NOVEL STING AGONISTS

• US 20200131209A1
• Filed: 10/24/2019
• Published: 04/30/2020
• Est. Priority Date: 10/29/2018
• Status: Active Grant

• Current Assignee: Venenum BioDesign, LLC (Genesis Biotechnology Group LLC)
• Original Assignee: Venenum BioDesign, LLC (Genesis Biotechnology Group LLC)
• Inventors: Diller, David J., Metzger, Axel, Kaelin, JR., David E., Paget, Steven, Huang, Chia-Yu, Mcguinness, Brian F., Hospital, Audrey Julie, Solvibile, JR., William Ronald
• Granted Patent: US 11,161,864 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07F 9/65746 the molecule containing more than one cyclic phosphorus atom
• CPC Class Codes: C07F 9/6587 having two phosphorus atoms as ring hetero atoms in the same ring

Abstract

The present invention provides compounds of Formula I′:

wherein , W, X, Y, Z, Z₁, Z₂, R₁, R₂, R₃, R₄ and R₅ are as defined herein, or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug ester or solvate form thereof, wherein all of the variables are as defined herein. These compounds are effective at modulating the STING protein and thus can be used as medicaments for treating or preventing disorders affected by the agonism of STING.

Claims

1. A compound of Formula I′

having the structure;

2. The compound of claim 1, wherein the compound is of Formula I:

3. The compound or the pharmaceutically acceptable salt thereof of claim 1 or 2, wherein:

W is O or —

NR₆;

Y is O or —

NR₇;

is a 7- to 10-membered bicyclic heteroaryl ring containing at least three N atoms;

which is optionally substituted with R₁₀ and R₁₁;

Z is independently selected from C₁-C₆ alkyl and halo-C₁-C₆-alkyl;

Z₁ is independently selected from C₁-C₆ alkyl and halo-C₁-C₆-alkyl;

Z₂ is independently selected from C₁-C₄ alkyl and halo-C₁-C₄-alkyl;

R₁ is a 7- to 10-membered bicyclic heteroaryl containing at least three N atoms, which is optionally substituted with R₁₂ and R₁₃;

R₂ is independently selected from H, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkyl, halo-C₁-C₄ alkoxy, —

NR₈R₉ and OH;

R₃ is independently selected from H, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkyl, halo-C₁-C₄ alkoxy, and OH;

R₄ is selected from OH, SH, C₁-C₆ alkoxy-carbonyl-oxy-C₁-C₆ alkoxy, and BH₃;

R₅ is selected from OH, SH, C₁-C₆ alkoxy-carbonyl-oxy-C₁-C₆ alkoxy, and BH₃;

R₆ is independently selected from H, C₁-C₄ alkyl, C₂-C₃ alkenyl, C₃-C₆ cycloalkyl and C₁-C₄ alkoxy;

R₇ is independently selected from H, C₁-C₄ alkyl, C₂-C₃ alkenyl, C₃-C₆ cycloalkyl and C₁-C₄ alkoxy;

R₈ is independently selected from H, C₁-C₄ alkyl, and halo-C₁-C₄-alkyl;

R₉ is independently selected from H, C₁-C₄ alkyl, and halo-C₁-C₄-alkyl;

R₁₀ is independently selected from H, ═

O, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkyl, halo-C₁-C₄ alkoxy, —

NR₁₄R₁₅, —

NR₁₄C(═

O)R₁₅ and OH;

R₁₁ is independently selected from H, ═

O, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkyl, halo-C₁-C₄ alkoxy, —

NR₁₄R₁₅, —

NR₁₄C(═

O)R₁₅ and OH;

R₁₂ is independently selected from H, ═

O, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkyl, halo-C₁-C₄ alkoxy, —

NR₁₆R₁₇, —

NR₁₆C(═

O)R₁₇ and OH;

R₁₃ is independently selected from H, ═

O, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkyl, halo-C₁-C₄ alkoxy, —

NR₁₆R₁₇, —

NR₁₆C(═

O)R₁₇ and OH;

R₁₄, at each occurrence, is independently selected from H, C₁-C₄ alkyl, and halo-C₁-C₄-alkyl;

R₁₅, at each occurrence, is independently selected from H, C₁-C₄ alkyl, and halo-C₁-C₄-alkyl;

R₁₆, at each occurrence, is independently selected from H, C₁-C₄ alkyl, and halo-C₁-C₄-alkyl; and

R₁₇, at each occurrence, is independently selected from H, C₁-C₄ alkyl, and halo-C₁-C₄-alkyl.

4. The compound or the pharmaceutically acceptable salt thereof of claim 1 or 2, wherein:

W is O or —

NR₆;

Y is O or —

NR₇;

is selected from purinyl, dihydropurinyl, dihydroimidazopyridazinyl, dihydropyrrolopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, and pyrrolopyrimidinyl;

all of which are optionally substituted with R₁₀ and R₁₁;

Z is independently selected from C₁-C₆ alkyl and halo-C₁-C₆-alkyl;

Z₁ is independently selected from C₁-C₆ alkyl and halo-C₁-C₆-alkyl;

Z₂ is independently selected from C₁-C₄ alkyl and halo-C₁-C₄-alkyl;

R₁ is selected from dihydropurinyl, purinyl, pyrrolopyrimidinyl, dihydrotriazolopyrimidinyl, triazolopyrimidinyl, dihydroimidazopyridazinyl, and dihydropyrrolopyrimidinyl;

all of which are optionally substituted with R₁₂ and R₁₃;

R₂ is independently selected from H, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkyl, —

NR₈R₉ and OH;

R₃ is independently selected from H, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkyl, and OH;

R₄ is selected from OH, SH, and C₁-C₆ alkoxy-carbonyl-oxy-C₁-C₆ alkoxy;

R₅ is selected from OH, SH, and C₁-C₆ alkoxy-carbonyl-oxy-C₁-C₆ alkoxy;

R₆ is independently selected from H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl and C₁-C₄ alkoxy;

R₇ is independently selected from H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl and C₁-C₄ alkoxy;

R₈ is independently selected from H, C₁-C₄ alkyl, and halo-C₁-C₄-alkyl;

R₉ is independently selected from H, C₁-C₄ alkyl, and halo-C₁-C₄-alkyl;

R₁₀ is independently selected from H, ═

O, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkyl, —

NR₁₄R₁₅, —

NR₁₄C(═

O)R₁₅ and OH;

R₁₁ is independently selected from H, ═

O, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkyl, —

NR₁₄R₁₅, —

NR₁₄C(═

O)R₁₅ and OH;

R₁₂ is independently selected from H, ═

O, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkyl, —

NR₁₆R₁₇, —

NR₁₆C(═

O)R₁₇ and OH;

R₁₃ is independently selected from H, ═

O, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkyl, —

NR₁₆R₁₇, —

NR₁₆C(═

O)R₁₇ and OH;

R₁₄, at each occurrence, is independently selected from H, C₁-C₄ alkyl, and halo-C₁-C₄-alkyl;

R₁₅, at each occurrence, is independently selected from H, C₁-C₄ alkyl, and halo-C₁-C₄-alkyl;

R₁₆, at each occurrence, is independently selected from H, C₁-C₄ alkyl, and halo-C₁-C₄-alkyl; and

R₁₇, at each occurrence, is independently selected from H, C₁-C₄ alkyl, and halo-C₁-C₄-alkyl.

5. The compound or the pharmaceutically acceptable salt thereof of claim 1 or 2, wherein:

W is O or —

NR₆;

Y is O or —

NR₇;

is selected from

6. The compound or the pharmaceutically acceptable salt thereof of claim 1 or 2, wherein:

W is O or —

NR₆;

Y is O or —

NR₇;

is selected from

7. The compound or the pharmaceutically acceptable salt thereof of claim 1 or 2, wherein:

W is O or —

NR₆;

Y is O or —

NR₇;

is selected from

8. The compound or the pharmaceutically acceptable salt thereof of claim 1 or 2, wherein:

W is O or —

NR₆;

Y is O or —

NR₇;

is selected from

9. The compound or the pharmaceutically acceptable salt thereof of claim 1 or 2, wherein the compound is represented by any one of the following formulae:

10. The compound or the pharmaceutically acceptable salt thereof of any one of claims 1-9, wherein the 5- or 6-membered monocyclic heteroaryl group of R₁₀ or R₁₁ is selected from any one of the following groups:

11. The compound or the pharmaceutically acceptable salt thereof of claim 9, wherein:

Z₁ is selected from —

CH₂— and

—

CH(CH₃)—

,

Z is selected from —

CH₂CH₂—

, —

CH(CH₃)CH₂—

, —

CH₂CH(CH₃)—

, —

CH₂CH₂CH₂—

, —

CH₂CF₂CH₂, —

CH₂CH(CH₃)CH₂—

, and cyclobutyl,

R₂ is selected from H, F, OH, —

OCH₃ and —

NH₂,

R₃ is selected from H and F;

R₄ is selected from SH and OH,

R₅ is selected from SH, OH and BH₃;

R₁₀ is selected from H, —

NH₂, —

Cl, —

C(═

O)NH₂, —

CN, —

CH₃, cyclopropyl, thiazolyl, pyridyl, and 2-aminothiazol-5-yl; and

R₁₁ is H.

12. The compound or the pharmaceutically acceptable salt thereof of claim 9, wherein the compound is represented by any one of the following formulae:

13. The compound or the pharmaceutically acceptable salt thereof of claim 12, wherein:

X_1a and X_1b are both H;

X_2a and X_2b are each independently selected form H, halo and C_1-4 alkyl; and

n is 0.

14. The compound or the pharmaceutically acceptable salt thereof of claim 12, wherein:

R₁₀ is selected from H, C₁, —

C(═

O)NH₂, —

CN, —

CH₃, —

CH₂—

O—

CH₃, —

NH₂, pyridyl, and thiazolyl;

X_1a and X_1b are both H;

X_2a and X_2b are independently selected from H, F and methyl;

R₄ and R₅ are independently selected from —

OH and SH;

R₂ is selected from H, F, —

OCH₃ and OH; and

(i) n is 0;

or

(ii) n is 1; and

X_3a and X_3b are F.

15. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is selected from any one of the compounds in Table 1.

16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound as defined in any one of claims 1-15, or pharmaceutically acceptable salts thereof, alone or in combination with another therapeutic agent.

17. The pharmaceutical composition of claim 16, wherein the other therapeutic agent is selected from the group consisting of an anti-cancer agent, an anti-viral compound, an antigen, an adjuvant, a lipid, a liposome, a peptide, a cytotoxic agent, a chemotherapeutic agent, an immunomodulatory cell line, a checkpoint inhibitor, a biotherapeutic agent, an immunogenic agent, and cells transfected with genes encoding immune stimulating cytokines.

18. A method of treating a disorder, disease, syndrome, or condition, wherein said disorder, disease, syndrome, or condition is affected by the agonism of STING, comprising administering to a subject in need thereof a therapeutically effective amount of the compound, or pharmaceutically acceptable salt of claims 1-15.

19. The method of claim 18, wherein said disorder, disease, syndrome, or condition is cancer.

20. The method of claim 18 wherein said disorder, disease, syndrome, or condition is bladder cancer.

21. The method of claim 18, wherein said disorder, disease, syndrome, or condition is a viral infection.

22. Use of a compound, or pharmaceutically acceptable salt of any one of claims 1-15 for the preparation of a medicament for treating a disorder, disease, syndrome, or condition selected from the group consisting of viral infection, melanoma, colon cancer, colorectal cancer, bladder cancer, breast cancer, prostate cancer, lung cancer, and fibrosarcoma, in a subject in need thereof.

23. A compound, or pharmaceutically acceptable salt of any one of claims 1-15, for use in a method for treating a disorder, disease, syndrome, or condition selected from the group consisting of viral infection, melanoma, colon cancer, colorectal cancer, bladder cancer, breast cancer, prostate cancer, lung cancer, and fibrosarcoma, in a subject in need thereof.

24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound as defined in any one of claims 1-15, or pharmaceutically acceptable salts thereof, in combination with radiation therapy.

25. The method of claim 18 wherein said disorder, disease, syndrome, or condition is colon adenocarcinoma or colorectal carcinoma.

26. The method of claim 21, wherein the viral infection is Herpes simplex virus 1.