JPWO2019195124A5 - - Google Patents

Claims (39)

General formula (I):

[In the ceremony,
Each AR ¹ is independently selected from the group consisting of CR ¹ and N;
Here, each R ¹ is independently substituted with H, halogen, OR ⁶ , N (R ⁶ ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, OR ⁶ C _1- . Selected from the group consisting of C ₁ -C ₆ alkyl substituted with C ₆ alkyl, N (R ⁶ ) ₂ , COOR ⁶ and C (O) N (R ⁶ ) ₂ .
Each R ² is independently H, 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 alkyne substituted with OR ⁶ , C ₂ -C ₆ alkyne, C ₂ -C ₆ halo alkyne, C ₂ -C ₆ alkyne substituted with OR ⁶ , C2 _- C6 alkynyl, C2 _- C6 haloalkynyl, _C2 ^{-C6 alkynyl substituted with OR 6} _, C3 _- C6 cycloalkyl and _3- to _{6 -} membered heterocyclic ring (here). , The ring is selected from the group consisting of 1-2 ring members selected from the group consisting of O, S and N (R ⁶ );
R ³ and R ⁴ are independently O- (C ₁ -C ₄ alkylene or halo alkylene), C ₁ -C ₅ alkylene or halo alkylene and N (R ⁶ )-(C ₁ -C ₄ alkylene or halo alkylene). Selected from the group consisting of (alkylene);
Optionally, R ⁴ can be combined with adjacent CR ¹ and the atoms to which they are attached to form a fused ring E, where the ring E is phenyl or 5-membered or Selected from a 6-membered heterocyclic ring, wherein the heterocyclic ring comprises 1-2 ring members selected from the group consisting of O, S, N and N (R ⁶ ). So, the bond from ring E to R ³ is from an atom on said ring E that has an open valence for substitution, where the phenyl or heterocyclic ring is a halogen. It may be substituted with one or more members of the group consisting of C ₁ -C ₃ alkyl and C ₁ -C ₃ haloalkyl;
Each R ⁶ is independently selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl;
Each X ¹ is independently selected from the group consisting of C = O, -CH _2- , -CHF- and -CF _2- ;
Each X ² is independently selected from (C (R ⁸ ) ₂ ) _(1-3) , where each R ⁸ is independently H, halogen, C1 _{-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 with OR ⁶ and N (R ⁶ ) ₂ substituted Selected from the group consisting of C1 _- C6 _alkyls that are present;
Optionally, two ^R8s on different carbon atoms can come together to form a 3- to 6-membered fused ring with the atom to which they are bonded;
Optionally, two ^R8s on a single carbon atom can together form a 3- to 6-membered spiro ring with the atom to which they are bonded;
Each X ³ is independently COOR ⁶ , C (O) SR ⁶ , C (S) OR ⁶ ,

, SO ₂ R ⁶ , C (O) N (R ⁹ ) ₂ and CN; and selected from the group;
Each R ⁹ is independently selected from the group consisting of H, COOR ⁶ and SO ₂ R ⁶ ]
A compound represented by or a pharmaceutically acceptable salt thereof. each

But independently,

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. General formula (II):

[In the ceremony,
Each AR ¹ is independently selected from the group consisting of CR ¹ and N;
Here, each R ¹ is independently substituted with H, halogen, OR ⁶ , N (R ⁶ ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, OR ⁶ C _1- . Selected from the group consisting of C ₁ -C ₆ alkyl substituted with C ₆ alkyl, N (R ⁶ ) ₂ , COOR ⁶ and C (O) N (R ⁶ ) ₂ .
Each R ² is independently H, 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 alkyne substituted with OR ⁶ , C ₂ -C ₆ alkyne, C ₂ -C ₆ halo alkyne, C ₂ -C ₆ alkyne substituted with OR ⁶ , C2 _- C6 alkynyl, C2 _- C6 haloalkynyl, _C2 ^{-C6 alkynyl substituted with OR 6} _, C3 _- C6 cycloalkyl and _3- to _{6 -} membered heterocyclic ring (here). , The ring is selected from the group consisting of 1-2 ring members selected from the group consisting of O, S and N (R ⁶ );
R ³ and R ⁴ are independently O- (C ₁ -C ₄ alkylene or halo alkylene), C ₁ -C ₅ alkylene or halo alkylene and N (R ⁶ )-(C ₁ -C ₄ alkylene or halo alkylene). Selected from the group consisting of (alkylene);
Optionally, R ⁴ can be combined with adjacent CR ¹ and the atoms to which they are attached to form a fused ring E, where the ring E is phenyl or 5-membered or Selected from a 6-membered heterocyclic ring, wherein the heterocyclic ring comprises 1-2 ring members selected from the group consisting of O, S, N and N (R ⁶ ). So, the bond from ring E to R ³ is from an atom on said ring E that has an open valence for substitution, where the phenyl or heterocyclic ring is a halogen. It may be substituted with one or more members of the group consisting of C ₁ -C ₃ alkyl and C ₁ -C ₃ haloalkyl;
Each R ⁶ is independently selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl;
Each X ¹ is independently selected from the group consisting of C = O, -CH _2- , -CHF- and -CF _2- ;
Each X ² is independently selected from (C (R ⁸ ) ₂ ) _(1-3) , where each R ⁸ is independently H, halogen, C1 _{-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 with OR ⁶ and N (R ⁶ ) ₂ substituted Selected from the group consisting of C1 _- C6 _alkyls that are present;
Optionally, two ^R8s on different carbon atoms can come together to form a 3- to 6-membered fused ring with the atom to which they are bonded;
Optionally, two ^R8s on a single carbon atom can together form a 3- to 6-membered spiro ring with the atom to which they are bonded;
Each X ³ is independently COOR ⁶ , C (O) SR ⁶ , C (S) OR ⁶ ,

, SO ₂ R ⁶ , C (O) N (R ⁹ ) ₂ and CN; and selected from the group;
Each R ⁹ is independently selected from the group consisting of H, COOR ⁶ and SO ₂ R ⁶ ]
A compound represented by or a pharmaceutically acceptable salt thereof. each

But independently,

The compound according to claim 3 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. General formula (III):

[In the ceremony,
Each AR ¹ is independently selected from the group consisting of CR ¹ and N;
Here, each R ¹ is independently substituted with H, halogen, OR ⁶ , N (R ⁶ ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, OR ⁶ C _1- . Selected from the group consisting of C ₁ -C ₆ alkyl substituted with C ₆ alkyl, N (R ⁶ ) ₂ , COOR ⁶ and C (O) N (R ⁶ ) ₂ .
Each R ² is independently H, 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 alkyne substituted with OR ⁶ , C ₂ -C ₆ alkyne, C ₂ -C ₆ halo alkyne, C ₂ -C ₆ alkyne substituted with OR ⁶ , C2 _- C6 alkynyl, C2 _- C6 haloalkynyl, _C2 ^{-C6 alkynyl substituted with OR 6} _, C3 _- C6 cycloalkyl and _3- to _{6 -} membered heterocyclic ring (here). , The ring is selected from the group consisting of 1-2 ring members selected from the group consisting of O, S and N (R ⁶ );
R ³ and R ⁴ are independently O- (C ₁ -C ₄ alkylene or halo alkylene), C ₁ -C ₅ alkylene or halo alkylene and N (R ⁶ )-(C ₁ -C ₄ alkylene or halo alkylene). Selected from the group consisting of (alkylene);
Optionally, R ³ can be combined with adjacent CR ¹ and the atoms to which they are attached to form a fused ring G, where the ring G is phenyl or 5-membered or Selected from a 6-membered heterocyclic ring, wherein the heterocyclic ring comprises 1-2 ring members selected from the group consisting of O, S, N and N (R ⁶ ). And the bond from the ring G to R ³ is from an atom on the ring G that has an open valence for substitution, where the phenyl or heterocyclic ring is a halogen. It may be substituted with one or more members of the group consisting of C ₁ -C ₃ alkyl and C ₁ -C ₃ haloalkyl;
Optionally, R ⁴ can be combined with adjacent CR ¹ and the atoms to which they are attached to form a fused ring E, where the ring E is phenyl or 5-membered or Selected from a 6-membered heterocyclic ring, wherein the heterocyclic ring comprises 1-2 ring members selected from the group consisting of O, S, N and N (R ⁶ ). So, the bond from ring E to ^R4 is from an atom on said ring E that has an open valence for substitution, where the phenyl or heterocyclic ring is a halogen. It may be substituted with one or more members of the group consisting of C ₁ -C ₃ alkyl and C ₁ -C ₃ haloalkyl;
Each R ⁶ is independently selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl;
Each X ¹ is independently selected from the group consisting of C = O, -CH _2- , -CHF- and -CF _2- ;
Each X ² is independently selected from (C (R ⁸ ) ₂ ) _(1-3) , where each R ⁸ is independently H, halogen, C1 _{-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 with OR ⁶ and N (R ⁶ ) ₂ substituted Selected from the group consisting of C1 _- C6 _alkyls that are present;
Optionally, two ^R8s on different carbon atoms can come together to form a 3- to 6-membered fused ring with the atom to which they are bonded;
Optionally, two ^R8s on a single carbon atom can together form a 3- to 6-membered spiro ring with the atom to which they are bonded;
Each X ³ is independently COOR ⁶ , C (O) SR ⁶ , C (S) OR ⁶ ,

, SO ₂ R ⁶ , C (O) N (R ⁹ ) ₂ and CN; and selected from the group;
Each R ⁹ is independently selected from the group consisting of H, COOR ⁶ and SO ₂ R ⁶ ]
A compound represented by or a pharmaceutically acceptable salt thereof.

But independently,

Selected from a group of, and

but,

The compound according to claim 5 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. General formula (IV):

[In the ceremony,
Each AR ¹ is independently selected from the group consisting of CR ¹ and N;
Here, each R ¹ is independently substituted with H, halogen, OR ⁶ , N (R ⁶ ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, OR ⁶ C _1- . Selected from the group consisting of C ₁ -C ₆ alkyl substituted with C ₆ alkyl, N (R ⁶ ) ₂ , COOR ⁶ and C (O) N (R ⁶ ) ₂ .
Each R ² is independently H, 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 alkyne substituted with OR ⁶ , C ₂ -C ₆ alkyne, C ₂ -C ₆ halo alkyne, C ₂ -C ₆ alkyne substituted with OR ⁶ , C2 _- C6 alkynyl, C2 _- C6 haloalkynyl, _C2 ^{-C6 alkynyl substituted with OR 6} _, C3 _- C6 cycloalkyl and _3- to _{6 -} membered heterocyclic ring (here). , The ring is selected from the group consisting of 1-2 ring members selected from the group consisting of O, S and N (R ⁶ );
R ³ and R ⁴ are independently O- (C ₁ -C ₄ alkylene or halo alkylene), C ₁ -C ₅ alkylene or halo alkylene and N (R ⁶ )-(C ₁ -C ₄ alkylene or halo alkylene). Selected from the group consisting of (alkylene);
Each R ⁶ is independently selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl;
Each X ¹ is independently selected from the group consisting of C = O, -CH _2- , -CHF- and -CF _2- ;
Each X ² is independently selected from (C (R ⁸ ) ₂ ) _(1-3) , where each R ⁸ is independently H, halogen, C1 _{-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 with OR ⁶ and N (R ⁶ ) ₂ substituted Selected from the group consisting of C1 _- C6 _alkyls that are present;
Optionally, two ^R8s on different carbon atoms can come together to form a 3- to 6-membered fused ring with the atom to which they are bonded;
Optionally, two ^R8s on a single carbon atom can together form a 3- to 6-membered spiro ring with the atom to which they are bonded;
Each X ³ is independently COOR ⁶ , C (O) SR ⁶ , C (S) OR ⁶ ,

, SO ₂ R ⁶ , C (O) N (R ⁹ ) ₂ and CN; and selected from the group;
Each R ⁹ is independently selected from the group consisting of H, COOR ⁶ and SO ₂ R ⁶ ]
A compound represented by or a pharmaceutically acceptable salt thereof.

But independently,

Selected from a group of, and

but,

The compound according to claim 7 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. General formula (V):

[In the ceremony,
Each AR ¹ is independently selected from the group consisting of CR ¹ and N;
Here, each R ¹ is independently substituted with H, halogen, OR ⁶ , N (R ⁶ ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, OR ⁶ C _1- . Selected from the group consisting of C ₁ -C ₆ alkyl substituted with C ₆ alkyl, N (R ⁶ ) ₂ , COOR ⁶ and C (O) N (R ⁶ ) ₂ .
R ³ and R ⁴ are independently O- (C ₁ -C ₄ alkylene or halo alkylene), C ₁ -C ₅ alkylene or halo alkylene and N (R ⁶ )-(C ₁ -C ₄ alkylene or halo alkylene). Selected from the group consisting of (alkylene);
Each X ¹ is independently selected from the group consisting of C = O, -CH _2- , -CHF- and -CF _2- ;
Each X ² is independently selected from (C (R ⁸ ) ₂ ) _(1-3) , where each R ⁸ is independently H, halogen, C1 _{-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 with OR ⁶ and N (R ⁶ ) ₂ substituted Selected from the group consisting of C1 _- C6 _alkyls that are present;
Optionally, two ^R8s on different carbon atoms can come together to form a 3- to 6-membered fused ring with the atom to which they are bonded;
Optionally, two ^R8s on a single carbon atom can together form a 3- to 6-membered spiro ring with the atom to which they are bonded;
Each X ³ is independently COOR ⁶ , C (O) SR ⁶ , C (S) OR ⁶ ,

, SO ₂ R ⁶ , C (O) N (R ⁹ ) ₂ and CN; and selected from the group;
Each R ⁹ is independently selected from the group consisting of H, COOR ⁶ and SO ₂ R ⁶ ]
A compound represented by or a pharmaceutically acceptable salt thereof. each

But independently,

The compound according to claim 9 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. General formula (VI):

[In the ceremony,
Each AR ¹ is independently selected from the group consisting of CR ¹ and N;
Here, each R ¹ is independently substituted with H, halogen, OR ⁶ , N (R ⁶ ) ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, OR ⁶ C _1- . Selected from the group consisting of C ₁ -C ₆ alkyl substituted with C ₆ alkyl, N (R ⁶ ) ₂ , COOR ⁶ and C (O) N (R ⁶ ) ₂ .
R ³ and R ⁴ are independently O- (C ₁ -C ₄ alkylene or halo alkylene), C ₁ -C ₅ alkylene or halo alkylene and N (R ⁶ )-(C ₁ -C ₄ alkylene or halo alkylene). Selected from the group consisting of (alkylene);
Each R ⁶ is independently selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₁ -C ₆ haloalkyl;
Each X ¹ is independently selected from the group consisting of C = O, -CH _2- , -CHF- and -CF _2- ;
Each X ² is independently selected from (C (R ⁸ ) ₂ ) _(1-3) , where each R ⁸ is independently H, halogen, C1 _{-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 with OR ⁶ and N (R ⁶ ) ₂ substituted Selected from the group consisting of C1 _- C6 _alkyls that are present;
Optionally, two ^R8s on different carbon atoms can come together to form a 3- to 6-membered fused ring with the atom to which they are bonded;
Optionally, two ^R8s on a single carbon atom can together form a 3- to 6-membered spiro ring with the atom to which they are bonded;
Each X ³ is independently COOR ⁶ , C (O) SR ⁶ , C (S) OR ⁶ ,

, SO ₂ R ⁶ , C (O) N (R ⁹ ) ₂ and CN; and selected from the group;
Each R ⁹ is independently selected from the group consisting of H, COOR ⁶ and SO ₂ R ⁶ ]
A compound represented by or a pharmaceutically acceptable salt thereof. each

But independently,

The compound according to claim 11 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. or below

And compounds selected from the group consisting of pharmaceutically acceptable salts thereof. The pharmaceutical composition comprising the compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical agent for inducing an immune response in a subject. The pharmaceutical composition of claim 14, which is for inducing an immune response in a subject. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of a drug for inducing STING-dependent type I interferon production in a subject. The pharmaceutical composition according to claim 14, which is for inducing STING-dependent type I interferon production in a subject. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical agent for treating a cell proliferative disease in a subject. The use according to claim 19, wherein the cell proliferation disease is cancer. The pharmaceutical composition according to claim 14, which is for the treatment of a cell proliferative disease in a subject. The pharmaceutical composition according to claim 21, wherein the cell proliferation disease is cancer. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for use in therapy. The compound according to any one of claims 1 to 13 for use in the treatment of cell proliferative disorders in a subject or a pharmaceutically acceptable salt thereof, the use of which is a therapeutically effective amount for the subject. A compound comprising administering the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof. A compound for use according to claim 24 or a pharmaceutically acceptable salt thereof, wherein the cell proliferation disease is cancer. The pharmaceutical composition according to claim 14 for use in the treatment of cell proliferative disorders in a subject, wherein the use comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 14. Including, pharmaceutical composition. The pharmaceutical composition for use according to claim 26, wherein the cell proliferation disease is cancer.

And a compound selected from the group consisting of pharmaceutically acceptable salts thereof. The compound is

28. The compound according to claim 28.

And a compound selected from the group consisting of pharmaceutically acceptable salts thereof. The compound is

The compound according to claim 30.

And a compound selected from the group consisting of pharmaceutically acceptable salts thereof. The compound is

32. The compound according to claim 32.

And a compound selected from the group consisting of pharmaceutically acceptable salts thereof. The compound is

The compound according to claim 34.

And a compound selected from the group consisting of pharmaceutically acceptable salts thereof. The compound is

36. The compound according to claim 36.

And a compound selected from the group consisting of pharmaceutically acceptable salts thereof. The compound is

38. The compound according to claim 38.