STING modulator compounds and methods of making and using

文档序号：1255899 发布日期：2020-08-21 浏览：29次中文

阅读说明：本技术 Sting调节剂化合物以及制备和使用方法 (STING modulator compounds and methods of making and using ) 是由 S·维斯科西尔 J·恰瓦利 C·卡利斯 D·B·英格兰 A·E·古尔德 P·格林斯潘胡于 2018-11-09 设计创作，主要内容包括：本公开提供了STING调节剂/激动剂和合成方法,以及用于预防或治疗癌症和其它STING相关疾病的方法。本公开涉及由式(I)表示的化合物：<Image he="415" wi="700" file="DPA0000288615790000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image> 其中每个符号如本说明书中所定义,或其药学上可接受的盐。(The present disclosure provides STING modulators/agonists and synthetic methodsMethods, and methods for preventing or treating cancer and other STING-related diseases. The present disclosure relates to compounds represented by formula (I):)

1. A compound of the formula I, wherein,

or a pharmaceutically acceptable salt thereof, wherein:

X¹is-SH or-OH;

X²is-SH or-OH;

Y^ais-O-, -S-or-CH₂-；

Y^bis-O-, -S-, -NH-or-NR^a-, wherein R^aIs C₁-C₄An alkyl group;

R¹is hydrogen, fluorine, -OH, -NH₂、-OR^bor-NHR^b；

R²Is hydrogen or fluorine;

R³is hydrogen; r⁴Is hydrogen, fluorine, -OH, -NH₂、-OR^bor-NHR^b(ii) a Or R³And R⁴Together form-CH₂O-；

R⁵Is hydrogen or fluorine;

R^bis C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

ring a is an optionally substituted 5-or 6-membered monocyclic heteroaryl ring containing 1-4 heteroatoms selected from N, O or S, or an optionally substituted 9-or 10-membered bicyclic heteroaryl ring containing 1-5 heteroatoms selected from N, O or S; wherein ring A contains at least one N atom in the ring, and wherein Y^bA carbon atom attached to ring a; and is

Ring B is an optionally substituted 9-or 10-membered bicyclic heteroaryl ring containing 2-5 heteroatoms selected from N, O or S; wherein ring B contains at least two N atoms in the ring.

2. The compound of claim 1, having formula II:

or a pharmaceutically acceptable salt thereof.

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

X¹and X²is-SH; and is

The phosphorus atom of each phosphorothioate bond is chiral and is independently R_pOr S_p。

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein:

X¹and X²is-SH; and is

Each phosphorothioate bond having a phosphorus atom as R_p。

5. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein

X¹And X²is-OH.

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

X¹and X²One of which is-OH and the other is-SH; and is

The phosphorus atom of the phosphorothioate linkage is chiral and is R_pOr S_p。

7. The method of any one of claims 1 to 6A compound or a pharmaceutically acceptable salt thereof, wherein Y^ais-O-.

8. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Y is^ais-CH₂-。

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Y is^bis-O-.

10. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Y is^bis-NH-or-NR^a-。

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R¹Is hydrogen, fluorine, -OH or-OCH₂CF₃And R is²Is hydrogen or fluorine.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein:

R³is hydrogen;

R⁴is hydrogen, fluorine or-OH; and is

R⁵Is hydrogen or fluorine.

13. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein:

R¹is fluorine or-OH;

R⁴is hydrogen or fluorine; and is

R²、R³And R⁵Is hydrogen.

14. The compound of claim 1, having formula (IV):

or a pharmaceutically acceptable salt thereof,

wherein R is¹And R⁴Each independently is hydrogen, fluorine, -OH or-OCH₂CF₃。

15. The compound of claim 1, having formula (IV-a):

or a pharmaceutically acceptable salt thereof,

wherein R is¹And R⁴Each independently is hydrogen, fluorine, -OH or-OCH₂CF₃。

16. The compound of claim 1, having formula (IV-B):

or a pharmaceutically acceptable salt thereof,

wherein R is¹And R⁴Each independently is hydrogen, fluorine, -OH or-OCH₂CF₃。

17. The compound of claim 1, having formula (IV-C):

or a pharmaceutically acceptable salt thereof,

wherein R is¹And R⁴Each independently is hydrogen, fluorine, -OH or-OCH₂CF₃。

18. The compound of claim 1, having formula (V):

or a pharmaceutically acceptable salt thereof,

wherein R is¹And R⁴Each independently is hydrogen, fluorine, -OH or-OCH₂CF₃。

19. The compound of claim 1, having formula (V-a):

or a pharmaceutically acceptable salt thereof,

wherein R is¹And R⁴Each independently is hydrogen, fluorine, -OH or-OCH₂CF₃。

20. The compound of claim 1, having formula (V-B):

or a pharmaceutically acceptable salt thereof,

wherein R is¹And R⁴Each independently is hydrogen, fluorine, -OH or-OCH₂CF₃。

21. The compound of claim 1, having formula (V-C):

or a pharmaceutically acceptable salt thereof,

wherein R is¹And R⁴Each independently is hydrogen, fluorine, -OH or-OCH₂CF₃。

22. The compound of any one of claims 14 to 16 and 18 to 20, or a pharmaceutically acceptable salt thereof, wherein:

the phosphorus atom of each phosphorothioate bond is chiral and is independently R_pOr S_p。

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein:

ring a is an optionally substituted 6-membered monocyclic heteroaryl ring containing 1-3N atoms.

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein:

ring A is

Each R¹⁰Independently hydrogen, halogen, -OH, -NH₂、C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl radical, C₃-C₆Cycloalkyl, -OR¹¹、-NHR¹¹、-CN、-NO₂or-C (O) NHR¹²；

R¹¹Is C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

R¹²is hydrogen, C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group; and is

m is 0, 1 or 2.

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein:

each R¹⁰Independently hydrogen, fluorine, chlorine, -OH, -NH₂、-CH₃、-CF₃、-OCH₃、-CN、-NO₂or-C (O) NH₂。

26. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein:

ring A is:

27. the compound of any one of claims 1-13 or 18-22, or a pharmaceutically acceptable salt thereof, wherein:

ring A is

Each R¹³Independently hydrogen, halogen, -OH, -NH₂、C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl radical, C₃-C₆Cycloalkyl, -OR¹¹、-NHR¹¹、-CN、-NO₂or-C (O) NHR¹²；

R¹¹Is C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

R¹²is hydrogen, C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group; and is

n is 0, 1 or 2.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein:

each R¹³Independently hydrogen, fluorine, chlorine, -OH, -NH₂、-CH₃、-CF₃、-OCH₃、-CN、-NO₂or-C (O) NH₂。

29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein:

ring A is:

30. the compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein:

ring a is an optionally substituted 5-membered monocyclic heteroaryl ring.

31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein:

ring B is an optionally substituted 9-membered bicyclic heteroaryl ring containing 3-5N atoms; and is

Containing Y^aIs connected to the nitrogen atom of ring B.

32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein ring B is:

Z¹、Z²、Z³and Z⁴Each independently is N or CR²⁰；

R²¹Is hydrogen or C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

R²³is hydrogen or-NH₂(ii) a And is

R²⁰、R²²And R²⁴Each independently of the others hydrogen, halogen, -OH, -NH₂、-CN、C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group.

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein:

Z¹、Z²、Z³and Z⁴Each independently N, CH or CF;

R²¹is hydrogen or-CH₃(ii) a And is

R²²And R²⁴Each independently is hydrogen, -NH₂or-CH₃。

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from:

35. the compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein ring B is:

36. the compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein when ring a or ring B is substituted, the substituent is halogen, -OH, -CN, -NO₂、C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl radical, C₃-C₆Cycloalkyl, -OR¹¹、-SR¹²、-N(R¹²)₂、-NR¹²C(O)R¹²、-C(O)R¹²、-C(O)OR¹²、-C(O)N(R¹²)₂or-SO₂N(R¹²)₂(ii) a Or two adjacent substituents together with intervening ring atoms form a 4-to 8-membered ring;

wherein R is¹¹Is C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group; and is

R¹²Is hydrogen, C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group.

37. The compound of claim 1, having formula (VI):

or a pharmaceutically acceptable salt thereof, wherein

X¹is-SH or-OH;

X²is-SH or-OH;

Y^bis composed of_-O-, -S-, -NH-or-NMe-;

R¹is hydrogen, fluorine, -OH OR-OR^b；

R²Is hydrogen or fluorine;

R³is hydrogen; r⁴Is hydrogen, fluorine or-OH;

R⁵is hydrogen or fluorine;

R^bis C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

each R¹⁰Independently hydrogen, halogen, -OH, -NH₂、C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl radical, C₃-C₆Cycloalkyl, -OR¹¹、-NHR¹¹、-CN、-NO₂or-C (O) NHR¹²；

R¹¹Is C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

R¹²is hydrogen, C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

m is 0, 1 or 2;

Z¹n, CH or CF;

R²¹is hydrogen or-CH₃(ii) a And is

R²²Is hydrogen, -NH₂or-CH₃。

38. A compound according to claim 37 or a medicament thereofA pharmaceutically acceptable salt, wherein Y^bis-O-.

39. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein Y^bis-NH-.

40. The compound of any one of claims 37 to 39, or a pharmaceutically acceptable salt thereof, wherein X¹And X²is-SH, and wherein the phosphorus atom of each phosphorothioate bond is chiral and is independently R_pOr S_p。

41. The compound of any one of claims 37 to 39, or a pharmaceutically acceptable salt thereof, wherein X¹And X²is-OH.

42. The compound of any one of claims 37 to 39, or a pharmaceutically acceptable salt thereof, wherein X¹And X²One is-OH and the other is-SH, and wherein the phosphorus atom of the phosphorothioate bond is chiral and is R_pOr S_p。

43. The compound of any one of claims 37 to 42, or a pharmaceutically acceptable salt thereof, wherein R²、R³And R⁵Is hydrogen.

44. The compound of any one of claims 37 to 43, or a pharmaceutically acceptable salt thereof, wherein R¹Is hydrogen, fluorine, -OH or-OCH₂CF₃。

45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein R¹Is hydrogen, fluorine or-OH.

46. The compound of any one of claims 37 to 45, or a pharmaceutically acceptable salt thereof, wherein R⁴Is hydrogen, fluorine or-OH.

47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein R⁴Is hydrogen or fluorine.

48. The compound of any one of claims 37 to 47, or a pharmaceutically acceptable salt thereof, wherein m is 0.

49. The compound of any one of claims 37 to 48, or a pharmaceutically acceptable salt thereof, wherein Z¹Is N.

50. The compound of any one of claims 37 to 49, or a pharmaceutically acceptable salt thereof, wherein R²¹Is hydrogen.

51. The compound of any one of claims 37 to 50, or a pharmaceutically acceptable salt thereof, wherein R²²is-NH₂。

52. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from table 1.

53. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

54. a pharmaceutical composition comprising (a) a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier.

55. A method of inducing an immune response in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof.

56. A method of inducing STING-dependent type I interferon production in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof.

57. A method of treating a cell proliferation disorder in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof.

58. The method of claim 57, wherein the cell proliferative disorder is cancer.

59. The method of claim 57 or 58, further comprising administering to the subject a therapeutically effective amount of a second therapeutic agent.

60. A vaccine composition comprising an antigen and a compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof.

61. A method of treating a disease in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of the vaccine composition of claim 60.

Technical Field

The present disclosure relates to compounds useful as STING (stimulator of interferon genes) modulators/agonists, methods of synthesis, and methods for preventing or treating cancer and other diseases.

Background

STING is a transmembrane receptor that is localized to the ER, which recognizes and binds cyclic dinucleotides. Natural ligands recognized by STING include Cyclic Dinucleotides (CDNs) of bacterial/protozoal origin, 2 ', 3' -cGAMP synthesized by upstream cGAS (cyclic GMP-AMP synthase), and the like. See Trends in Immunology 35, 88-93 (2014). It was reported that the natural ligand 2 ', 3' -cGAMP was decomposed by pyrophosphatase/phosphodiesterase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase) and other CDNs were decomposed by other phosphodiesterases. See Nat Chem Biol 10, 1043-; cell Res 25, 539-550 (2015); and Biochemistry 55, 837-849 (2016). STING activation by these natural ligands induces phosphorylation of TBK1(TANK binding kinase 1) and IRF3 (interferon regulatory factor 3), leading to activation of NFkB and type I Interferon (IFN) responses, respectively. See Trends in Immunology 35, 88-93 (2014).

The effect of STING on cancer cell growth control was demonstrated in assays using genetically modified mice. STING-deficient and IRF 3-deficient mice have been reported to exhibit uncontrolled tumor growth compared to wild-type mice. See Immunity41, 830-842 (2014). In addition, it has also been reported that radiation therapy suppresses cancer cell growth in tumor allograft mice, but the effect of radiation therapy is reduced in mice genetically deficient in STING and IFNAR1 (receptor for interferon (α and β) receptor 1, i.e., type I IFN produced by downstream signaling). See Immunity41, 843-. Taken together with the above-mentioned evidence, STING is believed to play a key role in suppressing cancer cell growth. Therefore, STING agonists are useful as anti-cancer agents. See, for example, WO 2015/074145, WO 2015/077354, WO 2015/185565, WO 2016/096174, WO 2016/096577, WO 2016/120305, WO 2016/145102, WO2017/027645, WO2017/027646, WO2017/075477, WO 2017/093933, WO 2017/106740, WO 2017/123657, WO 2017/123669 and WO 2017/161349. In addition, since STING is able to activate both innate and adaptive immunity, activation of STING potentiates the immune effects of traditional vaccines. See Ther Adv Vaccines 1, 131-143 (2013). Therefore, STING agonists are also useful as adjuvants for various vaccines.

Disclosure of Invention

The present disclosure provides novel compounds of formula (I) having STING agonist activity, which are useful as agents for preventing or treating cancer and other diseases.

The present disclosure provides compounds of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X¹is-SH or-OH;

X²is-SH or-OH;

Y^ais-O-, -S-or-CH₂-；

Y^bis-O-, -S-, -NH-or-NR^a-, wherein R^aIs C₁-C₄An alkyl group;

R¹is hydrogen, fluorine, -OH, -NH₂、-OR^bor-NHR^b；

R²Is hydrogen or fluorine;

R³is hydrogen; r⁴Is hydrogen, fluorine, -OH, -NH₂、-OR^bor-NHR^b(ii) a Or R³And R⁴Together form-CH₂O-；

R⁵Is hydrogen or fluorine;

R^bis C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

Ring B is an optionally substituted 9-or 10-membered bicyclic heteroaryl ring containing 2-5 heteroatoms selected from N, O or S; wherein ring B contains at least two N atoms in the ring.

The present disclosure also provides a pharmaceutical composition comprising (a) a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier.

The present disclosure further provides a method of inducing an immune response in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The present disclosure provides a method of inducing STING-dependent type I interferon production in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The present disclosure provides methods of treating a cell proliferation disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The present disclosure also provides vaccine compositions comprising an antigen and a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present disclosure further provides a method of treating a disease in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a vaccine composition.

Detailed Description

Definition of

In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.

As used herein, the term "aromatic" includes aryl and heteroaryl groups as generally described below and herein.

As used herein, the term "aliphatic" or "aliphatic group" means a straight or branched chain C_1-12Hydrocarbons or cyclic C_1-12Hydrocarbons, which are fully saturated or which contain one or more units of unsaturation but which are not aromatic (also referred to herein as "carbocyclics", "alicyclics", "cycloalkyls" or "cycloalkenyls"). Suitable aliphatic groups include, for example, straight-chain, branched-chain or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl. In various embodiments, aliphatic groups have 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or1 to 2 carbon atoms.

The terms "alicyclic", "carbocyclic", "carbocyclyl" or "carbocyclic" used alone or as part of a larger moiety refer to a saturated or partially unsaturated cyclic aliphatic ring system having from 3 to about 14 ring carbon atoms.

The term "alkyl" used alone or as part of a larger moiety refers to a straight or branched chain saturated C₁-C₁₂A hydrocarbyl group. In various embodiments, alkyl groups may have 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or1 to 2 carbon atoms. "C₁-C₆Examples of the alkyl group "include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1-dimethylbutyl, 2-dimethylbutyl, 3-dimethylbutyl and 2-ethylbutyl.

The term "cycloalkyl" refers to a saturated ring system having from about 3 to about 10 ring carbon atoms. In various embodiments, the alkyl group may have 3 to 8, 3 to 7, or 3 to 6, 3 to 5 carbon atoms. "C₃-C₆Examples of cycloalkyl "include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "haloalkyl" refers to an alkyl group optionally substituted with one or more halogen atoms. As used herein, the term "halogen" or "halo" means F, Cl, Br, or I. In the present specification, "halo (C)₁-C₆) Examples of "alkyl" include C having 1 to 7, typically 1 to 5, halogen atoms_1-6An alkyl group. Specific examples thereof include chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, 2-bromoethyl, 2, 2, 2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, 2, 2-difluoropropyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, 5, 5, 5-trifluoropentyl and 6, 6, 6-trifluorohexyl.

The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; quaternized form of any basic nitrogen; or heterocyclic substitutable nitrogen, such as N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺(as in N-substituted pyrrolidinyl)).

The term "aryl" refers to a C containing 1 to 3 aromatic rings_6-14An aromatic hydrocarbon moiety. At least one of the rollersIn the embodiment, aryl is C_6-10And (4) an aryl group. Aryl groups include, but are not limited to, optionally substituted phenyl, naphthyl, or anthracenyl. In certain embodiments, aryl groups may be optionally substituted as described herein. The term "aryl" as used herein also includes groups in which an aromatic ring is fused to one or more alicyclic or heterocyclic rings to form an optionally substituted cyclic structure (e.g., a tetrahydronaphthyl, indenyl, indanyl, or indolinyl ring). The term "aryl" is used interchangeably with the terms "aryl group", "aromatic ring" and "aromatic ring".

The terms "heteroaryl" and "heteroaryl" refer to groups having 5 to 14 ring atoms (e.g., 5, 6, 9, or 10 ring atoms), having 6, 10, or 14 pi electrons shared in a cyclic array, and having 1 to 5 heteroatoms in addition to carbon atoms. Heteroaryl groups can be monocyclic, bicyclic, tricyclic, or polycyclic, e.g., monocyclic, bicyclic, or tricyclic, e.g., monocyclic or bicyclic. In the context of "heteroaromatic" entities, the term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen. For example, the nitrogen atom of the heteroaryl group can be a basic nitrogen atom and can also be optionally oxidized to the corresponding N-oxide. When a heteroaryl group is substituted with a hydroxy group, it also includes its corresponding tautomer. The terms "heteroaryl" and "heteroar" as used herein also include groups in which a heteroaromatic ring is fused to one or more aromatic, alicyclic or heteroalicyclic rings. Non-limiting examples of heteroaryl groups include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, indolyl, isoindolyl, benzothienyl, benzofuryl, dibenzofuryl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, and pyrido [2, 3-b ] -1, 4-oxazin-3 (4H) -one. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic", "heteroaryl group" or "heteroaromatic". In certain embodiments, heteroaryl groups may be optionally substituted as described herein.

As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic group" and "heterocyclic ring" are used interchangeably and refer to a stable 3-to 8-membered monocyclic or 7-to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more (e.g., 1 to 4) heteroatoms as defined above in addition to carbon atoms. The term "nitrogen" when used in reference to a ring atom of a heterocyclic ring includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺(as in N-substituted pyrrolidinyl).

The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom, thereby resulting in a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiomorpholinyl. The heterocyclic group may be monocyclic, bicyclic, tricyclic or polycyclic, such as monocyclic, bicyclic or tricyclic, and such as monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, and the alkyl and heterocyclyl portions may be independently optionally substituted. In addition, heterocyclic also includes groups in which the heterocyclic is fused to one or more aromatic rings.

As used herein, the term "partially unsaturated" refers to a cyclic moiety that includes at least one double or triple bond between ring atoms. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moieties as defined herein. The term "partially unsaturated" is intended to encompass rings having tautomers that include at least one double or triple bond between ring atoms. For example, a ring including a carbonyl group exists as an enol tautomer, and thus is also considered "partially unsaturated".

Aryl (including aralkyl, aralkoxy, aryloxyalkyl, and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy, and the like) may contain one or more substituents and thus may be "optionally substituted. Suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group include, and are typically selected from-halo, -NO, in addition to the substituents defined above and herein₂、-CN、-R⁺、-C(R⁺)＝C(R⁺)₂、-C≡C-R⁺、-OR⁺、-SR^○、-S(O)R^○、-SO₂R^○、-SO₃R⁺、-SO₂N(R⁺)₂、-N(R⁺)₂、-NR⁺C(O)R⁺、-NR⁺C(S)R⁺、-NR⁺C(O)N(R⁺)₂、-NR⁺C(S)N(R⁺)₂、-N(R⁺)C(＝NR⁺)-N(R⁺)₂、-N(R⁺)C(＝NR⁺)-R^○、-NR⁺CO₂R⁺、-NR⁺SO₂R^○、-NR⁺SO₂N(R⁺)₂、-O-C(O)R⁺、-O-CO₂R⁺、-OC(O)N(R⁺)₂、-C(O)R⁺、-C(S)R^○、-CO₂R⁺、-C(O)-C(O)R⁺、-C(O)N(R⁺)₂、-C(S)N(R⁺)₂、-C(O)N(R⁺)-OR⁺、-C(O)N(R⁺)C(＝NR⁺)-N(R⁺)₂、-N(R⁺)C(＝NR⁺)-N(R⁺)-C(O)R⁺、-C(＝NR⁺)-N(R⁺)₂、-C(＝NR⁺)-OR⁺、-N(R⁺)-N(R⁺)₂、-C(＝NR⁺)-N(R⁺)-OR⁺、-C(R^○)＝N-OR⁺、-P(O)(R⁺)₂、-P(O)(OR⁺)₂、-O-P(O)-OR⁺and-P (O) (NR)⁺)-N(R⁺)₂Wherein R is⁺Independently hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, alicyclic or heterocyclic group, or two independently occurring R⁺Together with one or more intervening atoms thereof, form an optionally substituted 5-to 7-membered aryl, heteroaryl, alicyclic or heterocyclic group. In some embodiments, R⁺Independently of one another is hydrogen, C_1-6Aliphatic or C_3-6Alicyclic. Each R^○Independently an optionally substituted aliphatic, aryl, heteroaryl, alicyclic or heterocyclic group.

An aliphatic or heteroaliphatic group or a non-aromatic carbocyclic or heterocyclic ring may contain one or more substituents and may thus be "optionally substituted". Unless defined otherwise above and herein, suitable substituents on saturated carbons of an aliphatic or heteroaliphatic group or a non-aromatic carbocyclic or heterocyclic ring are selected from those listed above for the unsaturated carbons of an aryl or heteroaryl group and additionally include the following: either O, S, C (R)₂、＝N-N(R*)₂、＝N-OR*、＝N-NHC(O)R*、＝N-NHCO₂R^○、＝N-NHSO₂R^○Or N-R, wherein R^○As defined above, and each R is independently selected from hydrogen or optionally substituted C_1-6An aliphatic group.

Optional substituents on the nitrogen of the non-aromatic heterocyclic ring include, and are typically selected from-R in addition to the substituents defined above and herein⁺、-N(R⁺)₂、-C(O)R⁺、-C(O)OR⁺、-C(O)C(O)R⁺、-C(O)CH₂C(O)R⁺、-S(O)₂R⁺、-S(O)₂N(R⁺)₂、-C(S)N(R⁺)₂、-C(＝NH)-N(R⁺)₂or-N (R)⁺)S(O)₂R⁺(ii) a Wherein each R⁺As defined above. The ring nitrogen atom of the heteroaryl or non-aromatic heterocycle may also be oxidized to form the corresponding N-hydroxy or N-oxide compound. A non-limiting example of such heteroaryl groups having an oxidized ring nitrogen atom is the N-oxidopyridyl group.

As detailed above, in some embodiments, two independently occurring R⁺(or any other variable similarly defined herein in the specification and claims) together with one or more intervening atoms thereof form a monocyclic or bicyclic ring selected from: a 3-to 13-membered cycloaliphatic; a 3-12 membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 6-to 10-membered aryl group; or a 5-to 10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

For clarity, all divalent groups set forth herein are intended to be read from left to right, and the formulae or structures in which the variables appear are read from left to right, respectively.

In two independent occurrences of R⁺Exemplary rings formed (or any other variable similarly defined herein in the specification and claims) together with one or more intervening atoms thereof include, but are not limited to, the following: a) two independently occurring R⁺(or any other variable similarly defined herein in the specification or claims) are bound to the same atom and together with said atom form a ring, e.g. N (R)⁺)₂In which R appears twice⁺Together with the nitrogen atom, form piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl; and b) two independently occurring R⁺(OR any other variable similarly defined herein in the specification OR claims) are bound to different atoms and together with two of those atoms form a ring, e.g. phenyl via two occurrences of OR⁺Situation of substitutionThese two occurrences of R⁺Together with the oxygen atom to which they are bound form a fused 6-membered oxygen containing ring:it will be appreciated that at two independently occurring R⁺(or any other variable similarly defined herein in the specification and claims) together with one or more intervening atoms may form a variety of other rings (e.g., spiro and bridged rings), and as described aboveThe detailed examples are not intended to be limiting.

Unless otherwise indicated, structures depicted herein are also intended to include all stereoisomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers for each asymmetric center. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the present invention are within the scope of the disclosure. Unless otherwise indicated, all tautomeric forms of the compounds disclosed herein are within the scope of the disclosure. In addition, unless otherwise indicated, the structures depicted herein are also intended to include compounds that differ only by the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention with hydrogen replaced by deuterium or tritium or with a carbon replaced by a 13C or 14C enriched carbon are within the scope of the present disclosure. By way of non-limiting example, these compounds may be used as analytical tools or probes in bioassays.

It is understood that when the disclosed compounds have at least one chiral center, the disclosure encompasses one enantiomer free or substantially free of the corresponding optical isomer, a racemic mixture of inhibitors, and a mixture enriched in one enantiomer (relative to its corresponding optical isomer). When a mixture is enriched in one enantiomer (relative to its optical isomers), the mixture contains, for example, an enantiomeric excess of at least 50%, 75%, 80%, 85%, 90%, 95%, 99%, or 99.5%.

Enantiomers of the present disclosure can be resolved by methods known to those skilled in the art, for example, by forming diastereomeric salts, which can be separated, for example, by crystallization; forming diastereomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selectively reacting one enantiomer with an enantiomer-specific reagent, e.g., enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, e.g. on a chiral support bound to a chiral ligand, e.g. on silica, or in the presence of a chiral solvent. In the case of conversion of the desired enantiomer to another chemical by one of the above separation procedures, a further step is required to release the desired enantiomeric form. Alternatively, a particular enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

When the disclosed compounds have at least two chiral centers, the present disclosure encompasses diastereomers that are free or substantially free of other diastereomers, a pair of diastereomers that are free or substantially free of other diastereomers, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer, and mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer. When a mixture is enriched in one diastereomer or diastereomer pair relative to the other diastereomer or diastereomer pair, the mixture is enriched in the diastereomer or diastereomer pair depicted or mentioned in a molar excess, e.g., at least 50%, 75%, 80%, 85%, 90%, 95%, 99% or 99.5% relative to the other diastereomer or diastereomer pair of the compound.

Diastereomeric pairs can be separated by methods known to those skilled in the art (e.g., chromatography or crystallization), and the individual enantiomers within each pair can be separated as set forth above. Specific procedures for the chromatographic separation of diastereomeric pairs of precursors used in the preparation of the compounds disclosed herein are provided in the examples herein.

A compound of formula (I)

The present disclosure provides compounds of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X¹is-SH or-OH;

X²is-SH or-OH;

Y^ais-O-, -S-or-CH₂-；

Y^bis-O-, -S-, -NH-or-NR^a-, wherein R^aIs C₁-C₄An alkyl group;

R¹is hydrogen, fluorine, -OH, -NH₂、-OR^bor-NHR^b；

R²Is hydrogen or fluorine;

R³is hydrogen; r⁴Is hydrogen, fluorine, -OH, -NH₂、-OR^bor-NHR^b(ii) a Or R³And R⁴Together form-CH₂O-；

R⁵Is hydrogen or fluorine;

R^bis C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

Ring B is an optionally substituted 9-or 10-membered bicyclic heteroaryl ring containing 2-5 heteroatoms selected from N, O or S; wherein ring B contains at least two N atoms in the ring.

In some embodiments, the compound of formula (I) is represented by formula (I-A), (I-B), (I-C), or (I-D):

wherein Y is^a、Y^b、R¹、R²、R³、R⁴、R⁵Ring a and ring B have the values described herein.

In some embodiments, the compound of formula (I) is represented by formula (I-E) or (I-F):

wherein X¹、X²、Y^a、R¹、R²、R³、R⁴、R⁵Ring a and ring B have the values described herein.

In some embodiments, the compound of formula (I) is represented by formula (II):

or a pharmaceutically acceptable salt thereof, wherein

X¹is-SH or-OH;

X²is-SH or-OH;

Y^ais-O-, -S-or-CH₂-；

Y^bis-O-, -S-, -NH-or-NR^a-, wherein R^aIs C₁-C₄An alkyl group;

R¹is hydrogen, fluorine, -OH, -NH₂、-OR^bor-NHR^b；

R²Is hydrogen or fluorine;

R³is hydrogen; r⁴Is hydrogen, fluorine, -OH, -NH₂、-OR^bor-NHR^b(ii) a Or R³And R⁴Together form-CH₂O-；

R⁵Is hydrogen or fluorine;

R^bis C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

Ring B is an optionally substituted 9-or 10-membered bicyclic heteroaryl ring containing 2-5 heteroatoms selected from N, O or S; wherein ring B contains at least two N atoms in the ring.

In some embodiments, the compound of formula (I) is represented by formula (II-A) or (II-B):

wherein Y is^a、Y^b、R¹、R²、R³、R⁴、R⁵Ring a and ring B have the values described herein.

In some embodiments, the compound of formula (I) is represented by formula (II-AA) or (II-BB):

wherein Y is^a、Y^b、R¹、R²、R³、R⁴、R⁵Ring a and ring B have the values described herein.

In some embodiments, the compound of formula (I) is represented by formula (II-C) or (II-D):

wherein X¹、X²、R¹、R²、R³、R⁴、R⁵Ring a and ring B have the values described herein. In some embodiments, X¹And X²Both are-OH. In some embodiments, X¹And X²Both are-SH. In some embodiments, X¹is-OH and X²is-SH. In some embodiments, X¹is-SH and X²is-OH.

In some embodiments, the compound of formula (I) is represented by formula (II-E) or (II-F):

wherein R is¹、R²、R³、R⁴、R⁵Ring a and ring B have the values described herein.

In some embodiments, the compound of formula (I) is represented by formula (II-EE) or (II-FF):

wherein R is¹、R²、R³、R⁴、R⁵Ring a and ring B have the values described herein.

In some embodiments, the compound of formula (I) is represented by formula (II-G) or (II-H):

wherein R is¹、R²、R³、R⁴、R⁵Ring a and ring B have the values described herein.

In some embodiments, the compound of formula (I) is represented by formula (II-GG) or (II-HH):

wherein R is¹、R²、R³、R⁴、R⁵Ring a and ring B have the values described herein.

In some embodiments, the compound of formula (I) is represented by formula (II-J) or (II-K):

wherein X¹、X²、Y^a、Y^b、R¹、R²、R³、R⁴、R⁵Ring a and ring B have the values described herein. In some embodiments, X¹And X²Both are-OH. In some embodiments, X¹And X²Both are-SH. In some embodiments, X¹is-OH and X²is-SH. In some embodiments, X¹is-SH and X²is-OH.

In some embodiments, the compound of formula (I) is represented by formula (II-L) or (II-M):

wherein R is¹、R²、R³、R⁴、R⁵Ring a and ring B have the values described herein. In some embodiments, X¹And X²Both are-OH. In some embodiments, X¹And X²Both are-SH. In some embodiments, X¹is-OH and X²is-SH. In some embodiments, X¹is-SH and X²is-OH. In some embodiments, R²、R³And R⁵Is hydrogen; r¹And R⁴Each independently is hydrogen, fluorine, -OH or-OCH₂CF₃. In some embodiments, R²、R³And R⁵Is hydrogen; r¹Is hydrogen, fluorine, -OH or-OCH₂CF₃(ii) a And R is⁴Is hydrogen, fluorine or-OH. In some embodiments, R²、R³And R⁵Is hydrogen; r¹Is hydrogen or-OH; and R is⁴Is hydrogen or fluorine.

In some embodiments, the compound of formula (I) is represented by formula (III):

or a pharmaceutically acceptable salt thereof, wherein

X¹is-SH or-OH;

X²is-SH or-OH;

Y^ais-O-, -S-or-CH₂-；

Y^bis-O-, -S-, -NH-or-NR^a-, wherein R^aIs C₁-C₄An alkyl group;

R¹is hydrogen, fluorine, -OH, -NH₂、-OR^bor-NHR^b；

R²Is hydrogen or fluorine;

R^bis C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

Ring B is an optionally substituted 9-or 10-membered bicyclic heteroaryl ring containing 2-5 heteroatoms selected from N, O or S; wherein ring B contains at least two N atoms in the ring.

In some embodiments, the compound of formula (I) is represented by formula (III-a):

wherein X¹、X²、Y^a、Y^b、R¹、R²Ring a and ring B have the values described herein.

In some embodiments, the compound of formula (I) is represented by formula (IV):

or a pharmaceutically acceptable salt thereof, wherein R¹、R⁴Ring a and ring B have the values described herein. In some embodiments, R¹And R⁴Each independently is hydrogen, fluorine, -OH or-OCH₂CF₃. In some embodiments, R¹Is hydrogen, fluorine, -OH or-OCH₂CF₃And R is⁴Is hydrogen, fluorine or-OH. In some embodiments, R¹is-OCH₂CF₃And R is⁴Is hydrogen, fluorine or-OH. In some embodiments, R¹is-OH and R⁴Is hydrogen. In some embodiments, R¹Is fluorine and R⁴Is hydrogen. In some embodiments, R¹is-OH and R⁴Is fluorine. In some embodiments, R¹And R⁴Both are hydrogen. In some embodiments, R¹And R⁴Both of which are fluorine.

In some embodiments, the compound of formula (I) is represented by formula (IV-A) or (IV-B):

In some embodiments, the compound of formula (I) is represented by formula (IV-C):

In some embodiments, the compound of formula (I) is represented by formula (V):

or a pharmaceutically acceptable salt thereof, wherein R¹、R⁴Ring a and ring B have the values described herein. In some embodiments, R¹And R⁴Each independently is hydrogen, fluorine, -OH or-OCH₂CF₃. In some embodiments, R¹Is hydrogen, fluorine, -OH or-OCH₂CF₃And R is⁴Is hydrogen, fluorine or-OH. In some embodiments, R¹is-OCH₂CF₃And R is⁴Is hydrogen, fluorine or-OH. In some embodiments, R¹is-OH and R⁴Is hydrogen. In some embodiments, R¹Is fluorine and R⁴Is hydrogen. In some embodiments, R¹is-OH and R⁴Is fluorine. In some embodiments, R¹And R⁴Both are hydrogen.In some embodiments, R¹And R⁴Both of which are fluorine.

In some embodiments, the compound of formula (I) is represented by formula (V-A) or (V-B):

In some embodiments, the compound of formula (I) is represented by formula (V-C):

or a pharmaceutically acceptable salt thereof, wherein R¹、R⁴Ring a and ring B have the values described herein. In some embodiments, R¹And R⁴Each independently is hydrogen, fluorine, -OH or-OCH₂CF₃. In some embodiments, R¹Is hydrogen, fluorine, -OH or-OCH₂CF₃And R is⁴Is hydrogen, fluorine or-OH. In some embodiments, R¹is-OCH₂CF₃And R is⁴Is hydrogen, fluorine or-OH. In some embodiments，R¹is-OH and R⁴Is hydrogen. In some embodiments, R¹Is fluorine and R⁴Is hydrogen. In some embodiments, R¹is-OH and R⁴Is fluorine. In some embodiments, R¹And R⁴Both are hydrogen. In some embodiments, R¹And R⁴Both of which are fluorine.

The following values are described for any of the following formulas: (I) (I-A), (I-B), (I-C), (I-D), (I-E), (I-F), (II-A), (II-B), (II-AA), (II-BB), (II-C), (II-D), (II-E), (II-F), (II-EE), (II-FF), (II-G), (II-H), (II-GG), (II-HH), (II-J), (II-K), (II-L), (II-M), (III-A), (IV-A), (IV-B), (IV-C), (V-A), (V-B) and (V-C). The following values also apply to any of the following formulae described below: (VI), (VI-A), (VI-B), (VI-C), (VI-D), (VI-E), (VI-F), (VI-G), (VI-H), (VII-A), (VII-B), (VII-C) and (VII-D).

In some embodiments, X¹And X²is-SH, and the phosphorus atom of each phosphorothioate bond is chiral and is independently R_pOr S_p。

In some embodiments, X¹And X²is-SH, and the phosphorus atom of each phosphorothioate bond is R_p。

In some embodiments, X¹And X²is-OH.

In some embodiments, X¹And X²One of which is-OH and the other is-SH, and the phosphorus atom of the phosphorothioate bond is chiral and is R_pOr S_p。

In some embodiments, Y is^ais-O-, -S-or-CH₂-. In some embodiments, Y is^ais-O-or-S-. In some embodiments, Y is^ais-O-. In some embodiments, Y is^ais-S-. In some embodiments, Y is^ais-CH₂-。

In some embodiments, Y is^bis-O-, -S-, -NH-or-NR^a-, wherein R^aIs C₁-C₄An alkyl group. In some embodiments, Y is^bis-O-. In some embodiments, Y is^bis-NH-. In some embodiments, Y is^bis-NMe-.

In some embodiments, R¹Is hydrogen, fluorine, -OH, -NH₂、-OR^bor-NHR^bWherein R is^bIs C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group. In some embodiments, R¹Is hydrogen, fluorine, -OH or-OCH₂CF₃. In some embodiments, R¹Is fluorine or-OH. In some embodiments, R¹Is hydrogen. In some embodiments, R¹Is fluorine. In some embodiments, R¹is-OH. In some embodiments, R¹is-OCH₂CF₃。

In some embodiments, R²Is hydrogen or fluorine. In some embodiments, R²Is hydrogen. In some embodiments, R²Is fluorine.

In some embodiments, R¹And R²Both are hydrogen. In some embodiments, R¹And R²Both of which are fluorine. In some embodiments, R¹is-OH and R²Is hydrogen. In some embodiments, R¹Is fluorine and R²Is hydrogen.

In some embodiments, R³Is hydrogen; r⁴Is hydrogen, fluorine, -OH, -NH₂、-OR^bor-NHR^bWherein R is^bIs C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group. In some embodiments, R³And R⁴Together form-CH₂O-is formed. In some embodiments, R³And R⁴Together form-CH₂O-, wherein-CH₂The carbon atom of O-being directly linked to R³Directly bonded carbon atoms.

In some embodiments, R³And R⁴Both are hydrogen. In some embodiments, R³Is hydrogen and R⁴Is fluorine. In some embodiments, R³Is hydrogen and R⁴is-OH.

In some embodiments, R⁵Is hydrogen or fluorine. In some embodiments, R⁵Is hydrogen. In some embodiments, R⁵Is fluorine.

In some embodiments, R³、R⁴、R⁵Are all hydrogen. In some embodiments, R³Is hydrogen, R⁴Is fluorine, and R⁵Is hydrogen. In some embodiments, R³Is hydrogen, R⁴Is hydrogen, and R⁵Is fluorine. In some embodiments, R³Is hydrogen, and R⁴And R⁵Both of which are fluorine.

In some embodiments, ring a is an optionally substituted 5-or 6-membered monocyclic heteroaryl ring containing 1-4 heteroatoms selected from N, O or S, or an optionally substituted 9-or 10-membered bicyclic heteroaryl ring containing 1-5 heteroatoms selected from N, O or S; wherein ring A contains at least one N atom in the ring, and wherein Y^bTo the carbon atom of ring a.

In some embodiments, ring a is an optionally substituted 6-membered monocyclic heteroaryl ring containing 1-3N atoms. In some embodiments, ring a is an optionally substituted 6-membered monocyclic heteroaryl ring containing 1N atom, such as pyridinyl. In some embodiments, ring a is an optionally substituted 6-membered monocyclic heteroaryl ring containing 2N atoms, such as pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments, ring a is an optionally substituted 6-membered monocyclic heteroaryl ring containing 3N atoms, such as 1, 2, 4-triazinyl, 1, 3, 5-triazinyl, thymidylyl, and uracil.

In some embodiments, ring a is

Wherein:

each R¹⁰Independently hydrogen, halogen, -OH, -NH₂、C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl radical, C₃-C₆Cycloalkyl, -OR¹¹、-NHR¹¹、-CN、-NO₂or-C (O) NHR¹²；

R¹¹Is C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

R¹²is hydrogen, C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group; and is

m is 0, 1 or 2.

In some embodiments, m is 0.

In some embodiments, each R is¹⁰Independently hydrogen, fluorine, -OH, -NH₂、-CH₃、-CF₃、-OCH₃、-CN、-NO₂or-C (O) NH₂。

In some embodiments, each R is¹⁰Independently hydrogen, fluorine, chlorine, -CN or C₁-C₃An alkyl group.

In some embodiments, R¹⁰Is fluorine. In some embodiments, R¹⁰Is chlorine. In some embodiments, R¹⁰is-CN. In some embodiments, R¹⁰is-CH₃. In some embodiments, R¹⁰is-C (O) NH₂。

In some embodiments, ring a is

Wherein:

each R¹³Independently hydrogen, halogen, -OH, -NH₂、C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl radical, C₃-C₆Cycloalkyl, -OR¹¹、-NHR¹¹、-CN、-NO₂or-C(O)NHR¹²；

R¹¹Is C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

R¹²is hydrogen, C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group; and is

n is 0, 1 or 2.

In some embodiments, n is 0.

In some embodiments, each R is¹³Independently hydrogen, fluorine, chlorine, -OH, -NH₂、-CH₃、-CF₃、-OCH₃、-CN、-NO₂or-C (O) NH₂。

Examples of optionally substituted 6-membered monocyclic heteroaryl rings include, but are not limited to, the following:

in some embodiments, ring a is an optionally substituted 5-membered monocyclic heteroaryl ring containing 1-4 heteroatoms selected from N, O or S. Examples of 5-membered monocyclic heteroaryl rings include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, pyrazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, tetrazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 3-oxadiazolyl, 1, 3, 4-thiadiazolyl, and 1, 2, 5-thiadiazolyl.

Examples of optionally substituted 5-membered monocyclic heteroaryl rings may also include the following:

in some embodiments, ring a is an optionally substituted 9-or 10-membered bicyclic heteroaryl ring containing 1-5 heteroatoms selected from N, O or S. In some embodiments, ring a is an optionally substituted 9-membered bicyclic heteroaryl ring containing at least 2N atoms. In some embodiments, ring a is an optionally substituted 9-membered bicyclic heteroaryl ring comprising a pyrimidine ring.

Examples of optionally substituted 9-membered bicyclic heteroaryl rings include (but are not limited to) the following:

in some embodiments, ring a may comprise a 6-membered monocyclic heteroaryl ring (e.g., a pyrimidine ring) fused to a non-aromatic ring, for example:

in some embodiments, ring B is an optionally substituted 9-or 10-membered bicyclic heteroaryl ring containing 2-5 heteroatoms selected from N, O or S. In some embodiments, ring B comprises at least two N atoms in the ring. For example, WO2017/027645 and WO2017/027646 describe various 9-membered bicyclic heteroaryl rings. WO2017/027645 and WO2017/027646 are incorporated herein by reference in their entirety.

In some embodiments, ring B is an optionally substituted 9-membered bicyclic heteroaryl ring containing 3-5N atoms; and contains Y^aIs connected to the nitrogen atom of ring B.

In some embodiments, ring B is:

Z¹、Z²、Z³and Z⁴Each independently is N or CR²⁰；

R²¹Is hydrogen or C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

R²³is hydrogen or-NH₂(ii) a And is

R²⁰、R²²And R²⁴Each independently of the others hydrogen, halogen, -OH, -NH₂、-CN、C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group.

In some embodiments, Z¹、Z²、Z³And Z⁴Each independently N, CH or CF;

R²¹is hydrogen or-CH₃(ii) a And R is²²And R²⁴Each independently is hydrogen, -NH₂or-CH₃。

In some embodiments, ring B is a 9-membered bicyclic heteroaryl ring having the structure:

wherein R is²⁰、R²¹、R²²、R²³And R²⁴Having the values described herein.

In some embodiments, R²⁰Is hydrogen or fluorine. In some embodiments, R²¹Is hydrogen or-CH₃And R is²²Is hydrogen, -NH₂or-CH₃. In some embodiments, R²³Is hydrogen or-NH₂And R is²⁴Is hydrogen, -NH₂or-CH₃。

In some embodiments, ring B is selected from:

in some embodiments, ring B is:

ring a and ring B in the compounds disclosed herein may be optionally substituted. When ring a or ring B is substituted, the substituent is one or more substituents independently selected from the group consisting of: halogen, -OH, -CN, -NO₂、C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl radical, C₃-C₆Cycloalkyl, -OR¹¹、-SR¹²、-N(R¹²)₂、-NR¹²C(O)R¹²、-C(O)R¹²、-C(O)OR¹²、-C(O)N(R¹²)₂and-SO₂N(R¹²)₂(ii) a Or two adjacent substituents together with intervening ring atoms form a 4-to 8-membered ring; wherein R is¹¹Is C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group; and R is¹²Is hydrogen, C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group.

In some embodiments, ring a and ring B may be optionally substituted with one or more substituents independently selected from the group consisting of: fluorine, -OH, -CN, -NO₂、-CH₃、-OCH₃、-NH₂、-NHMe、-NMe₂or-C (O) NH₂。

In some embodiments, two adjacent substituents on ring a or ring B, together with intervening ring atoms, form a 4-to 8-membered ring, wherein the 4-to 8-membered ring can be a saturated or partially unsaturated alicyclic or heterocyclic ring.

In some embodiments, the compound of formula (I) is represented by formula (VI):

or a pharmaceutically acceptable salt thereof, wherein:

X¹is-SH or-OH;

X²is-SH or-OH;

Y^bis-O-, -S-, -NH-or-NMe-;

R¹is hydrogen, fluorine, -OH OR-OR^b；

R²Is hydrogen or fluorine;

R³is hydrogen; r⁴Is hydrogen, fluorine or-OH; or R³And R⁴Together form-CH₂O-；

R⁵Is hydrogen or fluorine;

R^bis C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

each R¹⁰Independently hydrogen, halogen, -OH, -NH₂、C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl radical, C₃-C₆Cycloalkyl, -OR¹¹、-NHR¹¹、-CN、-NO₂or-C (O) NHR¹²；

R¹¹Is C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

R¹²is hydrogen, C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

m is 0, 1 or 2;

Z¹n, CH or CF;

R²¹is hydrogen or-CH₃(ii) a And is

R²²Is hydrogen, -NH₂or-CH₃。

In some embodiments, X¹And X²is-SH; and the phosphorus atom of each phosphorothioate bond is chiral and is independently R_pOr S_p。

In some embodiments, X¹And X²is-SH; and the phosphorus atom of each phosphorothioate bond is R_p。

In some embodiments, X¹And X²is-OH.

In some embodiments, X¹And X²One of which is-OH and the other is-SH; and the phosphorus atom of the phosphorothioate bond is chiral and is R_pOr S_p。

In some embodiments, Y is^bis-O-. In some embodiments, Y is^bis-NH-or-NMe-.

In some embodimentsIn, Z¹Is N.

In some embodiments, R¹Is hydrogen, fluorine, -OH or-OCH₂CF₃And R is²Is hydrogen or fluorine.

In some embodiments, R³Is hydrogen; r⁴Is hydrogen, fluorine or-OH; and R is⁵Is hydrogen or fluorine.

In some embodiments, R³And R⁴Together form-CH₂O-; and R is⁵Is hydrogen.

In some embodiments, R²、R³And R⁵Is hydrogen.

In some embodiments, R¹Is hydrogen, fluorine, -OH or-OCH₂CF₃. In some embodiments, R¹Is hydrogen, fluorine or-OH. In some embodiments, R¹Is fluorine or-OH.

In some embodiments, R⁴Is hydrogen, fluorine or-OH. In some embodiments, R⁴Is hydrogen or fluorine.

In some embodiments, m is 0.

In some embodiments, R²¹Is hydrogen.

In some embodiments, R²²is-NH₂。

In some embodiments, the compounds of formula (I) are represented by formulas (VI-A) to (VI-D):

or a pharmaceutically acceptable salt thereof, wherein R¹、R⁴、R¹⁰、R²¹、R²²、Z¹And m has the values described herein.

In some embodiments, the compounds of formula (I) are represented by formulas (VI-E) through (VI-H):

or a pharmaceutically acceptable salt thereof, wherein R¹、R⁴、R¹⁰、R²¹、R²²、Z¹And m has the values described herein.

In some embodiments, the compound of formula (I) is represented by formula (VII):

or a pharmaceutically acceptable salt thereof, wherein:

X¹is-SH or-OH;

X²is-SH or-OH;

Y^bis-NH-or-NMe-;

R¹is hydrogen, fluorine, -OH OR-OR^b；

R²Is hydrogen or fluorine;

R³is hydrogen; r⁴Is hydrogen, fluorine or-OH; or R³And R⁴Together form-CH₂O-；

R⁵Is hydrogen or fluorine;

R^bis C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

each R¹³Independently hydrogen, halogen, -OH, -NH₂、C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl radical, C₃-C₆Cycloalkyl, -OR¹¹、-NHR¹¹、-CN、-NO₂or-C (O) NHR¹²；

R¹¹Is C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

R¹²is hydrogen, C₁-C₆Alkyl, halo (C)₁-C₆) Alkyl or C₃-C₆A cycloalkyl group;

n is 0, 1 or 2;

Z¹n, CH or CF;

R²¹is hydrogen or-CH₃(ii) a And is

R²²Is hydrogen, -NH₂or-CH₃。

In some embodiments, X¹And X²is-SH; and the phosphorus atom of each phosphorothioate bond is chiral and is independently R_pOr S_p。

In some embodiments, X¹And X²is-SH; and the phosphorus atom of each phosphorothioate bond is R_p。

In some embodiments, X¹And X²is-OH.

In some embodiments, X¹And X²One of which is-OH and the other is-SH; and the phosphorus atom of the phosphorothioate bond is chiral and is R_pOr S_p。

In some embodiments, Y is^bis-NH-.

In some embodiments, Z¹Is N.

In some embodiments, R¹Is hydrogen, fluorine, -OH or-OCH₂CF₃And R is²Is hydrogen or fluorine.

In some embodiments, R³Is hydrogen; r⁴Is hydrogen, fluorine or-OH; and R is⁵Is hydrogen or fluorine.

In some embodiments, R³And R⁴Together form-CH₂O-; and R is⁵Is hydrogen.

In some embodiments, R²、R³And R⁵Is hydrogen.

In some embodiments, R¹Is hydrogen, fluorine, -OH or-OCH₂CF₃. In some embodiments, R¹Is hydrogen, fluorine or-OH. In some embodiments, R¹Is fluorine or-OH.

In some embodiments, R⁴Is hydrogen, fluorine or-OH. In some embodiments, R⁴Is hydrogen or fluorine.

In some embodiments, n is 0.

In some embodiments, R²¹Is hydrogen.

In some embodiments, R²²is-NH₂。

In some embodiments, the compounds of formula (I) are represented by formulas (VII-a) through (VII-D):

or a pharmaceutically acceptable salt thereof, wherein R¹、R⁴、R¹³、R²¹、R²²、Z¹And n has the values described herein.

Representative examples of compounds of formula (I) are shown in table 1.

TABLE 1

In table 1, some structures correspond to more than one compound. In these cases, the compounds are diastereomers of each other.

The compounds in table 1 can also be identified by the following chemical names:

when the compound of formula (I) includes two phosphorothioate linkages, each phosphorus atom may be R_pOr S_p. Thus, with respect to the chiral phosphorus atom, the compounds exist in four diastereomers, i.e., R_pS_p、R_pR_p、S_pS_pAnd S_pR_p. Each compound number listed in Table 1 (e.g., I-1a, I-1b, or I-1c) refers to a single diastereomer. The absolute stereochemistry of the phosphorothioate linkages in the compounds has not been determined and the compound number refers to one of the four possible diastereomers.

When compound (I) is in the form of a salt, the salt is usually a pharmacologically acceptable salt. Examples include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.

Useful examples of the salt with an inorganic base include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; aluminum salts and ammonium salts.

Useful examples of salts with organic bases include salts with: trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [ tris (hydroxymethyl) methylamine ], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine and N, N-dibenzylethylenediamine.

Useful examples of the salt with an inorganic acid include salts with: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid.

Useful examples of the salt with an organic acid include salts with: formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

Useful examples of salts with basic amino acids include salts with arginine, lysine and ornithine.

Useful examples of the salt with an acidic amino acid include salts with aspartic acid and glutamic acid.

When the compound of formula (I) is in the form of a salt, in one embodiment, the salt is a salt with triethylamine or sodium. In some embodiments, the salt is a salt with sodium. In some embodiments, the salt is a salt with triethylamine.

General synthetic methods and intermediates

The compounds of the present disclosure may be prepared by methods known to those skilled in the art and/or by reference to the schemes and synthetic examples shown below. See, e.g., org.lett., 2010, 12(14), pages 3269-3271; WO2017/075477 (A1). Starting materials and intermediates were purchased from commercial sources and prepared via published or hereinafter described procedures. Exemplary synthetic routes are set forth in the schemes and examples below.

Scheme 1: general route to Cyclic bisphosphates

Scheme 1 shows a general route for the preparation of compounds of formula v, which are derived from an appropriately protected H-phosphonate i (wherein R is⁴Is hydroxy protected by silyl, hydrogen, fluorine, or with R³Together form OCH₂，R₃Is H, and R⁵Hydrogen or fluorine), with a suitably protected compound ii having a phosphoramidite functionality at the 2' position in the presence of a weak acid such as ethylthio-tetrazole. The resulting phosphite is oxidized with t-butyl hydroperoxide or other oxidizing agent. With AcOH/water (if the protecting group is dimethoxytrityl ether) or with TFA/water (if the protecting group is silyl-based (where R is R)¹And OPG via OSi (iPr)₂OSi(iPr)₂O-linked)) to remove the protecting group on the 5' oxygen to provide the phosphate ester iii. Treatment of compound iii with 2-chloro-5, 5-dimethyl-1, 3, 2-dioxaphosphorinane 2-oxide or other coupling agent followed by oxidation with iodine or other mild oxidizing agent provides the protected cyclic diphosphate iv. Removal of the protecting groups from the phosphate ester and rings a and B is achieved by treatment with ethanol containing methylamine. Any silyl-based protecting groups are removed with hydrogen fluoride-triethylamine and a cyclic diphosphate compound v is produced that is completely deprotected.

Scheme 2: general route to Cyclic dithiophosphates

Scheme 2 shows a general route for the preparation of dithiophosphate compounds of formula viii from H-phosphonates i (wherein R is derived from cyclopentane and is suitably protected)⁴Is hydroxy, hydrogen or fluorine protected by silyl, or with R³Together form OCH₂，R³Is H, and R⁵Hydrogen or fluorine), with a suitably protected compound ii having a phosphoramidite functionality at the 2' position, in the presence of a weak acid such as ethylthio-tetrazole or under 4, 5-dicyanoimidazole. The resulting phosphite is oxidized to the phosphorothioate using a sulfur transfer reagent such as ((dimethylamino-methylene) amino) -3H-1, 2, 4-dithiazoline-3-thione) or bis (phenylacetyl) disulfide. With AcOH/water (if the protecting group is dimethoxytrityl ether) or with TFA/water (if the protecting group is silyl-based (where R is R)¹And OPG via OSi (iPr)₂OSi(iPr)₂O-linkage)) to remove the protecting group on the 5' oxygen to provide a phosphorothioate vi. Treatment of compound vi with 2-chloro-5, 5-dimethyl-1, 3, 2-dioxaphosphorinane 2-oxide or diphenylphosphoryl fluoride followed by treatment with a sulfur transfer reagent (e.g., 3H-1, 2-benzodithiol-3-one 1, 1-dioxide or 3H-1, 2-benzodithiol-3-one) provides a cyclic dithiophosphate vii. Removal of the protecting groups from the phosphorothioate and rings a and B was achieved by treatment with ethanol containing methylamine. Any silyl-based protecting groups are removed with hydrogen fluoride-triethylamine and a completely deprotected cyclic dithiophosphate compound viii is produced.

Scheme 3: alternative routes to cyclic bisphosphates or cyclic dithiophosphates

Scheme 3 shows an alternative route for preparing compounds of formula II. When X is present¹And X²When both are OH, the H-phosphonate ix is reacted with a suitably protected phosphoramidite x (wherein R is R) derived from cyclopentane in the presence of a weak acid such as ethylthio-tetrazole⁴Is hydroxy protected by silyl, hydrogen, fluorine, or with R³Together form OCH₂，R³Is H) coupling. The resulting phosphite is oxidized with t-butyl hydroperoxide or other oxidizing agent. With AcOH/water (if the protecting group is dimethoxytrityl ether) or with TFA/water (if the protecting group is based on methyl)Silyl) removes the protecting group on the 5' oxygen to provide the phosphate xi. Treatment of compound xi with 2-chloro-5, 5-dimethyl-1, 3, 2-dioxaphosphorinane 2-oxide or other coupling agent, followed by oxidation with iodine or other mild oxidizing agent, provides the protected cyclic diphosphate xii. Removal of the protecting groups from the phosphate ester and rings a and B is achieved by treatment with ethanol containing methylamine. Removal of any silyl-based protecting groups with hydrogen fluoride-triethylamine and generation of X wherein¹And X²Both are completely deprotected cyclic diphosphate compounds II of OH.

Wherein X¹And X²The compounds of formula II which are SH may be prepared in an analogous manner. Reacting an H-phosphonate ix with a suitably protected phosphoramidite x (wherein R is a substituted phosphoramidite x) derived from cyclopentane in the presence of a weak acid such as ethylthio-tetrazole⁴Is hydroxy protected by silyl, hydrogen, fluorine, or with R³Together form OCH₂，R³Is H) coupling. The resulting phosphite is oxidized to the phosphorothioate using a sulfur transfer agent, such as ((dimethylamino-methylene) amino) -3H-1, 2, 4-dithiazoline-3-thione). Removal of the protecting group on the 5' oxygen with AcOH/water (if the protecting group is dimethoxytrityl ether) or with TFA/water (if the protecting group is silyl based) affords the phosphorothioate xi. Treatment of compound xi with 2-chloro-5, 5-dimethyl-1, 3, 2-dioxaphosphorinane 2-oxide or other coupling agent followed by treatment with a sulfur transfer reagent (e.g., 3H-1, 2-benzodithiol-3-one 1, 1-dioxide or 3H-1, 2-benzodithiol-3-one) provides a cyclic dithiophosphate xii. Removal of the protecting groups from the phosphorothioate and rings a and B was achieved by treatment with ethanol containing methylamine. Removal of any silyl-based protecting groups with hydrogen fluoride-triethylamine and generation of X wherein¹And X²Both are completely deprotected cyclic dithiophosphate compounds II of SH.

Scheme 4: route for preparing cyclic monothiophosphates

Scheme 4 shows monothiophosphates (wherein X¹Is SH and X²Synthesis of Compound II) which is OH. Treatment of compound iii with 2-chloro-5, 5-dimethyl-1, 3, 2-dioxaphosphorinane 2-oxide or diphenylphosphoryl chloride followed by treatment with a sulfur transfer reagent (e.g., 3H-1, 2-benzodithiol-3-one 1, 1-dioxide or 3H-1, 2-benzodithiol-3-one) affords cyclic monothiophosphate xiii. Removal of the protecting groups from the phosphate ester and rings a and B is achieved by treatment with ethanol and/or tert-butylamine containing methylamine. Removal of any silyl-based protecting groups with hydrogen fluoride-triethylamine and generation of X wherein¹Is SH and X²Cyclic monothiophosphate compound II which is completely deprotected to OH.

Scheme 5: alternative route to cyclic monothiophosphates

Scheme 5 shows monothiophosphates (wherein X¹Is OH and X²Synthesis of Compound II) as SH. Treatment of the compound with 2-chloro-5, 5-dimethyl-1, 3, 2-dioxaphosphorinane 2-oxide or other coupling agent, wherein X¹Compound xi which is O, followed by treatment with a sulfur transfer reagent (e.g., 3H-1, 2-benzodithiol-3-one 1, 1-dioxide or 3H-1, 2-benzodithiol-3-one) provides a cyclic monothiophosphate xii (X)²Is SH). Removal of the protecting groups from the phosphate ester and rings a and B is achieved by treatment with ethanol containing methylamine. Removal of any silyl-based protecting groups with hydrogen fluoride-triethylamine and generation of X wherein¹Is OH and X²A cyclic monothiophosphate compound II which is a complete deprotection of SH.

Scheme 6: another method for preparing cyclic monothiophosphates

Scheme 6 showsMonothiophosphate (wherein X¹Is OH and X²Synthesis of Compound II) as SH. Treatment of compound vi with 2-chloro-5, 5-dimethyl-1, 3, 2-dioxaphosphorinane 2-oxide or other coupling agent followed by oxidation with iodine or other mild oxidizing agent provides cyclic monothiophosphates xiv. Removal of the protecting groups from the phosphorothioate and rings a and B was achieved by treatment with ethanol containing methylamine. Removal of any silyl-based protecting groups with hydrogen fluoride-triethylamine and generation of X wherein¹Is OH and X²A cyclic monothiophosphate compound II which is a complete deprotection of SH.

Scheme 7: synthesis of heteroaryl N and O linked cyclopentane H-phosphonates

Scheme 7 shows the preparation of cyclopentane H-phosphonate intermediate i (where R is⁴Is hydroxy protected by silyl, hydrogen, fluorine, or with R³Together form OCH₂，R³Is H, and R⁵Hydrogen or fluorine). Cyclopentane xv (where PG is a suitable protecting group, e.g. trityl, benzyl or silyl derivative) under basic conditions (using, e.g. LDA, DIPEA, K)₂CO₃Or a base such as KOtBu) with a heterocyclic halide xvi to provide intermediate xvii. In some embodiments, heterocycle A in intermediate xvii can be substituted with chlorine using palladium on carbon or Pd (OH)₂Hydrogenation is carried out for reduction. In which Y is^bIn some embodiments, Y is NH^bThe alkylation may be carried out using an alkyl halide (e.g., MeI) and a base (e.g., NaH). The alcohol protecting group is then removed using an acid (e.g., TFA or HCl) or a fluoride source (e.g., TBAF) to provide the diol xviii. Followed by treatment with a base (e.g. DBU, NEt)₃Or pyr) temporary protection of the primary alcohol with a dimethoxytrityl group using diphenyl phosphite and a base (e.g. Et)₃N or pyr) and using a weak acid (e.g., AcOH or DCA) to remove the dimethoxytrityl group, provides compound i. In the examples where the primary alcohol is protected with a benzyl group, trichloro is usedBoron deprotects the protecting group to produce compound i.

Scheme 8: substitutional synthesis of heteroaryl O-linked cyclopentane intermediates

Scheme 8 shows the preparation of xvii (when Y^bO) in the case of a chemical vapor deposition process. Treating under Mitsunobu transformation conditions (e.g., benzoic acid, triphenylphosphine and DIAD) wherein Y^bCyclopentane xv being O. The benzoate group is removed under mildly alkaline conditions, such as potassium carbonate, to provide the inverted alcohol xxi. Subsequent mitsunobu reaction with a heteroaromatic alcohol xxii using triphenylphosphine and a diazodicarboxylate reagent (e.g., DEAD, DIAD or DBAD) under standard conditions provides compound xvii.

Scheme 9: synthesis of cyclopentane phosphoramidite

Scheme 9 depicts a general scheme for the preparation of cyclopentane phosphoramidite x. Cyclopentane xxiii and 2-cyanoethyl N, N, N ', N' -tetraisopropyl phosphoramidite xxiv are combined under conditions such as tetrazole and N-methylimidazole.

Scheme 10: synthetic route for the preparation of H-phosphonates

Scheme 10 shows a route for the preparation of compounds of formula ix, starting from compound ii with phosphoramidite functionality at the 2' position, which is converted to H-phosphonate in the presence of aqueous TFA/pyridine, followed by treatment with a base such as tert-butylamine. The primary alcohol is then deprotected using mildly acidic conditions such as AcOH.

Scheme 11: general route for the preparation of phosphoramidites

Scheme 11 shows the preparation of phosphoramidite intermediates ii (where PG is a suitable protecting group, e.g., trityl, or where R is¹And OPG via OSi (iPr)₂OSi(iPr)₂O links). Alcohol xxv and 2-cyanoethyl N, N, N ', N' -tetraisopropyl phosphoramidite xxiv are combined under conditions such as tetrazole and N-methylimidazole.

Methods of use of compounds of formula (I)

The compounds of the present disclosure exhibit STING modulating/agonistic activity. Certain compounds of the present disclosure can be excellent in terms of potency expression, pharmacokinetics (e.g., absorption, distribution, metabolism, excretion), solubility (e.g., water solubility), interaction with other agents (e.g., drug metabolizing enzyme inhibition), safety (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, central toxicity), and/or stability (e.g., chemical stability, enzymatic stability), and can be useful as pharmaceutical agents.

The compounds of the present disclosure can be used to increase STING activity in a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human).

The compounds of the present disclosure may be used as an agent, for example, an agent for preventing or treating a disease (in the present specification, sometimes abbreviated as "STING-related disease") that can be affected by STING, such as cancer, e.g., colorectal cancer (e.g., colorectal cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor), lung cancer (e.g., non-small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic ductal cancer, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), duodenal cancer, small intestinal cancer, breast cancer (e.g., invasive ductal cancer, noninvasive ductal cancer, inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial cancer, gonadal ectogenital cell tumor), Ovarian germ cell tumor, ovarian low malignant potential tumor), testicular tumor, prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer, castration-resistant prostate cancer), liver cancer (e.g., hepatocellular cancer, primary liver cancer, extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid cancer), kidney cancer (e.g., renal cell cancer (e.g., clear cell renal cell cancer), transitional cell cancer of renal pelvis and ureter), uterine cancer (e.g., cervical cancer, uterine corpus cancer, uterine sarcoma), choriocarcinoma of pregnancy, brain tumor (e.g., medulloblastoma, glioma, pineal astrocytoma, hairy cell astrocytoma, diffuse astrocytoma, poorly differentiated astrocytoma, pituitary adenoma), retinoblastoma, skin cancer (e.g., basal cell tumor), and the like, Malignant melanoma), sarcoma (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, spindle cell sarcoma), malignant bone tumor, bladder cancer, blood cancer (e.g., multiple myeloma, leukemia (e.g., acute myelogenous leukemia), malignant lymphoma, Hodgkin's disease, chronic myeloproliferative disease), unknown primary cancer; an inhibitor of cancer growth; inhibitors of cancer metastasis; an apoptosis-promoting agent; agents for treating precancerous lesions (e.g., myelodysplastic syndrome), and the like.

In certain embodiments, the compounds of the present disclosure are useful as agents for colorectal cancer, breast cancer, skin cancer, malignant lymphoma, or lung cancer.

The compounds of the present disclosure may be administered to a mammal (typically a human) orally or parenterally as medicaments, as such or in admixture with pharmacologically acceptable carriers.

The medicament containing the compound of the present disclosure (hereinafter sometimes abbreviated as "the medicament of the present disclosure") is explained in detail below. Examples of dosage forms of the agents of the present disclosure include oral formulations, such as tablets (e.g., sugar-coated tablets, film-coated tablets, sublingual tablets, buccal tablets, orally disintegrating tablets), pills, granules, powders, capsules (e.g., soft capsules, microcapsules), syrups, emulsions, suspensions, films (e.g., orally disintegrating films, oral mucoadhesive films), and the like. In addition, examples of dosage forms of the agent of the present disclosure include parenteral preparations such as injections, instillations, transdermal absorption type preparations (e.g., iontophoretic transdermal absorption type preparations), suppositories, ointments, nasal preparations, pulmonary preparations, eye drops, and the like. Further, the agents of the present disclosure may be release-controlled formulations, such as immediate-release formulations, sustained-release formulations (e.g., sustained-release microcapsules), and the like.

As the dosage form of the agent of the present disclosure, a nanoparticle preparation and a preparation using a bacteria-derived membrane can also be used.

The agents of the present disclosure can be prepared according to methods known per se (e.g., methods set forth in the united states pharmacopoeia (us pharmacopoeia) and the like) generally used in the formulation field. In addition, the agent of the present disclosure may contain, as necessary, additives generally used in the field of formulation, such as excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers, colorants, preservatives, aromatics, flavors, stabilizers, thickeners, and the like, in an appropriate amount. Examples of the pharmacologically acceptable carrier include these additives.

For example, tablets may be prepared using excipients, binders, disintegrants, lubricants, etc., and pills or granules may be prepared using excipients, binders and disintegrants. Powders or capsules may be prepared using excipients and the like, syrups may be prepared using sweeteners and the like, and emulsions or suspensions may be prepared using suspending agents, surfactants, emulsifiers and the like.

Examples of useful excipients include lactose, sucrose, glucose, starch, sucrose, crystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, and calcium sulfate.

Examples of usable binders include 5 to 10 wt% of starch liquid paste, 10 to 20 wt% of acacia gum solution or gelatin solution, 1 to 5 wt% of tragacanth gum solution, carboxymethyl cellulose solution, sodium alginate solution and glycerin.

Examples of useful disintegrants include starch and calcium carbonate.

Examples of useful lubricants include magnesium stearate, stearic acid, calcium stearate, and talc.

Examples of useful sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, and simple syrup.

Examples of useful surfactants include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid esters, and polyoxyl 40 stearate.

Examples of useful suspending agents include acacia, sodium alginate, sodium carboxymethylcellulose, methylcellulose, and bentonite.

Examples of useful emulsifying agents include gum arabic, tragacanth gum, gelatin, and polysorbate 80.

For example, when the pharmaceutical agent of the present disclosure is, for example, a tablet, an excipient (e.g., lactose, sucrose, starch), a disintegrant (e.g., starch, calcium carbonate), a binder (e.g., starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose) or a lubricant (e.g., talc, magnesium stearate, polyethylene glycol 6000) is added to the compound of the present disclosure, and the mixture is compression-molded according to a method known per se, and then, when necessary, the molded product is coated according to a method known per se to obtain a tablet for the purpose of masking taste, enteric solubility, or durability. As the coating agent for coating, for example, hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose succinate, Eudragit (methacrylic acid-acrylic acid copolymer, manufactured by Rohm, DE) and pigments (e.g., iron oxide red, titanium dioxide) can be used.

Examples of injections include intravenous injections as well as subcutaneous injections, intradermal injections, intramuscular injections, intraperitoneal injections, drip injections, intratumoral injections, and the like.

These injections are prepared according to methods known per se or by dissolving, suspending or emulsifying the compounds of the present disclosure in sterile aqueous or oily liquids. Examples of aqueous liquids include physiological saline, isotonic solutions containing glucose or other auxiliary drugs (e.g., D-sorbitol, D-mannitol, sodium chloride), and the like. The aqueous liquid may contain a suitable solubilizing agent, such as an alcohol (e.g., ethanol), a polyol (e.g., propylene glycol, polyethylene glycol), a non-ionic surfactant (e.g., polysorbate 80, HCO-50), and the like. Examples of the oily liquid include sesame oil, soybean oil, and the like. The oily liquid may contain a solubilizer. Examples of the solubilizing agent include benzyl benzoate, benzyl alcohol and the like. Additionally, the injection may be blended with: buffers (e.g., phosphate buffer, sodium acetate buffer), soothing agents (e.g., benzalkonium chloride, procaine hydrochloride), stabilizers (e.g., human serum albumin, polyethylene glycol), preservatives (e.g., benzyl alcohol, phenol), and the like. The prepared injection can be filled in an ampoule.

Although the content of the compound of the present disclosure in the medicament of the present disclosure varies depending on the form of the pharmaceutical preparation, it is usually about 0.01 wt% to about 100 wt%, usually about 2 wt% to about 85 wt% or about 5 wt% to about 70 wt% with respect to the whole preparation.

Although the content of the additive in the agent of the present disclosure varies depending on the form of the pharmaceutical preparation, it is usually about 1 wt% to about 99.9 wt%, usually about 10 wt% to about 90 wt% with respect to the whole preparation.

Although the daily dose of the compound of the present disclosure varies depending on the condition and body weight of a patient, the type of the compound, the administration route, and the like, in the case of, for example, oral administration to a patient for the treatment of cancer, the daily dose for an adult (body weight about 60kg) is about 1mg to about 1000mg, usually about 3mg to about 300mg or about 10mg to about 200mg of the compound of the present disclosure, which may be given in a single administration or 2 or 3 divided administrations per day.

When the compounds of the present disclosure are administered parenterally, they are typically administered in liquid form (e.g., as an injection). Although the dose of the compound of the present disclosure varies depending on the subject to be administered, the target organ, the symptom, the administration method, and the like, for example, it is about 0.01mg to about 100mg, usually about 0.01mg to about 50mg or about 0.01mg to about 20mg, relative to 1kg body weight, which is usually administered by intravenous injection.

The present disclosure also includes compounds of the present disclosure having the following uses: (i) for use in (a) inducing an immune response in a patient or (b) inducing STING-dependent cytokine production in a patient; (ii) for use as an agent for (a) inducing an immune response in a patient or (b) inducing STING-dependent cytokine production in a patient; or (iii) for use in the preparation of a medicament for (a) inducing an immune response in a patient or (b) inducing STING-dependent cytokine production in a patient. In these uses, the compounds of the present disclosure may optionally be used in combination with one or more second therapeutic agents.

As used herein, the term "immune response" relates to any one or more of the following: specific immune response, non-specific immune response, specific and non-specific response, innate response, primary immune response, adaptive immune response, secondary immune response, memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation, and cytokine expression.

In one embodiment, the compounds of formula (I) disclosed herein are useful for inducing STING-dependent type I interferon production in a subject. The compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered by contacting the active agent with the site of action of the agent. They can be administered as individual therapeutic agents or combinations of therapeutic agents by conventional means available for use in conjunction with medicine. They can be administered alone, but are typically administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

The compounds of the present disclosure may also be used as adjuvants to improve the immune response generated against any given antigen and/or to reduce the reactogenicity/toxicity of patients, especially humans, in need thereof. Thus, the compounds of the present disclosure may be used in combination with vaccine compositions to improve, particularly enhance, immune responses, for example, by increasing the degree or duration of protection and/or decreasing the antigen dose. The compounds of formula (I) and pharmaceutically acceptable salts thereof may be used in combination with one or more vaccines or immunogenic antigens useful in the prevention or treatment of viral infections.

The present disclosure also provides vaccine compositions comprising an antigen and a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The compounds of the present disclosure may be used in parallel with other drugs. In particular, the compounds of the present disclosure may be used with agents such as: hormonal therapeutic agents, chemotherapeutic agents, immunotherapeutic agents, agents that inhibit the action of a cell growth factor or cell growth factor receptor, and the like. Hereinafter, drugs that can be used in combination with the compounds of the present disclosure are abbreviated as concomitant drugs.

Examples of "hormonal therapy agents" include fosfestrol, diethylstilbestrol (diethylstilbestrol), chlorendamide (chlorotrianisene), medroxyprogesterone acetate, megestrol acetate (megestrol acetate), chlormadinone acetate (chlormadinone acetate), cyproterone acetate (cyproterone acetate), danazol (danazol), allylestrenol, gestrinone (gestrinone), mepartricin (mepartricin), raloxifene (raloxifene), oxymetafene (levomexilene), levomexiloxifene (levoxeloxoxifene), antiestrogens (e.g., tamoxifen citrate), toremifene citrate (toremifene), pellet formulations, meletidine (medetorphine), androsterone , amitriptyline (aminoglutethinyl), estriol acetate (estradiol acetate), leuprolifene (estradiol), estradiol acetate (estradiol), levoloxifetroburin (e), levofloxacin, levoloxifene (levofloxacin), levofloxacin, and a suitable for example, a suitable hormone, such as a hormone, a, Aromatase inhibitors (e.g. fadrozole (hydrochloride), anastrozole (anastrozole), letrozole (retrozole), exemestane (exemestane), vorozole (vorozole), formestane (formestane)), antiandrogens (e.g. flutamide), bicalutamide (bicalutamide), nilutamide (nilutamide), enzalutamide (enzalutamide)), 5 α -reductase inhibitors (e.g. finasteride (finasteride), epristeride (epristeride), dutasteride (dutasteride)), adrenocortical drugs (e.g. dexamethasone (dexamehasone), prednisolone (prednisone), betamethasone (betamethasone), triamcinolone (triamcinolone)), androgen synthesis inhibitors (e.g. arbinolone (arbinolide)), and delayed-metabolism drugs (e.g. thyrotoxicoid (s)), and thyroid hormone (thyroid hormone), and their metabolism-like preparations.

Examples of "chemotherapeutic agents" include alkylating agents, antimetabolites, anticancer antibiotics, and plant-derived anticancer agents.

Examples of "alkylating agents" include nitrogen mustard, mechlorethamine-N-oxide hydrochloride, chlorambucil (chlorambutyl), cyclophosphamide, ifosfamide, thiotepa (thiotepa), carboquone (carboquone), inprophan tosylate (imsulfan tosylate), busulfan (busufan), nimustine hydrochloride (nimustine hydrochloride), dibromomannitol, melphalan (melphalan), dacarbazine (dacarbazine), ramustine (ranimustine), estramustine sodium phosphate (sodium estramustine phosphate), triethylenemelamine, carmustine (carmustine), lomustine (lomustine), streptozotocin (streptazocin), pipobroman (pipobroman), etoglucid (etoglucamide), carboplatin (carboplatin), platinum (oxaliplatin), platinum (platinum chloride), platinum (platinum chloride), platinum (platinum) and platinum (platinum) salts), platinum (platinum) and platinum (platinum, Puritipie (pumitepa), ribostamine (ribomustin), temozolomide (temozolomide), busulfan (treosulphan), trophosfamide (tropphamide), netstatin temalamide (zinostatin stimamer), adolesin (adozelesin), cysteamine nitrosurea (cystemustine), bizelesin (bizelesin) and DDS formulations thereof.

Examples of "antimetabolites" include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate (methotrexate), pemetrexed (pemetrexed), enocitabine (enocitabine), cytarabine (cytarabine), cytarabine octadecylphosphate (cytarabine ocfosfate), ancetabine hydrochloride (ancetabine hydrochloride), 5-FU drugs (e.g., fluorouracil, tegafur (tegafur), UFT, deoxyfluorouridine, carmofur (carmofur), galocitabine (gallocitabine), emizofure (emiteur), capecitabine (capecitabine), aminopterine (aminopterine), nezarabbine (nelzarabine), leucovorin, tazobactam (betalaine), glycothioprine (butoridine), leucovorin, leucovorabine (cladribine), calcium folinate (levofloxacin, calcium citrate), calcium citrate (pyridoxine), calcium (pyridoxine (citrate), calcium (pyridoxine), levofloxacin, calcium (pyridoxine (e), pyridoxine (e), calcium (pyridoxine), calcium) and (pyridoxine (e), calcium (pyridoxine (e), fluvastatin), levofloxacin, calcium (pyridoxine (e), levofloxacin, calcium (e, Idoxuridine, mitoguazone (mitoguzone), thiazophenazone (thiazoprine), ambamustine (ambamustine), bendamustine (bendamustine) and DDS formulations thereof.

Examples of "anticancer antibiotics" include actinomycin-D (actinomycin-D), actinomycin-C, mitomycin-C (mitomycin-C), chromomycin-A3 (chromomycin-A3), bleomycin hydrochloride (bleomycin hydrochloride), bleomycin sulfate, pelomycin sulfate (pemomycin sulfate), daunorubicin hydrochloride (daunorubicin hydrochloride), doxorubicin hydrochloride (doxorubicin hydrochloride), aclarubicin hydrochloride (aclarubicin hydrochloride), pirarubicin hydrochloride (pirarubicin hydrochloride), epirubicin hydrochloride (epirubicin hydrochloride), neocarzinostacin (neocarzinostatin), mithramycin (mithramycin), doxorubicin (sarcin), phetaminins (phytomycin), phytochrome (phytochrome DDS), mitomycin (mitomycin hydrochloride), and mitomycin hydrochloride (e.g., a preparation thereof, such as mitomycin hydrochloride).

Examples of "plant-derived anticancer agents" include etoposide (etoposide), etoposide phosphate, vinblastine sulfate (vinblastine sulfate), vincristine sulfate (vincristine sulfate), vindesine sulfate (vindesine sulfate), teniposide (teniposide), paclitaxel (paclitaxel), docetaxel (docetaxel), cabazitaxel (cabazitaxel), vinorelbine (vinorelbine), and DDS formulations thereof.

Examples of "immunotherapeutic agents" (BRMs) include streptolysin (picibanil), polysaccharose, sizopyran (sizofian), lentinan, ubenimex (ubenimex), interferons, interleukins, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum (Corynebacterium parvum), levamisole, polysaccharide K, procodazole (procodazole), anti-CTLA 4 antibodies (e.g., ipilimumab (ipilimumab), tremelimumab (tremelimumab)), anti-PD-1 antibodies (e.g., nivolumab), pembrolizumab (pembrolizumab)), and anti-PD-L1 antibodies.

Examples of the "cell growth factor" in the "agent inhibiting the action of a cell growth factor or a cell growth factor receptor" include any substance that promotes cell proliferation, which is generally a peptide having a molecular weight of not more than 20,000 and capable of exhibiting its activity by binding to a receptor at a low concentration, including (1) EGF (epidermal growth factor) or a substance having substantially the same activity as EGF [ e.g., TGF α ], (2) insulin or a substance having substantially the same activity as insulin [ e.g., insulin, IGF (insulin-like growth factor) -1, IGF-2], (3) FGF (fibroblast growth factor) or a substance having substantially the same activity as FGF [ e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10], and (4) other cell growth factors [ e.g., CSF (CSF stimulating colony factor); TGF-10 ], EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGF (transforming growth factor beta), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), regulatory protein (heregulin) and angiogenin.

Examples of "cell growth factor receptors" include any receptor capable of binding to the above-mentioned cell growth factors, including EGF receptors, regulatory protein receptors (e.g., HER3), insulin receptors, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, VEGF receptors, angiopoietin receptors (e.g., Tie2), PDGF receptors, and the like.

Examples of the "agent inhibiting the action of a cell growth factor or a cell growth factor receptor" include EGF inhibitors, TGF α inhibitors, regulatory protein inhibitors, insulin inhibitors, IGF inhibitors, FGF inhibitors, KGF inhibitors, CSF inhibitors, EPO inhibitors, IL-2 inhibitors, NGF inhibitors, PDGF inhibitors, TGF β inhibitors, HGF inhibitors, VEGF inhibitors, angiogenin inhibitors, EGF receptor inhibitors, HER2 inhibitors, HER4 inhibitors, insulin receptors, IGF-1 receptor inhibitors, IGF-2 receptor inhibitors, FGF receptor-1 inhibitors, FGF receptor-2 inhibitors, FGF receptor-3 inhibitors, FGF receptor-4 inhibitors, VEGF receptor inhibitors, Tie-2 inhibitors, PDGF receptor inhibitors, Abl inhibitors, Raf inhibitors, FLT3 inhibitors, c-Kit inhibitors, Src inhibitors, PKC inhibitors, Smo inhibitors, ALK inhibitors, ROR1 inhibitors, Trk inhibitors, Ret inhibitors, mTOR inhibitors, Aurora inhibitors, PLK inhibitors, MEK (MEK1/2) inhibitors, MET inhibitors, CDK inhibitors, Akt inhibitors, ERK inhibitors, PI3K inhibitors, and the like. More specifically, anti-VEGF antibodies (e.g., Bevacizumab (Bevacizumab), ramucirumab (Ramucumab)), anti-HER 2 antibodies (e.g., Trastuzumab (Trastuzumab), Pertuzumab (Pertuzumab)), anti-EGFR antibodies (e.g., Cetuximab), Panitumumab (Panitumumab), Matuzumab (Matuzumab), Nimotuzumab (Nimotuzumab)), anti-HGF antibodies, Imatinib (Imatinib), Erlotinib (Erlotinib), Gefitinib (Gefitinib), Sorafenib (Sorafenib), Sunitinib (Sunitinib), Dasatinib (Dasatinib), Lapatinib (Lapatinib), Vatalinib (Vatamarib), ibrib (Ibritinib), Sunitinib (Botutinib), Botinib (Botinib), Netinib (Piranibizib), Piranibizine (Piranibizib-4 (Arctinib-1-Spininib), Piperab (Arctinib-4), Arctinib (Piranibizib), Piperab (Piperab), Piperab (Piranibizib), Piperab (E-4), and Abxitinib (Piranibizib), or Ab-4), wherein (R) -phenylethyl ] -7H-pyrrolo [2, 3-d ] pyrimidin-4-amine (AEE-788), Vandetanib (Vandetanib), Temsirolimus (Temsirolimus), Everolimus (Everolimus), Enzastaurin (Enzastaurin), Tozasertib (Tozasertib), 2- [ N- [3- [4- [5- [ N- (3-fluorophenyl) carbamoylmethyl ] -1H-pyrazol-3-ylamino ] quinazolin-7-yloxy ] propyl ] -N-ethylamino ] ethyl phosphate (AZD-1152), 4- [ 9-chloro-7- (2, 6-difluorophenyl) -5H-pyrimido [5, 4-d ] [2] benzazepin-2-ylamino ] benzoic acid, N- [ 2-methoxy-5- [ (E) -2- (2, 4, 6-trimethoxyphenyl) vinylsulfonylmethyl ] phenyl ] glycine sodium salt (ON-1910Na), Volasertib (Volasertib), Selumitinib (Selumetinib), Trametinib (Trametinib), N- [2(R), 3-dihydroxypropoxy ] -3, 4-difluoro-2- (2-fluoro-4-iodophenylamino) benzamide (PD-0325901), bosutinib, Regorafenib, Afatinib, Idelalisib (Idelalisib), Ceritinib (Ceritinib), Dabrafenib (Dabrafenaib), and the like.

In addition to the above-mentioned drugs, the following may be used as concomitant drugs: l-asparaginase; l-arginase; arginine deiminase; acetoglucuronolactone (acegultone); procarbazine hydrochloride (procarbazine hydrochloride); protoporphyrin-cobalt complex salts; hematoporphyrin-sodium mercury; topoisomerase I inhibitors (e.g., irinotecan (irinotecan), topotecan (topotecan), indotecan (indotecan), netilmicin (Indimitecan)); topoisomerase II inhibitors (e.g., sobuzoxane); differentiation inducers (e.g., retinoids, vitamin D); other angiogenesis inhibitors (e.g., humagin (humagillin), shark extracts, COX-2 inhibitors); an α -blocker (e.g., tamsulosin hydrochloride); bisphosphonic acids (e.g., pamidronate, zoledronate); thalidomide (thalidomide); leilidomide (Lelidomide); pommalidomide (pomalidomide); azacytidine; decitabine (decitabine); proteasome inhibitors (e.g., bortezomib (bortezomib), carfilzomib (carfilzomib), esxazomib (ixazoib)); NEDD8 inhibitors (e.g., pevesitat (pevon edistat)); a UAE inhibitor; PARP inhibitors (e.g., Olaparib (Olaparib), nilapaib (Niraparib), viliparib (Veliparib)); anti-tumor antibodies, such as anti-CD 20 antibodies (e.g., Rituximab (Rituximab), otuzumab), anti-CCR 4 antibodies (e.g., moglicazumab (Mogamulizumab)), and the like; antibody-drug conjugates (e.g., trastuzumab emtansine (trastuzumab ibemabensine), brentuzumab vedotti (Brentuximab vedotin)), and the like.

By combining the compound of the present disclosure with a concomitant drug, excellent effects can be achieved, for example, (1) the dose can be reduced as compared with single administration of the compound of the present disclosure or the concomitant drug, (2) a drug to be combined with the compound of the present disclosure can be selected depending on the condition of a patient (mild case, severe case, etc.), (3) the treatment period can be set longer, (4) a sustained therapeutic effect can be designed, (5) combined use of the compound of the present disclosure and the concomitant drug can provide a synergistic effect, and the like.

In the present specification, a compound of the present disclosure and an accompanying drug used in combination are referred to as "a combined agent of the present disclosure".

For use of the combination of the present disclosure, the administration time of the compound of the present disclosure and the concomitant drug is not limited, and the compound of the present disclosure and the concomitant drug may be administered to the subject of administration at the same time, or may be administered at different times. When administered at certain time intervals, the intervals vary depending on the active ingredient to be administered, the dosage form, and the method of administration, and for example, when the concomitant drug is first administered, the compound of the present disclosure may be administered within a time range of 1 minute to 3 days, usually 10 minutes to 1 day, or 15 minutes to 1 hour after the administration of the concomitant drug. When the compound of the present disclosure is administered first, the concomitant drug is administered within a time range of 1 minute to 1 day, typically 10 minutes to 6 hours or 15 minutes to 1 hour after administration of the compound of the present disclosure. The dose of the concomitant drug can be determined according to a clinically set dose, and can be appropriately selected depending on the subject of administration, administration route, disease, combination, and the like.

Examples of modes of administration for the combined use of a compound of the present disclosure and concomitant drugs include the following methods: (1) the compound of the present disclosure and concomitant drug are produced simultaneously to obtain a single formulation, which is then administered. (2) The compound of the present disclosure and concomitant drug are produced separately to obtain two types of formulations, which are administered simultaneously by the same route of administration. (3) The compound of the present disclosure and concomitant drug are produced separately to obtain two types of formulations, administered at different times by the same route of administration. (4) The compound of the present disclosure and concomitant drug are produced separately to obtain two types of formulations, which are administered simultaneously by different routes of administration. (5) The compound of the present disclosure and the concomitant drug are produced separately to obtain two types of formulations, administered at different times by different routes of administration (e.g., the compound of the present disclosure and the concomitant drug are administered in this order or in the reverse order).

The dose of the concomitant drug can be appropriately determined according to its clinical dose, and the ratio of the compound of the present disclosure to the concomitant drug can be appropriately determined depending on the subject of administration, the route of administration, the target disease, symptoms, combination, and the like. For example, when the administration subject is a human, the concomitant drug is used at 0.01 to 100 (parts by weight) relative to 1 part by weight of the compound of the present disclosure.

Furthermore, a compound of the present disclosure or a combination of the present disclosure may be used concurrently with non-drug therapy. Specifically, the compound of the present disclosure or the combination agent of the present disclosure may be combined with non-drug therapies such as (1) surgery, (2) hypertension chemotherapy using vasoconstrictor peptide II or the like, (3) gene therapy, (4) thermotherapy, (5) cryotherapy, (6) laser cauterization, and (7) radiotherapy.

For example, by using the compounds of the present disclosure or the combination agents of the present disclosure before or after the above-mentioned surgery or the like, or before or after two or three types of combination treatment thereof, effects such as prevention of the occurrence of resistance, prolongation of disease-free survival, suppression of cancer metastasis or recurrence, prolongation of life span, and the like can be provided.

In addition, treatment with a compound of the present disclosure or a combination of agents of the present disclosure may be combined with supportive therapy: (i) administration of antibiotics (e.g., beta-lactams such as vaseline (pansporin), macrocyclics such as clarithromycin) for complications of various infectious diseases; (ii) administering high calorie infusion, amino acid preparation or general vitamin preparation for improving malnutrition; (iii) administering morphine for pain relief; (iv) (iv) administering a medicine for ameliorating side effects such as nausea, vomiting, anorexia, diarrhea, leukopenia, thrombocytopenia, reduced hemoglobin concentration, alopecia, liver disease, kidney disease, DIC, fever, and the like, and (v) administering a medicine for suppressing multidrug resistance of cancer, and the like.

In one embodiment, the present disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) or a pharmaceutically acceptable salt thereof. The kits of the present disclosure can be used to administer different dosage forms (e.g., oral and parenteral), to administer separate compositions at different dosing intervals, or to titrate separate compositions against one another. To aid compliance, the kits of the present disclosure typically comprise instructions for administration.

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