Compounds containing polysubstituted benzo[d][1,3]oxathiole, benzo[d][1,3]oxathiole 3-oxide or benzo[d][1,3]oxathiole 3,3-dioxide and methods/uses thereof as agonists of G protein-coupled receptor 119

{
  "publication_number": "US11358956B2",
  "country": "US",
  "kind": "B2",
  "title": "Compounds containing polysubstituted benzo[d][1,3]oxathiole, benzo[d][1,3]oxathiole 3-oxide or benzo[d][1,3]oxathiole 3,3-dioxide and methods/uses thereof as agonists of G protein-coupled receptor 119",
  "abstract": "There are provided compounds having formula (I), in which: X 1 and X 2 are selected from certain combinations of O, S, SO and SO 2; X 3 is selected from CH, CF and N; X 4 is selected from CH and N; X 6, X 6′ and X 6″ are selected from H, halogen, and certain alkyl, haloalkyl, alkoxy, hydroxyalkyl, and amide groups; X 7 and X 7′ are selected from H, halogen, and certain alkyl, haloalkyl, alkoxy, hydroxyalkyl, aminoalkyl and amide groups, or both X 7 and X 7′ together form a cycloalkyl or heterocycle; and A is selected from certain optionally substituted, alkoxy, piperazinyl and pyrrolidinyl groups. Also provided are compositions comprising these compounds, as well as uses/methods related thereto, including treatment of diseases and conditions associated with GPR119 dysregulation, Type 2 diabetes mellitus, and related metabolic disorders. (I)",
  "claims": [
    "1. A compound having formula (I): or an enantiomer, diastereomer, hydrate, solvate, or pharmaceutically acceptable salt of formula (I), or a prodrug or complex thereof, wherein: X 1 is O and X 2 is S, SO or SO 2; or X 2 is O and X 1 is S, SO or SO 2; X 3 is CH, CF and N; each X 4 is independently CH and N; A is R is R 1 is hydrogen, C(O)O-tert-butyl or R 2a is hydrogen or C 1-6 alkyl; R 2b is hydrogen or C 1-6 alkyl; R 3 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C(O)R 9, C(O)OR 10, C(O)NR 10a R 10b, CH 2 C(O)OR 10a, R 4 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C(O)R 9, C(O)OR 10, C(O)NR 10a R 10b, R 5 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C(O)R 9, C(O)OR 10, C(O)NR 10a R 10b, R 6 is NHR 11 or CH 2 NHR 12; R 7a is hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, C 1-6 haloalkyl or C 1-6 alkoxy; R 7b is hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, C 1-6 haloalkyl or C 1-6 alkoxy; R 7c is hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl, C 1-6 haloalkyl or C 1-6 alkoxy; R 8 is hydrogen, halogen, C 1-6 alkyl, C 3-7 branched alkyl or C 3-7 cycloalkyl; R 9 is C 1-6 alkyl, C 3-7 branched alkyl or R 10 is C 1-6 alkyl or C 3-7 branched alkyl; R 10a is hydrogen, C 1-6 alkyl or C 3-7 branched alkyl; R 10b is hydrogen, C 1-6 alkyl or C 3-7 branched alkyl; R 11 is R 12 is each R 13a is independently hydrogen, C 1-6 alkyl or C 3-7 branched alkyl; each R 13b is independently hydrogen, C 1-6 alkyl or C 3-7 branched alkyl; each R 14a is independently hydrogen, C 1-6 alkyl, C 3-7 branched alkyl or C(O)O-tert-butyl; each R 14b is independently hydrogen, C 1-6 alkyl or C 3-7 branched alkyl; X 5 is N or CR 7b; n 1 is 1 or 2; n 2 is 1 or 2; and m is 1, 2, 3, 4, 5, 6 or 7; each of X 6, X 6′ and X 6″ is independently H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, or C 1-3 (O)NR 15a R 15b; each of X 7 and X 7′ is independently hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl or C 1-3 (O)NR 15a R 15b or both X 7 and X 7′ together form C 3-6 cycloalkyl or a heterocycle ring having 3-6 carbons and 0 or 1 oxygen, sulphur or nitrogen atom in the ring, wherein each carbon ring atom of the C 3-6 cycloalkyl or the heterocycle is independently substituted with hydrogen, C 1-3 alkyl, hydroxyl, halogen, amino, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl or C 1-3 (O)NR 15a R 15b; when each of X 6, X 6′ and X 6″ is hydrogen, at least X 7 or X 7′ is not hydrogen; when both X 7 and X 7′ are hydrogen, at least one of X 6, X 6′ and X 6″ is not hydrogen; and each of R 15a and R 15b is independently hydrogen, C 1-3 alkyl or C 3 branched alkyl.",
    "2. The compound of claim 1, wherein one, two or three of X 6, X 6′ and X 6″ are fluorine, optionally wherein X 6, X 6′ and X 6″ are: F, H and H, respectively; H, F and H, respectively; or H, H and F, respectively.",
    "3. The compound of claim 1, wherein X 6, X 6′ and X 6″ are each H.",
    "4. The compound of claim 1, wherein A is",
    "5. The compound of claim 4, wherein R is",
    "6. The compound of claim 5, wherein R is and R 3 is",
    "7. The compound of claim 5, wherein R is and wherein R 4 is",
    "8. The compound of claim 5, wherein R is and wherein R 5 is",
    "9. The compound of claim 1, wherein A is optionally wherein R 1 is",
    "10. The compound of claim 1, wherein A is",
    "11. The compound of claim 1, wherein both of X 7 and X 7′ are hydrogen and at least one of X 6, X 6′ and X 6″ is not hydrogen.",
    "12. The compound of claim 1, wherein both of X 7 and X 7′ are CH 3.",
    "13. The compound of claim 1, wherein at least one of X 7 and X 7′ is halogen.",
    "14. The compound of claim 1, having: formula (II) or an enantiomer, diastereomer, hydrate, solvate, or pharmaceutically acceptable salt of formula (II), or a complex thereof formula (III) or an enantiomer, diastereomer, hydrate, solvate, or pharmaceutically acceptable salt of formula (III), or a complex thereof formula (IV) or an enantiomer, diastereomer, hydrate, solvate, or pharmaceutically acceptable salt of formula (IV), or a complex thereof formula (V) or an enantiomer, diastereomer, hydrate, solvate, or pharmaceutically acceptable salt of formula (V), or a complex thereof wherein X 8 is NH or O; formula (VI) or an enantiomer, diastereomer, hydrate, solvate, or pharmaceutically acceptable salt of formula (VI), or a complex thereof wherein: one X 8 is NH or O; and one X 8 is CH 2; or formula (VII) or an enantiomer, diastereomer, hydrate, solvate, or pharmaceutically acceptable salt of formula (VII), or a complex thereof wherein one X 8 is NH or O, and wherein each of two X 8 is CH 2.",
    "15. The compound of claim 1, wherein both X 7 and X 7′ together form wherein R is H or C 1-3 alkyl.",
    "16. The compound of claim 1, wherein: X 1 is O and X 2 is SO 2; X 1 is SO 2 and X 2 is O; X 1 is O and X 2 is SO; X 1 is SO and X 2 is O; X 1 is O and X 2 is S; or X 1 is S and X 2 is O.",
    "17. The compound of claim 1, wherein X 3 is selected from the group consisting of CF and N.",
    "18. A compound, which is: 5-chloro-2-(4-{[4-(2,2-dimethyl-3,3-dioxido-1,3-benzoxathiol-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine; 5-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclopentan]-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine; 5-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclohexan]-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine; or 5-chloro-2-(4-{[4-(3,3-dioxidospiro[1,3-benzoxathiole-2,1′-cyclobutan]-6-yl)-2-fluorophenoxy]methyl}piperidin-1-yl)pyrimidine.",
    "19. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient and/or an anti-diabetic agent.",
    "20. A method of treating a disease associated with GPR119 dysregulation, said method comprising administering to a subject (i): the compound of claim 1; or (ii) a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient and/or an anti-diabetic agent; optionally wherein the disease is Type 2 diabetes mellitus."
  ],
  "description_excerpt": "The present invention relates to polysubstituted benzo[d][1,3]oxathioles, benzo[d][1,3]oxathiole 3-oxides, benzo[d][1,3]oxathiole 3,3-dioxides, and related compounds and pharmaceutical compositions comprising the compounds, as well as uses and methods related thereto.\n\nInsulin is a hormone that regulates blood sugar produced by the pancreas. Diabetes is a chronic disease that occurs either when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces. Hyperglycemia, or raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious damage to many of the body's systems, especially the nerves and blood vessels. The global prevalence of diabetes is estimated to be over 9% of adults aged 18+ years, corresponding to about 2-fold increase in the last ten years. There are three types of diabetes: Type 1 also known as insulin-dependent or juvenile requires daily administration of insulin. Type 2 diabetes (T2DM) also known as non-insulin dependent diabetes mellitus results from the body's ineffective use or ability to regulate insulin. Gestational diabetes is a condition where the blood glucose values are above normal but below those characteristic of diabetes occurring during pregnancy. Diabetes increases the risk of heart failure, stroke, neuropathy in the feet, retinopathy which is an important cause of blindness and kidney failure.",
  "cpc": [
    "C07D 411/14",
    "A61K 31/506",
    "A61K 31/53",
    "A61K 45/06",
    "A61P 3/10",
    "C07D 327/04",
    "C07D 413/14",
    "C07D 417/14"
  ],
  "ipc": [
    "A61K 45/06",
    "C07D 411/14"
  ],
  "assignees": [
    "Pramana Pharmaceuticals Inc"
  ],
  "inventors": [
    "Mikhail Chafeev"
  ],
  "filing_date": "2018-11-06",
  "publication_date": "2022-06-14",
  "grant_date": "2022-06-14",
  "priority_date": "2017-11-30",
  "application_number": "US-201816768293-A",
  "family_id": "66664679",
  "cited_by_count": 3,
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}