWELL, David Andrew • Sheng, Tao
Assignees
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Publication Number
US-10968201-B2
Publication Date
2021-04-06
Expiration Date
Abstract
Compounds, compositions and methods are provided for modulating the activity of EP2 and EP4 receptors, and for the treatment, prevention and amelioration of one or more symptoms of diseases or disorders related to the activity of EP2 and EP4 receptors. In certain embodiments, the compounds are antagonists of both the EP2 and EP4 receptors.
Core Innovation
The invention relates to compounds of Formula (I) and pharmaceutically acceptable derivatives thereof, including salts, solvates, hydrates, single stereoisomers, mixtures of stereoisomers, racemic mixtures of stereoisomers, isotopic variants, and prodrugs. The compound is defined by X1 being N, X3, X4, and X5 being CR3, CR4, and CR5, L1 being —CRb2—, and Ring A being aryl, with R1 as aryl optionally substituted with one, two, or three Ry groups and multiple substituent variables R2 through R12.
Y1 and Y2 are each independently a bond or —(CRa2)n—, with the proviso that Y1 and Y2 are not both a bond, while Z1 and Z2 are each —CRa2— and L2 is —(CRc2)m—. G is selected from —C(O)OR12, —C(O)NHOH, —SO3H, —SO2NH2, —SO2NHRd, —SO2NHC(O)Rd, —NHC(O)NHSO2Rd, 1H-tetrazolyl, —P(O)(OH)2, 1,2,4-oxadiazol-5(4H)-one, tetrazol-5(4H)-one, or —C(O)NHSO2Rd, and R12 is selected from H, C1-C6 alkyl, aryl, aralkyl, CH(R13)OC(O)R14, CH(R13)OC(O)OR14, and a (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl group.
The provided content also includes narrower formula-defined subclasses, including embodiments where Ring A is phenyl and R1 is phenyl, where R7 is hydrogen or deuterium, where q is 0 or 1, and where Formula (V) has p=1 with R1 as phenyl optionally substituted with one, two, or three Ry groups. The document further includes pharmaceutical composition coverage comprising the compound with a pharmaceutically acceptable carrier.
Claims Coverage
The consolidated claim coverage centers on one independent claim for Formula (I), with dependent refinements that narrow substituent choices and define a Formula (V) subclass, plus a pharmaceutical composition embodiment. In total, the claims present 6 inventive features.
Formula (I) compound with pharmaceutically acceptable derivative forms
A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, isotopic variant or prodrug thereof, wherein X1 is N, X3 is CR3, X4 is CR4, X5 is CR5, L1 is —CRb2—, and Ring A is aryl.
Aryl Ring A and aryl-substituted R1
Ring A is aryl and R1 is aryl optionally substituted with one, two, or three Ry groups.
Substituent rules for R7 and R8/R9
R7 is hydrogen, halogen, alkyl, alkoxy, haloalkoxy, hydroxyl, or haloalkyl; each R8 and each R9 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R8 and R9 together with the atom or atoms to which they are attached form a heterocyclyl optionally substituted with one, two, or three groups selected from halogen, alkyl, and haloalkyl; each R10 is hydrogen or alkyl; and each R11 is alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl with optional substitution.
Functional group G and R12-defined moiety options
G is —C(O)OR12, —C(O)NHOH, —SO3H, —SO2NH2, —SO2NHRd, —SO2NHC(O)Rd, —NHC(O)NHSO2Rd, 1H-tetrazolyl, —P(O)(OH)2, 1,2,4-oxadiazol-5(4H)-one, tetrazol-5(4H)-one, or —C(O)NHSO2Rd, where R12 is H, C1-C6 alkyl, aryl, aralkyl, CH(R13)OC(O)R14, CH(R13)OC(O)OR14, or a (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl group.
Narrower phenyl/phenyl and isotopic subclasses
Narrower claim scope includes compounds where Ring A is phenyl and R1 is phenyl, where R7 is hydrogen or deuterium, where q is 0 or 1, and where Formula (V) has p=1 and R1 is phenyl optionally substituted with one, two, or three Ry groups.
Pharmaceutical composition with a pharmaceutically acceptable carrier
A pharmaceutical composition containing the compound of claim 1 or specified pharmaceutically acceptable derivatives/variants together with a pharmaceutically acceptable carrier.
The claims are anchored by a broad Formula (I) scaffold with extensive structural variables and explicit inclusion of salts, solvates, hydrates, stereoisomers, isotopic variants, and prodrugs. Dependent and related claims narrow the scope through phenyl substitutions, isotopic limitation at R7, discrete q and p values, a Formula (V) subclass, and a pharmaceutical composition embodiment.
Stated Advantages
Enantiomerically enriched "more active" enantiomers are obtained by resolution using chiral SFC.
Documented Applications
Racemic example compounds are resolved to obtain enantiomerically enriched "more active" enantiomers using chiral SFC, with chromatographic retention times and yields reported.
Pharmaceutical compositions are described as containing the disclosed compound and a pharmaceutically acceptable carrier.
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