Compounds and compositions for treating diseases associated with STING activity

文档序号：473789 发布日期：2021-12-31 浏览：9次中文

阅读说明：本技术 用于治疗与sting活性有关的疾病的化合物和组合物 (Compounds and compositions for treating diseases associated with STING activity ) 是由 H·M·塞德尔 W·R·劳世 S·范卡彻曼于 2020-01-16 设计创作，主要内容包括：本发明提供了抑制(例如拮抗)干扰素基因刺激物(STING)的化学实体(例如化合物或药学上可接受的盐和/或水合物和/或共晶体和/或化合物的药物组合)。所述化学实体可用于例如治疗其中STING活化(例如,STING信号转导)增加(例如,过度)导致对象(例如人)的病状、疾病或病症(例如癌症)的病态/或症状和/或进展的病状、疾病或病症。本发明还提供了包含该化学实体的组合物以及使用和制备该组合物的方法。(The present invention provides chemical entities (e.g., compounds or pharmaceutically acceptable salts and/or hydrates and/or co-crystals and/or pharmaceutical combinations of compounds) that inhibit (e.g., antagonize) interferon gene Stimulator (STING). The chemical entities are useful, for example, in treating conditions, diseases or disorders in which increased (e.g., excessive) STING activation (e.g., STING signaling) results in the pathology, morbidity/symptoms and/or progression of a disease or disorder (e.g., cancer) in a subject (e.g., a human). The invention also provides compositions comprising the chemical entities and methods of using and making the compositions.)

1. A method of inhibiting STING activity, comprising contacting STING with a compound of formula I:

wherein:

L^ABis-N (R)^N)S(O)₂-*，-N(R^N)S(O)₂-(W^AB1-W^AB2-W^AB3)-*，–S(O)₂N(R^N)-*，

Wherein the asterisks indicate the points of attachment to B;

W^AB1is C_1-3Alkylene optionally substituted with 1-4 independently selected R^aSubstitution;

W^AB2is a bond, -O-, -NR-^Nor-S-;

W^AB3is a bond or C_1-3Alkylene optionally substituted with 1-4 independently selected R^aSubstitution;

a is selected from the following group:

(i) heteroaryl comprising 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)¹)、N(R²) O, and S, and wherein 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of: C. CH, CR¹And CR³With the proviso that at least one ring atom is replaced by R¹Substitution; and

(ii) heteroaryl comprising 7 to 20 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)¹)、N(R²) O and S (O)_0-2And wherein 3 to 19 ring atoms are carbon atoms, each independently selected from the group consisting of: C. CH, CH₂、CR¹、CHR¹、C(R¹)₂、CR³、CHR³And C (R)³)₂；

B is:

(a)C_1-15alkyl optionally substituted with 1-6R^aSubstitution;

(b)C_3-20cycloalkyl optionally substituted with 1-4R^bSubstitution;

(c)C_6-20aryl optionally substituted with 1-4R^cSubstitution;

(d) heteroaryl group comprising 5 to 20 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N (H), N (R)^d) O, and S (O)_0-2And wherein said heteroaryl ring is optionally substituted with 1-4 independently selected R^cSubstitution; or

(e) Heterocyclyl comprising 3 to 16 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n (H), N (R)^d) O and S (O)_0-2And wherein said heterocyclyl ring is optionally substituted with 1-4 independently selected R^bSubstitution;

R^Nthe method comprises the following steps:

(i) h, or

(ii)C_1-6Alkyl, optionally substituted with 1-3R^aThe substitution is carried out by the following steps,

R¹the method comprises the following steps:

(i)-(U¹)_q-U²wherein:

q is 0 or 1;

·U¹is C_1-6Alkylene optionally substituted by 1 to 6R^aSubstitution; and

·U²the method comprises the following steps:

(a)C_3-12cycloalkyl optionally substituted with 1-4R^bThe substitution is carried out by the following steps,

(b)C_6-10aryl optionally substituted with 1-4R^cSubstitution;

(c) heteroaryl group comprising 5 to 20 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N (H), N (R)^d)、O，S(O)_0-2And wherein said heteroaryl ring is optionally substituted with 1-4 independently selected R^cIs substituted, or

(d) Heterocyclyl comprising 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)^d) O and S (O)_0-2And wherein said heterocyclyl ring is optionally substituted1-4 independently selected R^bThe substitution is carried out by the following steps,

(ii)C_1-10Alkyl optionally substituted with 1-6 independently selected R^aSubstitution;

each occurrence of R²Independently selected from the group consisting of:

(i)C_1-6alkyl optionally substituted with 1-2 independently selected R^aSubstitution;

(ii)C_3-6a cycloalkyl group;

(iii) heterocyclyl comprising 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)^d) O and S (O)_0-2，

(iv)-C(O)(C_1-4Alkyl groups);

(v)-C(O)O(C_1-4alkyl groups);

(vi)-CON(R’)(R”)；

(vii)-S(O)_1-2(NR’R”)；

(viii)-S(O)_1-2(C_1-4alkyl groups);

(ix) -OH; and

(x)C_1-4an alkoxy group;

each occurrence of R³Independently selected from the group consisting of: halogen, cyano, optionally substituted by 1-2R^aSubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, -S (O)_1-2(C_1-4Alkyl), -NR^eR^f-OH, oxo, -S (O)_1-2(NR’R”)，-C_1-4Thioalkoxy, -NO₂，-C(＝O)(C_1-4Alkyl group, -C (═ O) O (C)_1-4Alkyl, -C (═ O) OH and-C (═ O) N (R') (R ");

each occurrence of R^aIndependently selected from the group consisting of: -OH; -F; -Cl; -Br; -NR^eR^f；C_1-4An alkoxy group; c_1-4A haloalkoxy group; -C (═ O) O (C)_1-4Alkyl groups); -C (═ O) (C)_1-4Alkyl groups); -C (═ O) OH; -CON (R') (R "); -S (O)_1-2(NR’R”)；-S(O)_1-2(C_1-4Alkyl groups); a cyano group; and C_3-6Cycloalkyl optionally substituted by 1-4 independently selected C_1-4Alkyl substitution;

each occurrence of R^bIndependently selected from the group consisting of: optionally substituted with 1-6 independently selected R^aSubstituted C_1-10An alkyl group; c_1-4A haloalkyl group; -OH; oxo; -F; -Cl; -Br; -NR^eR^f；C_1-4An alkoxy group; c_1-4A haloalkoxy group; -C (═ O) (C)_1-4Alkyl groups); -C (═ O) O (C)_1-4Alkyl groups); -C (═ O) OH; -C (═ O) N (R') (R "); -S (O)_1-2(NR’R”)；-S(O)_1-2(C_1-4Alkyl groups); a cyano group; and-L¹-L²-R^h；

Each occurrence of R^cIndependently selected from the group consisting of:

(a) halogen;

(b) a cyano group;

(c)C_1-15alkyl optionally substituted with 1-6 independently selected R^aSubstitution;

(d)C_2-6an alkenyl group;

(e)C_2-6an alkynyl group;

(g)C_1-4alkoxy, optionally substituted with 1-3 independently selected R^aSubstitution;

(h)C_1-4a haloalkoxy group;

(i)-S(O)_1-2(C_1-4alkyl groups);

(j)-NR^eR^f；

(k)–OH；

(l)-S(O)_1-2(NR’R”)；

(m)-C_1-4a thioalkoxy group;

(n)-NO₂；

(o)-C(＝O)(C_1-4alkyl groups);

(p)-C(＝O)O(C_1-4alkyl groups);

(q)-C(＝O)OH；

(R) -C (═ O) N (R') (R "); and

(s)–L¹-L²-R^h；

R^dselected from the group consisting of: c_1-6An alkyl group; c_3-6A cycloalkyl group; -C (O) (C)_1-4Alkyl groups); -C (O) O (C)_1-4Alkyl groups); -CON (R') (R "); -S (O)_1-2(NR’R”)；-S(O)_1-2(C_1-4Alkyl groups); -OH; and C_1-4An alkoxy group;

each occurrence of R^eAnd R^fIndependently selected from the group consisting of: h; c_1-6An alkyl group; c_1-6A haloalkyl group; c_3-6A cycloalkyl group; -C (O) (C)_1-4Alkyl groups); -C (O) O (C)_1-4Alkyl groups); -CON (R') (R "); -S (O)_1-2(NR’R”)；-S(O)_1-2(C_1-4Alkyl groups); -OH; and C_1-4An alkoxy group; or R^eAnd R^fTogether with the nitrogen atom to which they are each attached form a ring comprising 3 to 8 ring atoms, wherein the ring comprises: (a)1-7 ring carbon atoms, each carbon atom being independently selected from H and C by 1-2_1-3Alkyl substituent substitution; (b)0-3 ring heteroatoms (other than the nitrogen atom to which R 'and R' are attached), each independently selected from N (R)^d) NH, O and S;

-L¹is a bond or C_1-3An alkylene group;

-L²is-O-, -N (H) -, -S-or a bond;

R^hselected from:

·C_3-8cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl and C_1-4Haloalkyl (in some embodiments, with the proviso that when R is^hIs C optionally selected from 1 to 4 independently_1-4Alkyl substituted C_3-6When cycloalkyl is, -L¹Is a bond, or-L²is-O-, -N (H) -or-S-;

a heterocyclyl group, wherein said heterocyclyl group comprises 3 to 16 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)^d) O and S (O)_0-2Wherein said heterocyclyl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl and C_1-4Haloalkyl group；

Heteroaryl comprising 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)^d) O and S (O)_0-2And wherein said heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl and C_1-4A haloalkyl group; and

·C_6-10aryl optionally substituted with 1-4 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl or C_1-4A haloalkyl group; and

each occurrence of R 'and R' is independently selected from the group consisting of: H. c_1-4Alkyl and C_6-10Aryl, optionally substituted by a halogen atom, C_1-4Alkyl and C_1-41-2 substituents of haloalkyl; or R' and R "together with the nitrogen atom to which they are each attached form a ring comprising 3 to 8 ring atoms, wherein the ring comprises: (a)1-7 ring carbon atoms, each carbon atom being independently selected from H and C by 1-2_1-3Alkyl substituent substitution; (b)0-3 ring heteroatoms (other than the nitrogen atom to which R 'and R' are attached), each independently selected from the group consisting of: n (H), N (R)^d) O and S.

2. The method of claim 1, wherein a is: heteroaryl comprising 7 to 20 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)¹)、N(R²) O and S (O)_0-2And wherein 3 to 19 ring atoms are carbon atoms, each independently selected from the group consisting of: C. CH, CH₂、CR¹、CHR¹、C(R¹)₂、CR³、CHR³And C (R)³)2。

3. The method of any one of claims 1-2, wherein A is: heteroaryl comprising 8 to 12 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)¹)、N(R²) O and S (O)_0-2And wherein 4 to 11 ring atoms are carbon atoms,each independently selected from the group consisting of: C. CH, CH₂、CR¹、CHR¹、C(R¹)₂、CR³、CHR³And C (R)³)₂。

4. The method of any one of claims 1-3, wherein A is: heteroaryl comprising 8 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)¹)、N(R²) O and S (O)_0-2And wherein 4 to 9 ring atoms are carbon atoms, each independently selected from the group consisting of: C. CH, CH₂、CR¹、CHR¹、C(R¹)₂、CR³、CHR³And C (R)³)₂。

5. The method of any one of claims 1-4, wherein A is: heteroaryl comprising 8 to 9 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)¹)、N(R²) O and S (O)_0-2And wherein 4 to 8 ring atoms are carbon atoms, each independently selected from the group consisting of: C. CH, CH₂、CR¹、CHR¹、C(R¹)₂、CR³、CHR³And C (R)³)₂。

6. The method of any one of claims 1 to 5, wherein A is (A-1):

wherein

Z is selected from the group consisting of:

bond, CH, CR¹、CR³、N、NH、N(R¹) And N (R)²)；

Y¹、Y²And Y³Each independently selected from the group consisting of: o, S, CH, CR¹、CR³、N、NH、N(R¹) And NR²；

Y⁴Is C or N;

X¹selected from the group consisting of: o, S, N, NH, NR¹、NR²、CH、CR¹And CR³；

X²Selected from the group consisting of: o, S, N, NH, NR¹、NR²、CH、CR¹And CR³(ii) a And

each one ofIndependently a single or double bond, provided that Y is comprised⁴、X¹And X²The five-membered ring of (a) is heteroaryl; and comprises Z, Y¹、Y²、Y³And Y⁴Is aromatic (i.e., aromatic carbocyclic or heterocyclic).

7. The method of claim 6, wherein Z is independently selected from the group consisting of:

CH、CR¹、CR³n and N (R)²)。

8. The method of any one of claims 6-7, wherein Z is selected from: CH. CR¹、CR³And N.

9. The method of any one of claims 6-8, wherein Z is selected from: CH. CR¹And CR³(e.g., Z is CH).

10. The method of any one of claims 6-9, wherein Y is¹、Y²And Y³Each independently selected from: CH. CR¹、CR³And N.

11. Such as rightThe method of any one of claims 6-10, wherein Y is¹、Y²And Y³Each independently selected from the group consisting of: CH. CR¹And CR³。

12. The method of any one of claims 6-11, whereinIs partially

Wherein m1 is 0, 1,2 or 3; and m3 ═ 0, 1,2, or 3 (e.g., m1 ═ 0 or 1; and m3 ═ 0, 1, or 2).

13. The method of any one of claims 6-10, wherein 1-2Y¹、Y²And Y³Independently is N.

14. The method of any one of claims 6-10 and 13, wherein one Y¹、Y²And Y³Independently is N.

15. The method of claim 14, wherein the remaining Y¹、Y²And Y³Each independently selected from CH and CR¹And CR³。

16. The method of any of claims 6-10, and 13-15, wherein the method is performed in a batch processIs partiallyWherein:

asterisk indicates Y⁴A point of connection; and is

m1 is 0, 1 or 2; and m3 ═ 0, 1, or 2 (e.g., m1 ═ 0 or 1; and m3 ═ 0 or 1).

17. The method of any one of claims 1-16, wherein Y is⁴Is C.

18. The method of any one of claims 1-17, wherein X¹Selected from: o, S, NH, NR¹And NR²。

19. The method of any one of claims 1-18, wherein X¹Selected from the group consisting of: NH, NR¹And NR²(e.g., X)¹May be NH).

20. The method of any one of claims 1-19, wherein X²Selected from the group consisting of: n, CH, CR¹And CR³。

21. The method of any one of claims 1-20, wherein X²Selected from the group consisting of: n, C (C)_1-3Alkyl) and CH.

22. The method of any one of claims 1-21, wherein X²Is CH.

23. The method of any one of claims 1-22, X¹And X²Together areWherein the asterisks indicate⁴The point of connection.

24. The method of any one of claims 1-12 and 17-23, wherein a is:

wherein m1 is 0, 1,2 or 3; and m3 ═ 0, 1,2, or 3 (e.g., m1 ═ 0 or 1; and m3 ═ 0, 1, or 2).

25. The method of any one of claims 1-10 and 13-16, wherein a is

Wherein m1 is 0, 1 or 2; and m3 ═ 0, 1, or 2 (e.g., m1 ═ 0 or 1; and m3 ═ 0 or 1).

26. The method of any one of claims 1-2, wherein a is (a-2):

wherein

Ring A^3AIs monocyclic or bicyclic containing 5 to 12 ring atoms, of which 0 to 2 are heteroatoms (when Y is⁴When N is Y⁴) Wherein each additional heteroatom is independently selected from the group consisting of: n, N (H), N (R)¹)、N(R²) O and S (O)_0-2And 3-12 are ring carbon atoms, each independently selected from: C. CH, CH₂、CR¹、CHR¹、C(R¹)₂、CR³、CHR³And C (R)³)₂Provided that ring A^3AIs non-aromatic;

X¹selected from the group consisting of: o, S, N, NH, NR¹、NR²、CH、CR¹And CR³；

X²Selected from the group consisting of: o, S, N, NH, NR¹、NR²、CH、CR¹And CR³(ii) a Provided that Y is contained⁴、X¹And X²The ring(s) of (a) is heteroaromatic; and

Y⁴selected from: n or C.

27. The method of claim 26, wherein Y is⁴Is N.

28. The method of claim 27, wherein ring a^3AIs a monocyclic or bicyclic ring containing 5 to 11 ring atoms, of which 1 to 2 are heteroatoms (including Y)⁴) Wherein the additional heteroatoms are independently selected from N, N (H), N (R)¹)、N(R²) O, and S (O)_0-2And 3-11 are ring carbon atoms, each independently selected from: C. CH, CH₂、CR¹、CHR¹、C(R¹)₂、CR³、CHR³And C (R)³)₂Provided that ring A^3AIs non-aromatic.

29. The method of claim 28, wherein ring a^3AIs a monocyclic or bicyclic ring containing 5 to 11 ring atoms, of which 2 are heteroatoms (including Y)⁴) Wherein the additional heteroatoms are independently selected from N, N (H), N (R)¹)、N(R²) O, and S (O)_0-2And 3-11 are ring carbon atoms, each independently selected from: C. CH, CH₂、CR¹、CHR¹、C(R¹)₂、CR³、CHR³And C (R)³)₂Provided that ring A^3AIs non-aromatic.

30. The method of claim 28, wherein ring a^3AIs bicyclic (e.g., helical bicyclic) at Y⁴No further heteroatoms are included.

31. The method of claim 30, wherein a is:

wherein m1 is 0, 1 or 2; and m3 ═ 0, 1, or 2 (e.g., m1 ═ 0 or 1; and m3 ═ 0 or 1).

32. The method of claim 29, wherein ring a^3AIs a monocyclic ring containing an O atom.

33. The method of claim 32, wherein a is:

wherein m1 is 0, 1 or 2; and m3 ═ 0, 1, or 2 (e.g., m1 ═ 0 or 1; and m3 ═ 0 or 1).

34. The method of any one of claims 26-33, wherein X¹Is N.

35. The method of any one of claims 26-34, wherein X²Selected from CH and CR¹(e.g., CH).

36. The method of claim 1, wherein a is heteroaryl comprising 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)¹)、N(R²) O, and S, and wherein 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of: C. CH, CR¹And CR³With the proviso that at least one ring atom is replaced by R¹And (4) substitution.

37. The method of claim 36, wherein a is heteroaryl comprising 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)¹)、N(R²) O and S, and wherein 1 to 4 ring atoms are carbon atoms, each independently selected from the group consisting of: C. CH, CR¹And CR^3.With the proviso that at least one ring atom is replaced by R¹And (4) substitution.

38. The method of any one of claims 36-37, wherein a is heteroaryl comprising 5 ring atoms, wherein 1-4 ring atoms are heteroatoms each independently selected fromThe following groups: n, N (H), N (R)¹)、N(R²) O and S, and wherein 1 to 4 ring atoms are carbon atoms, each independently selected from the group consisting of: C. CH, CR¹And CR³Provided that one ring atom is substituted by 1R¹And (4) substitution.

39. The method of any one of claims 1 and 36-38, wherein a is (a-3):

wherein:

Z²selected from: CH. R²And N;

X³selected from: o, S, N, NH, NR¹、NR²、CH、CR¹And CR³；

Y⁵And Y⁶Each independently selected from O, S, CH, CR¹、CR³、NR²NH and N; and

each one of which isIndependently is a single or double bond, provided that Y is comprised⁵、Y⁶、X³And Z²The five-membered ring of (a) is heteroaryl.

40. The method of claim 39, wherein:

when X is present³Is NR¹Or CR¹When, Y⁵And Y⁶Each independently selected from O, S, CH, CR³、NR²NH and N; and

when X is present³Selected from O, S, N, NH, NR²CH and CR³When, Y⁵And Y⁶Is CR¹(in some embodiments, Y⁵And Y⁶Another one of the groups is selected from O, S, CH, CR³、NR²NH and N).

41. The method of any one of claims 39-40, wherein Z²Selected from CH and N.

42. The method of any one of claims 39-41, wherein Z²Is CH.

43. The method of any one of claims 39-42, wherein Y is⁶Selected from: n, CH and CR³。

44. The method of any one of claims 39-43, wherein Y is⁶Is N.

45. The method of any one of claims 39-44, wherein Y is⁵Is CR¹。

46. The method of any one of claims 39-45, wherein X³Selected from S, O, NH and N (R)²) (e.g., NH).

47. The method of any one of claims 39-46, wherein A is

48. The method of any one of claims 1-47, wherein each occurrence of R¹Independently selected from:

(i)-(U¹)_q-U²wherein:

q is 0 or 1;

·U¹is C_1-6Alkylene optionally substituted by 1 to 6R^aSubstitution; and

·U²the method comprises the following steps:

(a)C_3-10cycloalkyl optionally substituted with 1-4R^bThe substitution is carried out by the following steps,

(b)C_6-10aryl optionally substituted with 1-4R^cSubstitution;

(c) heteroaryl group comprising 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N (H), N (R)^d) O, S, and S (O)₂And wherein said heteroaryl ring is optionally substituted with 1-4 independently selected R^cIs substituted, or

(d) (ii) heterocyclyl comprising 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)^d) And O, and wherein said heterocyclyl ring is optionally substituted with 1-4 independently selected R^bSubstituted, and

(ii)C_1-6alkyl optionally substituted with 1-6 independently selected R^aAnd (4) substitution.

49. The method of any one of claims 1-48, wherein R¹Is- (U)¹)_q-U²。

50. The method of any one of claims 1-49, wherein q is 0.

51. The method of any one of claims 1-50, wherein U is²Is C_6-10Aryl optionally substituted with 1-4R^cAnd (4) substitution.

52. The method of any one of claims 1-51, wherein U is²Is C_6-10Aryl optionally substituted with 1-2R^cAnd (4) substitution.

53. The method of any one of claims 1-52, wherein U is⁴Is phenyl, optionally substituted with 1-2 (e.g., 1) R^cAnd (4) substitution.

54. The method of any one of claims 51-53, wherein each occurrence of U is detected by a detector²R of (A) to^cThe substituents are independently selected from: halogen, cyano, C_1-6Alkyl and C_1-4A haloalkyl group.

55. The method of any one of claims 51-54, wherein each occurrence of U is detected by a detector²R of (A) to^cThe substituents are independently selected from halogen.

56. The method of any one of claims 1-55, wherein R¹Is phenyl optionally substituted with 1-2 (e.g., 0; e.g., 1) R^cAnd (4) substitution.

57. The method of claim 56, wherein R^cEach as defined in any one of claims 54 to 55.

58. The method of any one of claims 1-57, wherein each occurrence of R³Independently selected from the group consisting of: halogen, cyano, C_1-4Alkoxy radical, C_1-4Haloalkoxy, -S (O)_1-2(C_1-4Alkyl), -NR^eR^f，–OH，-S(O)_1-2(NR’R”)，-C_1-4Thioalkoxy, -C (═ O) (C)_1-4Alkyl group, -C (═ O) O (C)_1-4Alkyl, -C (═ O) OH and-C (═ O) N (R') (R ").

59. The method of any one of claims 1-58, wherein each occurrence of R³Independently selected from the group consisting of: halogen, cyano, C_1-4Alkoxy radical, C_1-4Haloalkoxy, -S (O)_1-2(C_1-4Alkyl group, -S (O)_1-2(NR’R”)，-C(＝O)(C_1-4Alkyl group, -C (═ O) O (C)_1-4Alkyl, -C (═ O) OH and-C (═ O) N (R') (R ").

60. The method of any one of claims 1-59, wherein each occurrence of R³Independently selected from the group consisting of: halogen, cyano, C_1-4Alkoxy and C_1-4Haloalkoxy (e.g., R)³May be a halogen).

61. The method of any one of claims 1-60, wherein each occurrence of R²Independently selected from:

(i)C_1-6alkyl (e.g., methyl);

(ii)C_3-6a cycloalkyl group;

(iv)-C(O)(C_1-4alkyl) (e.g., c (o) Me);

(v)-C(O)O(C_1-4alkyl groups);

(vi)-CON(R’)(R”)；

(vii)-S(O)_1-2(NR' R "); and

(viii)-S(O)_1-2(C_1-4alkyl) (e.g., S (O)₂Me)。

62. The method of any one of claims 12, 16, 24, 25, 31, and 33, wherein m1 is 1.

63. The method of claim 62, wherein m 3-0.

64. The method of any one of claims 62-63, wherein R¹As defined in any one of claims 48 to 57.

65. The method of any one of claims 12, 16, 24, 25, 31, and 33, wherein m1 is 0.

66. The method of claim 65, wherein m 3-0.

67. The method of claim 65, wherein m3 is 1 or 2 (e.g., 1).

68. The method of claim 67, wherein each occurrence of R^cAs defined in any one of claims 58 to 60.

69. The method of claim 68, wherein each occurrence of R^aIndependently of one another, halogen (e.g. halogen)Such as F).

70. The method of any one of claims 1-69, wherein B is substituted with 1-4R^cA substituted phenyl group.

71. The method of any one of claims 1-70, wherein B is substituted with 1-2R^cSubstituted phenyl, wherein 1R^cIn formula I to link L^ABA ring carbon para to a point of the moiety.

72. The method of any one of claims 1-71, wherein B is substituted with 1R^cSubstituted phenyl, wherein 1R^cIn formula I to link L^ABA ring carbon para to a point of the moiety.

73. The method of any one of claims 70-72, wherein each occurrence of R on B^cThe substituents are independently selected from:

(a) halogen;

(b) a cyano group;

(c)C_1-10alkyl optionally substituted with 1-6 independently selected R^aSubstitution;

(g)C_1-4an alkoxy group;

(h)C_1-4a haloalkoxy group;

(i)-S(O)_1-2(C_1-4alkyl groups);

(m)-C_1-4a thioalkoxy group;

(o)-C(＝O)(C_1-4alkyl groups);

(p)-C(＝O)O(C_1-4alkyl groups);

(R) -C (═ O) N (R') (R "); and

(s)–L¹-L²-R^h。

74. the method of any one of claims 70-73, wherein each occurrence of R on B^cThe substituents are independently selected from:

(a) halogen;

(b) a cyano group;

(c)C_1-10alkyl optionally substituted with 1-6 independently selected R^aSubstitution;

(g)C_1-4an alkoxy group;

(h)C_1-4a haloalkoxy group; and

(s)–L¹-L²-R^h。

75. the method of any one of claims 70-74, wherein each occurrence of R on B^cThe substituents are independently selected from:

(a) halogen;

(c)C_1-10alkyl optionally substituted with 1-6 independently selected R^aSubstitution; and

(s)–L¹-L²-R^h。

76. the method of any one of claims 70-75, wherein one occurrence of R^cIs C_1-10Alkyl optionally substituted with 1-6 independently selected R^aAnd (4) substitution.

77. The method of any one of claims 70-76, wherein one occurrence of R^cIs C_1-6Alkyl optionally substituted with 1-6 independently selected R^aAnd (4) substitution.

78. The method of any one of claims 70-77, wherein one occurrence of R^cIs unsubstituted C_1-10An alkyl group.

79. The method of claim 78, wherein one occurrence of R^cIs unsubstituted C_2-10(e.g., C)_2-3，E.g. C_3-4E.g. C_4-10) An alkyl group.

80. The method of any one of claims 70-77, wherein one occurrence of R^cIs C_1-6Alkyl, which is selected from 1 to 6 independentlyR of^aAnd (4) substitution.

81. The method of any one of claims 70-77 and 80, wherein one occurrence of R^cIs CF₃Or(e.g., R)^cMay be CF₃)。

82. The method of any one of claims 76-81, wherein a second occurrence of R^cIndependently when present, is halogen.

83. The method of any one of claims 76-81, wherein B is 1-3 occurrences of R^cSubstituted phenyl, in which one occurrence of R is^cIn formula I to link L^ABA ring carbon para to a point of the moiety.

84. The method of any one of claims 1-69 and 83, wherein B isWherein: n1 is 0 or 1; and R is^cAAnd R^cBEach independently selected R^c。

85. The method of claim 84, wherein R^cBIs R as defined in any one of claims 76 to 82^c。

86. The method of claim 84, wherein R^cBIs R as defined in any of claims 78 to 79^c。

87. The method of claim 85, wherein R^cBIs R as defined in any one of claims 80 to 81^c。

88. The method of any one of claims 84-87, wherein n1 is 0.

89. The method of any one of claims 84-87, wherein n1 is 1; and R is^cAIs a halogen.

90. The method of any one of claims 1-89, wherein L^ABis-N (R)^N)S(O)₂-*。

91. The method of any one of claims 1-89, wherein L^ABis-N (R)^N)S(O)₂-(W^AB1-W^AB2-W^AB3) -, e.g. N (R)^N)S(O)₂-(C_1-3Alkylene) -or-N (R)^N)S(O)₂-(C_1-3Alkylene) -O- (C)_1-3Alkylene).

92. The method of any one of claims 1-91, wherein R^NIs H.

93. The method of claim 1, wherein the compound has formula (I-1):

wherein n1 is 0 or 1; and R is^cAAnd R^cBEach independently selected R^c。

94. The method of claim 1, wherein the compound has formula (I-2):

wherein n1 is 0 or 1; and is

R^cAAnd R^cBEach independently selected R^c。

95. The method of any one of claims 93-94, wherein a is (a-1) as defined in claim 6.

96. The method of any one of claims 93 to 95, wherein a is as defined in claim 24.

97. The method of any one of claims 93 to 95, wherein a is as defined in claim 25.

98. The method of any one of claims 96-97, wherein m1 is 0.

99. The method of claim 98, wherein m 3-1.

100. The method of claim 99, wherein R³As defined in any one of claims 48 to 50.

101. The method of claim 98, wherein m 3-0.

102. The method of any one of claims 93-94, wherein a is (a-2) as defined in claim 26.

103. The method of any one of claims 93-94 and 102, wherein a is as defined in any one of claims 30-31 (e.g., claim 31).

104. The method of any one of claims 93-94 and 102, wherein a is as defined in any one of claims 32-33 (e.g., claim 33).

105. The method as set forth in any one of claims 103-104, wherein m 1-0.

106. The method as set forth in any one of claims 103-104, wherein m 3-0.

107. The method of any one of claims 93 to 94, wherein a is (a-3) as defined in claim 39.

108. The method of claim 107, wherein a is as defined in claim 47.

109. The method as set forth in any one of claims 107-108, wherein R¹As defined in any one of claims 56 to 57.

110. The method of any one of claims 93-109, wherein R^cBIs R as defined in any one of claims 76 to 82^c。

111. The method of any one of claims 93-109, wherein R^cBIs R as defined in any of claims 78 to 79^c。

112. The method of any one of claims 93-109, wherein R^cBIs R as defined in any one of claims 80 to 81^c。

113. The method of any one of claims 93-112, wherein n1 is 0.

114. The method of any one of claims 93-112, wherein n1 is 1; and R is^cAIs a halogen.

115. The method of claim 1, wherein a is selected from:

m1 is 0 or 1; and m3 is 0, 1 or 2;

L^ABis-N (H) S(O)₂-NHS (O)₂-(W^AB1) -; and is

B is selected from:

C₆aryl radicals substituted by 1 to 4R^cSubstitution;

heteroaryl group comprising 5 to 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N (H), N (R)^d) O, and S (O)_0-2And wherein said heteroaryl ring is substituted with 1-4 independently selected R^cSubstitution;

bicyclic or tricyclic heteroaryl containing 9 to 15 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N (H), N (R)^d) O, and S (O)_0-2And wherein said heteroaryl ring is optionally substituted with 1-4 independently selected R^cSubstitution;

C_5-15alkyl optionally substituted with 1-6R^aSubstitution;

C_6-20aryl optionally substituted with 1-4R^cSubstitution; and is

Heteroaryl group comprising 7 to 20 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N (H), N (R)^d) O, and S (O)_0-2And wherein said heteroaryl ring is optionally substituted with 1-4 independently selected R^cAnd (4) substitution.

116. The method of claim 1, wherein the compound is a compound selected from table C1; or a pharmaceutically acceptable salt thereof.

117. The method of claim 1, wherein the method comprises administering a pharmaceutical composition comprising a compound of claims 1-116 and one or more pharmaceutically acceptable excipients.

118. The method of any one of claims 1-116, wherein inhibiting comprises antagonizing STING.

119. The method of any one of claims 1-116 and 118, which is performed in vitro.

120. The method of claim 119, wherein the method comprises contacting a sample comprising one or more cells comprising STING with the compound.

121. The method of claim 120, wherein the one or more cells are one or more cancer cells.

122. The method of claim 120 or 121, wherein the sample further comprises one or more cancer cells (e.g., the cancer is selected from the group consisting of melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilms' tumor, or hepatocellular carcinoma).

123. The method of any one of claims 1-116 and 118, which is performed in vivo.

124. The method of claim 123, wherein the method comprises administering the compound to a subject having a disease in which increased (e.g., excessive) STING signaling leads to the pathology and/or symptomology and/or progression of the disease.

125. The method of claim 124, wherein the subject is a human.

126. The method of claim 124, wherein the disease is cancer.

127. The method of claim 126, wherein the cancer is selected from: melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, wilms' tumor, or hepatocellular carcinoma.

128. The method of claim 126 or 127, wherein the cancer is a refractory cancer.

129. The method of claim 124, wherein the compound is administered in combination with one or more additional cancer therapies.

130. The method of claim 129, wherein the one or more additional cancer therapies comprise: surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

131. The method of claim 130, wherein the chemotherapy comprises administration of one or more additional chemotherapeutic agents.

132. The method of claim 131, wherein the one or more additional chemotherapeutic agents are selected from the group consisting of: alkylating agents (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); antimetabolites (e.g., azathioprine and/or mercaptopurine); terpenoids (e.g., vinca alkaloids and/or taxanes; e.g., vincristine, vinblastine, vinorelbine and/or vindesine, taxol, paclitaxel and/or docetaxel); topoisomerase (e.g., type I and/or type 2 topoisomerase; e.g., camptothecin, e.g., irinotecan and/or topotecan; amsacrine, etoposide phosphate and/or teniposide); cytotoxic antibiotics (e.g., actinomycin, anthracycline, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin, and/or mitomycin); hormones (e.g., luteinizing hormone releasing hormone agonists; e.g., leuprolide, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, basiliximab, belimumab, bevacizumab, bretuximab, conatinumab, cetuximab, pemphilizumab, daclizumab, disitumumab, eculizumab, efavirumab, gemtuzumab, golimumab, ibritumomab, infliximab, ipilimumab, moruzumab-CD 3, natalizumab, ocvolumab, omalizumab, panlizumab, ranibizumab, rituximab, tuzumab, tositumomab, and/or trastuzumab); an anti-angiogenic agent; a cytokine; a thrombogenic active agent; a growth inhibitor; an anthelmintic agent; and an immune checkpoint inhibitor targeting an immune checkpoint receptor selected from the group consisting of: CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2, 3-dioxygenase (IDO), IL-10, transforming growth factor-beta (TGF β), T-cell immunoglobulin and mucin 3(TIM3 or HAVCR2), galectin 9-TIM3, phosphatidylserine-TIM 3, lymphocyte activator gene 3 protein (LAG3), MHC class II-LAG 3, 4-1 BB-4-1 BB ligand, OX 40-OX 40 ligand, GITR, GITR ligand-GITR, CD70-CD27, TNFRSF25, HVRSF 25-TL 1 HV9, CD40 6862, CD 40-CD 40 ligand, HVEM-LIGHT-LTA, EM, HVLA-160, HVRSF 25-TL 1-9, CD 6862, CD 40-CD 40 ligand, CD 86244, CD-CD 36244, CD 86244, CD244, ICOS, ICOS-ICOS ligands, B7-H3, B7-H4, VISTA, TMIGD2, HHLA 2-TMIGD 2, milk fat proteins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD 86-CD 28, CD 86-CTLA, CD 80-CD 28, CD39, CD73 adenosine-CD 39-CD 73, CXCR 4-CXCL 12, phosphatidylserine, TIM3, phosphatidylserine-TIM 3, SIRPA-CD 47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

133. The method of any one of claims 124-132, wherein the compound is administered intratumorally.

134. A method of treating cancer comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1-116 or a pharmaceutical composition according to claim 117.

135. The method of claim 134, wherein the cancer is selected from: melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, wilms' tumor, or hepatocellular carcinoma.

136. The method of claim 134 or 135, wherein the cancer is a refractory cancer.

137. The method of claim 134, wherein the compound is administered in combination with one or more additional cancer therapies.

138. The method of claim 137, wherein the one or more additional cancer therapies comprise: surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

139. The method of claim 138, wherein the chemotherapy comprises administration of one or more additional chemotherapeutic agents.

140. The method of claim 139, wherein the one or more additional chemotherapeutic agents are selected from: alkylating agents (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); antimetabolites (e.g., azathioprine and/or mercaptopurine); terpenoids (e.g., vinca alkaloids and/or taxanes; e.g., vincristine, vinblastine, vinorelbine and/or vindesine, taxol, paclitaxel and/or docetaxel); topoisomerase (e.g., type I and/or type 2 topoisomerase; e.g., camptothecin, e.g., irinotecan and/or topotecan; amsacrine, etoposide phosphate and/or teniposide); cytotoxic antibiotics (e.g., actinomycin, anthracycline, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin, and/or mitomycin); hormones (e.g., luteinizing hormone releasing hormone agonists; e.g., leuprolide, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, basiliximab, belimumab, bevacizumab, bretuximab, conatinumab, cetuximab, pemphilizumab, daclizumab, disitumumab, eculizumab, efavirumab, gemtuzumab, golimumab, ibritumomab, infliximab, ipilimumab, moruzumab-CD 3, natalizumab, ocvolumab, omalizumab, panlizumab, ranibizumab, rituximab, tuzumab, tositumomab, and/or trastuzumab); an anti-angiogenic agent; a cytokine; a thrombogenic active agent; a growth inhibitor; an anthelmintic agent; and an immune checkpoint inhibitor targeting an immune checkpoint receptor selected from the group consisting of: CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2, 3-dioxygenase (IDO), IL-10, transforming growth factor-beta (TGF β), T-cell immunoglobulin and mucin 3(TIM3 or HAVCR2), galectin 9-TIM3, phosphatidylserine-TIM 3, lymphocyte activator gene 3 protein (LAG3), MHC class II-LAG 3, 4-1 BB-4-1 BB ligand, OX 40-OX 40 ligand, GITR, GITR ligand-GITR, CD70-CD27, TNFRSF25, HVRSF 25-TL 1 HV9, CD40 6862, CD 40-CD 40 ligand, HVEM-LIGHT-LTA, EM, HVLA-160, HVRSF 25-TL 1-9, CD 6862, CD 40-CD 40 ligand, CD 86244, CD-CD 36244, CD 86244, CD244, ICOS, ICOS-ICOS ligands, B7-H3, B7-H4, VISTA, TMIGD2, HHLA 2-TMIGD 2, milk fat proteins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD 86-CD 28, CD 86-CTLA, CD 80-CD 28, CD39, CD73 adenosine-CD 39-CD 73, CXCR 4-CXCL 12, phosphatidylserine, TIM3, phosphatidylserine-TIM 3, SIRPA-CD 47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

141. The method of any one of claims 134-140, wherein the compound is administered intratumorally.

142. A method of inducing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1-116 or a pharmaceutical composition according to claim 117.

143. The method of claim 142, wherein the subject has cancer.

144. The method of claim 143, wherein the subject has undergone and/or is undergoing and/or will undergo one or more cancer therapies.

145. The method of claim 143, wherein the cancer is selected from: melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, wilms' tumor, or hepatocellular carcinoma.

146. The method of claim 145, wherein the cancer is a refractory cancer.

147. The method of claim 142, wherein the immune response is an innate immune response.

148. The method of claim 147, wherein the at least one or more additional cancer therapies comprises: surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

149. The method of claim 148, wherein the chemotherapy comprises administration of one or more additional chemotherapeutic agents.

150. The method of claim 149, wherein the one or more additional chemotherapeutic agents are selected from: alkylating agents (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); antimetabolites (e.g., azathioprine and/or mercaptopurine); terpenoids (e.g., vinca alkaloids and/or taxanes; e.g., vincristine, vinblastine, vinorelbine and/or vindesine, taxol, paclitaxel and/or docetaxel); topoisomerase (e.g., type I and/or type 2 topoisomerase; e.g., camptothecin, e.g., irinotecan and/or topotecan; amsacrine, etoposide phosphate and/or teniposide); cytotoxic antibiotics (e.g., actinomycin, anthracycline, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin, and/or mitomycin); hormones (e.g., luteinizing hormone releasing hormone agonists; e.g., leuprolide, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, basiliximab, belimumab, bevacizumab, bretuximab, conatinumab, cetuximab, pemphilizumab, daclizumab, disitumumab, eculizumab, efavirumab, gemtuzumab, golimumab, ibritumomab, infliximab, ipilimumab, moruzumab-CD 3, natalizumab, ocvolumab, omalizumab, panlizumab, ranibizumab, rituximab, tuzumab, tositumomab, and/or trastuzumab); an anti-angiogenic agent; a cytokine; a thrombogenic active agent; a growth inhibitor; an anthelmintic agent; and an immune checkpoint inhibitor targeting an immune checkpoint receptor selected from the group consisting of: CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2, 3-dioxygenase (IDO), IL-10, transforming growth factor-beta (TGF β), T-cell immunoglobulin and mucin 3(TIM3 or HAVCR2), galectin 9-TIM3, phosphatidylserine-TIM 3, lymphocyte activator gene 3 protein (LAG3), MHC class II-LAG 3, 4-1 BB-4-1 BB ligand, OX 40-OX 40 ligand, GITR, GITR ligand-GITR, CD70-CD27, TNFRSF25, HVRSF 25-TL 1 HV9, CD40 6862, CD 40-CD 40 ligand, HVEM-LIGHT-LTA, EM, HVLA-160, HVRSF 25-TL 1-9, CD 6862, CD 40-CD 40 ligand, CD 86244, CD-CD 36244, CD 86244, CD244, ICOS, ICOS-ICOS ligands, B7-H3, B7-H4, VISTA, TMIGD2, HHLA 2-TMIGD 2, milk fat proteins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD 86-CD 28, CD 86-CTLA, CD 80-CD 28, CD39, CD73 adenosine-CD 39-CD 73, CXCR 4-CXCL 12, phosphatidylserine, TIM3, phosphatidylserine-TIM 3, SIRPA-CD 47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

151. A method of treating a disease in which increased (e.g., excessive) STING signaling leads to the pathology and/or symptomology and/or progression of the disease, the method comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1-116 or a pharmaceutical composition of claim 117.

152. A method of treatment comprising administering to a subject having a disease in which increased (e.g., excessive) STING signaling leads to the pathology and/or symptomology and/or progression of the disease an effective amount of a compound according to any one of claims 1-116 or a pharmaceutical composition according to claim 117.

153. A method of treatment comprising administering to a subject a compound according to any one of claims 1-116 or a pharmaceutical composition according to claim 117, wherein the compound or composition is administered in an effective amount to treat a disease in which increased (e.g., excessive) STING signaling leads to the pathology and/or symptomology and/or progression of the disease, thereby treating the disease.

154. The method of any one of claims 151-153, wherein the disease is cancer.

155. The method of claim 154, wherein the cancer is selected from: melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, wilms' tumor, or hepatocellular carcinoma.

156. The method of claim 154 or 155, wherein the cancer is a refractory cancer.

157. The method of any one of claims 154-156, wherein the compound is administered in combination with one or more additional cancer therapies.

158. The method of claim 157, wherein the one or more additional cancer therapies comprise: surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy, or a combination thereof.

159. The method of claim 158, wherein the chemotherapy comprises administration of one or more additional chemotherapeutic agents.

160. The method of claim 159, wherein the one or more additional chemotherapeutic agents are selected from the group consisting of: alkylating agents (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); antimetabolites (e.g., azathioprine and/or mercaptopurine); terpenoids (e.g., vinca alkaloids and/or taxanes; e.g., vincristine, vinblastine, vinorelbine and/or vindesine, taxol, paclitaxel and/or docetaxel); topoisomerase (e.g., type I and/or type 2 topoisomerase; e.g., camptothecin, e.g., irinotecan and/or topotecan; amsacrine, etoposide phosphate and/or teniposide); cytotoxic antibiotics (e.g., actinomycin, anthracycline, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin, and/or mitomycin); hormones (e.g., luteinizing hormone releasing hormone agonists; e.g., leuprolide, goserelin, triptorelin, histrelin, bicalutamide, flutamide and/or nilutamide); antibodies (e.g., abciximab, adalimumab, alemtuzumab, basiliximab, belimumab, bevacizumab, bretuximab, conatinumab, cetuximab, pemphilizumab, daclizumab, disitumumab, eculizumab, efavirumab, gemtuzumab, golimumab, ibritumomab, infliximab, ipilimumab, moruzumab-CD 3, natalizumab, ocvolumab, omalizumab, panlizumab, ranibizumab, rituximab, tuzumab, tositumomab, and/or trastuzumab); an anti-angiogenic agent; a cytokine; a thrombogenic active agent; a growth inhibitor; an anthelmintic agent; and an immune checkpoint inhibitor targeting an immune checkpoint receptor selected from the group consisting of: CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2, 3-dioxygenase (IDO), IL-10, transforming growth factor-beta (TGF β), T-cell immunoglobulin and mucin 3(TIM3 or HAVCR2), galectin 9-TIM3, phosphatidylserine-TIM 3, lymphocyte activator gene 3 protein (LAG3), MHC class II-LAG 3, 4-1 BB-4-1 BB ligand, OX 40-OX 40 ligand, GITR, GITR ligand-GITR, CD70-CD27, TNFRSF25, HVRSF 25-TL 1 HV9, CD40 6862, CD 40-CD 40 ligand, HVEM-LIGHT-LTA, EM, HVLA-160, HVRSF 25-TL 1-9, CD 6862, CD 40-CD 40 ligand, CD 86244, CD-CD 36244, CD 86244, CD244, ICOS, ICOS-ICOS ligands, B7-H3, B7-H4, VISTA, TMIGD2, HHLA 2-TMIGD 2, milk fat proteins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD 86-CD 28, CD 86-CTLA, CD 80-CD 28, CD39, CD73 adenosine-CD 39-CD 73, CXCR 4-CXCL 12, phosphatidylserine, TIM3, phosphatidylserine-TIM 3, SIRPA-CD 47, VEGF, neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

161. The method of any one of claims 151-160, wherein the compound is administered intratumorally.

162. A method of treating a disease, disorder or condition associated with STING, comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1-116 or a pharmaceutical composition according to claim 117.

163. The method of claim 162, wherein the disease, disorder, or condition is selected from: type I interferon disease, Aicadi-Guttley syndrome (AGS), hereditary forms of lupus, inflammation-related disorders and rheumatoid arthritis.

164. The method of claim 163, wherein the disease, disorder, or condition is a type I interferon disease (e.g., a baby-onset STING-related vascular disease (SAVI)).

165. The method of claim 164, wherein the type I interferon disease is infant-onset STING-related vascular disease (SAVI).

166. The method of claim 163, wherein the disease, disorder or condition is acadi-guletide syndrome (AGS).

167. The method of claim 163, wherein the disease, disorder, or condition is a genetic form of lupus.

168. The method of claim 163, wherein the disease, disorder, or condition is an inflammation-related disorder.

169. The method of claim 168, wherein the condition associated with inflammation is systemic lupus erythematosus.

170. The method of claim 163, wherein the disease, disorder, or condition is rheumatoid arthritis.

171. The method as recited in any one of claims 118-170, wherein the method further comprises identifying an object.

172. A compound of formula I, or a pharmaceutically acceptable salt or tautomer thereof:

wherein:

L^ABis-N (R)^N)S(O)₂-*，-N(R^N)S(O)₂-(W^AB1-W^AB2-W^AB3)-*，–S(O)₂N(R^N)-*，

Wherein the asterisks indicate the points of attachment to B;

W^AB1is C_1-3Alkylene optionally substituted with 1-4 independently selected R^aSubstitution;

W^AB2is a bond, -O-, -NR-^Nor-S-;

W^AB3is a bond or C_1-3Alkylene optionally substituted with 1-4 independently selected R^aSubstitution;

a is selected from the following group:

B is:

(a)C_1-15alkyl optionally substituted with 1-6R^aSubstitution;

(b)C_3-20cycloalkyl optionally substituted with 1-4R^bSubstitution;

(c)C_6-20aryl optionally substituted with 1-4R^cSubstitution;

R^Nthe method comprises the following steps:

(i) h, or

(ii)C_1-6Alkyl, optionally substituted with 1-3R^aThe substitution is carried out by the following steps,

R¹the method comprises the following steps:

(i)-(U¹)_q-U²wherein:

q is 0 or 1;

·U¹is C_1-6Alkylene optionally substituted by 1 to 6R^aSubstitution; and

·U²the method comprises the following steps:

(a)C_3-12cycloalkyl optionally substituted with 1-4R^bThe substitution is carried out by the following steps,

(b)C_6-10aryl optionally substituted with 1-4R^cSubstitution;

(d) Heterocyclyl comprising 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, eachIndependently selected from the group consisting of: n, N (H), N (R)^d) O and S (O)_0-2And wherein said heterocyclyl ring is optionally substituted with 1-4 independently selected R^bThe substitution is carried out by the following steps,

(ii)C_1-10Alkyl optionally substituted with 1-6 independently selected R^aSubstitution;

each occurrence of R²Independently selected from the group consisting of:

(i)C_1-6alkyl optionally substituted with 1-2 independently selected R^aSubstitution;

(ii)C_3-6a cycloalkyl group;

(iii) heterocyclyl comprising 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)^d) O and S (O)_0-2，

(iv)-C(O)(C_1-4Alkyl groups);

(v)-C(O)O(C_1-4alkyl groups);

(vi)-CON(R’)(R”)；

(vii)-S(O)_1-2(NR’R”)；

(viii)-S(O)_1-2(C_1-4alkyl groups);

(ix) -OH; and

(x)C_1-4an alkoxy group;

Each occurrence of R^cIndependently selected from the group consisting of:

(a) halogen;

(b) a cyano group;

(c)C_1-15alkyl optionally substituted with 1-6 independently selected R^aSubstitution;

(d)C_2-6an alkenyl group;

(e)C_2-6an alkynyl group;

(g)C_1-4alkoxy, optionally substituted with 1-3 independently selected R^aSubstitution;

(h)C_1-4a haloalkoxy group;

(i)-S(O)_1-2(C_1-4alkyl groups);

(j)-NR^eR^f；

(k)–OH；

(l)-S(O)_1-2(NR’R”)；

(m)-C_1-4a thioalkoxy group;

(n)-NO₂；

(o)-C(＝O)(C_1-4alkyl groups);

(p)-C(＝O)O(C_1-4alkyl groups);

(q)-C(＝O)OH；

(R) -C (═ O) N (R') (R "); and

(s)–L¹-L²-R^h；

-L¹is a bond or C_1-3An alkylene group;

-L²is-O-, -N (H) -, -S-or a bond;

R^hselected from:

a heterocyclyl group, wherein said heterocyclyl group comprises 3 to 16 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)^d) O and S (O)_0-2Wherein said heterocyclic ringThe cyclic ring is optionally substituted with 1-4 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl and C_1-4A haloalkyl group;

heteroaryl comprising 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)^d) O and S (O)_0-2And wherein said heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl and C_1-4A haloalkyl group; and

·C_6-10aryl optionally substituted with 1-4 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl or C_1-4A haloalkyl group; and

173. The compound of claim 172, wherein a is (a-1):

wherein

Z is selected from the group consisting of:

bond, CH, CR¹、CR³、N、NH、N(R¹) And N (R)²)；

Y¹、Y²And Y³Each independently selected from the group consisting of: o, S, CH, CR¹、CR³、N、NH、N(R¹) And NR²；

Y⁴Is C or N;

X¹selected from the group consisting of: o, S, N, NH, NR¹、NR²、CH、CR¹And CR³；

X²Selected from the group consisting of: o, S, N, NH, NR¹、NR²、CH、CR¹And CR³(ii) a And

174. The compound of claim 173, wherein theIs partiallyWherein m1 is 0, 1,2 or 3; and m3 ═ 0, 1,2, or 3 (e.g., m1 ═ 0 or 1; and m3 ═ 0, 1, or 2).

175. The compound of claim 173, wherein 1-2Y are¹、Y²And Y³Independently is N.

176. The compound of claim 175,is partiallyWherein the asterisks indicate the attachment to Y⁴A point of (a); and m1 is 0, 1 or 2; and m3 ═0.1 or 2 (e.g., m1 ═ 0 or 1; and m3 ═ 0 or 1).

177. The compound of any one of claims 173-176 wherein Y is⁴Is C.

178. The compound of any one of claims 173-177 wherein X¹Selected from the group consisting of: NH, NR¹And NR²E.g. X¹Is NH.

179. The compound of any one of claims 173-178, wherein X²Selected from the group consisting of: n, C (C)_1-3Alkyl) and CH.

180. The compound of any one of claims 173-179, wherein X²Is CH.

181. The compound of any one of claims 172-174, wherein a is:wherein m1 is 0, 1,2 or 3; and m3 ═ 0, 1,2, or 3 (e.g., m1 ═ 0 or 1; and m3 ═ 0, 1, or 2).

182. The compound of any one of claims 172-173 and 175-176, wherein a isWherein m1 is 0, 1 or 2; and m3 ═ 0, 1, or 2 (e.g., m1 ═ 0 or 1; and m3 ═ 0 or 1).

183. The compound of claim 172, wherein a is (a-2):

wherein

X¹selected from the group consisting of: o, S, N, NH, NR¹、NR²、CH、CR¹And CR³；

X²Selected from the group consisting of: o, S, N, NH, NR¹、NR²、CH、CR¹And CR³(ii) a Provided that Y is contained⁴、X¹And X²The ring(s) of (a) is heteroaromatic; and

Y⁴selected from: n or C.

184. The compound of claim 183, wherein Y⁴Is N.

185. The compound of any one of claims 183-184, wherein a is:wherein m1 is 0, 1 or 2; and m3 ═ 0, 1, or 2 (e.g., m1 ═ 0 or 1; and m3 ═ 0 or 1).

186. The compound of any one of claims 183-184, wherein a is:wherein m1 is 0, 1 or 2; and m3 ═ 0, 1, or 2 (e.g., m1 ═ 0 or 1; and m3 ═ 0 or 1).

187. The compound of claim 172, wherein a is (a-3):

wherein:

Z²selected from: CH. R²And N;

X³selected from: o, S, N, NH, NR¹、NR²、CH、CR¹And CR³；

Y⁵And Y⁶Each independently selected from O, S, CH, CR¹、CR³、NR²NH and N; and

each one of which isIndependently is a single or double bond, provided that Y is comprised⁵、Y⁶、X³And Z²The five-membered ring of (a) is heteroaryl.

188. The compound of any one of claims 172 and 187, wherein a is

189. The compound of any one of claims 172-188, wherein each occurrence of R¹Independently selected from the group consisting of:

(i)-(U¹)_q-U²wherein:

q is 0 or 1;

·U¹is C_1-6Alkylene optionally substituted by 1 to 6R^aSubstitution; and

·U²the method comprises the following steps:

C_3-10cycloalkyl optionally substituted with 1-4R^bThe substitution is carried out by the following steps,

C_6-10aryl optionally substituted with 1-4R^cSubstitution;

heteroaryl group comprising 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N (H), N (R)^d) O, S, and S (O)₂And wherein said heteroaryl ring is optionally substituted with 1-4 independently selected R^cIs substituted, or

(ii) heterocyclyl comprising 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)^d) And O, and wherein said heterocyclyl ring is optionally substituted with 1-4 independently selected R^bIs substituted, and

(ii)C_1-6alkyl optionally substituted with 1-6 independently selected R^aAnd (4) substitution.

190. The compound of any one of claims 172-189, wherein R is¹Is- (U)¹)_q-U²。

191. The compound of any one of claims 172-190 wherein q is 0.

192. The compound of any one of claims 172-191 wherein U is⁴Is phenyl, optionally substituted with 1-2 (e.g., 1) R^cAnd (4) substitution.

193. The compound of any one of claims 190-192 wherein each occurrence of U²R of (A) to^cThe substituents are independently selected from: halogen, cyano, C_1-6Alkyl and C_1-4A haloalkyl group.

194. The compound of any one of claims 172-193, wherein each occurrence of R³Independently selected from the group consisting of: halogen, cyano, C_1-4Alkoxy radical, C_1-4Haloalkoxy, -S (O)_1-2(C_1-4Alkyl), -NR^eR^f，–OH，-S(O)_1-2(NR’R”)，-C_1-4Thioalkoxy, -C (═ O) (C)_1-4Alkyl group, -C: (C)＝O)O(C_1-4Alkyl, -C (═ O) OH and-C (═ O) N (R') (R ").

195. The compound of any one of claims 172-194 wherein each occurrence of R²Independently selected from:

(ii)C_1-6alkyl (e.g., methyl);

(iii)C_3-6a cycloalkyl group;

(iv)-C(O)(C_1-4alkyl) (e.g., c (o) Me);

(v)-C(O)O(C_1-4alkyl groups);

(vi)-CON(R’)(R”)；

(vii)-S(O)_1-2(NR' R "); and

(viii)-S(O)_1-2(C_1-4alkyl) (e.g., S (O)₂Me)。

196. The compound of any one of claims 174, 176, 181, 182, 185, and 186, wherein m1 is 1.

197. The compound of claim 196, wherein m3 ═ 0.

198. The compound of any one of claims 174, 176, 181, 182, 185, and 186, wherein m3 is 1 or 2; and m1 is 0.

199. The compound of any one of claims 172-198 wherein B is substituted with 1-4R^cA substituted phenyl group.

200. The compound of any one of claims 172-199, wherein B is substituted with 1-2R^cSubstituted phenyl, wherein 1R^cIn formula I to link L^ABA ring carbon para to a point of the moiety.

201. The compound of any one of claims 199-200, wherein each occurrence of R on B^cThe substituents are independently selectedFrom: halogen; a cyano group; optionally substituted with 1-6 independently selected R^aSubstituted C_1-10An alkyl group; c_1-4An alkoxy group; c_1-4A haloalkoxy group; -S (O)_1-2(C_1-4Alkyl groups); -C_1-4A thioalkoxy group; -C (═ O) (C)_1-4Alkyl groups); -C (═ O) O (C)_1-4Alkyl groups); -C (═ O) N (R') (R "); and-L¹-L²-R^h。

202. The compound of any one of claims 172-200 wherein B isWherein: n1 is 0 or 1; and R is^cAAnd R^cBEach independently selected R^c。

203. The compound of claim 202, wherein R^cBIs optionally 1-6 independently selected R^aSubstituted C_1-10Alkyl, such as R optionally selected by 1-6 independently^aSubstituted C_1-6An alkyl group;

optionally, R^cBIs unsubstituted C_1-10Alkyl radicals, e.g. unsubstituted C_2-10(e.g., C)₂-3, e.g. C_3-4E.g. C_4-10) An alkyl group; or

Optionally, R^cBIs optionally 1-6 independently selected R^aSubstituted C_1-6Alkyl radicals, e.g. R^cBIs CF₃Or(e.g., R)^cMay be CF₃) (ii) a And is

Optionally, wherein R is^cAIs an independently selected halogen.

204. The compound of any one of claims 202-203 wherein n1 is 0.

205. Such asThe compound of any one of claims 202-203 wherein n1 is 1; and R^cAIs a halogen.

206. The compound of any one of claims 172-205, wherein L^ABis-N (R)^N)S(O)₂-*。

207. The compound of any one of claims 172-205, wherein L^ABis-N (R)^N)S(O)₂-(W^AB1-W^AB2-W^AB3) -, e.g. N (R)^N)S(O)₂-(C_1-3Alkylene) -or-N (R)^N)S(O)₂-(C_1-3Alkylene) -O- (C)_1-3Alkylene).

208. The compound of any one of claims 172-207 wherein R is^NIs H.

209. The compound of claim 172, wherein the compound has formula (I-1):

wherein n1 is 0 or 1; and R is^cAAnd R^cBEach independently selected R^c。

210. The compound of claim 172, wherein the compound has formula (I-2):

wherein n1 is 0 or 1; and R is^cAAnd R^cBEach independently selected R^c。

211. The compound as claimed in any of claims 209-210, wherein a is (a-1) as defined in claim 173.

212. The compound of any one of claims 209-211, wherein a is:

wherein m1 is 0, 1,2 or 3; and m3 ═ 0, 1,2, or 3 (e.g., m1 ═ 0 or 1; and m3 ═ 0, 1, or 2).

213. The compound as claimed in any one of claims 209-211, wherein a is

Wherein m1 is 0, 1 or 2; and m3 ═ 0, 1, or 2 (e.g., m1 ═ 0 or 1; and m3 ═ 0 or 1).

214. The compound of any one of claims 212-213, wherein m 1-0.

215. The compound of claim 214, wherein m3 ═ 1; or wherein m3 is 2.

216. The compound of claim 215, wherein each occurrence of R³Independently selected from: halogen, cyano, C_1-4Alkoxy radical, C_1-4Haloalkoxy, -S (O)_1-2(C_1-4Alkyl), -NR^eR^f，–OH，-S(O)_1-2(NR’R”)，-C_1-4Thioalkoxy, -C (═ O) (C)_1-4Alkyl group, -C (═ O) O (C)_1-4Alkyl, -C (═ O) OH and-C (═ O) N (R') (R ").

217. The compound of claim 214, wherein m 3-0.

218. The compound as claimed in any one of claims 209-210, wherein a is (a-2) as defined in claim 183.

219. The compound as claimed in any one of claims 209-210, wherein a is as defined in claim 185.

220. The compound as claimed in any one of claims 209-210, wherein a is as defined in claim 186.

221. The compound of any one of claims 219-220, wherein m1 is 0.

222. The compound of any one of claims 219-221, wherein m3 is 0.

223. The compound as claimed in any one of claims 209-210, wherein a is (a-3) as defined in claim 187.

224. The compound of claim 223, wherein a is

225. The compound as recited in any one of claims 223-224, wherein R¹Is optionally substituted by 1-2 (e.g., 0; e.g., 1) R^cSubstituted phenyl; and optionally wherein R¹Each R of (A) to (B)^cThe substituents are independently selected from: halogen, cyano, C_1-6Alkyl, and C_1-4Haloalkyl radicals, e.g. each R^cAre independently selected halogens.

226. The compound as set forth in any one of claims 209-225 wherein R is^cBIs optionally 1-6 independently selected R^aSubstituted C_1-10Alkyl, such as R optionally selected by 1-6 independently^aSubstituted C_1-6An alkyl group;

optionally, R^cBIs unsubstituted C_1-10Alkyl radicals, e.g. unsubstituted C_2-10(e.g., C)₂-3, e.g. C_3-4E.g. C_4-10) An alkyl group; or

Optionally, R^cBIs optionally 1-6 independently selected R^aSubstituted C_1-6Alkyl radicals, e.g. R^cBIs CF₃Or(e.g., R)^cMay be CF₃) (ii) a And is

Optionally, wherein R is^cAIs an independently selected halogen.

227. The compound of any one of claims 209-226 wherein R^cBIs unsubstituted C_1-10Alkyl radicals, e.g. unsubstituted C_2-10(e.g., C)_2-3E.g. C_3-4E.g. C_4-10) An alkyl group.

228. The compound of any one of claims 209-226, wherein R is^cBIs optionally 1-6 independently selected R^aSubstituted C_1-6Alkyl radicals, e.g. R^cBIs CF₃Or(e.g., R)^cMay be CF₃)。

229. The compound as set forth in any one of claims 209-228 wherein n1 is 0.

230. The compound of any one of claims 209-228 wherein n1 is 1; and R^cAIs a halogen.

231. The compound of claim 172, wherein a is independently selected from the group consisting of:

m1 is 0 or 1; and m3 is 0, 1 or 2;

L^ABis-N (H) S (O)₂-NHS (O)₂-(W^AB1) -; and is

B is selected from:

C_6-20aryl radicals substituted by 1 to 4R^cSubstitution;

C_5-15alkyl optionally substituted with 1-6R^aSubstitution; and is

C_8-20Aryl optionally substituted with 1-4R^cAnd (4) substitution.

232. The compound of claim 231, wherein m1 is 0.

233. The compound of claim 231, wherein m1 is 1.

234. The compound of any one of claims 231-233, wherein m3 is 0.

235. The compound of any one of claims 231-233, wherein m3 is 1 or 2, such as 2.

236. The compound of claim 231, wherein m1 is 0; and m3 is 2.

237. The compound of claim 236, wherein a isSuch as

238. The compound of any one of claims 231-237, wherein each occurrence of R³Independently selected from the group consisting of: halogen, cyano, C_1-4Alkoxy radical, C_1-4Haloalkoxy, -S (O)_1-2(C_1-4Alkyl group, -S (O)_1-2(NR’R”)，-C(＝O)(C_1-4Alkyl group, -C (═ O) O (C)_1-4Alkyl, -C (═ O) OH and-C (═ O) N (R') (R ").

239. The compound of any one of claims 231-238, wherein L^ABIs NHS (O)₂-*。

240. The compound of any one of claims 231-238, wherein L^ABIs NHS (O)₂-(C_1-3Alkylene) -.

241. The compound of any one of claims 231-240 wherein B is selected from:wherein R is^cAAnd R^cBEach independently selected R^c(ii) a n1 is 0, 1, or 2; q¹，Q²，Q³，Q⁴，Q⁵And Q⁶Each independently selected from N and CH, with the proviso that at least one Q¹And Q²Is N; and at least one Q³，Q⁴，Q⁵And Q⁶Is N.

242. The compound of claim 241, wherein n1 is 0.

243. The compound of any one of claim 241, wherein n1 is 1; r^cAIs halogen (e.g., -F, or-Cl) or C_1-6Alkyl optionally substituted with 1-3 independently selected R^a(e.g., methyl or CF)₃) And (4) substitution.

244. The compound of any one of claims 241-243, wherein R^cBIs C_1-6Alkyl optionally substituted with 1-6 independently selected R^aAnd (4) substitution.

245. The compound as claimed in any one of claims 241-243, wherein R^cBis-L¹-L²-R^h。

246. The compound of any one of claims 231-240, wherein B is heteroaryl comprising 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from N, N (h), N (R)^d) O, and S (O)_0-2And wherein the heteroaryl ring is substituted with 1-4 independently selected R^cSubstituted, provided that one occurrence of R^cIs L¹-L²-R^h。

247. The compound of any one of claims 245-246 wherein L¹And L²Each is a bond.

248. The compound of any one of claims 245-247, wherein R is^hSelected from:

C_3-6cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl and C_1-4Haloalkyl (in some embodiments, with the proviso that when R is^hIs C optionally selected from 1 to 4 independently_1-4Alkyl substituted C_3-6When cycloalkyl is, -L¹Is a bond, or-L²is-O-, -N (H) -or-S-;

heteroaryl comprising 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)^d) O and S (O)_0-2And wherein said heteroaryl ring is optionally substituted with 1-4 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl and C_1-4A haloalkyl group; and

C₆aryl optionally substituted with 1-4 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl or C_1-4A haloalkyl group.

249. The compound of claim 172, wherein the compound is a compound selected from table C1; or a pharmaceutically acceptable salt thereof.

250. A pharmaceutical composition comprising the compound of any one of claims 172-249.

251. The compound of any one of claims 172-249, wherein the compound exhibits activity as a STING antagonist.

Technical Field

The present invention provides chemical entities (e.g., compounds or pharmaceutically acceptable salts and/or hydrates and/or co-crystals and/or pharmaceutical combinations of compounds) that inhibit (e.g., antagonize) interferon gene Stimulator (STING). The chemical entities are useful, for example, in treating conditions, diseases or disorders in which increased (e.g., excessive) STING activation (e.g., STING signaling) results in the pathology, morbidity/symptoms and/or progression of a disease or disorder (e.g., cancer) in a subject (e.g., a human). The invention also provides compositions comprising the chemical entities and methods of using and making the compositions.

Background

STING, also known as transmembrane protein 173(TMEM173) and MPYS/MITA/eri, is a protein encoded by the TMEM173 gene in humans. STING has been shown to play a role in innate immunity. STING induces type I interferon production when cells are infected with intracellular pathogens (e.g., viruses, mycobacteria, and intracellular parasites). Type I interferons mediated by STING protect infected cells and nearby cells from local infection in an autocrine and paracrine fashion.

The STING pathway is critical in mediating the recognition of cytoplasmic DNA. In this case, STING is a transmembrane protein localized to the Endoplasmic Reticulum (ER) and serves as a second messenger receptor for 2', 3' cyclic GMP-AMP (hereinafter cGAMP), produced by cGAS after binding of dsDNA. In addition, STING can also be used as a primary pattern recognition receptor for bacterial Circular Dinucleotides (CDNs) and small molecule agonists. Recognition of endogenous or prokaryotic CDNs proceeds through the carboxy-terminal domain of STING, facing the cytoplasm and creating a V-shaped binding pocket formed by STING homodimers. Ligand-induced STING activation triggers its relocation to the golgi, a process essential to promote STING interaction with TBK 1. This protein complex, in turn, signals through the transcription factor IRF-3, thereby inducing type I Interferons (IFNs) and other co-regulated antiviral factors. In addition, STING was shown to trigger NF-. kappa.B and MAP kinase activation. After initiation of signal transduction, STING rapidly degrades, which is important in terminating inflammatory responses.

Excessive activation of STING is associated with a subset of monogenic autoinflammatory disorders, so-called type I interferon disease. Examples of these diseases include the clinical syndrome known as baby-onset STING-associated vascular disease (SAVI), which is caused by gain-of-function mutations in TMEM173 (gene name for STING). In addition, STING is involved in the pathogenesis and genetic form of lupus of Aicardi-Gouti res Syndrome (AGS). Unlike SAVI, continuous innate immune activation in AGS underlies a dysregulation of nucleic acid metabolism. In addition to these genetic diseases, emerging evidence suggests that STING has a more general pathogenic role in a range of inflammation-related diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, and cancer). Therefore, small molecule-based pharmacological intervention of the STING signaling pathway has great potential in the treatment of a variety of diseases.

Summary of The Invention

"antagonists" of STING include compounds that directly bind to or modify STING at the protein level such that the activity of STING is reduced, e.g., by inhibiting, blocking or attenuating agonist-mediated responses, altering distribution or otherwise. STING antagonists include chemical entities that interfere with or inhibit STING signaling.

In one aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein A, B, and L^ABAs may be defined anywhere herein.

In one aspect, a pharmaceutical composition is characterized by comprising a chemical entity described herein (e.g., a compound or pharmaceutically acceptable salt thereof, or a composition comprising the same, as generally or specifically described herein) and one or more pharmaceutically acceptable excipients.

In one aspect, the invention provides methods of inhibiting (e.g., antagonizing) STING activity, comprising contacting STING with a chemical entity described herein (e.g., a compound described generally or specifically herein, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound). Methods include in vitro methods, such as contacting a sample comprising one or more STING-containing cells (e.g., innate immune cells, such as mast cells, macrophages, Dendritic Cells (DCs), and natural killer cells) with a chemical entity. The methods may also include in vivo methods; for example, a chemical entity is administered to a subject (e.g., a human) having a disease in which STING signaling is increased (e.g., excessive) resulting in the pathology and/or symptomology and/or progression of the disease.

In one aspect, the invention provides methods of treating a condition, disease, or disorder that is improved by antagonizing STING, wherein an increase (e.g., an excess) in STING activation (e.g., STING signaling) results in the morbidity and/or symptoms and/or progression of the condition, disease, or disorder in a subject (e.g., a human). The method comprises administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generally or specifically herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same).

In another aspect, the invention provides a method of treating cancer, comprising administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generally or specifically herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same).

In another aspect, the invention provides methods of treating other STING-related diseases, such as type I interferon diseases (e.g., baby-onset STING-related vascular disease (SAVI)), Aicardi-gooti Syndrome (AGS), inherited forms of lupus, and inflammation-related diseases such as systemic lupus erythematosus and rheumatoid arthritis. The method comprises administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generally or specifically herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same).

In another aspect, the present invention provides a method of inhibiting STING-dependent type I interferon production in a subject in need thereof, comprising administering to the subject an effective amount of a chemical entity described herein (e.g., a compound described generally or specifically herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same).

In another aspect, the invention provides methods of treating a disease, wherein an increase (e.g., an excess) in STING activation (e.g., STING signaling) results in the morbidity and/or symptoms and/or progression of the disease. The method comprises administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generally or specifically herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same).

In another aspect, the invention provides a method of treatment comprising administering to a subject an effective amount of a chemical entity described herein (e.g., a compound described generally or specifically herein or a pharmaceutically acceptable salt thereof or a composition comprising the same); wherein the subject has (or is predisposed to having) a disease in which an increase (e.g., an excess) in STING activation (e.g., STING signaling) leads to the morbidity and/or symptoms and/or progression of the disease.

In another aspect, the invention provides a method of treatment comprising administering to a subject a chemical entity described herein (e.g., a compound described generally or specifically herein or a pharmaceutically acceptable salt thereof or a composition comprising the same), wherein the chemical entity is administered in an amount effective to treat a disease in which STING activation (e.g., STING signaling) is increased (e.g., excessive) resulting in the pathology/or symptomology and/or progression of the disease, thereby treating the disease.

Implementations may include one or more of the following features.

The chemical entity may be administered in combination with one or more other therapeutic agents and/or regimens. For example, the method can further comprise administering one or more (e.g., two, three, four, five, six or more) additional agents.

The chemical entity may be administered in combination with one or more other therapeutic agents and/or regimens useful for treating other STING-related diseases, such as, for example, type I interferon diseases (e.g., baby-onset STING-related vascular disease (SAVI)), Aicardi-Gouti Syndrome (AGS), hereditary forms of lupus, and inflammation-related diseases such as systemic lupus erythematosus and rheumatoid arthritis.

The chemical entity may be administered in combination with one or more additional cancer therapies (e.g., surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, or a combination thereof); for example, chemotherapy that includes administration of one or more (e.g., two, three, four, five, six, or more) additional chemotherapeutic agents. Non-limiting examples of other chemotherapeutic agents are selected from: alkylating agents (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin); antimetabolites (e.g., azathioprine and/or mercaptopurine); terpenoids (e.g., vinca alkaloids (vinca alkaloids) and/or taxanes; e.g., vincristine (vincristine), vinblastine (vinblastine), vinorelbine (vinorelbine) and/or vindesine (vindesine), taxol (taxol), paclitaxel (paclitaxel) and/or docetaxel (docetaxel)); topoisomerase (e.g. type I and/or type 2 topoisomerase; e.g. camptothecin (camptothecin), e.g. irinotecan (irinotecan) and/or topotecan (topotecan); amsacrine (amsacrine), etoposide (etoposide), etoposide phosphate and/or teniposide (teniposide)); cytotoxic antibiotics (e.g., actinomycin, anthracycline (anthracycline), doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin (bleomycin), plicamycin (plicamycin), and/or mitomycin)); hormones (e.g., luteinizing hormone releasing hormone agonists; e.g., leuprolide (leuprolide), goserelin (goserelin), triptorelin (triptorelin), histrelin (histrelin), bicalutamide (bicalutamide), flutamide (flutamide) and/or nilutamide); antibodies (e.g., Abciximab (Abciximab), Adalimumab (Adalilimumab), Alemtuzumab (Alemtuzumab), Alemtuzumab (Atlizumab), Basiliximab (Basiliximab), Belimumab (Belimumab), Bevacizumab (Bevacizumab), Brentuximab (Brentuximab Vedotin), conatinumab (Canakiumab), Cetuximab (Cetuximab), Petzumab (Certoluzumab), Daclizumab (Daclizumab), dessuzumab (Denosuub), Ekulizumab (Efalizumab), Efalizumab (Efalumab), Gemtuzumab (Gemtuzumab), Golimumab (Golimumab), Golimumab (Ibrimumab), ibritumomab (Ibriumumab), Infinizumab (Ribrizumab), Rijilizumab (Rijilizumab), Rituzumab (Rituzumab), (ii) Trastuzumab (Tocilizumab), Tositumomab (Tositumomab) and/or Trastuzumab (Trastuzumab); an anti-angiogenic agent; a cytokine; a thrombogenic active agent; a growth inhibitor; an anthelmintic agent; and an immune checkpoint inhibitor targeting an immune checkpoint receptor selected from the group consisting of: CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2, 3-dioxygenase (IDO), IL-10, transforming growth factor-beta (TGF β), T-cell immunoglobulin and mucin 3(TIM3 or HAVCR2), galectin 9-TIM3, phosphatidylserine-TIM 3, lymphocyte activator gene 3 protein (LAG3), MHC class II-LAG 3, 4-1 BB-4-1 BB ligand, OX 40-OX 40 ligand, GITR, GITR ligand-GITR, CD70-CD27, TNFRSF25, HVRSF 25-TL 1 HV9, CD40 6862, CD 40-CD 40 ligand, HVEM-LIGHT-LTA, EM, HVLA-160, HVRSF 25-TL 1-9, CD 6862, CD 40-CD 40 ligand, CD 86244, CD-CD 36244, CD 86244, CD244, ICOS, ICOS-ICOS ligands, B7-H3, B7-H4, VISTA, TMIGD2, HHLA 2-TMIGD 2, milk fat proteins, including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD 86-CD 28, CD 86-CTLA, CD 80-CD 28, CD39, CD73 adenosine-CD 39-CD 73, CXCR 4-CXCL 12, phosphatidylserine, TIM3, phosphatidylserine-TIM 3, SIRPA-CD 47, VEGF, Neuropilin (neuroxilin), CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L1).

The subject may have cancer; for example, the subject has undergone and/or is undergoing and/or will undergo one or more cancer treatments.

Non-limiting examples of cancer include: melanoma, cervical cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, urothelial cancer, bladder cancer, non-small cell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinal stromal tumor, gastroesophageal cancer, colorectal cancer, pancreatic cancer, renal cancer, hepatocellular carcinoma, malignant mesothelioma, leukemia, lymphoma, myelodysplastic syndrome, multiple myeloma, transitional cell carcinoma, neuroblastoma, plasmacytoma, Wilm's tumor, or hepatocellular carcinoma. In some embodiments, the cancer may be a refractory cancer.

The chemical entity may be administered intratumorally.

The method may further include identifying the object.

Other embodiments include those described in the detailed description and/or claims.

Other definitions

To facilitate an understanding of the disclosure set forth herein, a number of other terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, 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 document belongs. Each patent, application, published application and other publication referred to throughout this specification and the attached appendix is incorporated herein by reference in its entirety.

As used herein, the term "STING" is intended to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous STING molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species and active fragments thereof.

As used herein, the term "acceptable" with respect to a formulation, composition or ingredient means that there is no lasting deleterious effect on the overall health of the subject being treated.

By "API" is meant an active pharmaceutical ingredient.

As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a chemical entity sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent. The results include a reduction and/or alleviation of the signs, symptoms, or causes of disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from the symptoms of the disease. In any individual case, any suitable technique (e.g., a dose escalation study) may be used to determine the appropriate "effective" amount.

The term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, for example, Remington: The Science and Practice of Pharmacy, 21 st edition; lippincott Williams & Wilkins: philadelphia, pennsylvania, 2005; handbook of Pharmaceutical Excipients (Handbook of Pharmaceutical Excipients), 6 th edition; rowe et al, eds, Pharmaceutical Press and American society of pharmacy (The Pharmaceutical Press and The American Pharmaceutical Association): 2009; handbook of Pharmaceutical Additives (Handbook of Pharmaceutical Additives), 3 rd edition, authored by Ash and Ash, gaol Publishing Company (Gower Publishing Company): 2007; pharmaceutical Preformulation and Formulation (Pharmaceutical Preformulation and Formulation), 2 nd edition, edited by Gibson, CRC Press LLC: bocardon, florida, 2009.

The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound having an acidic group described herein with a base to form a salt, such as an ammonium salt, an alkali metal salt (e.g., sodium or potassium salt), an alkaline earth metal salt (e.g., calcium or magnesium salt), a salt of an organic base (e.g., dicyclohexylamine, N-methyl-D-glucosamine, tris (hydroxymethyl) methylamine), and a salt with an amino acid (e.g., arginine, lysine, and the like), or by other methods previously identified. The pharmaceutically acceptable salt is not particularly limited as long as it can be used for a medicament. Examples of salts formed with bases of the compounds described herein include the following: salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salt may be an acid addition salt, specific examples of which are acid addition salts formed with: inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid: organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and ethanesulfonic acid; acidic amino acids, such as aspartic acid and glutamic acid.

The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components (collectively referred to herein as "excipients"), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. There are a variety of techniques in the art for administering compounds, including but not limited to: rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary and topical administration.

The term "subject" may refer to an animal, including but not limited to a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, for example to refer to a mammalian subject, such as a human.

In the context of treating a disease, disorder, or condition, the terms "treat," "treating," and "therapy" are intended to include the alleviation or elimination of the disease, disorder, or condition, or one or more symptoms associated with the disease, or condition; or slowing the progression, spread, or worsening of the disease, disorder, or condition, or one or more symptoms thereof. "cancer treatment" refers to one or more of the following effects: (1) inhibit tumor growth to some extent, including (i) slowing and (ii) complete growth arrest; (2) reducing the number of tumor cells; (3) maintaining tumor size; (4) reducing the size of the tumor; (5) inhibition, including (i) reduction, (ii) slowing, or (iii) complete prevention of tumor cell infiltration into peripheral organs; (6) inhibition, including (i) reduction, (ii) slowing, or (iii) complete prevention of metastasis; (7) an enhanced anti-tumor immune response that may (i) maintain tumor size, (ii) reduce tumor size, (iii) slow tumor growth, (iv) reduce, slow or prevent invasiveness and/or (8) reduce to some extent the severity or number of one or more symptoms associated with the disorder.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "alkyl" refers to a hydrocarbon chain that may be straight or branched, containing the indicated number of carbon atoms. E.g. C_1-10Means that the group may have 1 to 10 (inclusive) carbon atoms. Non-limiting examples include methyl, ethyl, i-propyl, t-butyl, n-hexyl.

The term "haloalkyl" refers to an alkyl group wherein one or more hydrogen atoms are replaced with an independently selected halogen.

The term "alkoxy" refers to-O-alkyl (e.g., -OCH)₃)。

The term "alkylene" refers to a divalent alkyl group (e.g., -CH)₂-)。

The term "alkenyl" refers to a hydrocarbon chain that may be straight or branched having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. E.g. C_2-6Meaning that the group may have 2 to 6 (inclusive) carbon atoms in it.

The term "alkynyl" refers to a hydrocarbon chain that may be straight or branched having one or more carbon-carbon triple bonds. Alkynyl moieties contain the indicated number of carbon atoms. E.g. C_2-6Meaning that the group may have 2 to 6 (inclusive) carbon atoms in it.

The term "aryl" refers to a 6-20 carbon monocyclic, bicyclic, tricyclic, or polycyclic group in which at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1,2,3 or 4 atoms of each ring may be substituted with a substituent. Examples of aryl groups also include phenyl, naphthyl, tetrahydronaphthyl, and the like.

The term "cycloalkyl" as used herein includes cycloalkyl groups having from 3 to 20 ring carbons, preferably from 3 to 16 ring carbons, and more preferably from 3 to 12 ring carbons or from 3-10 ring carbons or from 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl group may include a plurality of fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl groups include: bicyclo [1.1.0] butane, bicyclo [2.1.0] pentane, bicyclo [1.1.1] pentane, bicyclo [3.1.0] hexane, bicyclo [2.1.1] hexane, bicyclo [3.2.0] heptane, bicyclo [4.1.0] heptane, bicyclo [2.2.1] heptane, bicyclo [3.1.1] heptane, bicyclo [4.2.0] octane, bicyclo [3.2.1] octane, bicyclo [2.2.2] octane, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirobicyclic rings in which the two rings are connected by only one atom). Non-limiting examples of spirocyclic cycloalkyl groups include: spiro [2.2] pentane, spiro [2.5] octane, spiro [3.5] nonane, spiro [4.4] nonane, spiro [2.6] nonane, spiro [4.5] decane, spiro [3.6] decane, spiro [5.5] undecane and the like.

The term "cycloalkenyl" as used herein includes partially unsaturated cyclic hydrocarbon groups having from 3 to 20 ring carbons, preferably from 3 to 16 ring carbons, and more preferably from 3 to 12 ring carbons or from 3-10 ring carbons or from 3-6 ring carbons, wherein cycloalkenyl may be optionally substituted. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkenyl groups can have any degree of saturation, provided that all rings in the ring system are not aromatic; and the cycloalkenyl group as a whole is not fully saturated. Cycloalkenyl groups can include multiple fused and/or bridged rings and/or spiro rings.

As used herein, the term "heteroaryl" refers to a mono-, di-, tri-or polycyclic group having 5 to 20 ring atoms, alternatively 5,6, 9, 10 or 14 ring atoms; and share 6, 10 or 14 pi electrons in a circular array; wherein at least one ring in the system is aromatic (but not necessarily a heteroatom-containing ring, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl), and at least one ring in the system contains one or more heteroatoms independently selected from N, O and S. Heteroaryl groups may be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include: thienyl, pyridyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzooxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridyl, pyrido [2,3-d ] pyrimidinyl, pyrrolo [2,3-b ] pyridyl, quinazolinyl, quinolyl, thieno [2,3-c ] pyridyl, pyrazolo [3,4-b ] pyridyl, pyrazolo [3,4-c ] pyridyl, pyrazolo [4,3-b ] pyridyl, Tetrazolyl, chromane, 2, 3-dihydrobenzo [ b ] [1,4] dioxine, benzo [ d ] [1,3] dioxole, 2, 3-dihydrobenzofuran, tetrahydroquinoline, 2, 3-dihydrobenzo [ b ] [1,4] oxathiadiene (oxathiine), isoindole, and the like. In some embodiments, heteroaryl is selected from: thienyl, pyridyl, furyl, pyrazolyl, imidazolyl, isoindolyl, pyranyl, pyrazinyl and pyrimidinyl.

The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic non-aromatic ring system having 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic), having 1-3 heteroatoms (if monocyclic), 1-6 heteroatoms (if bicyclic), or 1-9 heteroatoms (if tricyclic or polycyclic) selected from O, N, or S (e.g., having carbon atoms and 1-3, 1-6, or 1-9 heteroatoms selected from N, O or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1,2, or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclic groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl and the like. The heterocyclic group may include a plurality of fused and/or bridged rings. Non-limiting examples of fused/bridged heterocyclic groups include: 2-azabicyclo [1.1.0] butane, 2-azabicyclo [2.1.0] pentane, 2-azabicyclo [1.1.1] pentane, 3-azabicyclo [3.1.0] hexane, 5-azabicyclo [2.1.1] hexane, 3-azabicyclo [3.2.0] heptane, octahydrocyclopenta [ c ] pyrrole, 3-azabicyclo [4.1.0] heptane, 7-azabicyclo [2.2.1] heptane, 6-azabicyclo [3.1.1] heptane, 7-azabicyclo [4.2.0] octane, 2-azabicyclo [2.2.2] octane, 3-azabicyclo [3.2.1] octane, 2-oxabicyclo [1.1.0] butane, 2-oxabicyclo [2.1.0] pentane, 2-oxabicyclo [1.1 ] pentane, 3-oxabicyclo [3.1.0] hexane, 5-oxabicyclo [2.1.0] hexane, 3.0 ] heptane, 3-oxabicyclo [ 3.0 ] heptane, 3-oxabicyclo [4.1.0] heptane, 7-oxabicyclo [2.2.1] heptane, 6-oxabicyclo [3.1.1] heptane, 7-oxabicyclo [4.2.0] octane, 2-oxabicyclo [2.2.2] octane, 3-oxabicyclo [3.2.1] octane and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirobicyclic rings in which the two rings are connected by only one atom). Non-limiting examples of spirocyclic heterocyclic groups include: 2-azaspiro [2.2] pentane, 4-azaspiro [2.5] octane, 1-azaspiro [3.5] nonane, 2-azaspiro [3.5] nonane, 7-azaspiro [3.5] nonane, 2-azaspiro [4.4] nonane, 6-azaspiro [2.6] nonane, 1, 7-diazaspiro [4.5] decane, 7-azaspiro [4.5] decane 2, 5-diazaspiro [3.6] decane, 3-azaspiro [5.5] undecane, 2-oxaspiro [2.2] pentane, 4-oxaspiro [2.5] octane, 1-oxaspiro [3.5] nonane, 2-oxaspiro [3.5] nonane, 7-oxaspiro [3.5] nonane, 2-oxaspiro [4.4] nonane, 6-oxaspiro [2.6] nonane, 1, 7-oxaspiro [4.5] nonane, 2, 5-dioxaspiro [3.6] decane, 1-oxaspiro [5.5] undecane, 3-oxa-9-azaspiro [5.5] undecane and the like.

In addition, the atoms that make up the compounds of the embodiments of the present invention are intended to include all isotopic forms of the atoms recited. Isotopes used herein include those atoms having the same atomic number but different mass numbers. By way of general example, and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include¹³C and¹⁴C。

in addition, the compounds disclosed herein, either generically or specifically, are intended to include all tautomeric forms. Thus, for exampleSaid, containing partThe compound of (1) comprises a moiety containingIn tautomeric form (a). Similarly, a pyridyl or pyrimidinyl moiety described as optionally substituted with hydroxy includes pyridone or pyrimidone tautomeric forms.

The figures and the following description further illustrate one or more embodiments of the invention in detail. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

Detailed Description

A compound of formula I

In one aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof characterized by:

or a pharmaceutically acceptable salt or tautomer thereof,

wherein:

L^ABis-N (R)^N)S(O)₂-*，-N(R^N)S(O)₂-(W^AB1-W^AB2-W^AB3)-*，–S(O)₂N(R^N)-*，

Wherein the asterisks indicate the points of attachment to B;

W^AB1is C_1-3Alkylene optionally substituted with 1-4 independently selected R^aSubstitution;

W^AB2is a bond, -O-, -NR-^Nor-S-;

W^AB3is a bond or C_1-3Alkylene optionally substituted with 1-4 independently selected R^aSubstitution;

a is selected from the following group:

B is:

(a)C_1-15alkyl optionally substituted with 1-6R^aSubstitution;

(b)C_3-20cycloalkyl optionally substituted with 1-4R^bSubstitution;

(c)C6_-20aryl optionally substituted with 1-4R^cSubstitution;

(e) Comprising 3 to 16 rings(ii) heterocyclyl of atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n (H), N (R)^d) O and S (O)_0-2And wherein said heterocyclyl ring is optionally substituted with 1-4 independently selected R^bSubstitution;

R^Nthe method comprises the following steps:

(i) h, or

(ii)C_1-6Alkyl, optionally substituted with 1-3R^aThe substitution is carried out by the following steps,

R¹the method comprises the following steps:

(i)-(U¹)_q-U²wherein:

q is 0 or 1;

·U¹is C_1-6Alkylene optionally substituted by 1 to 6R^aSubstitution; and

·U²the method comprises the following steps:

(a)C_3-12cycloalkyl optionally substituted with 1-4R^bThe substitution is carried out by the following steps,

(b)C_6-10aryl optionally substituted with 1-4R^cSubstitution;

(d) Heterocyclyl comprising 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)^d) O and S (O)_0-2And wherein said heterocyclyl ring is optionally substituted with 1-4 independently selected R^bThe substitution is carried out by the following steps,

(ii)C_1-10Alkyl optionally substituted with 1-6 independently selected R^aSubstitution;

each occurrence of R²Independently selected from the group consisting of:

(i)C_1-6alkyl optionally substituted with 1-2 independently selected R^aSubstitution;

(ii)C_3-6a cycloalkyl group;

(iii) heterocyclyl comprising 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)^d) O and S (O)_0-2，

(iv)-C(O)(C_1-4Alkyl groups);

(v)-C(O)O(C_1-4alkyl groups);

(vi)-CON(R’)(R”)；

(vii)-S(O)_1-2(NR’R”)；

(viii)-S(O)_1-2(C_1-4alkyl groups);

(ix) -OH; and

(x)C_1-4an alkoxy group;

each occurrence of R^bIndependently selected from the group consisting of: optionally substituted with 1-6 independently selected R^aSubstituted C_1-10An alkyl group; c_1-4A haloalkyl group; -OH; oxo; -F; -Cl; -Br; -NR^eR^f；C_1-4An alkoxy group; c_1-4A haloalkoxy group; -C (═ C)O)(C_1-4Alkyl groups); -C (═ O) O (C)_1-4Alkyl groups); -C (═ O) OH; -C (═ O) N (R') (R "); -S (O)_1-2(NR’R”)；-S(O)_1-2(C_1-4Alkyl groups); a cyano group; and-L¹-L²-R^h；

Each occurrence of R^cIndependently selected from the group consisting of:

(a) halogen;

(b) a cyano group;

(c)C_1-15alkyl optionally substituted with 1-6 independently selected R^aSubstitution;

(d)C_2-6an alkenyl group;

(e)C_2-6an alkynyl group;

(g)C_1-4alkoxy, optionally substituted with 1-3 independently selected R^aSubstitution;

(h)C_1-4a haloalkoxy group;

(i)-S(O)_1-2(C_1-4alkyl groups);

(j)-NR^eR^f；

(k)–OH；

(l)-S(O)_1-2(NR’R”)；

(m)-C_1-4a thioalkoxy group;

(n)-NO₂；

(o)-C(＝O)(C_1-4alkyl groups);

(p)-C(＝O)O(C_1-4alkyl groups);

(q)-C(＝O)OH；

(R) -C (═ O) N (R') (R "); and

(s)–L¹-L²-R^h；

-L¹is a bond or C_1-3An alkylene group;

-L²is-O-, -N (H) -, -S-or a bond;

R^hselected from:

·C_6-10aryl radicalsOptionally substituted with 1-4 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl or C_1-4A haloalkyl group; and

In one aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof characterized by:

or a pharmaceutically acceptable salt or tautomer thereof,

wherein:

L^ABis-N (R)^N)S(O)₂-. or-S (O)₂N(R^N) Wherein the asterisks indicate the points of attachment to B;

a is selected from the following group:

(ii) heteroaryl comprising 7 to 20 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)¹)、N(R²) O and S (O)_0-2And wherein 3 to 19 ring atoms are carbon atoms,each independently selected from the group consisting of: C. CH, CH₂、CR¹、CHR¹、C(R¹)₂、CR³、CHR³And C (R)³)₂；

B is:

(a)C_1-15alkyl optionally substituted with 1-6R^aSubstitution;

(b)C_3-20cycloalkyl optionally substituted with 1-4R^bSubstitution;

(c)C_6-20aryl optionally substituted with 1-4R^cSubstitution;

R^Nthe method comprises the following steps:

(i) h, or

(ii)C_1-6Alkyl, optionally substituted with 1-3R^aThe substitution is carried out by the following steps,

R¹the method comprises the following steps:

(i)-(U¹)_q-U²wherein:

q is 0 or 1;

·U¹is C_1-6Alkylene optionally substituted by 1 to 6R^aSubstitution; and

·U²the method comprises the following steps:

(a)C_3-12cycloalkyl optionally substituted with 1-4R^bThe substitution is carried out by the following steps,

(b)C_6-10aryl optionally substituted with 1-4R^cSubstitution;

(c) heteroaryl comprising 5 to 20 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selectedFrom the following groups N, N (H), N (R)^d)、O，S(O)_0-2And wherein said heteroaryl ring is optionally substituted with 1-4 independently selected R^cIs substituted, or

(d) Heterocyclyl comprising 3 to 12 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)^d) O and S (O)_0-2And wherein said heterocyclyl ring is optionally substituted with 1-4 independently selected R^bThe substitution is carried out by the following steps,

(ii)C_1-10Alkyl optionally substituted with 1-6 independently selected R^aSubstitution;

each occurrence of R²Independently selected from the group consisting of:

(i)C_1-6alkyl optionally substituted with 1-2 independently selected R^aSubstitution;

(ii)C_3-6a cycloalkyl group;

(iii) heterocyclyl comprising 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)^d) O and S (O)_0-2，

(iv)-C(O)(C_1-4Alkyl groups);

(v)-C(O)O(C_1-4alkyl groups);

(vi)-CON(R’)(R”)；

(vii)-S(O)_1-2(NR’R”)；

(viii)-S(O)_1-2(C_1-4alkyl groups);

(ix) -OH; and

(x)C_1-4an alkoxy group;

each occurrence of R³Independently selected from the group consisting of: halogen, cyano, optionally substituted by 1-2R^aSubstituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, -S (O)_1-2(C_1-4Alkyl), -NR^eR^f-OH, oxo, -S (O)_1-2(NR’R”)，-C_1-4Thioalkoxy, -NO₂，-C(＝O)(C_1-4Alkyl group, -C (═ C)O)O(C_1-4Alkyl, -C (═ O) OH and-C (═ O) N (R') (R ");

Each occurrence of R^cIndependently selected from the group consisting of:

(a) halogen;

(b) a cyano group;

(c)C_1-15alkyl optionally substituted with 1-6 independently selected R^aSubstitution;

(d)C_2-6an alkenyl group;

(e)C_2-6an alkynyl group;

(g)C_1-4an alkoxy group;

(h)C_1-4a haloalkoxy group;

(i)-S(O)_1-2(C_1-4alkyl groups);

(j)-NR^eR^f；

(k)–OH；

(l)-S(O)_1-2(NR’R”)；

(m)-C_1-4a thioalkoxy group;

(n)-NO₂；

(o)-C(＝O)(C_1-4alkyl groups);

(p)-C(＝O)O(C_1-4alkyl groups);

(q)-C(＝O)OH；

(R) -C (═ O) N (R') (R "); and

(s)–L¹-L²-R^h；

-L¹is a bond or C_1-3An alkylene group;

-L²is-O-, -N (H) -, -S-or a bond;

R^hselected from:

·C_6-10aryl optionally substituted with 1-4 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl or C_1-4A haloalkyl group; and

Variable A

In some embodiments, a is: heteroaryl comprising 7 to 20 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)¹)、N(R²) O and S (O)_0-2And wherein 3 to 19 ring atoms are carbon atoms, each independently selected from the group consisting of: C. CH, CH₂、CR¹、CHR¹、C(R¹)₂、CR³、CHR³And C (R)³)₂。

In some embodiments, a is: heteroaryl comprising 8 to 12 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)¹)、N(R²) O and S (O)_0-2And wherein 4 to 11 ring atoms are carbon atoms, each independently selected from the group consisting of: C. CH, CH₂、CR¹、CHR¹、C(R¹)₂、CR³、CHR³And C (R)³)₂。

In some embodiments, a is: heteroaryl comprising 8 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)¹)、N(R²) O and S (O)_0-2And wherein 4 to 9 ring atoms are carbon atoms, each independently selected from the group consisting of: C. CH, CH₂、CR¹、CHR¹、C(R¹)₂、CR³、CHR³And C (R)³)₂。

In some embodiments, a is: heteroaryl comprising 8 to 9 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of: n, N (H), N (R)¹)、N(R²) O and S (O)_0-2And wherein 4 to 8 ring atoms are carbon atoms, each independently selected from the group consisting of: C. CH, CH₂、CR¹、CHR¹、C(R¹)₂、CR³、CHR³And C (R)³)₂。

In some embodiments, A is (A-1):

wherein

Z is selected from the group consisting of:

bond, CH, CR¹、CR³、N、NH、N(R¹) And N (R)²)；

Y¹、Y²And Y³Each of which isIndependently selected from the group consisting of: o, S, CH, CR¹、CR³、N、NH、N(R¹) And NR²；

Y⁴Is C or N;

X¹selected from the group consisting of: o, S, N, NH, NR¹、NR²、CH、CR¹And CR³；

X²Selected from the group consisting of: o, S, N, NH, NR¹、NR²、CH、CR¹And CR³(ii) a And

In some embodiments of (A-1), Z is selected from:

CH、CR¹、CR³n and N (R)²)。

In some embodiments of (A-1), Z is selected from: CH. CR¹、CR³And N.

In some embodiments of (A-1), Z is selected from CH, CR¹And CR³(e.g., Z is CH).

In some embodiments of (A-1), Y¹、Y²And Y³Each independently selected from CH and CR¹、CR³And N.

In some embodiments of (A-1), Y¹、Y²And Y³Each independently selected from CH and CR¹And CR³。

In some embodiments of (A-1),is partially

Wherein m1 is 0, 1,2 or 3; and m3 ═ 0, 1,2, or 3 (e.g., m1 ═ 0 or 1; and m3 ═ 0, 1, or 2).

In some embodiments of (A-1), 1-2Y¹、Y²And Y³Independently is N.

In some embodiments of (A-1), 1Y¹、Y²And Y³Independently is N.

In some of the foregoing embodiments, the remaining Y¹、Y²And Y³Each independently selected from CH and CR¹And CR³。

As a non-limiting example of (A-1),is partiallyWherein:

asterisk indicates Y⁴A point of connection; and

m1 is 0, 1 or 2; and m3 ═ 0, 1, or 2 (e.g., m1 ═ 0 or 1; and m3 ═ 0 or 1).

In some embodiments of (A-1), Y⁴Is C.

In some embodiments of (A-1), X¹Selected from the group consisting of: o, S, NH, NR¹And NR²。

In some embodiments of (A-1), X¹Selected from NH, NR¹And NR²(e.g., X)¹May be NH).

In some embodiments of (A-1), X²Selected from N, CH, CR¹And CR³。

In some embodiments of (A-1), X²Selected from N, C (C)_1-3Alkyl), and CH.

In some of these embodiments, X²Is CH.

In some embodiments of (A-1), X¹And X²Together areWherein the asterisks indicate⁴The point of connection.

As non-limiting examples of (A-1), A is:

wherein m1 is 0, 1,2 or 3; and m3 ═ 0, 1,2, or 3 (e.g., m1 ═ 0 or 1; and m3 ═ 0, 1, or 2).

As another non-limiting example of (A-1), A is:

wherein m1 is 0, 1 or 2; and m3 ═ 0, 1, or 2 (e.g., m1 ═ 0 or 1; and m3 ═ 0 or 1).

As another non-limiting example of (A-1), A is:

wherein m1 is 0, 1 or 2; and m3 ═ 0, 1, or 2 (e.g., m1 ═ 0 or 1; and m3 ═ 0 or 1).

As another non-limiting example of (A-1), A is:

wherein m1 is 0, 1 or 2; and m3 ═ 0, 1, or 2 (e.g., m1 ═ 0 or 1; and m3 ═ 0 or 1).

As another non-limiting example of (A-1), A is:

wherein m1 is 0, 1 or 2; and m3 ═ 0, 1, or 2 (e.g., m1 ═ 0 or 1; and m3 ═ 0 or 1).

In some embodiments, a is (a-2):

wherein

X¹selected from the group consisting of: o, S, N, NH, NR¹、NR²、CH、CR¹And CR³；

X²Selected from the group consisting of: o, S, N, NH, NR¹、NR²、CH、CR¹And CR³(ii) a Provided that Y is contained⁴、X¹And X²The ring(s) of (a) is heteroaromatic; and

Y⁴selected from: n or C.

In some embodiments of (A-2), Y⁴Is N.

In some embodiments of (A-2), Ring A^3AIs a monocyclic or bicyclic ring containing 5 to 11 ring atoms, of which 1 to 2 are heteroatoms (including Y)⁴) Wherein the additional heteroatoms are independently selected from N, N (H), N (R)¹)、N(R²) O, and S (O)_0-2And 3-11 are ring carbon atoms, each independently selected from: C. CH, CH₂、CR¹、CHR¹、C(R¹)₂、CR³、CHR³And C (R)³)₂Provided that ring A^3AIs non-aromatic。

In some of these embodiments, ring A^3AIs a monocyclic or bicyclic ring containing 5 to 11 ring atoms, of which 2 are heteroatoms (including Y)⁴) Wherein the additional heteroatoms are independently selected from N, N (H), N (R)¹)、N(R²) O, and S (O)_0-2And 3-11 are ring carbon atoms, each independently selected from: C. CH, CH₂、CR¹、CHR¹、C(R¹)₂、CR³、CHR³And C (R)³)₂Provided that ring A^3AIs non-aromatic.

In some embodiments, ring a^3AIs a monocyclic or bicyclic ring containing 5 to 11 ring atoms, of which 1 ring atom is a heteroatom (including Y)⁴) And 4-11 are ring carbon atoms, each independently selected from: C. CH, CH₂、CR¹、CHR¹、C(R¹)²、CR³、CHR³And C (R)³)²Provided that ring A^3AIs non-aromatic.

In certain of the foregoing embodiments, ring a^3AIs bicyclic (e.g., helical bicyclic) at Y⁴No further heteroatoms are included.

As non-limiting examples of (A-2), A is:

wherein m1 is 0, 1 or 2; and m3 ═ 0, 1, or 2 (e.g., m1 ═ 0 or 1; and m3 ═ 0 or 1).

In some embodiments of (A-2), Ring A^3AIs a monocyclic ring containing an O atom.

As non-limiting examples of (A-2), A is:

wherein m1 is 0, 1 or 2; and m3 ═ 0, 1, or 2 (e.g., m1 ═ 0 or 1; and m3 ═ 0 or 1).

In some embodiments of (A-2), X¹Is N.

In some embodiments of (A-2), X²Selected from CH and CR¹(e.g., CH).

In some embodiments, a is heteroaryl comprising 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from: n, N (H), N (R)¹)、N(R²) O, and S, and wherein 1-5 ring atoms are carbon atoms, each independently selected from the group consisting of: C. CH, CR¹And CR³With the proviso that at least one ring atom is replaced by R¹And (4) substitution.

In certain of these embodiments, A is heteroaryl comprising 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N (H), N (R)¹)、N(R²) O, and S, and wherein 1 to 4 ring atoms are carbon atoms, each independently selected from C, CH, CR¹And CR³(ii) a With the proviso that at least one ring atom is replaced by R¹And (4) substitution.

In certain of the foregoing embodiments, a is heteroaryl comprising 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N (H), N (R)¹)、N(R²) O, and S, and wherein 1 to 4 ring atoms are carbon atoms, each independently selected from C, CH, CR¹And CR³(ii) a Provided that one ring atom is substituted by R¹And (4) substitution.

In some embodiments, A is (A-3):

wherein:

Z²selected from: CH. R²And N;

X³selected from: o, S, N, NH, NR¹、NR²、CH、CR¹And CR³；

Y⁵And Y⁶Each independently selected from O, S, CH, CR¹、CR³、NR²NH and N; and

each one of which isIndependently is a single or double bond, provided that Y is comprised⁵、Y⁶、X³And Z²The five-membered ring of (a) is heteroaryl.

In some embodiments of (A-3):

when X is present³Is NR¹Or CR¹When, Y⁵And Y⁶Each independently selected from O, S, CH, CR³、NR²NH and N; and

when X is present³Selected from O, S, N, NH, NR²CH and CR³When, Y⁵And Y⁶Is CR¹(in some embodiments, Y⁵And Y⁶Another one of the groups is selected from O, S, CH, CR³、NR²NH and N).

In some embodiments of (A-3), Z²Selected from CH and N.

In certain embodiments of (A-3), Z²Is CH.

In some embodiments of (A-3), Y⁶Selected from N, CH, and CR³。

In certain embodiments of (A-3), Y⁶Is N.

In some embodiments of (A-3), Y⁵Is CR¹。

In some embodiments of (A-3), X³Selected from S, O, NH, and N (R)²) (e.g., NH).

As a non-limiting example of (A-3), A is

Variable R¹

In some embodiments, each occurrence of R¹Independently selected from:

(i)-(U¹)_q-U²wherein:

q is 0 or 1;

·U¹is C_1-6Alkylene optionally substituted by 1 to 6R^aSubstitution; and

·U²the method comprises the following steps:

(a)C_3-10cycloalkyl optionally substituted with 1-4R^bThe substitution is carried out by the following steps,

(b)C_6-10aryl optionally substituted with 1-4R^cSubstitution;

and

(ii)C_1-6alkyl optionally substituted with 1-6 independently selected R^aAnd (4) substitution.

In some embodiments, R¹Is- (U)¹)_q-U²。

In some of these embodiments, q is 0.

In some embodiments (when R is¹Is- (U)¹)_q-U²)，U²Is C_6-10Aryl optionally substituted with 1-4R^cAnd (4) substitution.

In some of these embodiments, U²Is C_6-10Aryl optionally substituted with 1-2R^cAnd (4) substitution.

By way of non-limiting example, U²Is phenyl optionally substituted with 1-2 (e.g., 1) R^cAnd (4) substitution.

In some embodiments (when U is used)²Is C_6-10Aryl optionally substituted with 1-2R^cSubstituted), U²Each occurrence of R^cThe substituents are independently selected from: halogen, cyano, C_1-6Alkyl radicals andC_1-4a haloalkyl group.

In some embodiments (when U is used)²Is C_6-10Aryl optionally substituted with 1-2R^cSubstituted), U²Each occurrence of R^cThe substituents are independently halogen.

In some embodiments, R¹Is phenyl optionally substituted with 1-2 (e.g., 0; e.g., 1) R^cAnd (4) substitution.

In some of these embodiments, U²R of (A) to^cThe substituents are independently selected from: halogen, cyano, C_1-6Alkyl and C_1-4A haloalkyl group.

In some embodiments, each occurrence of U²R of (A) to^cThe substituents are independently selected from halogen (e.g., -F).

Variable R³

In some embodiments, each occurrence of R³Independently selected from the group consisting of: halogen, cyano, C_1-4Alkoxy radical, C_1-4Haloalkoxy, -S (O)_1-2(C_1-4Alkyl), -NR^eR^f，–OH，-S(O)_1-2(NR’R”)，-C_1-4Thioalkoxy, -C (═ O) (C)_1-4Alkyl group, -C (═ O) O (C)_1-4Alkyl, -C (═ O) OH and-C (═ O) N (R') (R ").

In some embodiments, each occurrence of R³Independently selected from the group consisting of: halogen, cyano, C_1-4Alkoxy radical, C_1-4Haloalkoxy, -S (O)_1-2(C_1-4Alkyl group, -S (O)_1-2(NR’R”)，-C(＝O)(C_1-4Alkyl group, -C (═ O) O (C)_1-4Alkyl, -C (═ O) OH and-C (═ O) N (R') (R ").

In some embodiments, each occurrence of R³Independently selected from the group consisting of: halogen, cyano, C_1-4Alkoxy and C_1-4Haloalkoxy (e.g., R)³May be a halogen).

Variable R²

In some embodiments, each occurrence of R²Independently selected from:

(i)C_1-6alkyl (e.g., methyl);

(ii)C_3-6a cycloalkyl group;

(iv)-C(O)(C_1-4alkyl) (e.g., c (o) Me);

(v)-C(O)O(C_1-4alkyl groups);

(vi)-CON(R’)(R”)；

(vii)-S(O)_1-2(NR' R "); and

(viii)-S(O)_1-2(C_1-4alkyl) (e.g., S (O)₂Me)。

¹ ³A. R, and non-limiting combinations of R

In some embodiments, a is as defined in any one of claims 12, 16, 24, 25, 31, and 33; and m1 is 1.

In some of these embodiments, m3 is 0.

In some embodiments (when a is as defined in any one of claims 12, 16, 24, 25, 31, and 33; and m1 is 1), R is¹As defined in any one of claims 48 to 57.

In some embodiments, a is as defined in any one of claims 12, 16, 24, 25, 31, and 33; and m1 is 0.

In some of these embodiments, m3 is 0.

In some other embodiments, m3 is 1 or 2 (e.g., 1).

In some embodiments (when a is as defined in any one of claims 12, 16, 24, 25, 31, and 33; m1 ═ 0; and m3 ═ 1 or 2 (e.g., 1)), each occurrence of R³As defined in any one of claims 58 to 60.

In some of the foregoing embodiments, each occurrence of R is^aIndependently a halogen (e.g., F).

Variable B

In some embodiments, B is substituted with 1-4R^cA substituted phenyl group.

In some embodiments, B is substituted with 1-2R^cSubstituted phenyl, wherein 1R^cIn formula I to link L^ABA ring carbon para to a point of the moiety.

In some embodiments, B is substituted with 1R^cSubstituted phenyl, wherein 1R^cIn formula I to link L^ABThe ring carbon para to the point of the moiety (i.e.,)。

in some embodiments (e.g., when B is optionally substituted with 1-4R^cSubstituted phenyl), R on B for each occurrence^cThe substituents are independently selected from:

(a) halogen;

(b) a cyano group;

(c)C_1-10alkyl optionally substituted with 1-6 independently selected R^aSubstitution;

(g)C_1-4an alkoxy group;

(h)C_1-4a haloalkoxy group;

(i)-S(O)_1-2(C_1-4alkyl groups);

(m)-C_1-4a thioalkoxy group;

(o)-C(＝O)(C_1-4alkyl groups);

(p)-C(＝O)O(C_1-4alkyl groups);

(R) -C (═ O) N (R') (R "); and

(s)–L¹-L²-R^h。

in some embodiments, each occurrence of R of B is^cThe substituents are independently selected from:

(a) halogen;

(b) a cyano group;

(c)C_1-10alkyl optionally substituted with 1-6 independently selected R^aSubstitution;

(g)C_1-4an alkoxy group;

(h)C_1-4a haloalkoxy group; and

(s)–L¹-L²-R^h。

in some embodiments, each occurrence of R of B is^cThe substituents are independently selected from:

(a) halogen;

(b) a cyano group;

(c)C_1-10alkyl optionally substituted with 1-6 independently selected R^aSubstitution;

(g)C_1-4alkoxy, optionally substituted with 1-2 independently selected R^aSubstitution;

(h)C_1-4a haloalkoxy group; and

(s)–L¹-L²-R^h。

in some embodiments, each occurrence of R of B is^cThe substituents are independently selected from:

(a) halogen;

(c)C_1-10alkyl optionally substituted with 1-6 independently selected R^aSubstitution; and

(s)–L¹-L²-R^h。

in some embodiments, one occurrence of R^cIs C_1-10Alkyl optionally substituted with 1-6 independently selected R^aAnd (4) substitution.

In some embodiments, one occurrence of R^cIs C_1-6Alkyl optionally substituted with 1-6 independently selected R^aAnd (4) substitution.

In some of these embodiments, one occurrence of R^cIs unsubstituted C_1-10An alkyl group.

As a non-limiting example, R occurs once^cIs unsubstituted C_2-10(e.g., C)₂-3, e.g. C_3-4E.g. C_4-10) An alkyl group.

In some embodiments, one occurrence of R^cIs C_1-6Alkyl, which is substituted with 1-6 independently selected R^aAnd (4) substitution.

As a non-limiting example, R occurs once^cIs CF₃Or(e.g., R)^cMay be CF₃)。

In any of the foregoing embodiments (e.g., when R occurs at one time)^cIs optionally 1-6 independently selected R^aSubstituted C_1-10Alkyl), the second occurrence of R^cIndependently when present, is halogen.

In any of the foregoing embodiments (e.g., when R occurs at one time)^cIs optionally 1-6 independently selected R^aSubstituted C_1-10Alkyl), B is R which is present 1 to 3 times^cSubstituted phenyl; and R appears once^cIn formula I to link L^ABA ring carbon para to a point of the moiety.

In certain embodiments, B is selected from: wherein R is^cAAnd R^cBEach independently selected R^c(ii) a n1 is 0, 1, or 2; q¹，Q²，Q³，Q⁴，Q⁵And Q⁶Each independently selected from N and CH, with the proviso that at least one Q¹And Q²Is N; and at least one Q³，Q⁴，Q⁵And Q⁶Is N.

In some of these embodiments, n1 is 0.

In some of the other embodiments, n1 is 1. In some of these embodiments, R^cAIs halogen (e.g., -F, or-Cl) or C_1-6Alkyl optionally substituted with 1-3 independently selected R^a(e.g., methyl or CF)₃) And (4) substitution.

In some embodiments, R^cBIs C_1-6Alkyl optionally substituted with 1-6 independently selected R^aAnd (4) substitution.

For example, R^cBMay be unsubstituted C_2-10(e.g., C)_2-3E.g. C_3-4E.g. C_4-10) An alkyl group.

As another non-limiting example, R^cBMay be C_1-6Alkyl, which is substituted with 1-6 independently selected R^aAnd (4) substitution. For example, R^aEach may be halogen (e.g., F), NR^eR^f，OH，C_1-3Alkoxy, or C_1-3A haloalkoxy group.

In some embodiments, R^cBis-L¹-L²-R^h. In some of these embodiments, L¹And L²Each is a bond. In some other embodiments, L¹Is a bond; and L is²is-O-.

In certain embodiments, R^hSelected from:

C₆aryl optionally substituted with 1-4 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl or C_1-4A haloalkyl group.

In some embodiments, B is heteroaryl comprising 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from N, N (h), N (R)^d) O, and S (O)_0-2And wherein the heteroaryl ring is substituted with 1-4 independently selected R^cSubstituted, provided that one occurrence of R^cIs L¹-L²-R^h. In some of these embodiments, L¹And L²Each is a bond. In some other embodiments, L¹Is a bond; and L is²is-O-.

In certain embodiments, R^hSelected from:

C₆aryl optionally substituted with 1-4 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl or C_1-4A haloalkyl group.

In some embodiments, B isWherein:

n1 is 0 or 1; and

R^cAand R^cBEach independently selected R^c。

In some of these embodiments, R^cBIs R as defined in any one of claims 76 to 82^c。

In certain of the foregoing embodiments, R^cBIs R as defined in any of claims 78 to 79^c。

In certain embodiments, R^cBIs unsubstituted C_1-10An alkyl group.

In some embodiments of the present invention, the substrate is,R^cBis unsubstituted C_2-10(e.g., C)_2-3E.g. C_3-4E.g. C_4-10) An alkyl group.

In certain of the foregoing embodiments, R^cBIs R as defined in any one of claims 80 to 81^c。

In some embodiments, R^cBIs C_1-6Alkyl, which is substituted with 1-6 independently selected R^aAnd (4) substitution.

In some embodiments, R^cBIs CF₃Or(e.g., R)^cMay be CF₃)。

In some embodiments (when B is) And n1 is 0.

In some embodiments (when B is) N1 is 1; and R is^cAIs a halogen.

In some embodiments, B is optionally substituted with 1-6R^aSubstituted C_5-15(e.g., C)_5-7，C_8-10，C_11-13Or C_14-15) An alkyl group.

In some embodiments, B is optionally substituted with 1-3R^aSubstituted C_5-15(e.g., C)_5-7，C_8-10，C_11-13Or C_14-15) An alkyl group.

In some embodiments, B is C_5-15(e.g., C)_5-7，C_8-10，C_11-13Or C_14-15) An alkyl group. For example, B may be C₈，C₉，C₁₀，C₁₁，C₁₂，C₁₃，C₁₄Or C₁₅Alkyl (e.g., straight chain alkyl).

Variable L^AB

In some embodiments, L^ABis-N (R)^N)S(O)₂-*。

In some embodiments, L^ABis-S (O)₂N(R^N)-*。

In some embodiments, L^ABis-N (R)^N)S(O)₂-(W^AB1-W^AB2-W^AB3)-*。

In some of these embodiments, W^AB1Is C_1-3An alkylene group.

In some of the foregoing embodiments, W^AB2Is a bond. In some other embodiments, W^AB2is-O-or-S- (e.g., -O-).

In certain embodiments, W^AB3Is a bond. In some other embodiments, W^AB3Is C_1-3An alkylene group.

By way of non-limiting example, when L^ABis-N (R)^N)S(O)₂-(W^AB1-W^AB2-W^AB3)-*，L^ABCan be as follows: CH (CH)₂，CH₂CH₂，CH₂CH₂CH₂Or CH₂CH₂CH₂OCH₂*。

In some embodiments, R^NIs H.

Non-limiting combinations

[I-1]

In some embodiments, the compound has formula (I-1):

wherein n1 is 0 or 1; and

R^cAand R^cBEach independently selected R^c。

[I-2]

In some embodiments, the compound has formula (I-2):

wherein n1 is 0 or 1; and

R^cAand R^cBEach independently selected R^c。

In some embodiments of [ I-1] and [ I-2], A is (A-1) as defined in claim 6.

In some embodiments of [ I-1] and [ I-2], A is as defined in claim 24.

In some embodiments of [ I-1] and [ I-2], A is as defined in claim 25.

In some embodiments of [ I-1] and [ I-2] (when a is as defined in claim 24; or when a is as defined in claim 25), m1 is 0.

In some of these embodiments, m3 is 1.

In certain of the foregoing embodiments, R³As defined in any one of claims 48 to 50.

In some embodiments of [ I-1] and [ I-2] (when a is as defined in claim 24; or when a is as defined in claim 25; and m1 ═ 0), m3 ═ 0.

In some embodiments of [ I-1] and [ I-2], A is (A-2) as defined in claim 26.

In some embodiments of [ I-1] and [ I-2], a is as defined in any one of claims 30-31 (e.g., claim 31).

In some embodiments of [ I-1] and [ I-2], a is as defined in any one of claims 32-33 (e.g., claim 33).

In some embodiments of [ I-1] and [ I-2] (when a is as defined in any one of claims 30 to 31 (e.g. claim 31; or when a is as defined in any one of claims 32 to 33 (e.g. claim 33)), m1 is 0.

In some of these embodiments, m3 is 0.

In some embodiments of [ I-1] and [ I-2], A is (A-3) as defined in claim 39.

In some embodiments of [ I-1] and [ I-2], A is as defined in claim 47.

In [ I-1]]And [ I-2]In some embodiments of (a) when a is (a-3) as defined in claim 39, R¹As defined in any one of claims 56 to 57.

In [ I-1]]And [ I-2]In some embodiments, R^cBIs R as defined in any one of claims 76 to 82^c。

In [ I-1]]And [ I-2]In some embodiments, R^cBIs R as defined in any of claims 78 to 79^c。

In [ I-1]]And [ I-2]In some embodiments, R^cBIs R as defined in any one of claims 80 to 81^c。

In some embodiments of [ I-1] and [ I-2], n1 is 0.

In [ I-1]]And [ I-2]In some embodiments, n1 is 1; and R is^cAIs a halogen.

[I-3]

In some embodiments, a is selected from:

R^2Nis H or R²；

m1 is 0 or 1; and m3 is 0, 1 or 2;

L^ABis-N (H) S (O)₂-NHS (O)₂-(W^AB1) -; and is

B is selected from:

C₆aryl radicals substituted by 1 to 4R^cSubstitution;

C_5-15alkyl optionally substituted with 1-6R^aSubstitution; and is

C_8-20Aryl optionally substituted with 1-4R^cSubstitution;

in [ I-3]In some embodiments, R^2NIs H.

In some embodiments of [ I-3], m1 is 0.

In some other embodiments of [1-3], m1 is 1.

In some embodiments of [ I-3], m3 is 0.

In some other embodiments, m3 is 1 or 2.

In some embodiments of [1-3], m1 is 0; and m3 is 1 or 2 (e.g., 2).

In [1-3]]In some embodiments, A isFor example, R³Each may be halogen (e.g., F).

In [1-3]]In some embodiments, each occurrence of R³Independently selected from: halogen, cyano, C_1-4Alkoxy radical, C_1-4Haloalkoxy, -S (O)_1-2(C_1-4Alkyl group, -S (O)_1-2(NR’R”)，-C(＝O)(C_1-4Alkyl group, -C (═ O) O (C)_1-4Alkyl, -C (═ O) OH and-C (═ O) N (R') (R ").

In [1-3]]In some embodiments, each occurrence of R³Independently selected from: halogen, cyano, C_1-4Alkoxy and C_1-4Haloalkoxy (e.g., R)³May be a halogen).

In [1-3]]In some embodiments, R¹Is- (U)¹)_q-U²。

In some of these embodiments, q is 0.

In [1-3]]In some embodiments (when R is¹Is- (U)¹)_q-U²)，U²Is C_6-10Aryl of (1), which is optionalGround quilt 1-4R^cAnd (4) substitution.

In [1-3]]In some of these embodiments of (1), U²Is C_6-10Aryl optionally substituted with 1-2R^cAnd (4) substitution.

By way of non-limiting example, U²Is phenyl optionally substituted with 1-2 (e.g., 1) R^cAnd (4) substitution.

In [1-3]]In some embodiments (when U is used)²Is C_6-10Aryl optionally substituted with 1-2R^cSubstituted), U²Each occurrence of R^cThe substituents are independently selected from: halogen, cyano, C_1-6Alkyl and C_1-4A haloalkyl group.

In [1-3]]In some embodiments (when U is used)²Is C_6-10Aryl optionally substituted with 1-2R^cSubstituted), U²Each occurrence of R^cThe substituents are independently selected from halogen.

In [1-3]]In some embodiments, L^ABIs NHS (O)₂- *. In some other embodiments, L^ABIs NHS (O)₂-(C_1-3Alkylene) -.

In [1-3]]In some embodiments, B is selected from: wherein R is^cAAnd R^cBEach independently selected R^c(ii) a n1 is 0, 1, or 2; q¹，Q²，Q³，Q⁴，Q⁵And Q⁶Each independently selected from N and CH, with the proviso that at least one Q¹And Q²Is N; and at least one Q³，Q⁴，Q⁵And Q⁶Is N.

In some of these embodiments, n1 is 0.

In some of the other embodiments, n1 is 1. In some of these embodiments, R^cAIs halogen (e.g., -F, or-Cl)Or C_1-6Alkyl optionally substituted with 1-3 independently selected R^a(e.g., methyl or CF)₃) And (4) substitution.

In some embodiments, R^cBIs C_1-6Alkyl optionally substituted with 1-6 independently selected R^aAnd (4) substitution.

For example, R^cBMay be unsubstituted C_2-10(e.g., C)₂-3, e.g. C_3-4E.g. C_4-10) An alkyl group.

In some embodiments, R^cBis-L¹-L²-R^h. In some of these embodiments, L¹And L²Each is a bond. In some other embodiments, L¹Is a bond; and L is²is-O-.

In certain embodiments, R^hSelected from:

C₆aryl optionally substituted with 1-4 substituents independently selected from the group consisting of: halogen, halogen,C_1-4Alkyl or C_1-4A haloalkyl group.

In [1-3]]In some embodiments, B is heteroaryl comprising 5 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from N, N (H), N (R)^d) O, and S (O)_0-2And wherein the heteroaryl ring is substituted with 1-4 independently selected R^cSubstituted, provided that one occurrence of R^cIs L¹-L²-R^h. In some of these embodiments, L¹And L²Each is a bond. In some other embodiments, L¹Is a bond; and L is²is-O-.

In certain embodiments, R^hSelected from:

C₆aryl optionally substituted with 1-4 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl or C_1-4A haloalkyl group.

Non-limiting exemplary Compounds

In some embodiments, the compound is selected from the following or a pharmaceutically acceptable salt thereof:

TABLE C1

Or a pharmaceutically acceptable salt thereof.

The specification includes 170 claims. For ease of description, certain variable definitions refer to one or more specific claim numbers, and thus, it should be understood that the entire subject matter of each claim referenced is incorporated by reference in its entirety into the portion of the disclosure to which it is referenced. For the avoidance of doubt, and as a non-limiting example, the use of expressions such as "a is as defined in claim 24" is intended to represent a brief description of the following set of definitions:

a is:

wherein m1 is 0, 1,2 or 3; and m3 ═ 0, 1,2, or 3 (e.g., m1 ═ 0 or 1; and m3 ═ 0, 1, or 2).

Pharmaceutical compositions and administration

SUMMARY

In some embodiments, a chemical entity (e.g., a compound that inhibits (e.g., antagonizes) STING, or a pharmaceutically acceptable salt, and/or hydrate, and/or co-crystal, and/or a pharmaceutical combination thereof) is administered as a pharmaceutical composition comprising the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more other therapeutic agents described herein.

In some embodiments, the chemical entity may be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), such as d- α -tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tweens (Tweens), poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphates, tris (hydroxymethyl) aminomethane (tris), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or dielectrics, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and lanolin. Cyclodextrins, such as alpha-, beta and gamma-cyclodextrins, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2-and 3-hydroxypropyl-beta-cyclodextrins, or other solubilized derivatives may also be used to provide delivery of the compounds described herein. Dosage forms or compositions may be prepared comprising in the range of 0.005% to 100% of the chemical entity described herein, the balance being made up by non-toxic excipients. Contemplated compositions may comprise from 0.001% to 100%, in one embodiment from 0.1% to 95%, in another embodiment from 75% to 85%, and in yet another embodiment from 20% to 80% of the chemical entity provided herein. The actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington: pharmaceutical sciences and practices (Remington: The Science and Practice of Pharmacy), 22 nd edition (Pharmaceutical Press, 2012, London, UK).

Route of administration and composition Components

In some embodiments, a chemical entity described herein or a pharmaceutical composition thereof can be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to: buccal, transdermal, intracervical, intranasally, intratracheally, enterally, epidurally (epidural), interstitial, intraperitoneal, intraarterial, intrabronchial, intracapsular (intraburst), intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intracisternal, intraepithelial, intragastric, intragingival, retrointestinal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intraspinal, intrasynovial, intratesticular, intrathecal, intrarenal, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, transdermal, epidural (peridural), rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, and vaginal. In some embodiments, the preferred route of administration is parenteral (e.g., intratumoral).

The compositions may be formulated for parenteral administration, for example, for injection by the intravenous, intramuscular, subcutaneous or even intraperitoneal routes. Generally, such compositions may be prepared as injectables, either in liquid solution or suspension form; solid forms suitable for addition of liquid preparation solutions or suspensions prior to injection may also be prepared; also, the formulation may be emulsified. The preparation of such formulations is known to those skilled in the art in light of this disclosure.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; including sesame oil, peanut oil or aqueous propylene glycol formulations; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy injection is possible. It should also be stable under the conditions of manufacture and storage and must be resistant to the contaminating action of microorganisms such as bacteria and fungi during storage.

The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains an alkaline dispersion medium and the other required ingredients enumerated above. When sterile powders for the preparation of sterile injectable solutions are employed, the preferred methods of preparation are vacuum drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Intratumoral Injection see, for example, Lammers et al, "effects of Intratumoral Injection on Biodistribution and Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems" ("effective of Integrated Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems") Neopalasia.2006, 10, 788-.

Pharmaceutically acceptable excipients that may be used as gels, creams, enemas, or rectal suppositories in rectal compositions include, but are not limited to, one or more of the following: cocoa butter glycerides, synthetic polymers (e.g. polyvinylpyrrolidone, PEG (e.g. PEG ointment)), glycerol, glycerogelatin, hydrogenated vegetable oils, poloxamers, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, antioxidant SBN, vanilla essential oil, aerosols, parabens in phenoxyethanol, sodium methyl paraben, sodium propyl paraben, diethylamine, carbomer, carbopol, methyl paraben, polyethylene glycol cetostearyl ether, decyl cocoate octanoate, isopropanol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins (e.g., vitamins a and E) and potassium acetate.

In some embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ambient temperature but liquid at body temperature, and therefore melt in the rectum and release the active compound. In other embodiments, the composition for rectal administration is in the form of an enema.

In other embodiments, the compounds described herein or pharmaceutical compositions thereof are suitable for topical delivery to the alimentary or gastrointestinal tract by oral administration (e.g., solid or liquid dosage forms).

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders, for example starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) wetting agents, for example glycerol, d) disintegrating agents, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates and sodium carbonate, e) slow-dissolving agents, for example paraffin, f) absorption promoters, for example quaternary ammonium compounds, g) wetting agents, for example cetyl alcohol and glycerol monostearate, h) absorbents, for example kaolin and bentonite, and i) lubricants, for example talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft-filled and hard-filled gelatin capsules using such excipients as lactose or lactose fractions and high molecular weight polyethylene glycols and the like.

In one embodiment, the composition may take the form of a unit dosage form such as a pill or tablet, and thus the composition may comprise, in addition to the chemical entities provided herein: diluents such as lactose, sucrose, dicalcium phosphate, and the like; lubricants such as magnesium stearate and the like; binding agents such as starch, acacia, polyvinylpyrrolidone, gelatin, cellulose derivatives, etc. In another solid dosage form, a powder, pill, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides) is encapsulated within a capsule (gelatin or cellulose-based capsules). Unit dosage forms in which one or more chemical entities or other active agents provided herein are physically separated are also contemplated, such as capsules (or tablets in capsules) containing individual drug particles; a bilayer tablet; dual chamber gel capsules, and the like. Enteric coated or delayed release oral dosage forms are also contemplated.

Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives, preservatives being particularly useful for preventing microbial growth or action. Various preservatives are well known and include, for example, phenol and ascorbic acid.

In certain embodiments, the excipient is sterile and generally free of undesirable substances. The composition may be sterilized by conventional, well known sterilization techniques. Sterility is not required for various oral dosage form excipients, such as tablets and capsules. The USP/NF standard is generally sufficient.

In some embodiments, the solid oral dosage form may further comprise one or more components that chemically and/or structurally facilitate the delivery of the chemical entity to the stomach or lower GI; for example, the ascending colon and/or the transverse colon and/or the distal colon and/or the small intestine. Exemplary formulation techniques are described, for example, in Filipski, K.J. et al, Current Topics in Medicinal Chemistry, 2013, 13, 776-.

Examples include upper GI targeting technologies such as Accordion pills (accoridon Pill) (Intec Pharma corporation), floating capsules and materials that can adhere to mucosal walls.

Other examples include lower GI targeting techniques. To target various regions of the intestinal tract, several enteric/pH responsive coatings and excipients may be used. These materials are typically polymers designed to dissolve or erode within a particular pH range, selected based on the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric erosion or to limit exposure to gastric fluids in cases where the active ingredient may stimulate the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (vinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymer) and marcoat.

Ophthalmic compositions may include, but are not limited to, any one or more of the following: mucocollagens (viscogens) (e.g., carboxymethylcellulose, glycerol, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g. Pluronic (triblock copolymers), cyclodextrins); preservatives (e.g. benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol and zinc chloride; Elkang Laboratories Inc.), Purite (stabilized chlorine oxide complex; Allergan, Inc.)).

Topical compositions may include ointments and creams. Ointments are semisolid preparations, usually based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, usually oil-in-water or water-in-oil. Cream bases are typically water-washable and comprise an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes also referred to as the "inner" phase, is typically composed of petrolatum and a fatty alcohol (such as cetyl or stearyl alcohol); the aqueous phase typically, although not necessarily, exceeds the volume of the oil phase and typically contains a humectant. Emulsifiers in cream formulations are generally nonionic, anionic, cationic or amphoteric surfactants. As with the other carriers or vehicles, the ointment base should be inert, stable, non-irritating, and non-irritating.

In any of the preceding embodiments, the pharmaceutical compositions described herein may comprise one or more of the following: lipids, multilamellar vesicles crosslinked between bilayers, biodegradable poly (D, L-lactic-co-glycolic acid) [ PLGA ] -based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

Dosage form

The dosage may vary depending on the requirements of the patient, the severity of the condition being treated and the particular compound being used. Determination of the appropriate dosage for a particular situation may be determined by one skilled in the medical arts. The total daily dose may be divided and administered in portions throughout the day or by providing continuous delivery.

In some embodiments, the compounds described herein are administered in a dose of about 0.001mg/Kg to about 500mg/Kg (e.g., about 0.001mg/Kg to about 200 mg/Kg; about 0.01mg/Kg to about 150 mg/Kg; about 0.01mg/Kg to about 100 mg/Kg; about 0.01mg/Kg to about 50 mg/Kg; about 0.01mg/Kg to about 10 mg/Kg; about 0.01mg/Kg to about 5 mg/Kg; about 0.01mg/Kg to about 1 mg/Kg; about 0.01mg/Kg to about 0.5 mg/Kg; about 0.01mg/Kg to about 0.1 mg/Kg; about 0.1mg/Kg to about 200 mg/Kg; about 0.1mg/Kg to about 150 mg/Kg; about 0.1mg/Kg to about 100 mg/Kg; about 0.1 mg/Kg; about 50 mg/Kg; about 1 mg/Kg; and about 1 Kg; and about 1 Kg; or 1 Kg; and 1 Kg; or 1 mg/Kg; or 1 mg/Kg; or 1 Kg; or a About 5 mg/Kg; about 0.1mg/Kg to about 1 mg/Kg; about 0.1mg/Kg to about 0.5 mg/Kg).

Dosing regimens

The foregoing doses may be administered daily (e.g., as a single dose or as two or more divided doses) or non-daily (e.g., every other day, every second day, every third day, once a week, twice a week, once every second week, once a month).

In some embodiments, a compound described herein is administered for a period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In another embodiment, the cessation of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In one embodiment, the therapeutic compound is administered to the individual for a period of time, followed by separate periods of time. In another embodiment, the therapeutic compound is administered for a first period of time, administration is discontinued for a second period of time after the first period of time, administration of the therapeutic compound is resumed for a third period of time, and administration is discontinued for a fourth period of time after the third period of time. In one aspect of this embodiment, the administration of the therapeutic compound and the subsequent discontinuation of administration are repeated over a defined or an undefined period of time. In another embodiment, the administration is for a period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In another embodiment, the time period for discontinuing administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer.

Method of treatment

In some embodiments, methods are provided for treating a subject having a condition, disease, or disorder, wherein increased (e.g., excessive) STING activity (e.g., STING signaling) contributes to the morbidity and/or symptoms and/or progression of the condition, disease, or disorder (e.g., immune disorder, cancer).

Indications of

In some embodiments, the condition, disease, or disorder is cancer. Non-limiting examples of cancer include: melanoma, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples of such cancers include: breast cancer, colon cancer, rectal cancer, large intestine cancer, kidney cancer, clear cell lung cancer, including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and squamous carcinoma of the lung, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), cervical cancer, ovarian cancer, prostate tumor, liver cancer, bladder cancer, peritoneal cancer, hepatocellular cancer, gastric cancer, including gastrointestinal tract cancer, gastrointestinal stromal tumor, pancreatic cancer, head and neck cancer, glioblastoma, retinoblastoma, astrocytoma, ependymoma, wilms 'cancer (hepatoma), hematologic malignancies, including non-hodgkin's lymphoma (NHL), multiple myeloma, myelodysplasia, myeloproliferative disorders, chronic myelogenous leukemia, and acute hematologic malignancies, endometrial or uterine carcinoma, endometriosis, endometrial interstitial sarcoma, fibrosarcoma, choriocarcinoma, salivary gland carcinoma, vulval cancer, thyroid cancer, esophageal cancer, liver cancer (hepatoma), anal cancer, penile cancer, nasopharyngeal cancer, laryngeal cancer, kaposi's sarcoma, mast cell sarcoma, ovarian sarcoma, uterine sarcoma, melanoma, malignant mesothelioma, skin cancer, Schwannoma (Schwannoma), glioma, neuroblastoma, neuroectodermal tumor, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcoma, ewing's sarcoma, peripheral primitive neuroectodermal tumor, urinary tract cancer, thyroid cancer, wilms ' tumor and abnormal angiogenesis associated with phagocytosis, edema (e.g., edema associated with brain tumors) and meigs syndrome. In some cases, the cancer is melanoma.

In some embodiments, the condition, disease or disorder is a neurological disease, including those involving the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves) and the autonomic nervous system (which is partially located in the central and peripheral nervous systems). Non-limiting examples of cancer include: acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; age-related macular degeneration; agenesis of the corpus callosum; agnosia; aicardi syndrome; alexander disease; alpers 'disease (Alpers' disease; ex.; alternating hemiplegia; Alzheimer's disease; vascular dementia; amyotrophic lateral sclerosis; cerebral anencephalia; Angelman syndrome; hemangiomatosis; hypoxia; aphasia; apraxia; arachnoid cyst; arachnoiditis; Anronl-Chiari malformation; arteriovenous malformations; Asperger syndrome; ataxia; attention deficit hyperactivity disorder; autism; autonomic dysfunction; back pain; white's disease; Behcet's disease; Bell's paralysis; Bell 'spasys; benign essential blepharospasm; benign focal; muscular atrophy; intracranial benign hypertension; Binswaner's disease; blech Sulzger syndrome; brachial nerve injury; brain abscess; brain injury; brain tumor including neuroblastoma; spinal cord syndrome; spinal cord disease; spinal cord syndrome; spinal cord pain; spinal cord disease; central pontine myelination; headache; a cerebral aneurysm; cerebral arteriosclerosis; brain atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; neuropathy and neuropathic pain resulting from chemotherapy; a Chiari deformity; chorea; chronic inflammatory demyelinating polyneuropathy; chronic pain; chronic local pain syndrome; coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial paralysis; degeneration of the cortical basal lamina; cerebral arteritis; anterior cranial process; Creutzfeldt-Jakob disease; cumulative trauma disease; cushing's syndromePerforming sign; giant cell inclusion body disease; cytomegalovirus infection; dancing eye and foot syndrome; Dandy-Walker syndrome (Dandy-Walker syndrome); dawson disease (Dawson disease); demoxier syndrome (De Morsier's syndrome); jielin-kruke palsy (Dejerine-Klumke palsy); dementia; dermatomyositis; diabetic neuropathy; diffuse hardening; autonomic abnormalities; difficulty writing (dysgraphia); reading disability; dystonia; early epileptic encephalopathy of infants; empty pommel syndrome; encephalitis; a bulging of the brain; cerebral trigeminal angiomatosis (encephalotriginial angiomatosis); epilepsy; erbu's palsy; essential tremor; fabry's disease; fahr's syndrome; faint; familial spastic paralysis; febrile convulsions; -the Fisher syndrome (Fisher syndrome); friedreich's ataxia; frontotemporal dementia and other "tauophathies" (tauopathies); gaucher's disease; gerstmann's syndrome; giant cell arteritis; giant cell inclusion body disease; globular leukodystrophy; Guillain-Barre syndrome (Guillain-Barre syndrome); HTLV-1 related myelopathy; Hallervorden-Spatz disease; head injury; headache; facial spasm; hereditary spastic paraplegia; amorphous hereditary polyneuropathy (heredopathia atactica polyneuritiformis); herpes zoster of the ear; herpes zoster; mountain syndrome (Hirayama syndrome); HIV-associated dementia and neuropathy (also a neurological manifestation of AIDS); the whole forebrain; huntington's disease and other glutamine repeat diseases; bulimia; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; pigmentary incontinence (incontinentia pigment); infantile phytic acid storage disease; nasal discharge disease of infants; infant cramps; inflammatory myopathy; an intracranial cyst; intracranial hypertension; arbor-burt syndrome; Kearns-Sayre syndrome; kennedy disease (Kennedy disease) kinson syndrome (Kinsbourne syndrome); klippel Feil syndrome; krabbe disease (Krabbe disease); Kugelberg-Welander disease; kuru (kuru); laford disease (Lafora disease); Lambert-Eaton myasthenia syndrome (Lambert-Eaton myasthenic syndrome); Landau-Kleffner syndrome; lateral medulla oblongata (Wall)enberg) syndrome; learning disability; leigh's disease; Lennox-Gustaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; dementia with lewy bodies; anocephaly (Lissencephaly); a lock-in syndrome; lou Gehrig's disease (i.e., motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; lyme disease-neurological sequelae; macchado-Joseph disease (Machado-Joseph disease); hydrocephalus; the megacephalum; mererson-rosenbar syndrome (Melkersson-Rosenthal syndrome); meniere's disease (meniere disease); meningitis; menkes' disease; heterochromous white blood cell malnutrition; microcephaly; migraine headache; miller Fisher syndrome (Miller Fisher syndrome); minor stroke; mitochondrial myopathy; mobius syndrome (Mobius syndrome); muscular atrophy of the monomer; motor neuron disease; moyamoya disease; mucopolysaccharidosis; multi-infarct dementia; multifocal motor neuropathy; multiple sclerosis and other demyelinating diseases; multiple system atrophy with postural hypotension; p muscular dystrophy; myasthenia gravis; myelolytic diffuse sclerosis; infantile myoclonic encephalopathy; myoclonus; myopathy; myotonia congenita; narcolepsy; neurofibromatosis; antipsychotic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromuscular tetany; neuronal lipofuscinosis; neuronal migration disorders; Niemann-Pick disease (Niemann-Pick disease); o' Sullivan-McLeod syndrome; occipital neuralgia; recessive spinal dysplastic sequences; the field syndrome (Ohtahara syndrome); spinodal cerebellar atrophy; myoclonic myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; parkinson's disease; myotonia congenita; paraneoplastic disease; paroxysmal attacks; palindrome syndrome (Parry Romberg syndrome); Belgium-Merzbacher disease (Pelizaeus-Merzbacher disease); periodic paralysis; peripheral neuropathy; painful neuropathy and neuropathic pain; a sustained plant state; pervasive developmental disorder; sneeze and reflex; phytic acid storage disease; pick's disease; pinching nerves; pituitary tumors; polymyositis; porcupuloencephalopathy; post-polio syndrome (post-polio syndrome); post-herpetic neuralgia; post-infectious cerebrospinal fluidMyelitis; orthostatic hypotension; Prader-Willi syndrome (Prader-Willi syndrome); primary lateral sclerosis; a prion; progressive hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing polio; progressive supranuclear palsy; pseudobrain; Ramsay-Hunt syndrome (type I and type II); lamusisen's encephalitis; reflex sympathetic dystrophy syndrome; refsum disease (Refsum disease); repetitive dyskinesia; repetitive stress injuries; restless leg syndrome; retroviral-related myelopathy; rett syndrome (Rett syndrome); rey's syndrome; saint vita dances (Saint viteus dance); sandhoff disease (Sandhoff disease); hilde's disease (Schilder's disease); schizophrenia; atypical hyperplasia of the visual light; infant shaking syndrome; herpes zoster (shingles); Shy-Drager syndrome; sicca syndrome (A)syndrome); sleep apnea; soto's syndrome (Soto); spasm; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; stiff Person syndrome (stilff-Person syndrome); stroke; stecke-Weber syndrome (Sturge-Weber syndrome); subacute sclerosing panencephalitis; subcortical arteriosclerotic encephalopathy; schwann's chorea (Sydenham chorea); syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; spinal tethering syndrome; thomson disease (Thomsen disease); thoracic outlet syndrome; cramps (Tic douroureux); todd 'palsy (Todd' spasysis); tourette syndrome (Tourette syndrome); transient ischemic attacks; transmissible spongiform encephalopathy; transverse myelitis; traumatic brain injury; shaking; trigeminal neuralgia; tropical spastic paresis; nodular sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; von Hippel-Lindau disease (Von Hippel-Lindau disease); valenberg syndrome (Wallenberg's syndrome); Wednig-Hoffman disease (Werdnig-Hoffman disease); west syndrome (West syndrome); whip (whiplash); williams syndrome (Williams)syndrome); white's disease (Wildon's disease); amyotrophic lateral sclerosis and Zelweger syndrome.

In some embodiments, the condition, disease, or disorder is a condition associated with STING, such as type I interferon disease (e.g., baby-onset STING-related vascular disease (SAVI)), cardioid-portal Syndrome (AGS), inherited forms of lupus and inflammation-related diseases, such as systemic lupus erythematosus and rheumatoid arthritis. In some embodiments, the condition, disease, or disorder is an autoimmune disease (e.g., cytoplasmic DNA triggered autoinflammatory disease). Non-limiting examples include: rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Inflammatory Bowel Disease (IBD) including Crohn's Disease (CD) and Ulcerative Colitis (UC), which are chronic inflammatory diseases with polygenic susceptibility. In some embodiments, the disorder is inflammatory bowel disease. In some embodiments, the condition is crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated with one or more of the same immune diseases (e.g., graft versus host disease, such as acute graft versus host disease and chronic graft versus host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In some of these embodiments, the condition is an alloimmune disease (e.g., graft-versus-host disease, such as acute graft-versus-host disease and chronic graft-versus-host disease), a celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis, or intestinal mucositis).

In some embodiments, modulation of the immune system by STING provides treatment for diseases, including diseases caused by foreign factors. Exemplary infections of extrinsic factors that can be treated and/or prevented by the methods of the invention include: bacterial (e.g., gram positive or gram negative bacteria), fungal, parasitic, and viral infections. In one embodiment of the invention, the infection is a bacterial infection (e.g., infection by escherichia coli, Klebsiella pneumoniae (Klebsiella pneumoniae), Pseudomonas aeruginosa (Pseudomonas aeruginosa), Salmonella (Salmonella spp.), Staphylococcus aureus (Staphylococcus aureus), streptococcus or vancomycin-resistant enterococcus) or sepsis). In another embodiment, the infection is a fungal infection (e.g., a mold, yeast, or higher fungal infection). In another embodiment, the infection is a parasitic infection (e.g., an infection caused by a unicellular or multicellular parasite, including Giardia duodenalis, Cryptosporidium parvum, sporozoite (cyrospora cayetanensis) and Toxoplasma gondii). In yet another embodiment, the infection is a viral infection (e.g., viral infection associated with AIDS, avian flu, chicken pox, cold sores, common cold, gastroenteritis, glandular fever, influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, as well as lower or upper respiratory tract infections (e.g., respiratory syncytial virus).

In some embodiments, the disorder, disease, or condition is hepatitis b (see, e.g., WO 2015/061294).

In some embodiments, the condition, disease or disorder is selected from cardiovascular diseases (including, e.g., myocardial infarction).

In some embodiments, the condition, disease, or disorder is age-related macular degeneration.

In some embodiments, the condition, disease or disorder is mucositis, also known as stomatitis, which may occur as a result of chemotherapy or radiation therapy used alone or in combination, and as a result of damage caused by exposure to radiation outside the range of radiation therapy.

In some embodiments, the condition, disease, or disorder is uveitis, which is an inflammation of the uvea (e.g., anterior uveitis, such as iridocyclitis or iritis; intermediate uveitis (also known as parsplanitis), posterior uveitis; or chorioretinitis, e.g., pan-uveitis).

In some embodiments, the condition, disease, or disorder is selected from: cancer, neurological diseases, autoimmune diseases, hepatitis b, uveitis, cardiovascular diseases, age-related macular degeneration and mucositis.

Other examples may include those indications discussed herein and below in contemplated combination therapy regimens.

Combination therapy

The present disclosure encompasses monotherapy regimens as well as combination therapy regimens.

In some embodiments, the methods described herein may further comprise administering one or more additional therapies (e.g., one or more additional therapeutic agents and/or one or more treatment regimens) in combination with a compound described herein.

In some embodiments, the methods described herein may further comprise administering one or more additional cancer therapies.

One or more additional cancer therapies may include, but are not limited to: surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccines, hepatitis b vaccines, Oncophage, Provenge) and gene therapy, and combinations thereof. Immunotherapy, including but not limited to adoptive cell therapy, derivation of stem cells and/or dendritic cells, blood transfusion, lavage, and/or other therapies, including but not limited to freezing tumors.

In some embodiments, the one or more additional cancer therapies are chemotherapy, which may include administering one or more additional chemotherapy agents.

In some embodiments, the additional chemotherapeutic agent is an immune modulatory molecule, such as an immune checkpoint inhibitor. In some of these embodiments, the immune checkpoint inhibitor targets an immune checkpoint receptor selected from the group consisting of: CTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2), indoleamine 2, 3-dioxygenase (IDO), IL-10, transforming growth factor-beta (TGF β), T-cell immunoglobulin and mucin 3(TIM3 or HAVCR2), galectin 9-TIM3, phosphatidylserine-TIM 3, lymphocyte activator gene 3 protein (LAG3), MHC class II-LAG 3, 4-1 BB-4-1 BB ligand, OX 40-OX 40 ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF 25-TL 19, CD 686L, CD 40-CD 40 ligand, HVEM-LIGHT-LTA, EM, HVLA-160, HVRSF 25-TL 1-867, CD 86244, CD 36244-CD 8653 ligand, HVICLIDE-TICE-PDL 244, CD-TICOS-TIDE-FI-TIDE, CD-TIDE-FI, CD-FI-, B7-H3, B7-H4, VISTA, TMIGD2, HHLA 2-TMIGD 2, milk fat protein (Butyrophilins), including BTNL2, Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD 86-CD 28, CD 86-CTLA, CD 80-CD 28, CD39, CD73 adenosine-CD 39-CD 73, CXCR 4-CXCL 12, phosphatidylserine, 3, phosphatidylserine-TIM 3, SIRPA-CD 47, VEGF, Neuropilin, CD160, CD30, and CD 155; e.g., CTLA-4 or PD1 or PD-L1). See, for example, Postow, m.j.clin.oncol.2015, 33, 1.

In some of these embodiments, the immune checkpoint inhibitor is selected from the group consisting of: uluzumab (Urelumab), PF-05082566, MEDI6469, TRX518, vallizumab (Varllumab), CP-870893, Pembrolizumab (Pembrolizumab) (PD1), Nivolumab (Nivolumab) (PD1), Atezolizumab (Atezolizumab) (formerly MPDL3280A) (PDL1), MEDI4736(PD-L1), Avenumab (Avelumab) (PD-L1), PDR001(PD1), BMS-986016, MGA271, riluzumab (Liriluzumab), IPH2201, Ipomuzumab (Emactuzumab), IN024360, homolutinib (Galunertib KT), Ukekulimumab (Uluzumab), Blolizumab 140, Batuximab (Baviviximab), Bevacizumab (Bevacizumab), Bevacizumab 8602, Bevacizumab 1685A, and MGA A.

In some embodiments, the other chemotherapeutic agent is an alkylating agent. Alkylating agents are so named because they are capable of alkylating many nucleophilic functional groups under conditions present in a cell, including but not limited to a cancer cell. In another embodiment, alkylating agents include, but are not limited to: cisplatin, carboplatin, methylethylamine, cyclophosphamide, chlorambucil, ifosfamide and/or oxaliplatin. In one embodiment, alkylating agents may function by disrupting cellular function by forming covalent bonds with amino, carboxyl, sulfhydryl and phosphate groups in biologically important molecules, or they may function by modifying the DNA of the cell. In another embodiment, the alkylating agent is a synthetic, semi-synthetic, or derivative.

In some embodiments, the other chemotherapeutic agent is an antimetabolite. Antimetabolites can pretend to be purines or pyrimidines, which are essential parts of DNA and generally prevent these agents from incorporating into DNA during the "S" phase (cell cycle), thereby preventing normal development and division. Antimetabolites also affect RNA synthesis. In one embodiment, antimetabolites include, but are not limited to: azathioprine and/or mercaptopurine. In another embodiment, the antimetabolite is a synthetic, semi-synthetic or derivative.

In some embodiments, the additional chemotherapeutic agent is a plant alkaloid and/or a terpene. These alkaloids are usually derived from plants and prevent cell division by preventing microtubule function. In one embodiment, the plant alkaloid and/or terpenoid is a vinca alkaloid, a podophyllotoxin, and/or a taxane. In general, vinca alkaloids bind to specific sites on tubulin, usually in the M phase of the cell cycle, inhibiting the assembly of tubulin into microtubules. In one embodiment, vinca alkaloids are not limited to: madagas extra long spring (Madagascar periwinkle), Hedera helix (Catharanthus roseus) (formerly called Vinca rosea). In one embodiment, vinca alkaloids include, but are not limited to: vincristine, vinblastine, vinorelbine and/or vindesine. In one embodiment, taxanes include, but are not limited to: taxol, paclitaxel and/or docetaxel. In another embodiment, the plant alkaloid or terpenoid is synthetic, semi-synthetic or a derivative. In another embodiment, the podophyllotoxin is, but is not limited to, etoposide and/or teniposide. In one embodiment, the taxane is, but is not limited to, docetaxel and/or docetaxel. [021] In one embodiment, the cancer therapeutic is a topoisomerase. Topoisomerase is an essential enzyme for maintaining the topology of DNA. Inhibition of type I or type II topoisomerases interferes with transcription and replication of DNA by disrupting the appropriate DNA supercoils. In another embodiment, the topoisomerase is, but is not limited to, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In one embodiment, the type I topoisomerase inhibitor is, but is not limited to, camptothecin. In another embodiment, the camptothecin is, but is not limited to, irinotecan (exatecan), irinotecan, lutoform, topotecan, BNP 1350, CKD602, DB 67(AR67) and/or ST 1481. In one embodiment, the type II topoisomerase inhibitor is, but is not limited to, an epipodophyllotoxin. In another embodiment, the epipodophyllotoxin is, but is not limited to, amtriptyline (amsacrine), etoposide phosphate and/or teniposide. In another embodiment, the topoisomerase is synthetic, semi-synthetic or derivative, including those found in nature, such as, but not limited to, epipodophyllotoxin, a substance naturally found in the roots of American Mayapple (Podophyllum peltatum).

In some embodiments, the other chemotherapeutic agent is a stilbene. In further embodiments, stilbenes include, but are not limited to: resveratrol, Piceatannol (Piceatannol), Pinosylvin (Pinosylvin), Pterostilbene (Pterostilbene), Alpha-Viniferin (Alpha-Viniferin), Ampelopsin (Ampelopsin) a, ampeloptin E, diindolinone (diptindionesin) C, diindolinone F, Epsilon-Viniferin (Epsilon-Vinferin), fleirosol (Flexuosol) a, gonanin (gnetins) D, schillerenol (hopeapanol), trans-diindolinone B, atratin (astrin), picein (Piceid) and diindolinone a. In another embodiment, stilbenes are synthetic, semi-synthetic or derivatives.

In some embodiments, the other chemotherapeutic agent is a cytotoxic antibiotic. In one embodiment, the cytotoxic antibiotic is, but is not limited to: actinomycin, anthracenedione, anthracyclines, thalidomide, dichloroacetic acid, nicotinic acid, 2-deoxyglucose and/or chlorofluoro-zine (chlorfenamine). In one embodiment, actinomycin is, but is not limited to: actinomycin D, bacitracin, colistin (polymyxin E) and/or polymyxin B. In another embodiment, the anthraquinones are, but are not limited to, mitoxantrone and/or pixantrone. In another embodiment, the anthracycline is, but is not limited to, bleomycin, doxorubicin (Adriamycin), daunorubicin (daunorubicin), epirubicin, idarubicin, mitomycin, priomycin, and/or valsartan. In another embodiment, the cytotoxic antibiotic is synthetic, semi-synthetic or a derivative.

In some embodiments, the additional chemotherapeutic agent is selected from: endostatin, angiogenin, angiostatin, chemokines, angiogenin-resting (angioarestatin), angiostatin (plasminogen fragment), basement membrane collagen-derived anti-angiogenic factors (tumstatin, statin or arrestin), anti-angiogenic antithrombin III, signal transduction inhibitors, cartilage-derived inhibitors (CDI), CD59 complement fragment, fibronectin fragment, gro-beta, heparinase, heparin hexaose fragment, human chorionic gonadotropin (hCG), interferon alpha/beta/gamma, interferon inducible protein (IP-10), interleukin 12, kringle 5 (plasminogen fragment), metalloproteinase inhibitors (TIMP), 2-methoxyestradiol, riboplacental nuclease inhibitors, plasminogen activator inhibitors, platelet factor-4 (PF4), prolactin 16kD fragment, proliferation protein-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin 1(TSP-1), transforming growth factor-beta (TGF-beta), angiostatin (vasostatin) (calreticulin fragment), and the like.

In some embodiments, the additional chemotherapeutic agent is selected from: abiraterone acetate, altretamine (altretamine), anhydrovinblastine (anhydrovinblastine), auristatin (auristatin), bexarotene (bexarotene), bicalutamide (bicalutamide), BMS 184476, 2,3,4,5, 6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, bleomycin, N-dimethyl-L-valyl-N-methyl-L-valyl-L-prolyl-1-L proline-tert-butanamide, cachectin (cachectin), cimadrol (cemadotin), chlorambucil, cyclophosphamide, vinorelbine tartrate (3 ', 4' -didehydro-4 '-deoxy-8' -norvin-calukee), docetaxel (doxetaxetol), cyclophosphamide, carboplatin, carmustine (carmustine), cisplatin, cryptophycin (cryptophycin), cyclophosphamide, cytarabine, Dacarbazine (DTIC), actinomycin, daunorubicin, decitabine (decitabine) urocortin (dolastatin), doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyuramine taxanes, ifosfamide (ifosfamide), linazole (liarozole), lonidamine (lonidamine), lomustine (lomustine) (CCNU), MDV3100, mechlorethamine (mechlorethamine), melphalan, hydroxytryptamine (mevulin), rhizobian (rhixorin), sertraline (sertraline), streptococcin (streptacin), mitomycin, taxifoline, taxotene (taxol), predryptazine (rprodyne), prednimustine (RPnonastatin R), tamoxifen, tasonermin, paclitaxel, tretinoin, vinblastine, vincristine, vindesine sulfate and vinflunine.

In some embodiments, the additional chemotherapeutic agent is platinum, cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, azathioprine, mercaptopurine, vincristine, vinblastine, vinorelbine, vindesine, etoposide and teniposide, paclitaxel, docetaxel, irinotecan, topotecan, amlodipine (amsacrine), etoposide phosphate, teniposide, 5-fluorouracil, calcium folinate, methotrexate, gemcitabine, a taxane, folinic acid, mitomycin C, tegafur-uracil (tegafur-uracil), idarubicin, fludarabine, mitoxantrone, ifosfamide and doxorubicin. Other agents include mTOR (mammalian target of rapamycin) inhibitors, including but not limited to rapamycin, everolimus, temsirolimus, and deforolimus.

In other embodiments, the other chemotherapeutic agent may be selected from those described in U.S. patent 7,927,613, which is incorporated herein by reference in its entirety.

In some embodiments, the additional therapeutic agents and/or regimens can be used to treat other STING-related disorders, such as type I interferon diseases, e.g., baby-onset STING-related vascular disease (SAVI), cardioportal-portal syndrome (AGS), hereditary forms of lupus, inflammation-related disorders, such as systemic lupus erythematosus, and rheumatoid arthritis, among others.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating rheumatoid arthritis include: non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g., prednisone), disease modifying antirheumatic drugs (DMARDs; e.g., methotrexate)LeflunomideHydroxychloroquine (Plaquenil), PF-06650833, Iguratimod (iguratimod), tofacitinib (tofacitinib)ABBV-599, Evobritinib (evocrutinib) and sulfasalazine (sulfasalazine)And biologics (e.g., abatacept)Adalimumab (adalimumab)Anakinra (anakinra)Setuzumab (c)ertolizumab)Etanercept (etanercept)Golimumab (golimumab)Infliximab (infliximab)Rituximab (rituximab)Tuizumab (tocilizumab)Vobailizumab (Vobailizumab), Sariluzumab (sarilumab)Secukinumab (secukinumab), ABP 501, CHS-0214, ABC-3373, and toclizumab (tocilizumab))。

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating lupus include: steroids, local immunomodulators (e.g. tacrolimus ointment)And pimecrolimus cream) ThalidomideNon-steroidal anti-inflammatory drugs (NSAIDs; e.g. ibuprofen and naproxen), antimalarialsDisease agents (e.g., hydroxychloroquine (placonitl)), corticosteroids (e.g., prednisone), immunomodulators (e.g., efuzonib (evobrutinib), ibedomide (ibridomide), vorpocetine (voclosporin), cilimod (cenerimod), azathioprine (azathioprine)Cyclophosphamide The presence of cyclosporin (Neoral,) Mycophenolate mofetil), barrertinib (baricitinb), iguratimod (iguratimod), felotinib (filogltinib), GS-9876, rapamycin, and PF-06650833), biologicals (e.g., belimumab (belimumab)Afluoromab (anifluumab), plerucumab (prezalumab), MEDI0700, obinmezumab (obinutuzumab), wobaizumab (vobarilizumab), lulizumab (lulizumab), asecept (atacicept), PF-06823859, and lupezole (lupizor), rituximab (rituximab), BT063, BI655064, BIIB059, aldesleukin (aldesleukin)Dapipromab (dapirolizumab), edropeptide (edratide), IFN- α -kinoid, OMS721, RC18, RSLV-132, Serratia left monoclonal antibody (thermalizumab), XmAb5871, and Ulvacizumab (usekinumab)). For example, non-limiting treatment methods for systemic lupus erythematosus include: non-steroidal anti-inflammatory drugs (NSAIDs; e.g. ibuprofen and naproxen), antimalarials (e.g. hydroxyls)Chloroquine (placonil), corticosteroids (e.g., prednisone), and immunomodulators ((e.g., ibedroamine (iberdomide), vorosin (voclosporin), azathioprine (azathioprine)CyclophosphamideAnd cyclosporin (Neoral,) And mycophenolate mofetil, baricitinib (baricitinib), felotinib (filogltinib), and PF-06650833), and biologicals (e.g., belimumab)Afluoromab (anifrolumab), pleumumab (prezalumab), MEDI0700, wobbelizumab (vobarilizumab), lulizumab (lulizumab), asecept (atacicept), PF-06823859, lupezole (lupizor), rituximab (rituximab), BT063, BI655064, BIIB059, aldesleukin (aldesleukin)Dapirumab (dapirolizumab), edropeptide (edratide), IFN- α -kinoid, RC18, RSLV-132, Serioli left monoclonal antibody (thermizumab), XmAb5871, and Ulvacizumab (usekinumab)). As another example, non-limiting examples of treatments for cutaneous lupus include: steroids, immunomodulators (e.g. tacrolimus ointment)And pimecrolimus cream) GS-9876, felotinib (filogoti)nib) and thalidomideAgents and regimens for treating drug-induced and/or neonatal lupus may also be administered.

Non-limiting examples of additional therapeutic agents and/or regimens for treating baby-onset STING-related vascular disease (SAVI) include JAK inhibitors (e.g., tofacitinib, ruxotinib, feitinib, and baritinib).

Non-limiting examples of additional therapeutic agents and/or regimens for treating aicards-guletide syndrome (AGS) include: physical therapy, respiratory complication treatment, anticonvulsant therapy of seizures, gavage, nucleoside reverse transcriptase inhibitors (e.g., emtricitabine)) Tenofovir (tenofovir) (e.g. TM)) Emtricitabine/tenofovir (emtricitabine/tenofovir) (e.g. Emtricitabine/Tenofovir)) Zidovudine (zidovudine), lamivudine (lamivudine) and abacavir (abacavir)), and JAK inhibitors (e.g., tofacitinib, ruxotinib, fexotinib and baritinib).

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating IBD include: 6-mercaptopurine, AbGn-168H, ABX464, ABT-494, Adalimumab (Adalilimumab), AJM300, alikamab (alicafen), AMG139, Anuma-stuzumab (anrukinumab), Apremilast (apremilast), ATR-107(PF0530900), peripheral blood stem cell transplantation selected from autologous CD34, azathioprine (azathioprine), Bettuyimab (bertilimumab), BI655066, BMS-936557, Setuzumab (certolizumab pego-dego)l)Biximod (cobiolimod), corticosteroids (e.g., prednisone, methylprednisolone, prednisone), CP-690,550, CT-P13, cyclosporine, DIMS0150, E6007, E6011, Eltricirimod (itrasimod), Eletrozumab (etrolizumab), fecal microbial transplantation, Ferlotinib (figolinib), fingolimod (fingolimod), Ferrostate (firagrat) (SB-683699) (formerly T-0047), GED0301, GLPG0634, GLPG0974, Securizumab (gusukumab), golimumab (golimumab), GSK1399686, HMPL-004 (Andrographitis (Andrographis paniculata) extract), IMU-838, flixbizumab (infliximab), interleukin 2(IL-2), HMPL-004 (Andrographis paniculata) extract, MMT-0049), Messageusib kinase (Messajou kinase) inhibitors (MELSiE) such as MEI-S579, MEI-S579 (Messamicin (MEI) inhibitors, methotrexate, Mirikizumab (LY3074828), natalizumab (natalizumab), NNC 0142-0000-0002, NNC0114-0006, ozanimod (ozanimod), pefinitib (pefinitib) (JNJ-54781532), PF-00547659, PF-04236921, PF-06687234, QAX576, RHB-104, rifaximin (rifaximin), rizatrizumab (risankizumab), RPC1063, SB012, SHP647, sulfasalazine (Sulfasalazine), TD-1473, thalidomide, tiramizumab (tiltrakizumab) (MK 2), TJ301,tofacitinib (tofacitinib), trastuzumab (tralokinumab), TRK-170, apacetitinib (upaactinib), Ultezumab (usekinumab), UTTR1147A, V565, vatlizumab (vatelizumab), VB-201, vedolizumab (vedolizumab), and vedofluridim (vidofludimus).

Non-limiting examples of other therapeutic agents and/or treatment regimens for treating irritable bowel syndrome include: alosetron (alosetron), bile acid sequestrants (e.g., cholestyramine (cholestyramine), colestipol (celestipol), colesevelam (colesevelam), chloride channel activators (e.g., lubiprostone (lubiprostone)), coated peppermint oil capsules, desipramine (desipramine), dicyclomine (dicycromine), ebastine (ebastine), efavirenzine (eluxadoline), farnesol X receptor agonists (e.g., obeticholic acid), fecal microbial transplantation, fluoxetine (fluoxetine), gabapentin (gabapentin), guanylate cyclase C agonists (e.g., linaclotide (linaclotide), canecatide (pleatide), ibolotide (ibolotide), ibolotide (ibutatant), imipramine (ipramine), JCM-21, loperazone (loperazone), prohexadione (aride), piroctone (roxyperazine), propinebrodene (piroctone), propinebroderine (piroctone (roxypromine (paroxetine), probiotics, ramosetron, rifaximin and tanaprol.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating scleroderma include: non-steroidal anti-inflammatory drugs (NSAIDs; e.g., ibuprofen and naproxen), corticosteroids (e.g., prednisone), immunomodulators (e.g., azathioprine, methotrexate) CyclophosphamideAnd cyclosporinAnti-thymocyte globulin, mycophenolate, intravenous immunoglobulin, rituximab, sirolimus and alfapsep (alefacept)), calcium channel blockers (e.g., nifedipine), alpha blockers, serotonin receptor antagonists, angiotensin II receptor inhibitors, statins, topical nitrates, iloprost (iloprost), phosphodiesterase 5 inhibitors (e.g., sildenafil), bosentan (bosentan), tetracycline antibiotics, endothelin receptor antagonists, prostaglandins, and tyrosine kinase inhibitionAgents (e.g., imatinib, nilotinib, and dasatinib).

Non-limiting examples of additional therapeutic agents and/or regimens for treating Crohn's Disease (CD) include: adalimumab, autologous CD 34-selected peripheral blood stem cell transplantation, 6-mercaptopurine, azathioprine, polyethylene glycol certolizumabCorticosteroids (e.g., prednisone), eltromumab (etrolizumab), E6011, fecal microbial transplantation, felovinib (fillottinib), gusecazumab (gusekumab), Infliximab (Infliximab), IL-2, JAK inhibitors, matrix metalloproteinase 9(MMP9) inhibitors (e.g., GS-5745), MEDI2070, mesalamine, methotrexate, natalizumab, ozanimod (ozanimod), RHB-104, rifaximin (rifaximin), risazezumab (risakimab), SHP647, sulfasalazine, thalidomide, apacetinib (upacitinib), V565, and vedozumab (vedolizumab).

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating UC include: AbGn-168H, ABT-494, ABX464, apremilast (apremilast), PF-00547659, PF-06687234, 6-mercaptopurine, adalimumab, azathioprine, belituzumab, brazikumab (MEDI2070), Gubitomomod (cobiolimod), Pegylco-tuzumabCP-690,550, corticosteroids (e.g., Multiplexed budesonide, Methylprednisone), cyclosporin, E6007, Eltricisimod, Eletrexezumab, fecal microbe transplant, Floritinib, Gusenkumab (Guselkumab), Golimmumab, IL-2, IMU-838, infliximab, matrix metalloproteinase 9(MMP9) inhibitors (e.g., GS-5745), Maxiramine, Mirituzumab (Mirikizumab) (LY3074828), RPC1063, Lissamumab (RISankizumab) (BI 6555066), SHP647, sulfasalazine, TD-1473, TJ301, Tildakizumab (tiltrakizumab)b) (MK 3222), Tofacitinib (Tofacitinib), Ultezumab (ustekinumab), UTTR1147A, and vedolizumab.

Non-limiting examples of other therapeutic agents and/or treatment regimens for treating autoimmune colitis include: corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), dipheny-line/atropine, infliximab, loperamide (loperamide), mesalamine, TIP60 inhibitors (see, e.g., U.S. patent application publication No. 2012/0202848), and vedolizumab.

Non-limiting examples of other therapeutic agents and/or treatment regimens for treating iatrogenic autoimmune colitis include: corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), dipheny-line/atropine, infliximab, loperamide (loperamide), TIP60 inhibitors (see, e.g., U.S. patent application publication No. 2012/0202848), and vedolizumab.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating colitis induced by one or more chemotherapeutic agents include: corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), dipheny-line/atropine, infliximab, loperamide (loperamide), mesalamine, TIP60 inhibitors (see, e.g., U.S. patent application publication No. 2012/0202848), and vedolizumab.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating colitis caused by adoptive cell therapy include: corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), dipheny-line/atropine, infliximab, loperamide (loperamide), TIP60 inhibitors (see, e.g., U.S. patent application publication No. 2012/0202848), and vedolizumab.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating colitis associated with one or more alloimmune diseases include: corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), sulfasalazine, and eicosapentaenoic acid.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating radiation enteritis include: teduglutide (teduglutide), amifostine (amifostine), Angiotensin Converting Enzyme (ACE) inhibitors (e.g., benazepril (benazepril), captopril (captopril), enalapril (enalapril), fosinopril (fosinopril), lisinopril (lisinopril), moexipril (moexipril), perindopril (perindopril), quinapril (quinapril), ramipril (ramipril) and trandolapril (trandolapril)), probiotics, selenium supplements, statins (e.g., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin (rosuvastatin), simvastatin (simvastatin) and pitavastatin), sucralfate (sucralfate) and vitamin E).

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating collagen colitis include: 6-mercaptopurine, azazaprinine (azathainoprine), bismuth subhydroxide (bismuthate), Boswellia serrata (Boswellia serrata) extract, cholestyramine (cholestyramine), cholesterol (colestipol), corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), mesalamine, methotrexate, probiotics, and sulfasalazine.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating lymphocytic colitis include: 6-mercaptopurine, azazaprine (azathainoprine), bismuth subsalicylate (bismuth subsalicylate), cholestyramine (cholestyramine), cholesterol (colestipol), corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), mesalamine, methotrexate, and sulfasalazine.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating microbial colitis include: 6-mercaptopurine, azathioprine (azathioprine), bismuth subsalicylate (bismuth), Boswellia serrata (Boswellia serrata) extract, cholestyramine (cholestyramine), colestipol (colestipol), corticosteroids (e.g., budesonide, prednisone, prednisolone, beclomethasone dipropionate), fecal microbiome transplantation, loperamide (loperamide), mesalamine, methotrexate, probiotics, and sulfasalazine.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating alloimmune diseases include: intrauterine platelet infusion, intravenous immunoglobulin, maternal steroid, abacavir (abatacept), alemtuzumab (alemtuzumab), α 1-antitrypsin, AMG592, antithymocytocin, Barerinib (barcetinib), basiliximab (basiliximab), bortezomib (bortezomib), brentuximab (brentuximab), cannabidiol (canabidiol), corticosteroids (e.g., methylprednisolone, prednisone), cyclosporine, daclizumab (dacilzumab), defibrinide (defibrotide), dineburninium-toxin linker (denileukin diftitox), glargiib (glasedigib), ibrutinib (ibrutinib), IL-2, infliximab, itanib (itanibib), LBH589, malazizomib (vilac), Murrav (manivit), Murrav (leupeptizumab), leutinib (leupeptiz), leupeptizumab (e), sirolimus (sirolimus), sonnedjig (sonidegib), tacrolimus, tacitumumab (tocilizumab) and vismodegib (vismodegib).

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating Multiple Sclerosis (MS) include: alemtuzumabALKS 8700, amiloride (amiloride), ATX-MS-1467, azathioprine, baclofen (baclofen)Beta interferon (e.g., IFN-beta-1 a, IFN-beta-1 b), cladribine (cladribine), corticosteroids (e.g., methylprednisolone), daclizumab (daclizumab), dimethyl fumarateFingolimod (fingolimod)Fluoxetine (fluoxetine), glatiramer acetate (glatiramer acetate)Hydroxychloroquine, ibudilast (ibudilast), idebenone (idebenone), laquinimod (laquinimod), lipoic acid, losartan (losartan), masitinib (masitinib), MD1003 (biotin), mitoxantrone, montelukast (montelukast), natalizumabNeuroVax^TMOcrelizumab (ocrelizumab), ofatumumab (ofatumumab), pioglitazone (pioglitazone) and RPC 1063.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating graft-versus-host disease include: (ii) abatacept (abetacept), alemtuzumab (alemtuzumab), alpha 1-antitrypsin, AMG592, antithymocytocin, Barertinib (barcetinib), Baricizumab (basiliximab), Bortezomib (bortezomib), Bentuximab (Brentuximab), cannabidiol (canabidiol), corticosteroids (e.g. methylprednisolone, prednisone), cyclosporine, daclizumab (dacizumab), defibrotide (defibrotide), dineburnine-toxin linker (denileukin difittox), Glasgubib (glasdegibrib), ibrutinib (ibrutinib), IL-2, Imatinib (imatinib), Rigoxim, imatinib (itanibacilli), LBH589, Muraviviroc (berrubic), Murravex (berrubi), Begonizumab (delbruxib), Begonimus (Begonimus), Begonimus (Lucivorax (Begonimus), tacrolimus, tacitumumab (tocilizumab) and vismodegib (vismodegib).

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating acute graft-versus-host disease include: alemtuzumab (alemtuzumab), α 1-antitrypsin, antithymocytocin, basiliximab (basiliximab), brentuximab (brentuximab), corticosteroids (e.g., methylprednisolone, prednisone), cyclosporine, daclizumab (dacilzumab), defibroside (defibrotide), dinil-toxin linker (denileukin difitox), ibrutinib (ibrutinib), rituximab, itatinib (itacetinib), LBH589, mycophenolate, natalizumab, netilmib (neihulizumab), pentostatin, photoreolysis, ruxolitinib (ruxolitinib), sirolimus (sirolimus), tacrolimus and tacrolimus (tacrolimus).

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating chronic graft-versus-host disease include: abatacept (abatacept), alemtuzumab (alemtuzumab), AMG592, antithymocyte globulin, basiliximab (basiliximab), bortezomib (bortezomib), corticosteroids (e.g., methylprednisolone, prednisone), cyclosporine, daclizumab (daclizumab), dinil-toxin linker (denileukin difitox), glargiib (glasedegib), ibrutinib (ibrutinib), IL-2, imatinib (imatinib), infliximab, mycophenolate, pentostatin, photobiological regulation, photohemolysis, ruxolitinib (rulitinib), sirolimus (sirolimus), sonnedigig (sonigibb), tacrolimus (tosimizumab) and virgulibozumab (virgulibody).

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating celiac disease include: AMG 714, AMY01, Aspergillus niger (Aspergillus niger) prolyl endoprotease, BL-7010, CALY-002, GBR 830, Hu-Mik-Beta-1, IMGX003, KumaMax, Larazolazole Acetate (Larazoide Acetate),pancreatic lipase, TIMP-GLIA, Victoria and ZED 1227.

Non-limiting examples of additional therapeutic agents and/or regimens for treating psoriasis include: topical corticosteroid, topical Crisaborole/AN 2728, topical SNA-120, topical SAN021, topical Benzimod (tapanaof), topical Tocafanib (tocafinib), topical IDP-118Topical M518101, topical calcipotriene (calcipotriene) and betamethasone dipropionate (e.g., MC2-01 cream and) Topical P-3073, topical LEO 90100Topical use of betamethasone dipropionateBetasol propionateVitamin D analogs (e.g., calcipotriene)And calcitriol) Anthralin (anthralin) (e.g.,and) Topical retinoids (e.g., tazarotene (tazarotene) (e.g.,and) Calcineurin inhibitors (e.g., tacrolimus)And pimecrolimus) Salicylic acid, tar (tar), moisturizerPhototherapy (e.g., exposure to sunlight, UVB phototherapy, narrowband UVB phototherapy, golkmann therapy (Goeckerman therapy), psoralen plus ultraviolet a (puva) therapy and excimer laser (eximer laser)), retinoid (e.g., avilam (acitretin)Methotrexate (MTX) Apo805K1, baltinib (baricitinib), FP187, KD025, Pulusol (prurisol), VTP-43742, XP23829, ZPL-389, CF101 (piridonoson), LAS41008, VPD-737 (Servopitant), Apacitinib (upadacetitinib) (ABT-494), apremilast (apremilast), tofacibin (tofacitinib), Cyclosporin Biological agents (e.g., etanercept)Etanercept-szzsInfliximabAdalimumabAdalimumab-adbmUnimab you Tek (ustekinumab)GollimumabApremilast (apremilast)Sujin monoclonal antibody (secukinumab)Polyethylene glycol cetuximab, secukinumab, tiramizumab (tilbrakizumab) -asmn, infliximab-dyyb, abavacp (abatacept), eprezumab (ixekizumab)ABP 710, BCD-057, BI695501, bimezumab (bimekizumab) (UCB4940), CHS-1420, GP2017, Guselkumab (Guselkumab) (CNTO 1959), HD203, M923, MSB11022, MIRIKIzumab (Mirikizumab) (LY3074828), PF-06410293, PF-06438179, lissazole (risankizumab) (BI655066), SB2, SB4, SB5, siliq (brodalumab), Namerumab (namilumab) (203, tiramizumab (tiluzumab) (MK-2), and epratuzumab (ixekizumab)) Thioguanine, and hydroxyurea (e.g.,and)。

non-limiting examples of additional therapeutic agents and/or treatment regimens for treating cutaneous T cell lymphoma include: phototherapy (e.g., exposure to sunlight, UVB phototherapy, narrow band UVB phototherapy, golkmann therapy, psoralen plus ultraviolet a (puva) therapy and excimer laser), extracorporeal photopheresis (extracorporeal photethering)topheresis), radiation therapy (e.g., spot radiation and systemic electron beam skin therapy), stem cell transplantation, corticosteroids, imiquimod, bexarotene gel, topical dichloroethyl-nitrourea, methoxyethylamine gel, vorinostatRomidepsin (romidepsin)Pralatte (pralatrexate)Biological agents (e.g., alemtuzumab)Vectorius-tuximab (brentuximab vedotin) (SGN-35), moguazumab (mogamulizumab), and IPH 4102).

Non-limiting examples of additional therapeutic agents and/or regimens for treating uveitis include: corticosteroids (e.g., intravitreal triamcinolone acetonide injection), antibiotics, antiviral agents (e.g., acyclovir), dexamethasone, immunomodulators (e.g., tacrolimus, leflunomide, cyclophosphamide)And cyclosporin Chlorambucil (chlorembucil), azathioprine, methotrexate, and mycophenolate mofetil), biological agents (e.g., infliximabAdalimumabEtanerceptGollimumabCetuzumab ozogamicin (certolizumab)RituximabAbiraypuBasiliximabAnakinra (anakinra)Kana monoclonal antibody (Canakinumab)Gavorexazumab (gevokixumab) (XOMA052), toslizumab (tocilizumab)AlemtuzumabEfalizumab (Efalizumab)LFG316, sirolimusAbirapu, Saliluzumab (sarilumab)Hedakezhu monoclonal antibody (daclizumab)) Cytotoxic drugs, surgical implants (e.g., fluocinolone inserts), and vitrectomy.

Non-limiting examples of additional therapeutic agents and/or treatment regimens for treating mucositis include: AG013, SGX942 (dusquetide), amifostineCryotherapy, celadol (cefacol) lozenges (lonzenges), mucoadhesives (e.g.,) Oral administration of diphenhydramine (e.g.,elixirs), oral bioadhesives (e.g., polyvinylpyrrolidone-sodium hyaluronate gel)) Oral lubricant (e.g., Oral)) Comboshi (caposol), chamomile (chamomilla recutita) mouthwash, edible grape plant exosomes, germicidal mouthwash (e.g., chlorhexidine gluconate (e.g.,or) Local analgesics (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., 2% xylocaine), and(0.6% phenol), corticosteroids (e.g., prednisone), analgesics (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor;) ATL-104, clonidine (clonidine) lowry (lauriad), IZN-6N4, SGX942, rebamipide (rebamipide), nepideramine (nepidermin), soluble β -1,3/1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, granules containing Vaccinium myrtillus (Vaccinium myrtillus) extract, macleaya cordata (macleaya cordia) alkaloid and Echinacea purpurea (echinacea angusticea) extract (for example,) And gastrointestinal mixtures (an acid reducing agent such as aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungal agents (e.g., nystatin), and analgesic agents (e.g., hurricane liquid). For example, non-limiting examples of additional therapeutic agents and/or treatment regimens for treating oral mucositis include: AG013, amifostineCryotherapy, celadol (cefacol) lozenges (lonzenges), mucoadhesives (e.g.,) Oral administration of diphenhydramine (e.g.,elixirs), oral bioadhesives (e.g., polyvinylpyrrolidone-sodium hyaluronate gel)) Oral lubricant (e.g., Oral)) Comboshi (caposol), chamomile (chamomilla recutita) mouthwash, edible grape plant exosomes, germicidal mouthwash (e.g., chlorhexidine gluconate (e.g.,or) Local analgesics (e.g., lidocaine, benzocaine, dyclonine hydrochloride, xylocaine (e.g., 2% xylocaine), and(0.6% phenol), corticosteroids (e.g., prednisone), analgesics (e.g., ibuprofen, naproxen, acetaminophen, and opioids), GC4419, palifermin (keratinocyte growth factor;) ATL-104, clonidine (clonidine) lowry (lauriad), IZN-6N4, SGX942, rebamipide (rebamipide), nepidermin (nepidermin), soluble β -1,3/1,6 glucan, P276, LP-0004-09, CR-3294, ALD-518, IZN-6N4, quercetin, and gastrointestinal mixtures (an acid reducing agent such as aluminum and magnesium hydroxides (e.g., Mallox), antifungal agents (e.g., nystatin), and analgesic agents (e.g., hurricane liquid). As another example, non-limiting examples of treatment of esophageal mucositis include: xylocaine (e.g., 2% xylocaine on gel). As another example, treatment of intestinal mucositis, treatment to alter intestinal mucositis, and treatment of signs and symptoms of intestinal mucositis include: gastrointestinal tract mixtures (an acid reducing agent such as aluminum hydroxide and magnesium hydroxide (e.g., Maalox), antifungal agents (e.g., nystatin), and analgesics (e.g., hurricane liquids).

In some embodiments, the second therapeutic agent or regimen is administered to the subject prior to contact with or administration of the chemical entity (e.g., about one hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, about 1 week prior, or about 1 month prior).

In other embodiments, the second therapeutic agent or regimen is administered to the subject at about the same time as the chemical entity is contacted with or administered to the chemical entity. For example, the second therapeutic agent or regimen and the chemical entity are provided to the subject simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the chemical entity are provided to the subject simultaneously in separate dosage forms.

In other embodiments, the second therapeutic agent or regimen is administered to the subject after contact with or administration of the chemical entity (e.g., after about one hour, or after about 6 hours, or after about 12 hours, or after about 24 hours, or after about 48 hours, after about 1 week, or after about 1 month).

Patient selection

In some embodiments, the methods described herein further comprise the step of identifying a subject (e.g., a patient) in need of such treatment (e.g., by biopsy, endoscopy, or other conventional methods known in the art). In some embodiments, STING proteins can be used as biomarkers for some types of cancer, such as colon and prostate cancer. In other embodiments, identifying a subject may include analyzing a patient (e.g., a patient with one or more cold tumors) for the presence of T cells in the tumor microenvironment and/or for the presence of depleted T cells. Such patients may include patients resistant to treatment with checkpoint inhibitors. In some embodiments, such patients can be treated with a chemical entity herein, e.g., to recruit T cells into a tumor, and in some cases, e.g., once T cells are depleted, further treated with one or more checkpoint inhibitors.

In some embodiments, the chemical entities, methods, and compositions described herein can be administered to a population of patients that are resistant to treatment (e.g., patients that are resistant to checkpoint inhibitors; e.g., patients with one or more cold tumors (e.g., tumors that lack T cells or are depleted of T cells)).

Preparation of compounds

As will be appreciated by those skilled in the art, methods of synthesizing the compounds of the formulae described herein will be apparent to those of ordinary skill in the art. Synthetic chemical Transformations and protecting group methods (protection and deprotection) useful in the synthesis of the compounds described herein are known in the art and include, for example, those described in r.larock, Comprehensive Organic Transformations (Comprehensive Organic Transformations), VCH publishers (1989); greene and rgm wuts, Protective Groups in Organic Synthesis, 2 nd edition, John Wiley and Sons (1991); fieser and m.fieser, Organic synthetic Reagents of Fieser and Fieser (Fieser and Fieser's Reagents for Organic Synthesis), john wilkinson & ltd. (1994); paquette, ed., (Encyclopedia of Reagents for Organic Synthesis), John Willi (1995), and subsequent versions thereof. The starting materials for preparing the compounds of the invention are known, can be prepared by known methods, or are commercially available. Those skilled in the art will also recognize that the conditions and reagents described herein may be interchanged with alternative art-recognized equivalents. For example, in many reactions triethylamine can be exchanged with other bases, such as non-nucleophilic bases (e.g., diisopropylamine, 1, 8-diazabicycloundecen-7-ene, 2, 6-di-tert-butylpyridine, or tetrabutylphosphazene).

The skilled artisan will recognize a variety of analytical methods that may be used to characterize the compounds described herein, including, for example¹H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography and infrared spectroscopy. The foregoing list is a subset of the characterization methods available to those skilled in the art and is not intended to be limiting.

To further illustrate the foregoing, the following non-limiting exemplary synthetic schemes are included. Variations of these embodiments within the scope of the claims are within the knowledge of a person skilled in the art and should be considered to fall within the scope of the described claimed invention. The reader will appreciate that those skilled in the art, on the basis of this disclosure, will be able to prepare and use the invention without exhaustive exemplification.

The following abbreviations have the indicated meanings:

examples

For illustrative purposes, exemplary general methods for synthesizing compounds of formula I are described in schemes 1 and 2.

Referring to scheme 1, compounds of formula I (shown as compound 3-I in scheme 1, wherein L^ABis-N (R) as defined in formula I^N)S(O)₂-; and R is^NA, B are as defined for formula I) can be prepared by coupling 1-I with an amine 2-I (in 1-I, B is as defined for formula I, and Lg is a leaving atom (e.g., Cl, Br) or a leaving group (e.g., OMs, OTf, OTs); and in 2-I, RN and A are as defined for formula I).

Referring to scheme 2, compounds of formula I (shown as compounds 3-II in scheme 2, wherein L^ABIs as defined in formula I-S (O)₂N(R^N) -; and R is^NA, B are as defined for formula I) can be prepared by coupling 1-II with 2-II (in 1-II, R is^NAnd B is as defined for formula I; in 2-II, A is as defined for formula I, Lg is a leaving atom (e.g., Cl, Br) or a leaving group (e.g., OMs, OTf, OTs)).

The following compounds were prepared according to the methods shown in schemes 1 and 2:

abbreviations for chemical terms

DCM ═ dichloromethane

DMF ═ N, N-dimethylformamide

N-oxide of N- [ (dimethylamino) -1H-1,2, 3-triazolo- [4,5-b ] pyridin-1-ylmethylene ] -N-methylbetanin (methanaminium) hexafluorophosphate

HPLC ═ high performance liquid chromatography

LCMS (liquid chromatography-Mass Spectrometry)

NMR (nuclear magnetic resonance)

DIEA is N-ethyl-N-isopropylpropan-2-amine

FA ═ formic acid

TFA ═ trifluoroacetic acid

Speedvac (Savant SC250EXP speedVac) concentrator

LCMS analysis conditions

Method A

The instrument comprises the following steps: agilent (Agilent) LCMS system ion mode equipped with DAD and ELSD detectors: is just

A chromatographic column: waters X-Bridge C18, 50X 2.1mm X5 μm or equivalent specification

Mobile phase: a: h₂O(0.04％TFA)；B：CH₃CN(0.02％TFA)

Gradient: 4.5 min gradient method, the actual method depends on the clogP of the compound.

Flow rate: 0.6mL/min or 0.8mL/min

Column temperature: 40 ℃ or 50 DEG C

UV：220nm

Method B

The instrument comprises the following steps: agilent (Agilent) LCMS system equipped with DAD and ELSD detectors

Ion mode: is just

A chromatographic column: waters X-Bridge ShieldRP18, 50X 2.1mm X5 μm or equivalent specification

Mobile phase: a: h₂O(0.05％NH₃·H₂O) or 10mM ammonium bicarbonate; b: CH (CH)₃CN

Gradient: 4.5 min gradient method; the actual method depends on the clogP of the compound.

Flow rate: 0.6mL/min or 0.8mL/min

Column temperature: 40 deg.C

UV：220nm

Preparative HPLC conditions

The instrument comprises the following steps:

GILSON 281 and Shimadzu (Shimadzu) LCMS 2010A

GILSON 215 and Shimadzu LC-20AP

3.GILSON 215

Mobile phase:

A：NH₄OH/H₂O＝0.05％v/v；B：ACN

A：FA/H₂O＝0.225％v/v；B：ACN

chromatographic column

Xtimate C18 150*25mm*5μm

Flow rate: 25mL/min or 30mL/min

Monitoring wavelength: 220&254nm

Gradient: the actual method depends on the clogP of the compound

A detector: MS triggering or UV

Example 1: synthesis of Compound 113

And (2) a process:

synthesis of N- (5, 6-difluoro-1H-indol-3-yl) -4- (trifluoromethoxy) benzenesulfonamide

5, 6-difluoro-1H-indol-3-amine (42.8mg, 0.255mmol, 1.0 equiv.) is dissolved in DCM (2.0 mL). DIEA (168. mu.l, 1.02mmol, 4.0 equivalent) was then addedAmount) and pyridine (82. mu.l, 1.02mmol, 4.0 equiv.). A solution of 4- (trifluoromethoxy) benzene-1-sulfonyl chloride (72.8mg, 280.0. mu. mol, 1.1 equiv.) dissolved in 1.0mL DCM was added to the reaction mixture. The reaction mixture was stirred at 30 ℃ for 16 hours. The reaction mixture was concentrated with Speedvac. The resulting residue was purified by preparative HPLC to provide N- (5, 6-difluoro-1H-indol-3-yl) -4- (trifluoromethoxy) benzenesulfonamide (10.2mg, 26.0 μmol). MS-ESI, 393.1[ M + H ]⁺].

¹H NMR(400MHz、DMSO-d₆)δppm 11.19(br s、1H)9.81(br s、1H)7.76(d、2H)7.48(br d、2H)7.29(dd、1H)7.18(d、1H)6.95(dd、1H)

Table E1 the compounds in table E1 were prepared using the procedure described above.

Example 31: synthesis of Compound 143

Synthesis of 5-chloro-N- (5, 6-difluoro-1H-indol-3-yl) pyridine-3-sulfonamide

5, 6-difluoro-1H-indol-3-amine (8.4mg, 50.0. mu. mol, 1.0 equiv.) and 5-chloropyridine-2-sulfonyl chloride (11.5mg, 55.0. mu. mol, 1.1 equiv.) were taken in a microwave tube and dissolved in pyridine (0.3 mL). The sealed tube was heated at 60 ℃ for 15 minutes under microwave conditions. After cooling the reaction mixture to 55 ℃ it was heated for 15 minutes under microwave conditions at 90 ℃.6 parallel reaction batches were carried out. The 6 batches of reaction mixture were combined together and concentrated by Speedvac. The resulting residue was purified by preparative HPLC to provide 5-chloro-N- (5, 6-difluoro-1H-indol-3-yl) pyridine-2-sulfonamide (27.2mg, 79.3 μmol). MS-ESI, 344.0[ M + H ]⁺].

1H NMR(400MHz、DMSO-d6)δppm 11.16(br s、1H)10.09(s、1H)8.84(d、1H)8.07(dd、1H)7.75(d、1H)7.30(dd、6.78Hz、1H)7.10–7.19(m、2H).

Table 3: the compounds in table 3 were prepared using the procedure described above.

Biological detection

Using THP1-Dual^TMCells (KO-IFNAR2) measure activation of the STING pathway by the compounds described herein.

THP1-Dual^TMKO-IFNAR2 cells (obtained from a living source) were stored in RPMI, 10% FCS, 5ml P/S, 2mM L-glut, 10mM Hepes and 1mM sodium pyruvate. The compounds were found in empty 384-well tissue culture plates (Greiner 781182) with Echo to a final concentration of 0.0017-100. mu.M. Cells were seeded into TC plates at 40. mu.L, 2X 10E6 cells/mL per well. For activation with STING ligand, 2'3' cGAMP (MW 718.38, from english) was prepared in Optimem mediumAvailable from jie corporation (Invivogen).

The following solutions were prepared for each 1 × 384 plate:

solution A: 2mL Optimem with one of the following stimuli:

60uL of 10mM 2'3' cGAMP- > 150. mu.M stock solution

Solution B: 2mL Optimem was incubated with 60. mu.L Lipofectamine 2000- > for 5 min at room temperature

2mL of solution A and 2mL of solution B were mixed and incubated at Room Temperature (RT) for 20 minutes. mu.L of transfection solution (A + B) was added to the top of the plated cells, with a final 2'3' cGAMP concentration of 15. mu.M. The plates were then immediately centrifuged at 340g for 1 min and then at 37 ℃ with 5% CO₂、>Incubate 24 hours at 98% humidity. Luciferase reporter activity is then measured. EC is calculated by using standard methods known in the art₅₀The value is obtained.

Luciferase reporter assay: 10 μ L of the supernatant from the assay was transferred to a white 384 plate with flat bottom and square wells. Mixing a bag of QUANTI-Luc^TMPlus was dissolved in 25mL of water. QUANTI-Luc in an amount of 25mL per unit^TMPlus solution 100. mu.L of QLC stabilizer was added. Then 50. mu.L of QUANTI-Luc was added to each well^TMPlus/QLC solution. Luminescence was measured on a plate reader (e.g., Spectramax I3X (Molecular Devices GF 3637001)).

Luciferase reporter activity is then measured. EC is calculated by using standard methods known in the art₅₀The value is obtained.

Table BA shows the activity of the compounds in STING reporter assays: <0.008 μ M ═ ++++ "; 0.008 or more and <0.04 μ M ═ plus ++++ "; 0.04 and <0.2 μ M ═ plus +++ "; 0.2 or more and <1 μ M ═ plus ++ "; 1 or more and <5 μ M ═ plus "+"; not less than 5 and < 100. mu.M ═ plus'

TABLE BA

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