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EP-4007758-B1 - BIS-[N-((5-CARBAMOYL)-1H-BENZO[D]IMIDAZOL-2-YL)-PYRAZOL-5-CARBOXAMIDE] DERIVATIVES AND RELATED COMPOUNDS AS STING (STIMULATOR OF INTERFERON GENES) AGONISTS FOR THE TREATMENT OF CANCER

EP4007758B1EP 4007758 B1EP4007758 B1EP 4007758B1EP-4007758-B1

Inventors

  • DUVALL, JEREMY R.
  • BENTLEY, KEITH W.
  • JONES, BRIAN D.
  • KELLEHER, EUGENE W.
  • RAY, Soumya S.
  • THOMAS, JOSHUA D.
  • TOADER, DORIN

Dates

Publication Date
20260513
Application Date
20200731

Claims (12)

  1. A compound of Formula (V-f1), Formula (V-f2), Formula (V-f3), Formula (V-f4), Formula (V-f5), Formula (V-f6), Formula (V-f7), Formula (V-h1), Formula (V-h2), Formula (V-h3), Formula (V-h4), Formula (V-h5), Formula (V-h6), or Formula (V-h7): or a solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Ring 1 or Ring 2 is selected from or Y 1 , Z 1 , Y 2 , and Z 2 are each independently O, S, C, or N; X 1 , W 1 , X 2 , and W 2 are each independently C or N; X 3 and X 4 , when present, are each independently S or NR f ; X 5 is N or CR A2 ; X 6 , when present, is N or CR A1 ; X 9 , when present, is N or CH; R 3 and R 5 are each independently -CON(R d )(R f ), -CH 2 N(R d )(R f ), -N(R d )(R f ), - N(R d )CO(R f ), -CH 2 N(R d )CO(R f ) or one of R 3 and R 5 is -CON(R d )(R f ), -CH 2 N(R d )(R f ), -N(R d )(R f ), -N(R d )CO(R f ), or -CH 2 N(R d )CO(R f ), and the other of R 3 and R 5 is H, -COOH, or -CO 2 R c ; R c is C 1-4 alkyl; R A2 and R A1 , when present, are each independently halogen, amino(C 1-4 alkyl)-, hydroxy, optionally substituted (C 1-6 alkyl), or optionally substituted (C 1-6 alkyl)oxy-, wherein C 1-6 alkyl of said optionally substituted (C 1-6 alkyl), or optionally substituted (C 1-6 alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxy, C 1-4 alkoxyl, -N(R e )(R f ), -CO 2 (R f ), -CON(R e )(R f ), and -COOH; each R d is independently H, hydroxy, or C 1-4 alkyl; each R e is independently selected from H, (C 1-4 alkyl), -CO(C 1-4 alkyl), -OCO(C 1-4 alkyl), and -CO 2 (C 1-4 alkyl); each R f is independently H, hydroxy, or (C 1-4 alkyl); R 14 and R C2 are each independently absent or C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted by a substituent selected from halogen, -OR c , -NR c R d , -CO 2 R c , -CONR c R d , - SO 2 NR c R d , and -OCONR c R d ; R 16 and R C1 are each independently absent, H or C 1-4 alkyl; and R 15 , R 17 , R 18 , or R 19 are each independently absent, H, or C 1-4 alkyl, wherein C 1-4 alkyl is optionally substituted by a substituent selected from halogen, -OR c , -NR c R d , -CO 2 R c , -CONR c R d , -SO 2 NR c R d , and -OCONR c R d .
  2. The compound of claim 1, wherein the compound is Formula (V-i1), Formula (V-i2), Formula (V-i3), Formula (V-i4), Formula (V-i5), (Formula (V-i6), or Formula (V-i7): or a solvate, pharmaceutically acceptable salt, or tautomer thereof.
  3. The compound of any one of the preceding claims, wherein Ring 1 and Ring 2 are each independently selected from any one of the following:
  4. The compound of any one of the preceding claims, wherein the compound is Example No. 26, 27, 29, 32, 33, 35, 36, 39, 41, 43, 45, 46, 47, 48, 50, 50a, or 51 or Compound No. 111, 113, 120, 142, 143, 150, 151, 153, 155, 167, or 182, or a tautomer or pharmaceutically salt thereof:
  5. The compound of claim 1, wherein the compound is: or a solvate, pharmaceutically acceptable salt, or tautomer thereof.
  6. The compound of claim 1, wherein the compound is: or a solvate, pharmaceutically acceptable salt, or tautomer thereof.
  7. A pharmaceutical composition comprising the compound of any one of the preceding claims, and a pharmaceutically acceptable excipient.
  8. A pharmaceutical composition comprising the compound of claim 5, and a pharmaceutically acceptable excipient.
  9. A pharmaceutical composition comprising the compound of claim 6, and a pharmaceutically acceptable excipient.
  10. A compound of any one of claims 1-6, for use in therapy.
  11. A compound of any one of claims 1-6, for use in a method of treating a STING-mediated disorder, wherein the disorder is cancer.
  12. The compound for use of claim 11, wherein the cancer is breast cancer, head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung carcinoma, prostate cancer, colorectal cancer, ovarian cancer, or pancreatic cancer.

Description

RELATED APPLICATIONS This application claims priority to, and the benefit of, U.S. Provisional Application No. 62/882,081 filed August 2, 2019, U.S. Provisional Application No. 62/944,643 filed December 6, 2019, and U.S. Provisional Application No. 62/982,935 filed February 28, 2020. BACKGROUND Stimulator of Interferon Genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen derived- and self-DNA. STING is a 378 amino acid protein, which mainly contains three structural domains: (i) N-terminal transmembrane domain (aa 1-154); (ii) central globular domain (aa 155-341); and (iii) C-terminal tail (aa 342-379). STING may form symmetrical dimers combined with its ligands in V-shaped conformation, while not completely covering the bound ligands. A STING agonist can bind into the pocket region of STING. However, the STING activation process is easily inhibited in some severe disease conditions, resulting in the inactivation of the STING pathway. Therefore, screening and designing potent STING agonists is of great importance for cancer immune therapy and other disease treatments, including, but not limited to, obesity, liver injury, sugar-lipid metabolism, and virus infection. Specific targeting of immune pathways presents opportunities for cancer therapy, potentially offering greater specificity than cell population-based therapeutic approaches. Compounds for use in modulating the activity of STING are described in each of WO2019/134705, WO2019/069275, WO2019/069270, WO2019/069269, WO2017/175156, WO2017/175147, WO2020/010451, WO2020/132582, WO2020/115676, WO2020/132556, and Ramanjulu et al, Nature, Vol. 564, no. 7736, pages 439-443. The compounds of this disclosure modulate the activity of STING, and accordingly, may provide a beneficial therapeutic impact in treatment of diseases, disorders and/or conditions in which modulation of STING (Stimulator of Interferon Genes) is beneficial, including, but not limited to, inflammation, allergic and autoimmune diseases, infectious diseases, cancer, pre-cancerous syndromes, and as vaccine adjuvants. SUMMARY The present invention provides a compound of Formula (V-f1), Formula (V-f2), Formula (V-f3), Formula (V-f4), Formula (V-f5), Formula (V-f6), Formula (V-f7), Formula (V-h1), Formula (V-h2), Formula (V-h3), Formula (V-h4), Formula (V-h5), Formula (V-h6), or Formula (V-h7): or a solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Ring 1 or Ring 2 is selected from orY1, Z1, Y2, and Z2 are each independently O, S, C, or N;X1, W1, X2, and W2 are each independently C or N;X3 and X4, when present, are each independently S or NRf;X5 is N or CRA2;X6, when present, is N or CRA1;X9, when present, is N or CH;R3 and R5 are each independently -CON(Rd)(Rf), -CH2N(Rd)(Rf), -N(Rd)(Rf), - N(Rd)CO(Rf), -CH2N(Rd)CO(Rf) or one of R3 and R5 is -CON(Rd)(Rf), -CH2N(Rd)(Rf), -N(Rd)(Rf), -N(Rd)CO(Rf), or -CH2N(Rd)CO(Rf), and the other of R3 and R5 is H, -COOH, or -CO2Rc;Rc is C1-4 alkyl;RA2 and RA1, when present, are each independently halogen, amino(C1-4 alkyl)-, hydroxy, optionally substituted (C1-6 alkyl), or optionally substituted (C1-6 alkyl)oxy-,wherein C1-6 alkyl of said optionally substituted (C1-6 alkyl), or optionally substituted (C1-6 alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxy, C1-4 alkoxyl, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), and -COOH;each Rd is independently H, hydroxy, or C1-4 alkyl;each Re is independently selected from H, (C1-4 alkyl), -CO(C1-4 alkyl), -OCO(C1-4 alkyl), and -CO2(C1-4 alkyl);each Rf is independently H, hydroxy, or (C1-4 alkyl);R14 and RC2 are each independently absent or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORc, -NRcRd, -CO2Rc, -CONRcRd, - SO2NRcRd, and -OCONRcRd;R16 and RC1 are each independently absent, H or C1-4 alkyl; andR15, R17, R18, or R19 are each independently absent, H, or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORc, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd The present invention also provides a pharmaceutical composition comprising a compound as defined above, and a pharmaceutically acceptable excipient. The present invention also provides a compound as defined above for use in therapy. The present invention also provides a compound as defined above for use in a method of treating a STING-mediated disorder, wherein the disorder is cancer. Further embodiments of the invention are set out in the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and material