Benzo[b]thiophene STING agonists for cancer treatment

1. A method of treating a cell-proliferation disorder, said method comprising administering to a subject in need thereof a benzo[b]thiophene STING agonist; wherein

the benzo[b]thiophene STING agonist is administered once every 3 to 28 days; and

the benzo[b]thiophene STING agonist is selected from compounds of formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein

R 1 is selected from the group consisting of H, halogen, OR 6 , N(R 6 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 1 -C 6 alkyl substituted by N(R 6 ) 2 , COOR 6 , and C(O)N(R 6 ) 2 ;

R 2 is selected from the group consisting of halogen, CN, OR 6 , N(R 6 ) 2 , COOR 6 , C(O)N(R 6 ) 2 , SO 2 R 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkenyl substituted by OR 6 , C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 2 -C 6 alkynyl substituted by OR 6 , C 3 -C 6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 );

R 3 is selected from the group consisting of halogen, CN, OR 6 , N(R 6 ) 2 , COOR 6 , C(O)N(R 6 ) 2 , SO 2 R 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkenyl substituted by OR 6 , C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 2 -C 6 alkynyl substituted by OR 6 , C 3 -C 6 cycloalkyl, and a 3- to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, N, and N(R 6 );

R 4 is selected from the group consisting of H, halogen, OR 6 , N(R 6 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 1 -C 6 alkyl substituted by N(R 6 ) 2 , COOR 6 , and C(O)N(R 6 ) 2 ;

R 5 is selected from H, halogen, OR 6 , N(R 6 ) 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , COOR 6 , and C(O)N(R 6 ) 2 ;

each R 6 is independently selected from the group consisting of H, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; X 1 is C(O);

X 2 is (C(R 8 ) 2 ) (1-3) ;

each R 8 is independently selected from the group consisting of H, halogen, C 1 -C 6 alkyl, CN, OR 6 , N(R 6 ) 2 , C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted by OR 6 , and C 1 -C 6 alkyl substituted by N(R 6 ) 2 ;

optionally 2 R 8 may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered fused ring;

optionally 2 R 8 may be taken together, along with the atoms to which they are attached, to form a 3- to 6-membered spirocycle;

X 3 is selected from the group consisting of COOR 6 , C(O)SR 6 , C(S)OR 6 , SO 2 R 6 , and C(O)N(R 9 ) 2 ; and

each R 9 is independently selected from the group consisting of H, COOR 6 , and SO 2 R 6 ;

wherein when X 1 —X 2 —X 3 is X 1 —CHR 8 —X 3 or X 1 —CHR 8 CH 2 —X 3 , at least one of R 2 and R 3 is not selected from the group consisting of halogen, OR 6 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and

at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , and R 9 is not H.

2. The method according to claim 1 , wherein the cell-proliferation disorder is cancer.

3. The method according to claim 2 , wherein the cancer occurs as one or more solid tumors or lymphomas.

4. The method according to claim 2 , wherein the cancer is selected from the group consisting of advanced or metastatic solid tumors and lymphomas.

5. The method according to claim 2 , wherein the cancer is selected from the group consisting of malignant melanoma, head and neck squamous cell carcinoma, breast adenocarcinoma, and lymphoma.

6. The method according to claim 3 , wherein the lymphoma is selected from the group consisting of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, mediastinal large B-cell lymphoma, splenic marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (malt), nodal marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, primary effusion lymphoma, Burkitt lymphoma, anaplastic large cell lymphoma (primary cutaneous type), anaplastic large cell lymphoma (systemic type), peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, adult T-cell lymphoma, nasal type extranodal NK/T-cell lymphoma, enteropathy-associated T-cell lymphoma, gamma/delta hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides, and Hodgkin lymphoma.

7. The method according to claim 2 , wherein the cell-proliferation disorder is a cancer that has metastasized.

8. The method of claim 1 , wherein the benzo[b]thiophene STING agonist is administered orally, by intravenous infusion, by intertumoral injection or by subcutaneous injection.

9. A method of treating a cell-proliferation disorder, said method comprising administering to a subject in need thereof a benzo[b]thiophene STING agonist; wherein

the benzo[b]thiophene STING agonist is administered once every 3 to 28 days; and

the benzo[b]thiophene STING agonist is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

10. The method of claim 9 , wherein the benzo[b]thiophene STING agonist is administered orally, by intravenous infusion, by intertumoral injection or by subcutaneous injection.