阅读说明：本技术 活化sting转接蛋白的具有膦酸酯键的3’3’环状二核苷酸 (3'3' cyclic dinucleotides with phosphonate linkages that activate STING transducins ) 是由 加布里埃尔·比尔库斯 翁德雷·帕夫 托马斯·贾恩杜西克 伊万·罗森伯格 拉迪姆·内恩卡 于 2018-12-19 设计创作，主要内容包括：本文中提供通式J的3’3’环状膦酸酯二核苷酸、其药学上可接受的盐、含有其的医药组合物及所述物质与其他药剂或药品的组合。本发明还涉及所述化合物用于治疗或预防可通过STING蛋白质调节来改善的疾病或病状、诸如癌症或病毒性疾病、过敏性疾病及炎性疾病的用途。此外,这些物质可用作疫苗中的佐剂。(Provided herein are 3'3' cyclic phosphonate dinucleotides of general formula J, pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them and combinations of the same with other pharmaceutical agents or drugs. The invention also relates to the use of said compounds for the treatment or prevention of diseases or conditions which can be ameliorated by the modulation of STING proteins, such as cancer or viral diseases, allergic diseases and inflammatory diseases. In addition, these substances are useful as adjuvants in vaccines.)

1. A compound of the formula (J),

or a pharmaceutically acceptable salt thereof,

wherein

L¹is-C (R)⁶R⁷) -O-and L²is-C (R)¹³R¹⁴)-O-，

L¹is-C (R)⁶R⁷) -O-and L²is-O-C (R)¹³R¹⁴)-，

L¹is-O-C (R)⁶R⁷) And L is²is-C (R)¹³R¹⁴)-O-，

L¹is-C (R)⁶R⁷)-K¹-C(R⁶R⁷) And L is²is-C (R)¹³R¹⁴)-K¹-C(R¹³R¹⁴)-，

L¹is-C (R)⁶R⁷)-K¹-C(R⁶R⁷) And L is²is-O-C (R)¹³R¹⁴)-，

L¹is-O-C (R)⁶R⁷) And L is²is-C (R)¹³R¹⁴)-K¹-C(R¹³R¹⁴)-，

L¹is-CH (OR)¹⁵) And L is²is-CH (OR)¹⁵)-，

L¹is-CH (OR)¹⁵) And L is²is-O-C (R)¹³R¹⁴) -, or

L¹is-O-C (R)⁶R⁷) And L is²is-CH (OR)¹⁵)-；

Y¹And Y²Each independently of the otherGround is-O-, -S-or-CH₂-；

X¹And X³Each independently of the others OH, SH, OR¹⁵、SR¹⁵Or N (R)¹⁵)₂；

X²And X⁴Each independently is O or S;

R¹、R⁵、R⁸and R¹²Each independently is H, CN, N₃、F、Cl、Br、I、COOR¹⁵、CON(R¹⁵)₂、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, OR¹⁵、SR¹⁵Or N (R)¹⁵)₂；

R²、R³、R⁴、R⁹、R¹⁰And R¹¹Each independently is H, OH, F, Cl, Br, I, CN, N₃、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, OR¹⁵、SR¹⁵Or N (R)¹⁵)₂；

R⁶、R⁷、R¹³And R¹⁴Each independently is H, CN, N₃、F、Cl、Br、I、COOR¹⁵、CON(R¹⁵)₂、OR¹⁵、SR¹⁵、N(R¹⁵)₂、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₇Cycloalkyl radical, C₂-C₁₀Heterocycloalkyl radical, C₆-C₁₀Aryl or C₂-C₁₀A heteroaryl group;

each R¹⁵Independently is H, -C (═ Z) R¹⁶、-C(＝Z)OR¹⁶、-C(＝Z)SR¹⁶、-C(＝Z)N(R¹⁶)₂、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₇Cycloalkyl radical, C₂-C₁₀Heterocycloalkyl radical, C₆-C₁₀Aryl or C₂-C₁₀A heteroaryl group;

each R¹⁶Independently H, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₇Cycloalkyl radical, C₂-C₁₀Heterocycloalkyl radical, C₆-C₁₀Aryl or C₂-C₁₀A heteroaryl group;

each Z is independently O, S or NR¹⁵；

K¹Is represented by-O-, -S-, -S (O) -, -S (O)₂-, -NH-or-NR¹⁵-a variant of (a);

alkali¹And a base²Each independently is:

wherein

A、A¹、A²、A³And A⁴Each independently is H, OH, SH, F, Cl, Br, I, NH₂、OR¹⁵、SR¹⁵、NHR¹⁵、N(R¹⁵)₂Or R¹⁶(ii) a And

wherein, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₂-C₁₀Heterocycloalkyl radical, C₆-C₁₀Aryl or C₂-C₁₀Heteroaryl is optionally substituted at each occurrence independently with: 1.2 or 3-OH; -SH; -NH₂(ii) a O; NH; (ii) S; halogen; -N₃；C₆-C₁₀Aryl, optionally via 1,2 OR 3-OH, -CN, -O (C ═ O) OR^B、-O(C＝O)R^Bor-COOR^BSubstitution; unsubstituted C₁-C₆An alkyl group; unsubstituted C₁-C₆An alkoxy group; unsubstituted C₁-C₆An alkylthio group; unsubstituted C₁-C₆An alkylamino group; unsubstituted C₁-C₆A dialkylamino group; -CN; -O (C ═ O) OR^B；-O(C＝O)R^B(ii) a or-COOR^B(ii) a WhereinR^BIs H or unsubstituted C₁-C₆An alkyl group.

2. The compound of claim 1, having the structure of formula (I):

or a pharmaceutically acceptable salt thereof.

3. A compound according to any one of claims 1 to 2, wherein

Y¹And Y²Each independently is-O-or-CH₂-。

4. A compound according to any one of claims 1 to 3, wherein

R¹、R²、R³、R⁵、R⁸、R⁹、R¹¹And R¹²Each independently is H, OH, F, CN or C₁-C₆An alkyl group.

5. The compound of any one of claims 1 to 4, wherein

X¹And X³Each independently is OH or SH.

6. The compound of any one of claims 1 to 5, wherein

X²And X⁴Each is O.

7. The compound of claim 1, having the structure of formula (IIa):

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1, having the structure of formula (Ia):

or a pharmaceutically acceptable salt thereof.

9. The compound of any one of claims 1 to 8, wherein

L¹is-C (R)⁶R⁷) -O-and L²is-O-C (R)¹³R¹⁴)-，

L¹is-C (R)⁶R⁷) -O-and L²is-C (R)¹³R¹⁴) -O-, or

L¹is-C (R)⁶R⁷)-K¹-C(R⁶R⁷) And L is²is-O-C (R)¹³R¹⁴)-。

10. The compound of any one of claims 1 to 9, wherein K is¹is-O-.

11. The compound of claim 1, having the structure of formula (IIIa):

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, having the structure of formula (IVa):

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1, having the structure of formula (IIIb):

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1, having the structure of formula (IVb):

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1, having the structure of formula (IIIc):

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, having the structure of formula (IVc):

or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 1 to 16, wherein

R⁶、R⁷、R¹³And R¹⁴Each independently is H, CN, F, Cl, COOR¹⁵、CON(R¹⁵)₂、OR¹⁵、SR¹⁵、N(R¹⁵)₂Or C₁-C₆Alkyl radical, wherein each R¹⁵Independently is H or C₁-C₆An alkyl group.

18. The compound of any one of claims 1 to 17, wherein

R⁶、R⁷、R¹³And R¹⁴Each is H.

19. The compound of any one of claims 1 to 18, wherein

R⁴And R¹⁰Each independently H, OH or F.

20. The compound of any one of claims 1 to 19, wherein

Alkali¹And a base²Each independently is:

21. the compound of any one of claims 1 to 20, wherein a base¹And a base²Each independently is:

22. the compound of any one of claims 1 to 21, wherein a base¹And a base²Each independently is:

23. the compound of any one of claims 1 to 10, having the structure:

or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising a compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, and/or diluent.

25. Use of the pharmaceutical composition of claim 24 for modulating the activity of STING transducin to induce production of type I interferons, cytokines and/or chemokines dependent on the STING transducin.

26. Use of a pharmaceutical composition according to claim 24 for the treatment or prevention of a viral infection, a hepatitis B virus infection, an HIV infection, a hyperproliferative disease or a cancer in a human or an animal.

27. A method of treatment or prophylaxis of a disease or condition in a human or animal, which method comprises administering to said human or animal in need thereof a therapeutically effective amount of a compound as claimed in any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof.

28. A method of modulating the activity of STING transconnectin, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

29. A method of treating or preventing a disease or condition responsive to modulation of STING adaptor in a human or animal, the method comprising administering to the human or animal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

30. A method of inducing STING adaptor-dependent type I interferon, cytokine or chemokine in a human or animal comprising administering to said human or animal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

31. A method of treatment or prophylaxis of a viral infection in a human or animal comprising administering to said human or animal in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof.

32. A method of treatment or prophylaxis of hepatitis B virus infection or HIV infection in a human or animal comprising administering to said human or animal in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

33. A method of treatment or prophylaxis of a hyperproliferative disease or cancer in a human or animal, which method comprises administering to said human or animal in need thereof a therapeutically effective amount of a compound as claimed in any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

34. A method of enhancing the efficacy of a vaccine in a human or animal comprising administering to said human or animal in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

35. The method of any one of claims 27-34, wherein the compound is administered with another therapeutically active agent.

36. Use of a compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a disease or condition in a human or animal in need thereof.

37. Use of the compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, for modulating the activity of STING transconnectin.

38. Use of a compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more therapeutically active agents, for the treatment or prevention of a disease or condition responsive to modulation of STING transducin in a human or animal.

39. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, for inducing STING adaptor-dependent type I interferon, cytokine or chemokine in a human or animal.

40. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more therapeutically active agents, for the treatment or prevention of a viral infection in a human or animal.

41. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more therapeutically active agents, for the treatment or prevention of hepatitis B virus or HIV infection in a human or animal.

42. Use of a compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more therapeutically active agents, for the treatment or prevention of a hyperproliferative disease or cancer in a human or animal.

43. Use of a compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, for enhancing the efficacy of a vaccine in a human or animal.

44. Use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of hepatitis B virus infection, HIV infection, hyperproliferative disease or cancer in a human or animal.

Technical Field

The present invention relates to 3'3' cyclic di-nucleotides and derivatives thereof, which are useful for the treatment of diseases in which modulation of STING adaptor protein (a stimulator of interferon genes) would be beneficial, such as inflammation, allergic diseases and autoimmune diseases, cancer and viral infections, such as chronic hepatitis B and human immunodeficiency virus, and for the preparation of immunogenic compositions or vaccine adjuvants.

Background

The innate immune system recognizes the presence of a pathogen or disruption of host homeostasis by a cascade of Pattern Recognition Receptors (PRRs) that detect a collection of small ligands associated with the pathogen or damage. These ligands are commonly referred to as pathogens or damage-associated molecular patterns (PAMP and DAMP) (Takeuchi O et al, Cell,2010:140, 805-820). Over the past two decades, a variety of PRRs have been identified, including Toll-like receptors, retinoic acid inducible gene (RIG-I) -like receptors, nucleotide binding oligomerization domain-like (NOD) receptors, C-type lectin receptors, and cytoplasmic DNA sensors (Brubaker SW et al, AnnuRev Immunol,2015:33, 257-290). Recognition of PAMPs and DAMPs by PRRs ultimately leads to upregulation of cytokines and chemokines (including interferons), and recruitment of immune cells to the site of infection. All of these processes slow pathogen replication and promote the development of adaptive immunity.

Cellular DNA is usually restricted to the nucleus and mitochondria of healthy cells. DNA is present in the cytosol and therefore represents a signal indicative of the presence of a pathogen or disruption of homeostasis in the host. The sensing of exogenous DNA is initiated by several DNA sensors, such as DNA-dependent activating factor (DAI) of IRF or DEAD box polypeptide 41(DDX 41). It signals via the adaptor protein STING (stimulator of interferon genes, also known as TMEM173, MITA, ERIS) by recruiting the protein kinase TBK1 (Unterholzner L, Immunology,2013:218,1312-1321), which protein kinase TBK1 triggers the activation of the transcription factors NF-. kappa.B (nuclear factor. kappa.B) and IRF-3 (interferon regulatory factor 3). Activation of STING ultimately results in the release of type I and type III interferons as well as a variety of cytokines and chemokines, such as IL-6, TNF- α and INF- γ.

Alternatively, STING can be activated by the second messenger Cyclic Dinucleotide (CDN) (Burdette et al Nature 2011:478, 515-. CDNs with affinity for STING contain two purine nucleotide monophosphates linked to two 3 '-5' (3 '3' -CDN), two 2 '-5' (2 '2' -CDN) or 2 '-5' and 3 '-5' phosphodiester linkages (2 '3' -CDN). The prototype 2 '3' cGAMP (c [ G (2 ', 5') pA (3 ', 5') p ]) is the activation product of host cGAS in the presence of pathogens or dsDNA itself, and it has the highest binding affinity for STING of all the linked isoforms (Zhang et al, Molecular Cell 2013:51, 226-235).

Type I Interferons (IFNs) are immunoregulatory cytokines that play a key role in viral immunity. It induces Dendritic Cell (DC) and macrophage maturation and activation (Galluci et al, Nat Med,1999:5,1249-1255) and promotes T and B cell survival, activation and differentiation. In addition, it activates a number of intracellular pathways that inhibit viral replication. The clinical utility of type I interferons has been demonstrated by their effectiveness in treating chronic hepatitis B and C (Lin and Young, cytokine growth Factor Rev,2014:25, 369-376).

In addition, interferons have shown utility in the treatment of human cancers (Cohen et al, N Engl J Med,2005:353, 2477-. It can directly inhibit tumor cell proliferation and can exert synergistic effect with many approved anticancer agents. Furthermore, type I IFN may act on immune cells to induce an anti-tumor response (Musella et al, Oncoimmunology2017:6: e 1314424). Type I IFN signaling was shown to be important in tumor-initiated T cell activation in mice, and animals lacking IFN-. alpha./β receptors in dendritic cells were unable to reject immunogenic tumors and were deficient in antigen cross presentation to CD8+ T cells (Fuertes et al, J Exp Med,2011:208,2005-2016, Diamond et al, J Exp Med,2011:208: 1989-2003). Consistent with these observations, it has recently been demonstrated that intratumoral injection of STING agonists induces regression of existing tumors in mice and generates a substantial systemic immune response capable of inhibiting distant cancer metastasis and providing long-term survival of the immune memory (corales et al, Cell Rep,2015:11, 1018-1030).

CDN is believed to facilitate activation of cellular and humoral immunity. For example, CDN has been shown to be an effective adjuvant in animal models (Dubensky et al, Ther Adv Vaccines,2013:1, 131-.

Patent publications WO 2014/093936, WO 2014/189805, WO 2013/185052, US 2014/03441976, WO 2015/077354, WO 2015/185565, WO 2016/145102, WO 2017/093933, WO 2017/027646, WO 2017/027645, WO 2017/175156, WO 2017/175147, WO 2017/123657, WO 2018/013908, WO 2018/013887, WO2018/009652, WO 2018/009648 and WO 2018/009466 disclose certain CDNs and their use in inducing an immune response.

Disclosure of Invention

In one aspect, the invention describes novel 3'3' cyclic phosphonate di-nucleotides and derivatives thereof that bind to and activate the protein STING and, thus, stimulate signal transduction pathways that can induce interferons and other cytokines/chemokines. One advantage over previously disclosed CDNs arises from the replacement of the phosphate bond with a phosphonate bond that is resistant to hydrolysis by phosphodiesterases in tissues and body fluids. Such compounds may have utility as antiviral and anticancer agents, act as adjuvants in vaccines, or may be used to treat allergic or other inflammatory diseases.

In one embodiment, the present invention provides a compound of formula (J):

or an enantiomer or a pharmaceutically acceptable salt thereof,

wherein

L¹is-C (R)⁶R⁷) -O-and L²is-C (R)¹³R¹⁴)-O-，

L¹is-C (R)⁶R⁷) -O-and L²is-O-C (R)¹³R¹⁴)-，

L¹is-O-C (R)⁶R⁷) And L is²is-C (R)¹³R¹⁴)-O-，

L¹is-C (R)⁶R⁷)-K¹-C(R⁶R⁷) And L is²is-C (R)¹³R¹⁴)-K¹-C(R¹³R¹⁴)-，

L¹is-C (R)⁶R⁷)-K¹-C(R⁶R⁷) And L is²is-O-C (R)¹³R¹⁴)-，

L¹is-O-C (R)⁶R⁷) And L is²is-C (R)¹³R¹⁴)-K¹-C(R¹³R¹⁴)-，

L¹is-CH (OR)¹⁵) And L is²is-CH (OR)¹⁵)-，

L¹is-CH (OR)¹⁵) And L is²is-O-C (R)¹³R¹⁴) -, or

L¹is-O-C (R)⁶R⁷) And L is²is-CH (OR)¹⁵)-；

Y¹And Y²Each independently is-O-, -S-or-CH₂-；

X¹And X³Each independently of the others OH, SH, OR¹⁵、SR¹⁵Or N (R)¹⁵)₂；

X²And X⁴Each independently is O or S;

R¹、R⁵、R⁸and R¹²Each independently is H, CN, N₃、F、Cl、Br、I、COOR¹⁵、CON(R¹⁵)₂、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, OR¹⁵、SR¹⁵Or N (R)¹⁵)₂；

R²、R³、R⁴、R⁹、R¹⁰And R¹¹Each independently is H, OH, F, Cl, Br, I, CN, N₃、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, OR¹⁵、SR¹⁵Or N (R)¹⁵)₂；

R⁶、R⁷、R¹³And R¹⁴Each independently is H, CN, N₃、F、Cl、Br、I、COOR¹⁵、CON(R¹⁵)₂、OR¹⁵、SR¹⁵、N(R¹⁵)₂、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₇Cycloalkyl radical, C₂-C₁₀Heterocycloalkyl radical, C₆-C₁₀Aryl or C₂-C₁₀A heteroaryl group;

each R¹⁵Independently is H, -C (═ Z) R¹⁶、-C(＝Z)OR¹⁶、-C(＝Z)SR¹⁶、-C(＝Z)N(R¹⁶)₂、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₇Cycloalkyl radical, C₂-C₁₀Heterocycloalkyl radical, C₆-C₁₀Aryl or C₂-C₁₀A heteroaryl group;

each R¹⁶Independently H, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₇Cycloalkyl radical, C₂-C₁₀Heterocycloalkyl radical, C₆-C₁₀Aryl or C₂-C₁₀A heteroaryl group;

each Z is independently O, S or NR¹⁵；

K¹Is represented by-O-, -S-, -S (O) -, -S (O)₂-, -NH-or-NR¹⁵-a variant of (a);

alkali¹And a base²Each independently is:

wherein

A、A¹、A²、A³And A⁴Each independently is H, OH, SH, F, Cl, Br, I, NH₂、OR¹⁵、SR¹⁵、NHR¹⁵、N(R¹⁵)₂Or R¹⁶(ii) a And

wherein, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₂-C₁₀Heterocycloalkyl radical, C₆-C₁₀Aryl or C₂-C₁₀Heteroaryl is optionally substituted at each occurrence independently with: 1. 2 or 3-OH; -SH; -NH₂(ii) a O; NH; (ii) S; halogen; -N₃；C₆-C₁₀Aryl, optionally via 1,2 or3-OH, -CN, -O (C ═ O) OR^B、-O(C＝O)R^Bor-COOR^BSubstitution; unsubstituted C₁-C₆An alkyl group; unsubstituted C₁-C₆An alkoxy group; unsubstituted C₁-C₆An alkylthio group; unsubstituted C₁-C₆An alkylamino group; unsubstituted C₁-C₆A dialkylamino group; -CN; -O (C ═ O) OR^B；-O(C＝O)R^B(ii) a or-COOR^B(ii) a Wherein R is^BIs H or unsubstituted C₁-C₆An alkyl group.

The invention includes a pharmaceutical composition comprising a cyclic dinucleotide of formula (J), or an enantiomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, and/or diluent.

Also provided are methods of treating or preventing a disease or disorder, such as treating or preventing a viral infection, a hepatitis B virus infection, an HIV infection, a hyperproliferative disease, or a cancer, comprising administering to a human or animal in need thereof a therapeutically effective amount of a cyclic dinucleotide of formula (J), or an enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing.

Also provided is a method of enhancing the efficacy of a vaccine comprising administering a therapeutically effective amount of a cyclic dinucleotide of formula (J), or an enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing.

Furthermore, the present invention provides a method of modulating the activity of STING adaptor-induced type I interferon, cytokine and/or chemokine (depending on STING adaptor) production (e.g. inducing STING adaptor-dependent type I interferon) in a human or animal comprising administering a therapeutically effective amount of a cyclic dinucleotide of formula (J) or an enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing.

Detailed Description

I. General rule

The present invention provides novel 3'3' cyclic dinucleotides comprising at least one phosphonate group, which bind to STING eggsWhite matter and modulate its activity, e.g., activate STING proteins. Dinucleotides having at least one 4 'linkage and being variants of the naturally occurring methylphosphonite linked to a sugar, i.e. the naturally occurring 4' -CH₂-O-P-。

Definition of

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Dashes at the front or end of the chemical group indicate points of attachment to the parent group for convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. Prefixes, such as "C_u-v"or" C_u-C_v"indicates that subsequent groups have u to v carbon atoms, where u and v are integers. For example, "C_1-6Alkyl "or" C₁-C₆Alkyl "indicates that the alkyl has 1 to 6 carbon atoms.

An "alkyl" group is a linear or branched saturated monovalent hydrocarbon. For example, the alkyl group can have 1 to 10 carbon atoms (i.e., C)_1-10Alkyl), or 1 to 8 carbon atoms (i.e., C)_1-8Alkyl), or 1 to 6 carbon atoms (i.e., C)_1-6Alkyl), or 1 to 4 carbon atoms (i.e., C)_1-4Alkyl groups). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl (Et-CH)₂CH₃) 1-propyl (n-Pr, n-propyl, -CH)₂CH₂CH₃) 2-propyl (i-Pr, isopropyl, -CH (CH)₃)₂) 1-butyl (n-Bu, n-butyl, -CH)₂CH₂CH₂CH₃) 2-methyl-1-propyl (i-Bu, isobutyl, -CH)₂CH(CH₃)₂) 2-butyl (s-Bu, sec-butyl, -CH (CH)₃)CH₂CH₃) 2-methyl-2-propyl (t-Bu, tert-butyl, -C (CH)₃)₃) 1-pentyl (n-pentyl, -CH)₂CH₂CH₂CH₂CH₃) 2-pentyl-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) 1-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂)3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃And octyl (- (CH)₂)₇CH₃). The alkyl group may be unsubstituted or substituted.

"alkoxy" refers to the group-O-alkyl, wherein alkyl is as defined above. For example, C_1-4Alkoxy means an-O-alkyl group having 1 to 4 carbons.

An "alkenyl group" is a linear or branched monovalent hydrocarbon group having at least one carbon-carbon double bond. For example, the alkenyl group can have 2 to 8 carbon atoms (i.e., C)_2-8Alkenyl), or 2 to 6 carbon atoms (i.e., C)_2-6Alkenyl), or 2 to 4 carbon atoms (i.e., C)_2-4Alkenyl). Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)₂) Allyl (-CH)₂CH＝CH₂) and-CH₂-CH＝CH-CH₃. The alkenyl group may be unsubstituted or substituted.

An "alkynyl group" is a linear or branched monovalent hydrocarbon group having at least one carbon-carbon triple bond. For example, the alkynyl group can have 2 to 28 carbon atoms (i.e. C)_2-8Alkynyl), or 2 to 6 carbon atoms (i.e., C)_2-6Alkynyl), or 2 to 4 carbon atoms (i.e., C)_2-4Alkynyl). Examples of alkynyl groups include, but are not limited to, ethynyl (-C ≡ CH), propargyl (-CH)₂C ≡ CH) and-CH₂-C≡C-CH₃. Alkynyl groups may be unsubstituted or substituted.

Alkylamino is-HNR_bGroup, wherein R_bIs an alkyl group.

Alkylthio is-SR_bGroup, wherein R_bIs an alkyl group.

As used herein, "halo" or "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (-I).

As used herein, "haloalkyl" refers to an alkyl group, as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently replaced with a halo substituent, which halo substituents may be the same or different. For example, C_1-4Haloalkyl being C_1-4Alkyl radical, wherein C_1-4Has been replaced by a halo substituent. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl, and pentafluoroethyl.

As used herein, "aryl" refers to a single all-carbon aromatic ring or a plurality of fused all-carbon ring systems in which at least one ring is aromatic. For example, in certain embodiments, aryl groups have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes phenyl. Aryl also includes a plurality of fused ring systems having about 9 to 20 carbon atoms (e.g., ring systems comprising 2,3, or 4 rings) wherein at least one ring is aromatic and wherein the other rings may or may not be aromatic (i.e., carbocyclic). Such multiple fused ring systems are optionally substituted with one or more (e.g., 1,2, or 3) pendant oxy groups on any carbocyclic portion of the multiple fused ring system. The rings of the multiple fused ring system may be connected to each other via fused, spiro and bridged bonds as valency requirements permit. It will also be understood that when reference is made to an aryl group having a number of members in a certain atomic range (e.g., a 6-10 member aryl group), the atomic range is for all of the ring atoms of the aryl group. For example, a 6-membered aryl group would include phenyl and a 10-membered aryl group would include naphthyl and 1,2,3, 4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, anthracenyl, and the like. The aryl group may be unsubstituted or substituted.

As used herein, the term "heteroaryl" refers to a monocyclic aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur; "heteroaryl" also includes multiple fused ring systems having at least one such aromatic ring, which are further described below. Thus, "heteroaryl" includes monocyclic aromatic rings having about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may also be present in oxidized form, with the proviso that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furanyl. "heteroaryl" also includes multiple fused ring systems (e.g., ring systems comprising 2,3, or 4 rings) wherein a heteroaryl as defined above is fused to form a multiple fused ring system with one or more rings selected from heteroaryl (forming, for example, 1, 8-naphthyridinyl), heterocycle (forming, for example, 1,2,3, 4-tetrahydro-1, 8-naphthyridinyl), carbocycle (forming, for example, 5,6,7, 8-tetrahydroquinolinyl), and aryl (forming, for example, indazolyl). Thus, heteroaryl groups (mono-or multiple fused ring systems) have about 1 to 20 carbon atoms and about 1 to 6 heteroatoms in the heteroaryl ring. Such multiple fused ring systems may optionally be substituted with one or more (e.g., 1,2,3, or 4) pendant oxy groups on the carbocyclic or heterocyclic moiety of the fused ring. The rings of the multiple fused ring system may be connected to each other via fused, spiro and bridged bonds as valency requirements permit. It is understood that the individual rings of the multiple fused ring system can be linked in any order relative to each other. It is to be understood that the point of attachment of the heteroaryl or heteroaryl multiple fused ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple fused ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It is also understood that when a heteroaryl group is referred to by a number of members of an atomic range (e.g., a 5-to 10-membered heteroaryl group), the atomic range is for all ring atoms of the heteroaryl group and includes carbon atoms and heteroatoms. For example, a 5-membered heteroaryl group would include a thiazolyl group and a 10-membered heteroaryl group would include a quinolinyl group. Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7, 8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thioindenyl, pyrrolo [2,3-b ] pyridyl, quinazolinyl-4 (3H) -one, and triazolyl. Heteroaryl groups may be unsubstituted or substituted.

"cycloalkyl" means having 3 to 20 ring carbon atoms (i.e., C)_3-20Cycloalkyl), for example a mono-saturated or partially unsaturated all carbocyclic ring of 3 to 12 ring atoms, for example 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 3 to 4 ring atoms. The term "cycloalkyl" also includes multiple fused, saturated and partially unsaturated all carbocyclic ring systems (e.g., ring systems containing 2,3 or 4 carbocyclic rings). Thus, cycloalkyl includes polycyclic carbocycles, such as bicyclic carbocycles (e.g., bicyclic carbocycles having about 6 to 12 ring carbon atoms, such as bicyclo [3.1.0]Hexane and bicyclo [2.1.1]Hexane), and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles having up to about 20 ring carbon atoms). The rings of the multiple fused ring system may be connected to each other via fused, spiro and bridged bonds as valency requirements permit. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl. Cycloalkyl groups may be unsubstituted or substituted.

As used herein, "heterocyclyl" or "heterocycle" or "heterocycloalkyl" refers to a mono-saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic ring system having at least one heteroatom (i.e., at least one ring heteroatom selected from oxygen, nitrogen, and sulfur) in the ring. Unless otherwise specified, heterocyclyl groups have 3 to about 20 ring atoms, such as 3 to 12 ring atoms, for example 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 4 to 6 ring atoms, or 4 to 5 ring atoms. Thus, the term includes a mono-saturated or partially unsaturated ring (e.g., a3, 4, 5,6, or 7 membered ring) having from about 1 to 6 ring carbon atoms in the ring and from about 1 to 3 ring heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The rings of a multiple fused ring (e.g., bicyclic heterocyclyl) system may be connected to each other via fused, spiro, and bridged bonds, as valency requirements permit. Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidione, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro [3.3] hept-6-yl, 6-oxa-1-azaspiro [3.3] hept-1-yl, 2-thia-6-azaspiro [3.3] hept-6-yl, 2, 6-diazaspiro [3.3] hept-2-yl, 2-azabicyclo [3.1.0] hex-2-yl, 3-azabicyclo [3.1.0] hexyl, 2-azabicyclo [2.1.1] hexyl, 2-azabicyclo [2.2.1] hept-2-yl, 4-azaspiro [2.4] heptyl, 5-azaspiro [2.4] heptyl, and analogs thereof. The heterocyclic group may be unsubstituted or substituted.

As used herein, "oxo" refers to ═ O.

As used herein, "substituted" refers to substitution with one or more (e.g., 1,2,3, or 4 or more) substituents selected from the group consisting of: -OH, -SH, -NH₂-O, -NH, -S, -N halogen, -N₃、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Alkylamino radical, C_1-6Dialkylamino, -CN, -O (C ═ O) OR^B、-O(C＝O)R^Band-COOR^BWherein R is^BIs hydrogen or C₁To C₆An alkyl group.

"Compounds of the invention" include compounds disclosed herein, for example compounds of the invention include compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc), including the exemplified compounds.

As used herein, "treatment" refers to a method for obtaining a beneficial or desired result. For purposes of the present invention, beneficial or desired results include, but are not limited to, alleviation of symptoms and/or reduction of the extent of symptoms and/or prevention of worsening of symptoms associated with the disease or condition. In one embodiment, "treating" includes one or more of: a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and/or reducing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) ameliorating the disease or condition, e.g., resolving clinical symptoms, ameliorating the disease condition, delaying disease progression, improving quality of life, and/or prolonging survival.

As used herein, "delay" means delaying, hindering, slowing, stopping, stabilizing, and/or delaying the development of a disease or condition. This delay may be of varying lengths depending on the history of the disease and/or the individual being treated. As will be apparent to one of skill in the art, sufficient or significant delay may actually encompass prevention such that the individual does not develop a disease or condition.

As used herein, "preventing" or "prevention" refers to a therapy that prevents the onset of a disease or disorder such that the clinical symptoms of the disease do not develop. Thus, "preventing" refers to administering a therapy to a subject (e.g., administering a therapeutic substance, e.g., administering a therapeutic substance to a subject in the absence of detectable cancer (e.g., hepatocellular carcinoma) in the subject) before disease symptoms are detectable in the subject. The subject may be an individual at risk of developing a disease or disorder, such as an individual having one or more risk factors known to be associated with the development or onset of a disease or disorder. Thus, in certain embodiments, the term "preventing cancer" refers to administering an anti-cancer therapeutic to a subject that does not have detectable cancer. It is understood that the subject using an anti-cancer prophylactic therapy may be an individual at risk of developing cancer. It should also be understood that prevention does not require 100% success. In some instances, prevention may be understood as reducing the risk of cancer, rather than completely eliminating the occurrence of cancer.

In certain embodiments, the term "preventing HBV infection" refers to administering an anti-HBV therapeutic agent to a subject that does not have detectable HBV infection. It is understood that the subject of anti-HBV prophylactic therapy may be an individual at risk of infection with HBV virus. It should also be understood that prevention does not require 100% success. In some instances, prevention may be understood as reducing the risk of infection, rather than completely eliminating the occurrence of infection.

As used herein, "modulating" the activity of a protein (e.g., STING adaptor) refers to altering the activity such that the activity is increased or decreased. In some embodiments, modulation may increase activity.

As used herein, the term "viral infection" describes a disease state in which a virus invades a healthy cell, multiplies or replicates using the cell's reproductive machinery and eventually lyses the cell, causing cell death, releasing viral particles and infecting other cells with newly produced progeny virus. Potential infections caused by certain viruses are also a possible consequence of viral infection.

As used herein, the term "enhance" refers to any form of increase in the immunogenic activity of an effective dose of a vaccine caused by administration of a therapeutically effective dose of a compound of the invention to an animal or human, e.g., a cyclic dinucleotide of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc), wherein the compound is administered at any time, simultaneously, or immediately after administration of an effective dose of the vaccine to the same animal or human.

As used herein, "animal" refers to a non-human mammal, e.g., a domestic animal such as a pig, cow, horse, dog, cat, rat, or mouse, or a non-human primate such as a cynomolgus monkey or chimpanzee.

As used herein, "an individual at risk" refers to an individual at risk of developing the condition being treated. An individual "at risk" may or may not have a detectable disease or condition, and may or may not exhibit a detectable disease prior to treatment by the methods described herein. "at risk" indicates that the individual has one or more so-called risk factors, which are measurable parameters associated with the development of a disease or condition and are known in the art. Individuals with one or more of these risk factors have a higher chance of developing a disease or condition than individuals without these risk factors.

As used herein, "therapeutically effective amount" or "effective amount" refers to an amount effective to elicit a desired biological or medical response, including an amount of a compound that, when administered to a subject for treatment of a disease, is sufficient to effect treatment of such disease. The effective amount will vary depending on the compound, the disease and its severity in the subject being treated, as well as the age, weight, etc. An effective amount may include a range of amounts. As understood in the art, an effective amount may be one or more doses, i.e., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint. Thus, an "effective amount" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if a desired or advantageous result is obtained or achieved in combination with one or more other agents. Suitable dosages of any of the co-administered compounds may optionally be reduced by a combined effect (e.g., additive or synergistic effect) of the compounds.

In some embodiments, a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, can (i) reduce the number of diseased cells; (ii) reducing the size of the tumor; (iii) inhibit, arrest, slow and preferably stop to some extent the infiltration of diseased cells into peripheral organs; (iv) inhibit (e.g., slow to some extent and preferably stop) tumor metastasis; (v) inhibiting tumor growth; (vi) preventing or delaying the appearance and/or recurrence of a tumor; and/or (vii) alleviate to some extent one or more of the symptoms associated with cancer or hyperproliferative disease. In some embodiments, the therapeutically effective amount is sufficient to ameliorate, alleviate, reduce and/or delay one or more symptoms of cancer or hyperproliferative disease.

"pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and drug Administration as acceptable for use in humans or livestock.

As used herein, "co-administration" refers to administration of a unit dose of a compound disclosed herein before or after administration of a unit dose of one or more other therapeutic agents, for example, within seconds, minutes, or hours of administration of the one or more other therapeutic agents. For example, in some embodiments, a unit dose of a compound of the invention is administered first, followed by a unit dose of one or more other therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of a compound of the invention within seconds or minutes. In some embodiments, a unit dose of a compound of the invention is administered first, followed by a unit dose of one or more other therapeutic agents several hours (e.g., 1-12 hours) later. In other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of a compound of the invention several hours later (e.g., 1-12 hours later). Co-administration of a compound disclosed herein with one or more other therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein and one or more other therapeutic agents such that a therapeutically effective amount of each agent is present in the subject.

Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. "pharmaceutically acceptable" or "physiologically acceptable" means that the compounds, salts, compositions, dosage forms and other materials are suitable for use in the preparation of pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

The compounds described herein may be prepared and/or formulated as pharmaceutically acceptable salts or, where appropriate, as free bases. Pharmaceutically acceptable salts are non-toxic salts of the free base form of the compounds having the pharmacological activity of the desired free base. These salts may be derived from inorganic or organic acids or bases. For example, a compound containing a basic nitrogen may be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprate, caprylate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, benzenesulfonate, dihydrogenphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, octanoate, and octanoate, Xylene sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate and mandelate. A list of other suitable pharmaceutically acceptable salts is found in Remington, the science and Practice of Pharmacy, 21 st edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include salts derived from suitable bases such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and NX₄ ⁺(wherein X is C₁-C₄Alkyl groups). Also included are base addition salts, such as sodium or potassium salts.

Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, wherein n is the number of hydrogen atoms in the molecule. As known in the art, a deuterium atom is a nonradioactive isotope of a hydrogen atom. Such compounds may increase antimetabolite and, therefore, may be useful for extending the half-life of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to a mammal. See, e.g., Foster, "Deuterium Isotrope Effects in students of drug metabolism", Trends Pharmacol. Sci.,5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as respectively²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、³⁶Cl、¹²³I and¹²⁵I. with positron-emitting isotopes (such as¹¹C、¹⁸F、¹⁵O and¹³n) are suitable for use in Positron Emission Tomography (PET) studies to examine stromal receptor occupancy. Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the examples set forth below, using suitable isotopically-labelled reagents in place of the unlabelled reagents previously used.

The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms which may be defined in absolute stereochemistry as (R) -or (S) -or (D) -or (L) -for amino acids. The present invention is intended to include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R) -and (S) -or (D) -and (L) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation/separation of the individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral High Pressure Liquid Chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry and unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Where a compound is represented in its chiral form, it is understood that embodiments encompass, but are not limited to, particular diastereomerically or enantiomerically enriched forms. Where chirality is not specified but present, it is understood that embodiments are directed to particular diastereomerically or enantiomerically enriched forms; or a racemic or non-racemic mixture of such compounds. As used herein, a "non-racemic mixture" is a mixture of stereoisomers in a ratio other than 1: 1.

As used herein, "stereoisomer" refers to a compound composed of the same atoms to which the same bonds are bonded, but having different three-dimensional structures that are not interchangeable. The present invention encompasses various stereoisomers and mixtures thereof and includes "enantiomers", which refer to two stereoisomers whose molecules are nonsuperimposable mirror images of each other.

As used herein, "tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. The invention includes tautomers of any of the compounds.

As used herein, "solvate" refers to the product of the interaction of a solvent with a compound. Solvates of salts of the compounds described herein are also provided. Also provided are hydrates of the compounds described herein.

As used herein, "hydrate" refers to a compound of the invention that is chemically associated with one or more water molecules.

As used herein, "prodrug" refers to a derivative of a drug that is converted to the parent drug upon administration to the human body according to some chemical or enzymatic pathway. In some embodiments, a prodrug is a biologically inactive derivative of a drug that, upon administration to the human body, is converted to the biologically active parent drug according to some chemical or enzymatic pathway. Prodrugs of phosphonates and phosphates are known in the art. Exemplary prodrugs that may be used with the compounds of the present invention include esters, such as alkyl (e.g., methyl or ethyl),Benzyl (e.g., benzyl substituted with 4-OAc or 4-OMe), acyloxyalkyl (e.g., Pivaloyloxymethyl (POM)), alkoxycarbonyloxyalkyl (e.g., isopropoxycarbonyloxymethyl (POC)), S-acylsulfanyl (e.g., S-acyl-2-thioethyl (SATE), such as S-pivaloyl-2-thioethyl), steroid (e.g., cholesteryl), glycerol fatty alcohol (e.g., -CH-O-C or 4-OMe), and pharmaceutically acceptable salts thereof₂OCH₂(CH₂)₁₄CH₃) Esters and amides, such as amidated amino acids (e.g., amidated alanine O-alkyl esters).

Compounds of formula (I)

In one aspect, the invention provides a compound of formula (J), i.e., a cyclic dinucleotide:

or a regioisomer, enantiomer or pharmaceutically acceptable salt thereof,

wherein

L¹is-C (R)⁶R⁷) -O-and L²is-C (R)¹³R¹⁴)-O-，

L¹is-C (R)⁶R⁷) -O-and L²is-O-C (R)¹³R¹⁴)-，

L¹is-O-C (R)⁶R⁷) And L is²is-C (R)¹³R¹⁴)-O-，

L¹is-C (R)⁶R⁷)-K¹-C(R⁶R⁷) And L is²is-C (R)¹³R¹⁴)-K¹-C(R¹³R¹⁴)-，

L¹is-C (R)⁶R⁷)-K¹-C(R⁶R⁷) And L is²is-O-C (R)¹³R¹⁴)-，

L¹is-O-C (R)⁶R⁷) And L is²is-C (R)¹³R¹⁴)-K¹-C(R¹³R¹⁴)-，

L¹is-CH (OR)¹⁵) And L is²is-CH (OR)¹⁵)-，

L¹is-CH (OR)¹⁵) And L is²is-O-C (R)¹³R¹⁴) -, or

L¹is-O-C (R)⁶R⁷) And L is²is-CH (OR)¹⁵)-；

Y¹And Y²Each independently is-O-, -S-or-CH₂-；

X¹And X³Each independently of the others OH, SH, OR¹⁵、SR¹⁵Or N (R)¹⁵)₂；

X²And X⁴Each independently is O or S;

R¹、R⁵、R⁸and R¹²Each independently is H, CN, N₃、F、Cl、Br、I、COOR¹⁵、CON(R¹⁵)₂、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, OR¹⁵、SR¹⁵Or N (R)¹⁵)₂；

R²、R³、R⁴、R⁹、R¹⁰And R¹¹Each independently is H, OH, F, Cl, Br, I, CN, N₃、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, OR¹⁵、SR¹⁵Or N (R)¹⁵)₂；

R⁶、R⁷、R¹³And R¹⁴Each independently is H, CN, N₃、F、Cl、Br、I、COOR¹⁵、CON(R¹⁵)₂、OR¹⁵、SR¹⁵、N(R¹⁵)₂、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₇Cycloalkyl radical, C₂-C₁₀Heterocycloalkyl radical, C₆-C₁₀Aryl or C₂-C₁₀A heteroaryl group;

each R¹⁵Independently isH、-C(＝Z)R¹⁶、-C(＝Z)OR¹⁶、-C(＝Z)SR¹⁶、-C(＝Z)N(R¹⁶)₂、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₇Cycloalkyl radical, C₂-C₁₀Heterocycloalkyl radical, C₆-C₁₀Aryl or C₂-C₁₀A heteroaryl group;

each R¹⁶Independently H, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₇Cycloalkyl radical, C₂-C₁₀Heterocycloalkyl radical, C₆-C₁₀Aryl or C₂-C₁₀A heteroaryl group;

each Z is independently O, S or NR¹⁵；

K¹Is represented by-O-, -S-, -S (O) -, -S (O)₂-, -NH-or-NR¹⁵-a variant of (a);

alkali¹And a base²Each independently is:

wherein

A、A¹、A²、A³And A⁴Each independently is H, OH, SH, F, Cl, Br, I, NH₂、OR¹⁵、SR¹⁵、NHR¹⁵、N(R¹⁵)₂Or R¹⁶(ii) a And

wherein C is₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₂-C₁₀Heterocycloalkyl radical, C₆-C₁₀Aryl or C₂-C₁₀Heteroaryl is optionally substituted at each occurrence independently with: 1. 2 or 3-OH; -SH; -NH₂(ii) a O; NH; (ii) S; halogen; -N₃；C₆-C₁₀Aryl, optionally via 1,2 OR 3-OH, -CN, -O (C ═ O) OR^B、-O(C＝O)R^Bor-COOR^BSubstitution; unsubstituted C₁-C₆An alkyl group; unsubstituted C₁-C₆An alkoxy group; unsubstituted C₁-C₆An alkylthio group; unsubstituted C₁-C₆An alkylamino group; unsubstituted C₁-C₆A dialkylamino group; -CN; -O (C ═ O) OR^B；-O(C＝O)R^B(ii) a or-COOR^B(ii) a Wherein R is^BIs H or unsubstituted C₁-C₆An alkyl group.

In some embodiments, the compound is a compound of formula (J), or an enantiomer or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (J) has the structure of formula (IIa):

or an enantiomer or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (J) has the structure of formula (I):

or an enantiomer or a pharmaceutically acceptable salt thereof.

In some embodiments of the compounds of formula (J) and/or (I),

L¹is-C (R)⁶R⁷) -O-and L²is-C (R)¹³R¹⁴) -O-or-O-C (R)¹³R¹⁴)-；

Or

L¹is-C (R)⁶R⁷)-K¹-C(R⁶R⁷) And L is²is-C (R)¹³R¹⁴)-K¹-C(R¹³R¹⁴) -or-O-C (R)¹³R¹⁴)-；

Or

L¹is-CH (OR)¹⁵) And L is²is-CH (OR)¹⁵) -or-O-C (R)¹³R¹⁴)-；

Y¹And Y²Each independently selected from the group consisting of: -O-, -S-and-CH₂-；

X¹And X³Each independently selected from the group consisting of: OH, SH, OR¹⁵、SR¹⁵And N (R)¹⁵)₂；

X²And X⁴Each independently selected from the group consisting of: o and S;

R¹、R⁵、R⁸and R¹²Each independently selected from the group consisting of: H. CH (CH)₂F、CHF₂、CF₃、CN、N₃、F、Cl、Br、I、COOR¹⁵、CON(R¹⁵)₂、CH₂OH、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Substituted alkyl, C₂-C₆Substituted alkenyl, C₂-C₆Substituted alkynyl, OR¹⁵、SR¹⁵And N (R)¹⁵)₂；

R²、R³、R⁴、R⁹、R¹⁰And R¹¹Each independently selected from the group consisting of: H. OH, F, CI, Br, I, CN, N₃、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Substituted alkyl, C₂-C₆Substituted alkenyl, C₂-C₆Substituted alkynyl, OR¹⁵、SR¹⁵And N (R)¹⁵)₂；

R⁶、R⁷、R¹³And R¹⁴Each independently selected from the group consisting of: H. CH (CH)₂F、CHF₂、CF₃、CN、N₃、F、Cl、Br、I、COOR¹⁵、CON(R¹⁵)₂、CH₂OH、CH₂N₃、OR¹⁵、SR¹⁵、N(R¹⁵)₂、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Substituted alkyl, C₂-C₆Substituted alkenyl, C₂-C₆Substituted alkynyl, C₃-C₇Cycloalkyl radical, C₂-C₁₀Heterocycloalkyl radical, C₂-C₁₀Substituted heterocycloalkyl, C₂-C₁₀Aryl radical, C₂-C₁₀Substituted aryl, C₂-C₁₀Heteroaryl and C₂-C₁₀A substituted heteroaryl group;

each R¹⁵Independently selected from the group consisting of: H. -C (═ Z) R¹⁶、-C(＝Z)OR¹⁶、-C(＝Z)SR¹⁶、-C(＝Z)N(R¹⁶)₂、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Substituted alkyl, C₂-C₆Substituted alkenyl, C₂-C₆Substituted alkynyl, C₃-C₇Cycloalkyl radical, C₂-C₁₀Heterocycloalkyl radical, C₂-C₁₀Substituted heterocycloalkyl, C₆-C₁₀Aryl radical, C₆-C₁₀Substituted aryl, C₂-C₁₀Heteroaryl and C₂-C₁₀A substituted heteroaryl group;

each R¹⁶Independently selected from the group consisting of: H. c₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Substituted alkyl, C₂-C₆Substituted alkenyl, C₂-C₆Substituted alkynyl, C₃-C₇Cycloalkyl radical, C₂-C₁₀Heterocycloalkyl radical, C₂-C₁₀Substituted heterocycloalkyl, C₆-C₁₀Aryl radical, C₆-C₁₀Substituted aryl, C₂-C₁₀Heteroaryl and C₂-C₁₀A substituted heteroaryl group;

each Z is independently selected from the group consisting of: o, S and NR¹⁵；

K¹Is a variant selected from the group consisting of: -O-, -S (O) -or-S (O)₂-, -NH-and-NR¹⁵-；

Alkali¹And a base²Each independently selected from the group consisting of:

wherein

A、A¹、A²、A³And A⁴Each independently is H, OH, SH, F, Cl, Br, I, NH₂、OR¹⁵、SR¹⁵、NHR¹⁵、N(R¹⁵)₂Or R¹⁶。

In some embodiments of the compounds of formula (I), alkyl is a linear or branched C1 to C6, preferably C2 to C6, hydrocarbon chain; such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, n-hexyl and the like, which are unsubstituted or substituted with one or more substituents selected from the group consisting of: -OH, -SH, -NH₂-O, -NH, -S, -N, halogen, -N₃、C₁To C₆Alkyl radical, C₁To C₆Alkoxy radical, C₁To C₆Alkylthio radical, C₁To C₆Alkylamino radical, C₁To C₆Dialkylamino, -CN and-COOR_pWherein R is_pIs hydrogen or C₁To C₆An alkyl group.

In some embodiments of the compounds of formula (I), alkenyl is a linear or branched C2 to C6 hydrocarbon chain containing at least one double bond, such as vinyl, allyl, 2-butynyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and the like; wherein the alkenyl group may be substituted with one or more substituents selected from the group consisting of: -OH, -SH, -NH₂O, ═ NH, ═ S, ≡ N, halogenElement, -N₃、C₁To C₆Alkyl radical, C₁To C₆Alkoxy radical, C₁To C₆Alkylthio radical, C₁To C₆Alkylamino radical, C₁To C₆Dialkylamino, -CN and-COOR_pWherein R is_pIs hydrogen or C₁To C₆An alkyl group.

In some embodiments of the compounds of formula (I), alkynyl is a linear or branched C2 to C6 hydrocarbon chain containing at least one triple bond, and may optionally also contain a double bond; for example, ethynyl or propynyl, wherein alkynyl may be substituted with one or more substituents selected from the group consisting of: -OH, -SH, -NH₂-O, -NH, -S, -N, halogen, -N₃、C₁To C₆Alkyl radical, C₁To C₆Alkoxy radical, C₁To C₆Alkylthio radical, C₁To C₆Alkylamino radical, C₁To C₆Dialkylamino, -CN and-COOR_pWherein R is_pIs hydrogen or C₁To C₆An alkyl group.

In some embodiments of the compounds of formula (I), cycloalkyl is a cyclic hydrocarbon chain preferably having 3 to 9 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; optionally, it may be in the form of a fused ring or a bridged ring.

In some embodiments of the compounds of formula (I), the heterocycle or heterocyclyl or heterocycloalkyl is a hydrocarbyl group that satisfies the following condition: containing 2 to 10, preferably 4 to 10, carbon atoms and at least one heteroatom, preferably one to two heteroatoms, selected from the group consisting of O, S, N, and containing at least one saturated or partially unsaturated ring system having 3 to 12 ring members and 1 to 4 heteroatoms selected from N, O and S. In some embodiments, other heteroatoms may also be suitable, including (but not limited to) B, Al, Si, and P. In some embodiments, heteroatoms may also be oxidized, such as (but not limited to) -S (O) -and-S (O)₂-. In some embodiments, heterocycloalkyl groups can include any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8,5 to 8, 6 to 8,3 to 9, 3 to 10, 3 to 11, or 3To 12 ring members. Any suitable number of heteroatoms may be included in the heterocycloalkyl group, such as 1,2,3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3,2 to 4, or 3 to 4. In some embodiments, heterocycloalkyl groups may include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1, 2-isomers, 1, 3-isomers, and 1, 4-isomers), ethylene oxide, oxetane, tetrahydrofuran, dioxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiolane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or cyclopentane disulfide. In some embodiments, the heterocycloalkyl group may also be fused to an aromatic or non-aromatic ring system to form a member, including (but not limited to) indoline. In some embodiments, the heterocycloalkyl group can be further substituted with one or more substituents selected from the group consisting of: -OH, -SH, -NH₂Halogen, -N₃、C₁To C₆Alkyl radical, C₁To C₆Alkoxy radical, C₁To C₆Alkylthio radical, C₁To C₆Alkylamino radical, C₁To C₆Dialkylamino, -CN, -CR_pIs O and-COOR_pWherein R is_pIs hydrogen or C₁To C₆An alkyl group.

In some embodiments of the compounds of formula (I), alkoxy is-OR_aGroup, wherein R_aIs C₁-C₄An alkyl group.

In some embodiments of the compounds of formula (I), alkylamino is-HNR_bGroup, wherein R_bIs C₁-C₄An alkyl group.

In some embodiments of the compounds of formula (I), alkylthio is-SR_bGroup, wherein R_bIs C₁-C₄An alkyl group.

In some embodiments of the compounds of formula (I), aryl is a compound containing 6 to 10 carbon atoms and at least one(ii) hydrocarbyl of an aromatic ring, the at least one aromatic ring being substituted with one or more substituents selected from the group consisting of: OH, -SH, -NH₂Halogen, -N₃、C₁To C₆Alkyl radical, C₁To C₆Alkoxy radical, C₁To C₆Alkylthio radical, C₁To C₆Alkylamino radical, C₁To C₆Dialkylamino, -CN, -CR_pIs O and-COOR_pWherein R is_pIs hydrogen or C₁To C₆An alkyl group.

In some embodiments of the compounds of formula (I), heteroaryl is alkyl satisfying the following conditions: containing from 2 to 10, preferably from 4 to 10 carbon atoms, and at least one heteroatom, preferably one to two heteroatoms, selected from the group consisting of O, S, N, and containing at least one aromatic ring. In some embodiments, the heteroaryl group may be further substituted with one or more substituents selected from the group consisting of: -OH, -SH, -NH₂Halogen, -N₃、C₁To C₆Alkyl radical, C₁To C₆Alkoxy radical, C₁To C₆Alkylthio radical, C₁To C₆Alkylamino radical, C₁To C₆Dialkylamino, -CN, -CR_pIs O and-COOR_pWherein R is_pIs hydrogen or C₁To C₆An alkyl group. In certain embodiments, the heteroaryl group is selected from the group of pyrrole, furan, thiophene, imidazole, thiazole, oxazole, indole and pyridine.

In some embodiments of compounds of formula (J) and/or (I), R¹、R²、R³、R⁵、R⁸、R⁹、R¹¹And R¹²Each independently is H, OH, F, Cl, Br, I, CN, N₃Or C₁-C₆An alkyl group. In some embodiments, R¹、R²、R³、R⁵、R⁸、R⁹、R¹¹And R¹²Each independently is H, OH, F, CN or C₁-C₆An alkyl group. In some embodiments, R¹、R²、R³、R⁵、R⁸、R⁹、R¹¹And R¹²Each independently is H, CN or C₁-C₆An alkyl group. In some embodiments, R¹、R²、R³、R⁵、R⁸、R⁹、R¹¹And R¹²Each is H.

In some embodiments of compounds of formula (J) and/or (I), Y¹And Y²Each independently is-CH₂-or-O-. In some embodiments, Y¹is-CH₂-and Y²is-O-. In some embodiments, Y¹And Y²Each is-O-.

In some embodiments of the compounds of formula (J) and/or (I), X¹And X³Each independently is OR¹⁵Or SH. In some embodiments, X¹And X³Each independently is OR¹⁵. In some embodiments, R¹⁵Is optionally 1 OR 2-O (C ═ O) OR^B；-O(C＝O)R^B(ii) a or-COOR^BSubstituted C₁-C₆Alkyl radicals, for example R¹⁵May be via-O (C ═ O) OR^BSubstituted C₁-C₆An alkyl group. In some embodiments, R^BIs C₁-C₆An alkyl group such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a tert-butyl group, a sec-butyl group, a n-pentyl group, a n-hexyl group, a sec-hexyl group or a tert-hexyl group. In some embodiments, X¹And X³Each is OR¹⁵Wherein R is¹⁵Is a compound of formula (I) or (II) or (III)^BSubstituted CH₂Wherein R is^BIs a tert-butyl group. In some embodiments, X¹And X³Each is OR¹⁵Wherein R is¹⁵Is a compound of formula-O (C ═ O) OR^BSubstituted CH₂Wherein R is^BIs isopropyl. In some embodiments, X¹Is OH or SH, and X³Is OH. In some embodiments, X¹And X³Each is OH. In some embodiments, X¹Is SH and X³Is OH.

In some embodiments of the compounds of formula (J) and/or (I)In, X²And X⁴Each is O.

In some embodiments, the compounds of formula (J), (I), and/or (IIa) have the structure of formula (Ia):

or an enantiomer or a pharmaceutically acceptable salt thereof.

As depicted in formula (J), (I), (Ia) and/or (IIa), L¹And L²The attachment of the middle atom is from left to right. For example, in the compound of formula (IIa), when L²is-O-C (R)¹³R¹⁴) When an oxygen atom is bonded to a phosphorus atom and-C (R)¹³R¹⁴) The carbon in-is attached to the tetrahydrofuran ring, and when L²is-C (R)¹³R¹⁴) -O-is different, wherein the oxygen atom is attached to the tetrahydrofuran ring and-C (R)¹³R¹⁴) The carbon in-is attached to the phosphorus atom.

In some embodiments of compounds of formula (J), (I), (Ia) and/or (IIa), L¹And L²Each independently is-CH (OR)¹⁵)-、-C(R⁶R⁷)-O-、-O-C(R⁶R⁷) -or-C (R)⁶R⁷)-K¹-C(R⁶R⁷) -, wherein L¹And L²At least one of which is-CH (OR)¹⁵)、-C(R⁶R⁷) -O-or-C (R)⁶R⁷)-K¹-C(R⁶R⁷) -. In some embodiments, L¹And L²Each independently is-CH (OR)¹⁵)-、-C(R⁶R⁷)-O-、-O-C(R⁶R⁷) -or-C (R)⁶R⁷)-K¹-C(R⁶R⁷) -, wherein L¹And L²At least one of which is not-O-CH₂-. In some embodiments, L¹And L²Each independently is-C (R)⁶R⁷)-O-、-O-C(R⁶R⁷) -or-C (R)⁶R⁷)-K¹-C(R⁶R⁷) -, wherein L¹And L²At least one of which is-C (R)⁶R⁷) -O-or-C (R)⁶R⁷)-K¹-C(R⁶R⁷) -. In some embodiments, L¹is-C (R)⁶R⁷) -O-and L²is-C (R)¹³R¹⁴)-O-，L¹is-C (R)⁶R⁷) -O-and L²is-O-C (R)¹³R¹⁴)-，L¹is-O-C (R)⁶R⁷) And L is²is-C (R)¹³R¹⁴)-O-，L¹is-C (R)⁶R⁷)-K¹-C(R⁶R⁷) And L is²is-C (R)¹³R¹⁴)-K¹-C(R¹³R¹⁴)-，L¹is-C (R)⁶R⁷)-K¹-C(R⁶R⁷) And L is²is-O-C (R)¹³R¹⁴) -, or L¹is-O-C (R)⁶R⁷) And L is²is-C (R)¹³R¹⁴)-K¹-C(R¹³R¹⁴) -. In some embodiments, L¹is-C (R)⁶R⁷) -O-and L²is-C (R)¹³R¹⁴)-O-，L¹is-C (R)⁶R⁷) -O-and L²is-O-C (R)¹³R¹⁴)-，L¹is-O-C (R)⁶R⁷) And L is²is-C (R)¹³R¹⁴)-O-，L¹is-C (R)⁶R⁷)-K¹-C(R⁶R⁷) And L is²is-C (R)¹³R¹⁴)-K¹-C(R¹³R¹⁴)-，L¹is-C (R)⁶R⁷)-K¹-C(R⁶R⁷) And L is²is-O-C (R)¹³R¹⁴) -, or L¹is-O-C (R)⁶R⁷) And L is²is-C (R)⁶R⁷)-K¹-C(R⁶R⁷) -. In some embodiments, L¹is-C (R)⁶R⁷) -O-and L²is-C (R)¹³R¹⁴)-O-，L¹is-C (R)⁶R⁷) -O-and L²is-O-C (R)¹³R¹⁴)-，L¹is-O-C (R)⁶R⁷) And L is²is-C (R)¹³R¹⁴) -O-, or L¹is-C (R)⁶R⁷)-K¹-C(R⁶R⁷) And L is²is-O-C (R)¹³R¹⁴) -. In some embodiments, L¹is-C (R)⁶R⁷) -O-and L²is-O-C (R)¹³R¹⁴) -or-C (R)¹³R¹⁴) -O-. In some embodiments, L¹is-C (R)⁶R⁷) -O-and L²is-O-C (R)¹³R¹⁴) -, or L¹is-O-C (R)⁶R⁷) And L is²is-C (R)¹³R¹⁴) -O-. In some embodiments, L¹is-C (R)⁶R⁷) -O-and L²is-O-C (R)¹³R¹⁴) -. In some embodiments, L¹is-O-C (R)⁶R⁷) And L is²is-C (R)¹³R¹⁴) -O-. In some embodiments, L¹And L²At least one of which is not-O-CH₂-。

In some embodiments of compounds of formula (J), (I), (Ia) and/or (IIa), K¹is-O-.

In some embodiments, the compound of formula (J), (I), (Ia) and/or (IIa) has the structure of formula (IIIa):

or an enantiomer or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of formula (J), (I), (Ia), (IIa) and/or (IIIa) have the structure of formula (IVa):

or an enantiomer or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (J), (I), (Ia) and/or (IIa) has the structure of formula (IIIb):

or an enantiomer or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (J), (I), (Ia), (IIa) and/or (IIIb) has the structure of formula (IVb):

or an enantiomer or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (J), (I), (Ia) and/or (IIa) has the structure of formula (IIIc):

or an enantiomer or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (J), (I), (Ia), (IIa) and/or (IIIc) has the structure of formula (IVc):

or an enantiomer or a pharmaceutically acceptable salt thereof.

In some embodiments of compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc), R⁶And R⁷Each independently is H, CN, N₃、F、Cl、Br、I、COOR¹⁵、CON(R¹⁵)₂、OR¹⁵、SR¹⁵、N(R¹⁵)₂Or C₁-C₆An alkyl group. In some embodiments, R⁶And R⁷Each independently is H, CN, F, Cl, COOR¹⁵、CON(R¹⁵)₂、OR¹⁵、SR¹⁵、N(R¹⁵)₂Or C₁-C₆Alkyl radical, wherein each R¹⁵Independently is H or C₁-C₆An alkyl group. In some embodiments, R⁶And R⁷Each independently is H, CN, N₃、F、Cl、Br、I、CH₂OH or CH₂N₃. In some embodiments, R⁶And R⁷Each independently is H or C₁-C₆An alkyl group. In some embodiments, R⁶And R⁷Each is H.

In some embodiments of compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc), R⁶、R⁷、R¹³And R¹⁴Each independently is H, CN, N₃、F、Cl、Br、I、COOR¹⁵、CON(R¹⁵)₂、OR¹⁵、SR¹⁵、N(R¹⁵)₂Or C₁-C₆An alkyl group. In some embodiments, R⁶、R⁷、R¹³And R¹⁴Each independently is H, CN, F, Cl, COOR¹⁵、CON(R¹⁵)₂、OR¹⁵、SR¹⁵、N(R¹⁵)₂Or C₁-C₆Alkyl radical, wherein each R¹⁵Independently is H or C₁-C₆An alkyl group. In some embodiments, R⁶、R⁷、R¹³And R¹⁴Each independently is H, CN, N₃、F、Cl、Br、I、CH₂OH or CH₂N₃. In some embodiments, R⁶、R⁷、R¹³And R¹⁴Each independently is H or C₁-C₆An alkyl group. In some embodiments, R⁶、R⁷、R¹³Is R¹⁴Each is H.

In some embodiments of compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc), R¹⁰Is H, OH, F, Cl, Br, I, CN, N₃Or C₁-C₆An alkyl group. In some casesIn the embodiment, R¹⁰Is H, OH, F, Cl, Br, I, CN, N₃、OR¹⁵、SR¹⁵Or N (R)¹⁵)₂. In some embodiments, R¹⁰Is H, OH, F, CN, N₃、OR¹⁵、SR¹⁵Or N (R)¹⁵)₂. In some embodiments, R¹⁰Is H, OH, F, CN, OR¹⁵、SR¹⁵Or N (R)¹⁵)₂Wherein R is¹⁵Each independently is H or C₁-C₆An alkyl group. In some embodiments, R¹⁰Is H, OH, F, Cl, CN or C₁-C₆An alkyl group. In some embodiments, R¹⁰H, OH or F. In some embodiments, R¹⁰Is H. In some embodiments, R¹⁰Is OH. In some embodiments, R¹⁰Is F.

In some embodiments of compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc), R⁴Is H, OH, F, Cl, Br, I, CN, N₃Or C₁-C₆An alkyl group. In some embodiments, R⁴Is H, OH, F, Cl, Br, I, CN, N₃、OR¹⁵、SR¹⁵Or N (R)¹⁵)₂. In some embodiments, R⁴Is H, OH, F, CN, N₃、OR¹⁵、SR¹⁵Or N (R)¹⁵)₂. In some embodiments, R⁴Is H, OH, F, CN, OR¹⁵、SR¹⁵Or N (R)¹⁵)₂Wherein R is¹⁵Each independently is H or C₁-C₆An alkyl group. In some embodiments, R⁴Is H, OH, F, Cl, CN or C₁-C₆An alkyl group. In some embodiments, R⁴H, OH or F. In some embodiments, R⁴Is H. In some embodiments, R⁴Is OH. In some embodiments, R⁴Is F.

In some embodiments of compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc), R⁴And R¹⁰Each independently is H, OH, F, Cl, Br, I, CN, N₃Or C₁-C₆An alkyl group. In some embodiments, R⁴And R¹⁰Each independently is H, OH, F, Cl, Br, I, CN, N₃、OR¹⁵、SR¹⁵Or N (R)¹⁵)₂. In some embodiments, R⁴And R¹⁰Each independently is H, OH, F, CN, N₃、OR¹⁵、SR¹⁵Or N (R)¹⁵)₂. In some embodiments, R⁴And R¹⁰Each independently is H, OH, F, CN, OR¹⁵、SR¹⁵Or N (R)¹⁵)₂Wherein R is¹⁵Each independently is H or C₁-C₆An alkyl group. In some embodiments, R⁴And R¹⁰Each independently is H, OH, F or CN. In some embodiments, R⁴And R¹⁰Each independently H, OH or F. In some embodiments, R⁴Is OH, and R¹⁰H, OH or F. In some embodiments, R⁴And R¹⁰Each independently is H or OH. In some embodiments, R⁴And R¹⁰Each independently is OH or F. In some embodiments, R⁴And R¹⁰Each is OH. In some embodiments, R⁴Is H, and R¹⁰Is OH. In some embodiments, R⁴Is OH, and R¹⁰Is H. In some embodiments, R⁴Is OH, and R¹⁰Is F.

In some embodiments of compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc), R¹⁵Is H, -C (═ Z) R¹⁶、-C(＝Z)OR¹⁶、-C(＝Z)SR¹⁶、-C(＝Z)N(R¹⁶)₂、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl or C₃-C₇A cycloalkyl group. In some embodiments, R¹⁵Is H, -C (═ Z) R¹⁶、-C(＝Z)OR¹⁶、-C(＝Z)SR¹⁶、-C(＝Z)N(R¹⁶)₂Or C₁-C₆An alkyl group. In some embodiments, R¹⁵Is H, -C (═ Z) R¹⁶、-C(＝Z)OR¹⁶、-C(＝Z)N(R¹⁶)₂Or C₁-C₆An alkyl group. In some embodiments, R¹⁵Is H, -C (═ Z) OR¹⁶Or C₁-C₆Alkyl, optionally via C₆-C₁₀Aryl substituted, the aryl optionally substituted as follows:

1. 2 OR 3-OH, -CN, -O (C ═ O) OR^B、-O(C＝O)R^Bor-COOR^BWherein R is^BIs unsubstituted C₁-C₆An alkyl group. In some embodiments, R¹⁵Is optionally 1 OR 2-O (C ═ O) OR^B；-O(C＝O)R^B(ii) a or-COOR^BSubstituted C₁-C₆Alkyl radicals, for example R¹⁵May be via-O (C ═ O) OR^BSubstituted C₁-C₆An alkyl group. In some embodiments, R^BIs C₁-C₆An alkyl group such as a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a tert-butyl group, a sec-butyl group, a n-pentyl group, a n-hexyl group, a sec-hexyl group or a tert-hexyl group.

In some embodiments of compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc), R¹⁶Is C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₇Cycloalkyl radical, C₂-C₁₀Heterocycloalkyl radical, C₆-C₁₀Aryl or C₂-C₁₀A heteroaryl group. In some embodiments, R¹⁶Is C₁-C₆Alkyl radical, C₆-C₁₀Aryl or C₂-C₁₀Heteroaryl, each of which is optionally substituted as follows: 1. 2 OR 3-OH, -CN, -O (C ═ O) OR^B、-O(C＝O)R^Bor-COOR^BWherein R is^BIs unsubstituted C₁-C₆An alkyl group.

In the formulae (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IV)In some embodiments of the compounds of (IVc), a base¹And a base²Each independently is:

wherein

A、A¹、A²、A³And A⁴Each independently is H, OH, SH, F, Cl, Br, I, NH₂、OR¹⁵、SR¹⁵、NHR¹⁵、N(R¹⁵)₂Or R¹⁶。

In some embodiments, a base¹And a base²Each independently is:

wherein

A、A¹、A²、A³And A⁴Each independently is H, OH, SH, F, Cl, Br, I, NH₂、OR¹⁵、SR¹⁵、NHR¹⁵、N(R¹⁵)₂Or R¹⁶。

In some embodiments, a base¹And a base²Each independently is:

in some embodiments, a base¹And a base²Each independently is:

in some embodiments, a base¹Comprises the following steps:

and a base²Comprises the following steps:

in some embodiments, a base¹Comprises the following steps:

and a base²Is composed of

In some embodiments, a base¹Is composed of

And a base²Comprises the following steps:

in some embodiments, a base¹Is composed of

And a base²Is composed of

In some embodiments, a base¹Is composed of

And a base²Is composed of

In some embodiments of compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc), the compounds have the following structure:

or an enantiomer or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc) have the following structures:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc) have the following structures:

in some embodiments, the compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc) have the following structures:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc) have the following structures:

in some embodiments, the compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc) have the following structures:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc) have the following structures:

in some embodiments, the compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc) have the following structures:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc) have the following structures:

in some embodiments, the compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc) have the following structures:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc) have the following structures:

composition IV

In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of the invention (e.g., a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In certain embodiments, the pharmaceutical composition comprises one or more additional therapeutic agents, as described more fully below.

Pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, can be prepared with one or more pharmaceutically acceptable excipients, which can be selected according to conventional practice. Tablets may contain excipients including glidants, fillers, binders and the like. Aqueous compositions may be prepared in sterile form and may generally be isotonic when intended for delivery by routes other than oral administration. All compositions may optionally contain Excipients such as those set forth in Rowe et al, Handbook of Pharmaceutical Excipients, 6 th edition, American Pharmacists Association, 2009. Excipients include ascorbic acid and other antioxidants, chelating agents (such as EDTA), carbohydrates (such as dextrin), hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, and the like. In certain embodiments, the composition is provided in a solid dosage form, including a solid oral dosage form.

Compositions include compositions suitable for various routes of administration, including oral administration. The compositions may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of associating the active ingredient (e.g., a compound of the invention or a pharmaceutically salt thereof) with one or more pharmaceutically acceptable excipients. The compositions can be prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients or finely divided solid excipients or both, and then, if necessary, shaping the product. Techniques and formulations are generally found in Remington, The Science and practice of Pharmacy, 21 st edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

Compositions suitable for oral administration described herein may be presented as discrete units (unit dosage forms) including, but not limited to, capsules, sachets or tablets each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition is a tablet.

The pharmaceutical compositions disclosed herein comprise one or more compounds disclosed herein, or pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable excipient and optionally other therapeutic agents. The pharmaceutical composition containing the active ingredient may be in any form suitable for the intended method of administration. When used, for example, for oral use, tablets, dragees, buccal tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more excipients, including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide palatable preparations. Tablets containing the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed alone or with a wax.

The amount of active ingredient that can be combined with the inactive ingredients to produce a dosage form will vary depending upon the subject to be treated and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to a human may contain from about 1 to 1000mg of the active agent formulated with an appropriate and suitable amount of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutically acceptable excipient ranges from about 5% to about 95% (weight: weight) of the total composition.

In certain embodiments, a composition comprising a compound of the invention (e.g., a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc)) or a pharmaceutically acceptable salt thereof in one variation does not contain an agent that can affect the metabolic rate of the active ingredient. Thus, it is understood that compositions comprising a compound of the invention in one aspect do not comprise an agent that would affect (e.g., slow, hinder, or throttle) the metabolism of the compound of the invention or any other active ingredient administered separately, sequentially, or simultaneously with the compound of the invention. It is also understood that any methods, kits, articles of manufacture, and the like detailed herein do not, in one aspect, comprise an agent that would affect (e.g., slow, hinder, or throttle) the metabolism of the compound of the present invention or any other active ingredient administered separately, sequentially, or simultaneously with the compound of the present invention.

The invention also includes the use of a pharmaceutical composition as described above for modulating STING protein activity to induce STING-dependent production of type I interferons, cytokines or chemokines.

The invention also includes the use of a pharmaceutical composition as described above for the treatment or prevention of a viral infection, an infection caused by hepatitis B virus, HIV, a hyperproliferative disease or cancer.

In some embodiments, the pharmaceutical composition described above is for use in a human or animal.

The invention also encompasses compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc) which are administered as the single active ingredient of a pharmaceutically acceptable composition which can be prepared by conventional methods known in the art, for example by bringing the active ingredient into association or into admixture with a pharmaceutically acceptable therapeutically inert organic and/or inorganic carrier or excipient.

In one aspect, the invention provides the use of a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc) as a second or further active ingredient, which has a synergistic effect with other active ingredients in known medicaments, or the compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc) are co-administered with such medicaments.

The compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc) according to the invention can also be used in prodrug or other suitably modified form which releases the active ingredient in vivo.

V. Process

In one embodiment, the present invention provides a method of treating a disease or disorder comprising administering to a human or animal in need thereof a therapeutically effective amount of a cyclic dinucleotide as provided herein, comprising a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc), or an enantiomer or a pharmaceutically acceptable salt thereof.

Also provided are methods of modulating the activity of STING proteins comprising administering a therapeutically effective amount of a cyclic dinucleotide as provided herein, including a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc), or an enantiomer or a pharmaceutically acceptable salt thereof.

Stimulator of interferon gene adaptor (STING), also known as STING, STING protein, transmembrane protein 173(TMEM173), MPYS, IRF3 activation Mediator (MITA), or Endoplasmic Reticulum Interferon Stimulator (ERIS), is a protein encoded in humans by the TMEM173 gene (UniProt code Q86WV 6; NCBI reference sequence: NP _938023.1 (isoform 1) and NP _001288667 (isoform 2)). It is believed that STING transconnectins act as direct Cytoplasmic DNA Sensors (CDS) and transconnectors for type I interferon signaling via different molecular mechanisms. It has been demonstrated that STING adaptor protein can activate downstream transcription factors STAT6 and IRF3 via TBK1 and NF- κ B via IKK β, which can achieve an antiviral or innate immune response against intracellular pathogens. STING transconnectins play a role in innate immunity by inducing type I interferon production when cells are infected with intracellular pathogens, such as viruses, mycobacteria, and intracellular parasites. Type I interferons mediated by STING transducin protect infected and neighboring cells from local infection by autocrine and paracrine signaling.

Also provided is a method of preventing or treating a disease or condition responsive to modulation of STING transducin, comprising administering to a human or animal in need thereof a therapeutically effective amount of a cyclic dinucleotide as provided herein, comprising a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc), or an enantiomer or a pharmaceutically acceptable salt thereof.

Also provided is a method of inducing STING adaptor-dependent type I interferons, cytokines or chemokines in a human or animal comprising administering a therapeutically effective amount of a cyclic dinucleotide as provided herein, comprising a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc) or an enantiomer or a pharmaceutically acceptable salt thereof.

Activation of the STING adaptor in turn activates the protein kinase TBK1, which in turn activates the downstream transcription factors NF- κ B and IRF-3. It is believed that activation of STING transconnects ultimately results in the release of type I and type III interferons as well as a variety of cytokines and chemokines, such as IL-6, TNF- α and INF- γ. Thus, a type I interferon, cytokine or chemokine that induces STING adaptor dependence in a human or animal may cause activation of one or more of NF-. kappa. B, IRF-3, type I interferon, type III interferon, IL-6, TNF-. alpha.and INF-. gamma.in that human or animal.

Also provided is a method of treating or preventing a viral infection (e.g., an infection caused by hepatitis B or HIV) comprising administering to a human or animal in need thereof a therapeutically effective amount of a cyclic dinucleotide as provided herein, comprising a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc), or an enantiomer or a pharmaceutically acceptable salt thereof.

The viral infection that can be treated or prevented by the methods of the invention can be any infection caused by a virus, such as a virus from the Hepadnaviridae (Hepadnaviridae family) of viruses, e.g., hepatitis B; or any retrovirus, e.g., alpharetrovirus, such as Rous sarcoma virus (Rous sarcoma virus); beta retroviruses, such as monkey retroviruses; retroviruses, such as bovine leukemia virus or human T-lymphovirus (HTLV), including HTLV-1, HTLV-2 and HTLV-3; gammaretrovirus, such as murine leukemia virus or feline leukemia virus; or lentiviruses, such as Human Immunodeficiency Virus (HIV) (including HIV-1 and HIV-2), simian immunodeficiency virus, equine infectious anemia virus, bovine immunodeficiency virus, rabbit endogenous lentivirus type K (RELIK), or feline immunodeficiency virus.

Also provided is a method of treating or preventing a hyperproliferative disease or cancer comprising administering to a human or animal in need thereof a therapeutically effective amount of a cyclic dinucleotide as provided herein, comprising a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc), or an enantiomer or a pharmaceutically acceptable salt thereof.

Hyperproliferative diseases include diseases caused by the overgrowth of non-cancerous cells. Such conditions include, but are not limited to, psoriasis, actinic keratosis and seborrheic keratosis, warts, keloids, and eczema.

Cancers that can be treated or prevented by the methods of the invention include solid tumors and lymphomas, including, but not limited to, cancers of the adrenal gland, bladder, bone, brain, breast, colon, colorectal, eye, head and neck, kidney (such as renal cell carcinoma), liver, lung (such as non-small cell lung), ovary, pancreas, prostate, skin (such as squamous cell carcinoma and melanoma), thyroid, uterus, vagina, and myeloma (such as multiple myeloma). The cancer may be primary, or recurrent and/or refractory.

In some embodiments, the cancer is Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), refractory inh l, Multiple Myeloma (MM), Chronic Myelogenous Leukemia (CML), Acute Lymphoblastic Leukemia (ALL), B-cell ALL, Acute Myelogenous Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), myelodysplastic syndrome (MDS), myeloproliferative disorders (MPD), Mantle Cell Lymphoma (MCL), Follicular Lymphoma (FL), Waldestrom's Macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), or Marginal Zone Lymphoma (MZL). In one embodiment, the cancer is Minimal Residual Disease (MRD). In some embodiments, the cancer is selected from hodgkin's lymphoma, non-hodgkin's lymphoma (NHL), indolent non-hodgkin's lymphoma (iNHL), and refractory iNHL. In some embodiments, the cancer is indolent non-hodgkin's lymphoma (iNHL). In some embodiments, the cancer is refractory iNHL. In some embodiments, the cancer is Chronic Lymphocytic Leukemia (CLL). In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

In some embodiments, the cancer is a solid tumor selected from the group consisting of: pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; kidney or renal cancer, including, for example, metastatic renal cell carcinoma; hepatocellular carcinoma; lung cancer including, for example, non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and lung adenocarcinoma; ovarian cancer, including, for example, progressive epithelial or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, for example, squamous cell carcinoma of the head and neck; melanoma; neuroendocrine cancers, including metastatic neuroendocrine tumors; brain tumors, including, for example, glioma, oligodendroglioma multiforme, adult glioblastoma multiforme, and adult astrocytoma multiforme; bone cancer; and soft tissue sarcoma, hepatoma, rectal cancer, penile cancer, vulval cancer, thyroid cancer, salivary gland cancer, endometrial or uterine cancer, hepatoma, hepatocellular cancer, liver cancer, gastric or gastric cancer (including gastrointestinal cancer), peritoneal cancer, lung squamous carcinoma, gastroesophageal cancer, biliary tract cancer, gall bladder cancer, colorectal/appendiceal cancer, squamous cell cancer (e.g., epithelial squamous cell cancer).

Any of the treatment methods provided herein can be used to treat various stages of cancer. For example, cancer stages include, but are not limited to, early, advanced, locally advanced, remission, refractory, recurrent after remission, and progressive cancer.

Object

Any of the methods of treatment provided herein can be used to treat a subject (e.g., a human) that has been diagnosed with or is suspected of having cancer. As used herein, a subject refers to a mammal, including, for example, a human.

In some embodiments, the subject may be a human exhibiting one or more symptoms associated with cancer or a hyperproliferative disease. In some embodiments, the subject may be a human presenting one or more symptoms associated with cancer. In some embodiments, the subject is in an early stage of cancer. In other embodiments, the subject is in an advanced stage of cancer.

In some embodiments, the subject may be a human who is at risk or genetically or otherwise predisposed (e.g., risk factor) to develop cancer or a hyperproliferative disease and who has or has not been diagnosed. As used herein, a "at-risk" subject is a subject at risk of developing cancer. Prior to performing the methods of treatment described herein, the subject may or may not have a detectable disease, and may or may not show a detectable disease. A subject at risk may have one or more so-called risk factors, which are measurable parameters associated with the development of the cancers described herein. Subjects with one or more of these risk factors have a higher probability of developing cancer than individuals without these risk factors. These risk factors may include, for example, age, sex, race, diet, history of previous disease, presence of pre-disease, genetic (e.g., genetic) factors, and environmental exposure. In some embodiments, subjects at risk for cancer include, for example, subjects whose relatives have experienced the disease and subjects at risk as determined by analysis of genetic or biochemical markers.

Furthermore, the subject may be a human undergoing one or more standard therapies, such as chemotherapy, radiotherapy, immunotherapy, surgery, or any combination thereof. Thus, one or more of the compounds provided herein can be administered prior to, during, or after administration of chemotherapy, radiotherapy, immunotherapy, surgery, or a combination thereof.

In some embodiments, the subject may be a person who satisfies the following condition: (i) substantially refractory to at least one chemotherapy treatment, or (ii) relapse after chemotherapy treatment, or both (i) and (ii). In some embodiments, the subject is refractory to treatment with at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapy).

Also provided is a method of enhancing the efficacy of a vaccine comprising administering to a human or animal in need thereof a therapeutically effective amount of a cyclic dinucleotide as provided herein, comprising a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc), or an enantiomer or a pharmaceutically acceptable salt thereof.

The invention includes the use of a cyclic dinucleotide as provided herein, including compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc), or an enantiomer or a pharmaceutically acceptable salt thereof, as a medicament in a human or animal.

The invention includes the use of the cyclic dinucleotides provided herein, including compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc), or enantiomers or pharmaceutically acceptable salts thereof, for the treatment of a disease or condition in a human or animal.

The invention further includes the use of the cyclic dinucleotides provided herein, including compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc), or enantiomers or pharmaceutically acceptable salts thereof, for modulating the activity of STING proteins.

The invention further includes the use of the cyclic dinucleotides provided herein, including compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc), or enantiomers or pharmaceutically acceptable salts thereof, for the prevention or treatment of a disease or condition responsive to modulation of STING proteins in a human or animal.

The invention also includes the use of the cyclic dinucleotides provided herein, including the compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc) or an enantiomer or a pharmaceutically acceptable salt thereof, alone or in combination with one or more therapeutically active substances, for the STING-dependent induction of type I interferons, cytokines or chemokines in a human or animal.

The invention also includes the use of the cyclic dinucleotides provided herein, including compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc), or enantiomers or pharmaceutically acceptable salts thereof, alone or in combination with one or more therapeutically active agents, for the treatment or prevention of a viral infection in a human or animal.

The invention also includes the use of the cyclic dinucleotides provided herein, including the compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc) or an enantiomer or a pharmaceutically acceptable salt thereof, alone or in combination with one or more therapeutically active substances, for the treatment or prevention of an infection caused by the hepatitis B virus or HIV in a human or animal.

The invention also includes the use of the cyclic dinucleotides provided herein, including compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc), or enantiomers or pharmaceutically acceptable salts thereof, alone or in combination with one or more therapeutically active agents, for the treatment or prevention of hyperproliferative diseases or cancers in humans or animals.

The invention also includes the use of the cyclic dinucleotides provided herein, including compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc), or enantiomers or pharmaceutically acceptable salts thereof, for enhancing vaccine efficacy in humans or animals.

The invention also includes the use of a pharmaceutical composition comprising a cyclic dinucleotide as provided herein, including a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc), or an enantiomer or a pharmaceutically acceptable salt thereof, for modulating the activity of a STING protein to induce STING-dependent production of a type I interferon, cytokine or chemokine in a human or animal.

The invention also includes the use of a pharmaceutical composition comprising a cyclic dinucleotide as provided herein, including a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc) or an enantiomer or a pharmaceutically acceptable salt thereof, for treating or preventing a viral infection, an infection caused by hepatitis B virus, HIV, a hyperproliferative disease or cancer in a human or animal.

The invention also includes the use of a cyclic dinucleotide as provided herein for the preparation of a medicament for treating or preventing an infection, a hyperproliferative disease or a cancer caused by a hepatitis B virus, HIV, the pharmaceutical composition comprising a cyclic dinucleotide as provided herein, including a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc) or an enantiomer or a pharmaceutically acceptable salt thereof.

Administration of

The compounds of the present invention (also referred to herein as active ingredients) may be administered by any route suitable for the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratumoral, intrathecal and epidural) and the like. It will be appreciated that the preferred route may vary with the condition of, for example, the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

The compounds of the invention can be administered to an individual according to an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In one variation, the compound is administered to the individual for the duration of life on a daily or intermittent schedule.

The dosage or frequency of administration of the compounds of the invention may be adjusted during the course of therapy based on the judgment of the administering physician.

The compounds can be administered to an individual (e.g., a human) in a therapeutically effective amount. In certain embodiments, the compound is administered once daily.

The compounds may be administered by any suitable route and means, such as by oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of a compound may comprise from about 0.00001mg per kg body weight per day to about 10mg per kg body weight per day, such as from about 0.0001mg per kg body weight per day to about 10mg per kg body weight per day, or such as from about 0.001mg per kg body weight per day to about 1mg per kg body weight per day, or such as from about 0.01mg per kg body weight per day to about 1mg per kg body weight per day, or such as from about 0.05mg per kg body weight per day to about 0.5mg per kg body weight per day, or such as from about 0.3mg to about 30mg per day, or such as from about 30mg to about 300mg per day.

The compounds of the invention may be combined with one or more other therapeutic agents in any amount administered with the compounds of the invention (e.g., 1mg to 1000mg of the compound). A therapeutically effective amount may include from about 1mg per dose to about 1000mg per dose, such as from about 50mg per dose to about 500mg per dose, or such as from about 100mg per dose to about 400mg per dose, or such as from about 150mg per dose to about 350mg per dose, or such as from about 200mg per dose to about 300mg per dose. Other therapeutically effective amounts of the compounds of the invention are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or about 500mg per dose. Other therapeutically effective amounts of the compounds of the invention are about 100mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500mg per dose. A single dose may be administered hourly, daily or weekly. For example, a single dose may be administered once every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or once every 24 hours. A single dose may also be administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or once every 7 days. A single dose may also be administered once every 1 week, 2 weeks, 3 weeks, or once every 4 weeks. In certain embodiments, a single dose may be administered once every other week. A single dose may also be administered once a month.

Also included in the invention is a kit comprising a cyclic dinucleotide of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc) or an enantiomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of the above.

In one embodiment, a kit is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.

Combination therapy

In certain embodiments, a method is provided for treating or preventing a human having or at risk of having: an infectious disease, viral infection, hepatitis B infection, HIV infection, cancer, or hyperproliferative disease comprising administering to a human a therapeutically effective amount of a compound disclosed herein, e.g., a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) other therapeutic agents. In one embodiment, a method is provided for treating a human suffering from or at risk of suffering from: an infectious disease, viral infection, hepatitis B infection, HIV infection, cancer, or hyperproliferative disease comprising administering to a human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) other therapeutic agents.

In certain embodiments, the present invention provides a method for treating a viral infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) other therapeutic agents suitable for treating a viral infection. In some embodiments, the viral infection is a hepatitis B infection. In some embodiments, the viral infection is an HIV infection.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two other therapeutic agents. In other embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with three other therapeutic agents. In other embodiments the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with four other therapeutic agents. The one, two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and/or they may be selected from different classes of therapeutic agents.

Administration of combination therapy

In certain embodiments, a compound disclosed herein is administered with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more other therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein and one or more other therapeutic agents such that a therapeutically effective amount of the compound disclosed herein and one or more other therapeutic agents are present in the subject. When administered sequentially, the combination may be administered in two or more administrations.

Co-administration of a compound disclosed herein with one or more other therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein and one or more other therapeutic agents such that a therapeutically effective amount of each agent is present in the patient.

In certain embodiments, a compound as disclosed herein (e.g., any compound of formula I) may be combined with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) other therapeutic agents in any amount of compound of formula I administered (e.g., 10mg to 1000mg of compound).

Co-administration includes administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more other therapeutic agents. The compounds disclosed herein may be administered within seconds, minutes, or hours of administration of one or more other therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed by administration of a unit dose of one or more other therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed by a unit dose of one or more other therapeutic agents after a few hours (e.g., 1-12 hours). In other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of a compound disclosed herein after several hours (e.g., 1-12 hours).

In certain embodiments, the compounds disclosed herein are combined in a single dosage form with one or more other therapeutic agents for simultaneous administration to a subject, e.g., in a solid dosage form for oral administration.

In certain embodiments, the compounds of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb) and/or (IVc) are formulated in the form of a tablet, which may optionally contain one or more other compounds suitable for treating the disease being treated. In certain embodiments, the tablet may contain another active ingredient useful for treating viral diseases, such as hepatitis B virus or HIV.

In certain embodiments, such tablets are suitable for once-a-day administration.

In one embodiment, a pharmaceutical composition is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two or one to three) other therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient.

In one embodiment, a kit is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.

Viral combination therapy

The compounds described herein may be used with or in combination with one or more antiviral agents, including abacavir (abacavir), acyclovir (aciclovir), adefovir (adefovir), amantadine (amantadine), amprenavir (amprenavir), arbidol (arbidol), atazanavir (atazanavir), ritital (artipla), brivudine (brivudine), cidofovir (cidofovir), cobivir (combivir), edoxuridine (edoudine), efavirenz (efavirenz), altretastatin (emtricitabine), envivirtide (envirtide), entecavir (entecavir), fuviruse (fosvevir), sarenavir (sarenavir), foscarnet (foscarnet), foscarnet (alcohol), valacivir (indovir), valcanidine (indovir), valdecovir (indovir), valcanivir (indovir), a (indovir), valcanivir (indovir), valdecovir (indovir), valcanivir (indovir), a (indovir), foscarnitin (indovir), valcanivir (indomethacin), valcanivir (e), valcanivir (, Type II interferons, type I interferons, lamivudine (lamivudine), lopinavir (lopinavir), lovirdine (loviride), MK-0518, maraviroc (maraviroc), morpholinoguandine (moroxydine), nelfinavir (nelfinavir), nevirapine (nevirapine), polygimeramide (nexavir), nucleoside analogs, oseltamivir (oseltamivir), penciclovir (penciclovir), peramivir (peramivir), proconavir (procconaril), podophyllotoxin (podophylotoxin), protease inhibitors, reverse transcriptase inhibitors, ribavirin (ribivirin), rimantadine (rimatadine), ritonavir (ritonavir), saquinavir (saquinavir), stavudine (stavudine), tenofovir (tenofovir), trevativivir (trovir), trevativir (valtrevir), fosalvudine (valacivir), trevatividine (valtrevir), valacivir (trovir), valacivir (peruviorevir), pterivivir (pterivivir), pterocarpine (trovir), picavir (pteravidine), picavir (trovir), picavir, Vidarabine (vidarabine), veramidine (viramidine), zalcitabine (zalcitabine), zanamivir (zanamivir), zidovudine (zidovudine), and combinations thereof.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-30mg tenofovir alafenamide (tenofovir alafenamide fumarate), tenofovir alafenamide (tenofovir alafenamide hemifumarate), or tenofovir alafenamide (tenofovir alafenamide). In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10; 5-15; 5-20 parts of; 5-25; 25-30; 20-30 parts of; 15-30 parts of; or 10-30mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or a combination of tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. A compound as disclosed herein (e.g., a compound of formula J) can be combined with an agent provided herein in any amount administered of the compound (e.g., 50mg to 500mg of the compound) as if each dosage combination were specifically and individually enumerated.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 100-400mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 100-150; 100-200, 100-250; 100-300; 100-350; 150-200; 150- > 250; 150-300; 150-; 150-400; 200-250; 200-300; 200-350; 200-400; 250-350; 250-400; 350-400 or 300-400mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or a combination of tenofovir disoproxil fumarate. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 300mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 250mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 150mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. A compound as disclosed herein (e.g., a compound of formula J) can be combined with an agent provided herein in any amount administered of the compound (e.g., 50mg to 500mg of the compound) as if each dosage combination were specifically and individually enumerated.

HIV combination therapy

In certain embodiments, there is provided a method for treating or preventing an HIV infection in a human or animal suffering from or at risk of suffering from the infection, comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two or one to three) other therapeutic agents. In one embodiment, there is provided a method for treating an HIV infection in a human or animal suffering from or at risk of suffering from the infection, comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two or one to three) other therapeutic agents.

In certain embodiments, the present invention provides methods for treating HIV infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more other therapeutic agents suitable for treating HIV infection.

In certain embodiments, the compounds disclosed herein are formulated in tablet form, which may optionally contain one or more other compounds suitable for the treatment of HIV. In certain embodiments, the tablet may contain another active ingredient useful in the treatment of HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

In certain embodiments, such tablets are suitable for once-a-day administration.

In the above embodiments, the additional therapeutic agent may be an anti-HIV agent. In some embodiments, the additional therapeutic agent is selected from the group consisting of: HIV combination drugs, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutics, antibody-drug conjugates, gene modulators, gene editing agents (such as CRISPR/Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), cell therapies (such as chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T), latency reversal agents, compounds targeting the HIV capsid (including capsid inhibitors of the capsid), immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, alpha-4/beta-7 antagonists, HIV inhibitors of nucleoside or nucleotide reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, zinc finger nucleases, synthetic nucleases, TALENs, cell, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, disulfide protein isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV Vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectious agent inhibitors, TAT protein inhibitors, HIV-1Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splice inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splice factor modulators, protein 1 modulators containing COMM domains, HIV ribonuclease H inhibitors, anticyclin modulators, HIV-like therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, disulfide protein isomerase inhibitors, complement C5a receptor antagonists, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splice inhibitors, Rev protein inhibitors, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase activation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines and other HIV therapeutics, and combinations thereof.

In some embodiments, the additional therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof.

HIV combination drug

Examples of combination drugs include(efavirenz, tenofovir disoproxil fumarate, and android citabine);rilpivirine, tenofovir disoproxil fumarate, and ambocitabine;(elvitegravir), cobicistat, tenofovir disoproxil fumarate, and atroxitabine);(tenofovir disoproxil fumarate and android sitabine; TDF + FTC);(tenofovir alafenamide and android citabine);(tenofovir alafenamide, azelastine, and rilpivirine);(tenofovir alafenamide, atroxitabine, cobicistat and etifovir);(Bitelavavir (bictegravir), Atocitabine, tenofovir alafenalAmines); darunavir (darunavir), tenofovir alafenamide hemifumarate, amphetamine, and cobicistat; efavirenz, lamivudine (lamivudine) and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and android citabine; tenofovir alafenamide hemifumarate and android citabine; tenofovir alafenamide hemifumarate, azelastine and rilpivirine; tenofovir alafenamide hemifumarate, atroxibine, cobicistat and etifovir;(zidovudine and lamivudine; AZT +3 TC);(abacavir sulfate (abacavir sulfate) and lamivudine; ABC +3 TC);(lopinavir and ritonavir);(douglavir, abacavir and lamivudine);(abacavir sulfate, zidovudine and lamivudine; ABC + AZT +3 TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; douglavir (dolutegravir) and rilpivirine; douglavir and rilpivirine hydrochloride; douglavir, abacavir sulfate and lamivudine; lamivudine, nevirapine, and zidovudine; letergevir (r)altegravir) and lamivudine; doravirine (doravirine), lamivudine and tenofovir disoproxil fumarate; dolavrine, lamivudine and tenofovir disoproxil; douglavir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir; lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine; and tenofovir disoproxil fumarate + altocitabine + rilpivirine hydrochloride; lopinavir, ritonavir, zidovudine and lamivudine; vacc-4x and romidepsin; and APH-0812.

HIV protease inhibitors

Examples of HIV protease inhibitors include amprenavir, atazanavir, Becanavir (brecanavir), darunavir, fosamprenavir calcium, indinavir sulfate, lopinavir, nelfinavir mesylate, ritonavir, saquinavir (saquinavir), saquinavir mesylate, tipranavir, DG-17, TMB-657(PPL-100), T-169, BL-008, and TMC-310911.

HIV reverse transcriptase inhibitors

Examples of HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors include dapivirine (dapivirine), delavirdine (delavirdine), delavirdine mesylate, doraviline, efavirenz, etravirine (etravirine), lentinan (lentinan), nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005, and VM-1500.

Examples of HIV nucleoside or nucleotide reverse transcriptase inhibitors include adefovir, adefovir dipivoxil, azvudine (azvudine), atroxibin, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, adefovir disoproxil fumarate, and combinations thereof,And VIDEX(didanosine (ddl), abacavir sulfate, alovudine (alovudine), aprevitabine (apricitabine), semaphodine (censvudine), didanosine, elvucitabine (elvucitabine), filvinavir (felbinavir), fosalvudine tidoxil (fossiltation tidoxil), CMX-157, dapivirine, dolavirenzine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil (zivudine tidoxil), lamivudine, fosfild (phospazid), stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, MK-8504, and KP-1461.

HIV integrase inhibitors

Examples of HIV integrase inhibitors include Etegravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3, 5-dicaffeoylquinic acid, derivatives of 3, 5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrosine phosphorylation inhibitors, derivatives of tyrosine phosphorylation inhibitors, quercetin, derivatives of quercetin, raltegravir, douglavir, JTK-351, Bitegravir (bictegravir), AVX-15567, caberbravir (cabtegravir) (long acting injectable), diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins (ledgins), M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169 and cabbagewvir.

Examples of HIV non-catalytic site or ectopic integrase inhibitors (NCINI) include CX-05045, CX-05168, and CX-14442.

HIV entry inhibitors

Examples of HIV entry (fusion) inhibitors include seniviroc (cericiviroc), CCR5 inhibitors, gp41 inhibitors, CD 4-linked inhibitors, gp120 inhibitors, and CXCR4 inhibitors.

Examples of CCR5 inhibitors include apreviroc, vickers (viccriviroc), maraviroc (maraviroc), seniviroc, PRO-140, adaptavir (adaptavir) (RAP-101), nifeviroc (nifeviroc) (TD-0232), anti-GP 120/CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipouu)).

Examples of gp41 inhibitors include ribavirin (albivirtide), enfuvirdine (enfuvirtide), BMS-986197, biologically better drugs of enfuvirdine, biologically similar drugs of enfuvirdine, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer and sifuvirtide.

Examples of CD4 ligation inhibitors include illizomab (ibalizumab) and CADA analogs.

Examples of gp120 inhibitors include Radha-108 (recieptol) 3B3-PE38, BanLec, Bentonite-based nanomedicine, Fostemsavirenz tromethamine, IQP-0831, and BMS-663068.

Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide and vMIP.

HIV maturation inhibitors

Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.

Latent reversal agents

Examples of latency reversing agents include Histone Deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade (velcade), Protein Kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4(BRD4) inhibitors, ionomycin (ionomycin), PMA, SAHA (suberoylanilide hydroxamic acid, or suberoyl, aniline, and hydroxamic acid), AM-0015, ALT-803, NIZ-985, NKTR-255, IL-15 regulatory antibodies, JQ1, dithiols, amphotericin B, and ubiquitin inhibitors such as the Laggera analog (largazol analog), and GSK-343.

Examples of HDAC inhibitors include romidepsin, vorinostat, and pabinostat.

Examples of PKC activators include indolactam (indoctam), protistan (prostratin), ingenol B (ingenol B), and DAG lactone.

Capsid inhibitors

Examples of capsid inhibitors include capsid polymerization inhibitors or capsid cleavage compounds, HIV nucleocapsid p7(NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series.

Immunity-based therapy

Examples of immune-based therapies include toll-like receptor modulators such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR 13; programmed cell death protein 1(Pd-1) modulators; modulators of programmed death ligand 1 (Pd-L1); an IL-15 modulator; demavir (DermaVir); interleukin-7; chloroquine (plaquinil) (hydroxychloroquine); proleukin (aldesleukin), IL-2; interferon alpha; interferon alpha-2 b; interferon alpha-n 3; pegylated interferon alfa; an interferon gamma; a hydroxyurea; mycophenolic acid ethyl morpholine ester (MPA) and its ester derivative mycophenolic acid ethyl morpholine ester (MMF); ribavirin; ritalimod (ritatolimumod), polymer Polyethylenimine (PEI); jepenone (gepon); retaride; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15/Fc fusion protein, nomerfron (norferon), pegylated interferon alpha-2 a, pegylated interferon alpha-2 b, recombinant interleukin-15, RPI-MN, GS-9620, STING modulators, RIG-I modulators, NOD2 modulators, and IR-103.

Examples of TLR8 modulators include motomomod (motolimod), Rasimimod (resiquimod), 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and modulators disclosed in: US20140045849(Janssen), US20140073642(Janssen), WO2014/056953(Janssen), WO2014/076221(Janssen), WO2014/128189(Janssen), US20140350031(Janssen), WO2014/023813(Janssen), US20080234251(Array Biopharma), US 3062008020080050 (Array Biopharma), US20100029585(Ventirx Pharma), US20110092485(Ventirx Pharma), US 20118235 (Ventirx Pharma), US20120082658 658(Ventirx Pharma), US20120219615(Ventirx Pharma), US 0066432(Ventirx irrma), US 0085 (ventipp), US 02767 (viiera 5151513025148), US 201672014, US 6751672014, US tierneneap US patent No. (Gillex 462014), US2014 5929 (Gillex 462014) and U.g. application Ser. 2014 5929 (Gillex 462014).

Phosphatidylinositol 3-kinase (PI3K) inhibitors

Examples of PI3K inhibitors include idelbenib (idelalisib), tipexib (alpelisib), buparlixib (buparlisib), CAI orotate, cobbanxib (copanlisib), Duvelisib (duvelisib), Gedalisib (gedatolisib), neratinib (neratinib), panulib (panulisib), perifosine (perifosine), Pickerib (piculisib), Pilarisib (pilalisib), Prazitinib mesylate (puquitinibistmesilate), regia (rigoisib), regorab sodium (rigoisib sodium), Sonolib (sonolisib), Tanarisib (taquisibib), AMG-8186, BAY-1082439, CLR-1722, CLR-17223, CLR-040093, GSR-366723, GSK-366423, GSK-3647, GSG-3647, GSK-6723, GSK-3647, GSK-17223, GSK-3647, GSK-6423, GSK-3647, GSK-6423, GSK-53, GSK-RG-3647, GSK-3, GSK-3647, and GSK-369, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474.

Alpha-4/beta-7 antagonists

Examples of integrin alpha-4/beta-7 antagonists include PTG-100, TRK-170, Abbrizumab (abrilumab), Eprosazumab (etrolizumab), Carotetramethyl (carotegrast methyl), and Vidolizumab (vedolizumab).

HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins

Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins includeFab derivatives, bnABs (broadly neutralizing HIV-1 antibodies), BMS-936559, TMB-360 and antibodies targeting HIV gp120 or gp41, antibody recruiting molecules targeting HIV, anti-CD 63 monoclonal antibodies, anti-GB virus C antibodiesGP120/CD4, CCR5 bispecific antibody, anti nef single domain antibody, anti Rev antibody, camelid derived anti-CD 18 antibody, camelid derived anti-ICAM-1 antibody, DCVax-001, GP140 targeting antibody, GP41 based HIV therapeutic antibody, human recombinant mAb (PGT-121), illicium progenitor (ibalizumab), Immuglo and MB-66.

Examples of antibodies that target HIV in this manner include baviximab (bavituximab), UB-421, C2F5, 2G12, C4E10, C2F5+ C2G12+ C4E10, 8ANC195, 3BNC117, 3BNC60, 10-1074, PGT145, PGT121, PGT-151, PGT-133, MDX010 (ipilimumab), DH511, N6, VRC01 PGDM1400, A32, 7B2, 10E8, 10E8v4, CAP256-VRC26.25, DRVIA7, VRC-07-523, VRC-HIVMAB080-00-AB, VRC-VHAB 060-00-AB, MGD-014, and VRC 07. Examples of HIV bispecific antibodies include MGD 014.

Pharmacokinetic enhancer

Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

HIV vaccine

Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD 4-derived peptide vaccines, vaccine combinations, rgp120(AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (GP120) (RV144), monomeric GP120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVAx-001(CDX-2401), Vacc-4x, Vacc-C5, gag-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccines, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM 3/VSP ISA-51, poly-ICLC adjuvanted vaccines, Tatmone, GTU-06, HIV G-V III vaccine, HIV-V1-V59, HIV-V2G 1+ VrV 59 SeV-Gag vaccine, AT-20, DNK-4, Ad35-Grin/ENV, TBC-M4, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4(Ad4-ENV clade C + Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxtat, AE-H, MYM-V101, CombiVvacc, ADVAX, MYM-V201, MVA-DR, CMDNA-Ad 5 Gag/nef/nev (ModTN 505), MVATG-17401, CDV-01, ADRCX-1401, HIV-26.1.001, HIV-AGV-26, SAAVAV6409, AVATG-26, AVATG-B-10, AVATG-B-10, AVV-201, AVV-8, AVV-III, AVV-1 TUTI-16, VGX-3300, IHV-001, and virus-like particle vaccines (such as pseudovirion vaccines), CombiVICHvac, LFn-p 24B/C fusion vaccines, GTU-based DNA vaccines, HIV gag/pol/nef/Env DNA vaccines, anti-TAT HIV vaccines, conjugated polypeptide vaccines, dendritic cell vaccines, gag-based DNA vaccines, GI-2010, GP41 HIV-1 vaccines, HIV vaccines (PIKA adjuvant), I i-key/MHCII class epitope hybrid peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multi-clade Env vaccines, MVA vaccines, Pennvax-GP, pp71 deleted HCMV vector HIV gag vaccines, recombinant peptide vaccines (HIV infection), NCI, rgp160 HIV vaccine, RNve-active HIV, SCB-703, TAT OYi, TAT-4 HIV 4, Therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x + romidepsin, mutant gp120 polypeptide vaccine, rAd5 gag-pol env A/B/C vaccine, DNA.

Other HIV therapeutic agents

Examples of other therapeutic agents include the compounds disclosed in: WO 2004/096286(Gilead Sciences), WO 2006/015261(Gilead Sciences), WO 2006/110157(Gilead Sciences), WO2012/003497(Gilead Sciences), WO 2012/003498(Gilead Sciences), WO 2012/145728(Gilead Sciences), WO 2013/006738(Gilead Sciences), WO 2013/159064(Gilead Sciences), WO 2014/100323(Gilead Sciences), US 2013/0165489(University Pennsylvania), US 2014/0221378(Japan Tobacco), US 2014/0221380(Japan Tobacco), WO 2009/062285(Boehringer Ingelheim), WO 2010/130034(Boehringer Ingelheim), WO2013/006792(Pharma Resources), US 20140221356(Gilead Sciences), US20100143301 (Giledheengineread 2013/091096).

Examples of other drugs for the treatment of HIV include acetylmorphinan (acemannan), alisporivir (alicoporivir), BanLec, deferiprone (deferiprone), gamatin (Gamimune), meterfalin (metenkefalin), naltrexone (naltrexone), pravastatin (prolactin), REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1, 5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig Gene therapy, BlozMazF Gene therapy, BloAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, IND-1105, MK-635, MK-13791, MK-85V-24, MK-8600, MK-1050040-040, SB-24-1050040, MK-040, SB-PA-24, SB-8607, SB-1050040-11, SB-103, and SB-103, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.

Gene therapy and cell therapy

Gene therapy and cell therapy include gene modifications for silencing genes; genetic methods for direct killing of infected cells; an infusion of immune cells designed to replace the majority of the subject's autoimmune system to enhance the immune response to infected cells or to activate the subject's autoimmune system to kill infected cells or to seek out and kill infected cells; genetic methods for modifying cellular activity to further alter the endogenous immune response to infection.

An example of dendritic cell therapy includes AGS-004.

Gene editing agent

Examples of gene editing systems include CRISPR/Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems, and meganuclease systems.

Examples of HIV-targeted CRISPR/Cas9 systems include EBT 101.

CAR-T cell therapy

CAR-T cell therapy includes a population of immune effector cells engineered to express a Chimeric Antigen Receptor (CAR), wherein the CAR comprises an HIV antigen binding domain. The HIV antigen comprises HIV envelope protein or a part thereof, gp120 or a part thereof, a CD4 binding site on gp120, a CD4 induction binding site on gp120, a glycan on gp120, V2 of gp120 and a membrane-proximal region on gp 41. The immune effector cell is a T cell or an NK cell. In some embodiments, the T cell is a CD4+ T cell, a CD8+ T cell, or a combination thereof.

Examples of HIV CAR-T include VC-CAR-T.

TCR-T cell therapy

TCR-T cell therapy includes T cells engineered to target HIV-derived peptides on the surface of virus-infected cells.

One skilled in the art will appreciate that more than one of the above listed classes of other therapeutic agents may be included. The particular classes are not intended to limit the functionality of these compounds listed in these classes.

In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor and an HIV non-nucleoside reverse transcriptase inhibitor. In another specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor and an HIV protease inhibiting compound. In another embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV non-nucleoside reverse transcriptase inhibitor, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV nucleoside reverse transcriptase inhibitor, integrase inhibitor, and pharmacokinetic enhancer. In another embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with two HIV nucleoside or nucleotide reverse transcriptase inhibitors.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents selected from the group consisting of:(efavirenz, tenofovir disoproxil fumarate, and android citabine);(rilpivirine, tenofovir disoproxil fumarate, and altocitabine);(Etegravir, cobicistat, tenofovir disoproxil fumarate and android sitafloxacinA guest);(tenofovir disoproxil fumarate and android sitabine; TDF + FTC);(tenofovir alafenamide and android citabine);(tenofovir alafenamide, azelastine, and rilpivirine);(tenofovir alafenamide, atroxitabine, cobicistat and etifovir);(bi tiavir, atroxitabine, tenofovir alafenamide); adefovir dipivoxil; adefovir dipivoxil; cobicistat; android sitabine; tenofovir disoproxil fumarate; tenofovir disoproxil fumarate; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate;(douglavir, abacavir and lamivudine); douglavir, abacavir sulfate and lamivudine; letergevir; raltegravir and lamivudine; maraviroc; enfuvirdi;(lopinavir and ritonavir);(zidovudine and lamivudine; AZT +3 TC);(abacavir sulfate and lamivudine; ABC +3 TC);(abacavir sulfate, zidovudine and lamivudine; ABC + AZT +3 TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolulavir; (ii) eltamivir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; pravastatin; (ii) a fosamivir; efavirenz, fosavirenz; etravirine; nelfinavir; nelfinavir mesylate; an interferon; (ii) didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; radha-108 (Raspot); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine and tenofovir disoproxil fumarate; fosfungs; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with: abacavir sulfate, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide hemifumarate, or bi-telavavir.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with: tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide hemifumarate, or bi-telavavir.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with: a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir disoproxil fumarate, tenofovir alafenamide hemifumarate, and bi-tegravir; and a second additional therapeutic agent selected from the group consisting of android sitabine and lamivudine.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with: a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide hemifumarate, and bi-telavavir, and a second additional therapeutic agent, wherein the second additional therapeutic agent is altricitabine.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-30mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200mg android citabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200mg altretamine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200mg android citabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200mg android citabine. A compound as disclosed herein (e.g., a compound of formula J) can be combined with an agent provided herein in any amount administered of the compound (e.g., 1mg to 500mg of the compound) as if each dosage combination were specifically and individually enumerated.

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-400mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200mg android citabine. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 200-, 250-, 200-, 300-, 200-, 350-, 250-, 400-, 350-, 300-, 400-, or 250-, 400mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil fumarate and 200mg antaricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 300mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil fumarate and 200mg android citabine. A compound as disclosed herein (e.g., a compound of formula J) can be combined with an agent provided herein in any amount administered of the compound (e.g., 1mg to 500mg of the compound) as if each dosage combination were specifically and individually enumerated.

HBV combination therapy

In certain embodiments, there is provided a method for treating or preventing an HBV infection in a human afflicted with or at risk of developing the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) other therapeutic agents. In one embodiment, there is provided a method for treating an HBV infection in a human afflicted with or at risk of developing the infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) other therapeutic agents.

In certain embodiments, the present invention provides a method for treating HBV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) other therapeutic agent combinations useful for treating HBV infection.

The compounds described herein may be used or combined with one or more of the following: chemotherapeutic agents, immunomodulators, immunotherapeutics, therapeutic antibodies, therapeutic vaccines, bispecific antibodies, and "antibody-like" therapeutic proteins (such as Fab derivatives), antibody-drug conjugates (ADCs), gene modifying or gene editing agents (such as CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases, TALENs), cell therapies (such as CAR-T (chimeric antigen receptor T cells) and TCR-T (engineered T cell receptor) agents), or any combination thereof.

In certain embodiments, the compounds of formula (I) are formulated in tablet form, which may optionally contain one or more other compounds suitable for the treatment of HBV. In certain embodiments, the tablet may contain another active ingredient for treating HBV, such as a 3-dioxygenase (IDO) inhibitor, a lipoprotein A1 modulator, an arginase inhibitor, a B and T lymphocyte attenuation factor inhibitor, Bruton's Tyrosinase (BTK) inhibitor, a CCR2 chemokine antagonist, a CD137 inhibitor, a CD160 inhibitor, a CD305 inhibitor, a CD4 agonist and modulator, a compound targeting HBcAg, a compound targeting hepatitis B core antigen (HBcAg), a core protein allosteric modulator, a covalently closed circular DNA (cccDNA) inhibitor, a cyclophilin inhibitor, a cytotoxic T lymphocyte-associated protein 4(ipi4) inhibitor, a DNA polymerase inhibitor, an endonuclease modulator, an epigenetic modifier, a farnesol X receptor agonist, an HBsAg inhibitor, an HBsAg secretion or assembly inhibitor, HBV DNA polymerase inhibitors, HBV replication inhibitors, HBV RNase inhibitors, HBV viral entry inhibitors, HBx inhibitors, hepatitis B large envelope protein modulators, hepatitis B large envelope protein stimulators, hepatitis B structural protein modulators, hepatitis B surface antigen (HBsAg) inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, hepatitis B virus E antigen inhibitors, hepatitis B viral replication inhibitors, hepatitis virus structural protein inhibitors, HIV-1 reverse transcriptase inhibitors, uricase inhibitors, IAPs inhibitors, IL-2 agonists, IL-7 agonists, immunomodulators, indoleamine-2 inhibitors, ribonucleotide reductase inhibitors, interleukin-2 ligands, ipid 4 inhibitors, demethylase inhibitors, histone demethylase inhibitors, KDM1 inhibitors, KDM5 inhibitors, killer lectin-like receptor subfamily G member 1 inhibitors, lymphocyte activation gene 3 inhibitors, lymphotoxin beta receptor activators, Axl modulators, B7-H3 modulators, B7-H4 modulators, CD160 modulators, CD161 modulators, CD27 modulators, CD47 modulators, CD70 modulators, GITR modulators, HEVEM modulators, ICOS modulators, Mer modulators, NKG2A modulators, NKG2D modulators, OX40 modulators, SIRPa modulators, TIGIT modulators, Tim-4 modulators, Tyro modulators, sodium taurocholate co-transport polypeptide (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulators, nucleoprotein inhibitors, nucleoprotein modulators, PD-1 inhibitors, PD-L1 inhibitors, phosphatidylaminyl isomerase inhibitors, PI 3-3 isomerase inhibitors (PI 3-3K) K inhibitors, Retinoic acid inducible gene 1 agonists, reverse transcriptase inhibitors, ribonuclease inhibitors, RNA DNA polymerase inhibitors, SLC10a1 gene inhibitors, SMAC mimetics, Src tyrosine kinase inhibitors, interferon gene Stimulator (STING) agonists, NOD1 stimulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 modulators, thymosin agonists, thymosin alpha 1 ligands, Tim-3 inhibitors, TLR-3 agonists, TLR-7 agonists, TLR-9 agonists, TLR9 gene stimulators, toll-like receptor (TLR) modulators, viral ribonucleotide reductase inhibitors, and combinations thereof.

HBV combination medicine

For the treatment ofExamples of combinations of HBV include(tenofovir disoproxil fumarate and ambrosibin), ABX-203, lamivudine (lamivudine) and PEG-IFN- α, ABX-203 Adefovir (adefovir) and PEG-IFN α, and INO-1800(INO-9112 and RG 7944).

Other HBV drugs

Examples of other drugs for the treatment of HBV include alpha-hydroxycyclotropolone, amdoxovir (amdoxovir), beta-hydroxycytosine, AL-034, CCC-0975, elvucitabine (elvucitabine), ezetimibe (ezetimibe), cyclosporin A, gentiopicrin (gentiopicrin/gentiopicroside), JNJ-56136379, nitazoxanide (nitazoxanide), Bilinapantane (birinaprant), NJK14047, NOV-205 (molixan), BAM-205, oligonucleotides, milovitate (mivorilate), feferon (feron), HG-131, levamisole (levamisol), casu Nialung (Ka Shunferon), allofloron (IIoferon), Y-101 (Fei), FN-014-3, Nile (Tacro-3, FN-3-L), Helicon RNA (pB-L-Na-PC), Nile (Nile), and their pharmaceutically acceptable salts, such as a, cTP-5(rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna (Hepbarna), IBPB-006IA, and plectren (Hepuyinfen), DasKloster 0014-01, ISA-204, Jianzanai (Jiangantai) (Ganxikang)), MIV-210, OB-AI-004, PF-06, picroside (picroside), DasKloster-0039, and Poland (Hepulantai), IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551, and ZH-2N, and compounds disclosed in US20150210682(Roche), US 2016/0122344(Roche), WO2015173164, WO2016023877, US2015252057A (Roche), WO16128335a1(Roche), WO16120186a1(Roche), US2016237090A (Roche), WO16107833a1(Roche), WO16107832a1(Roche), US2016176899A (Roche), WO16102438a1(Roche), WO16012470a1(Roche), US2016220586A (Roche) and US2015031687A (Roche).

HBV vaccine

HBV vaccines include both prophylactic and therapeutic vaccines. Examples of HBV prophylactic vaccines include Vaxelis, Hexaxim, Heplinav, Mosquirix, DTwP-HBV vaccineBio-Hep-B, D/T/P/HBV/M (LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B preventive vaccine (Advax Super D), Hepatrol-07, GSK-223192A, ENGERIXRecombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine (Hanseng polymorphous yeast (Hansenu polymorpha), intramuscular, Hualan Biological Engineering), recombinant hepatitis B surface antigen vaccine, Bimmugen, Euforvac, Eutravac, anrix-DTaP-IPV-Hep B, HBAI-20, Infanrix-DTaP-IPV-Hep B-Hib, Pentobio Vaksin DTP-HB-Hib, Comvac 4, Comvarix, Euvax-B, Tritanix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV vaccine, DTP-63HBV vaccine, YITai, Hebivacac HB, TrivaHB, Gevap-Hevap B, Comvax, Shavax, HBV vaccine, HBV-Hib-HBr-3683, Henbx-DNA, Henbx-6, Henbx-DNA, Henberg-3, HBV vaccine, and HBV vaccine, rhHBsAG vaccine, HBI pentavalent vaccine, LBVD, Infanrix HeXa and DTaP-rHB-Hib vaccine.

Examples of HBV therapeutic vaccines include HBsAG-HBIG complex, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (PA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B +, MGN-1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP-02, FP-02.2, TG-1050, NU-500, HBVax, im/TriGrid/antigen vaccine, Mega-CD40L adjuvanted vaccine, HepB-v, RG7944(INO-1800), recombinant VLP-based therapeutic vaccine (HBV infection, VLP Biotech), AdTG-17909, AdTG-17910, AdTG-18202, ChronVac-B, TG-1050, and LmHBV.

HBV DNA polymerase inhibitors

Examples of HBV DNA polymerase inhibitors include adefovirAndroid sitabinTenofovir disoproxil fumarateTenofovir alafenamide (tenofovir alafenamide), tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil (tenofovir dipivoxil), tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157, Bessevir (besifovir), Yitiwei (entecavir)Citraconic acid Yitifer, telbivudine (telbivudine)Felodivir (filocilovir), peradfovir (pradefovir), clevudine (clevudine), ribavirin, lamivudineTriazophos (phosphazide), famciclovir (famciclovir), fosolin (fosolin), metavir (metacavir), SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate and HS-10234.

Immunomodulator

Examples of immunomodulators include ritalide, imidyl hydrochloride (imidol hydrochloride), Incolon (ingeron), dammarvir, chloroquine (hydroxychloroquine), propranol, hydroxyurea, mycophenolate Mofetil (MPA) and its ester derivative Mycophenolate Mofetil (MMF), JNJ-440, WF-10, AB-452, ribavirin, IL-12, INO-9112, polymeric Polyethylenimine (PEI), Gepon, VGV-1, MOR-22, CRV-431, JNJ-0535, TG-1050, ABI-H2158, BMS-936559, GS-9688, GS-7011785, RG-7854, AB-506, RO-6871765, AIC-649 and IR-103.

Toll-like receptor (TLR) modulators

TLR modulators include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR 13. Examples of TLR3 modulators include ritalid, poly-ICLC, and,Apoxxim、IPH-33, MCT-465, MCT-475 and ND-1.1.

Examples of TLR7 modulators include compounds disclosed in GS-9620, GSK-2245035, imiquimod, Rasimodet, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, D, Telratimod, SP-0509, TMX-30X, TMX-202, RG-7863, RG-7795, LHC-165, RG-7854, and US20100143301(Gilead Sciences), US20110098248(Gilead Sciences), and US20090047249(Gilead Sciences).

Examples of TLR8 modulators include motomot, Rasimotet, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, GS-9688 and compounds disclosed in: US20140045849(Janssen), US20140073642(Janssen), WO2014/056953(Janssen), WO2014/076221(Janssen), WO2014/128189(Janssen), US20140350031(Janssen), WO2014/023813(Janssen), US20080234251(Array Biopharma), US 3062008020080050 (Array Biopharma), US20100029585(VentirxPharma), US20110092485(Ventirx Pharma), US 0118235(Ventirx Pharma), 201us 20082658 658(Ventirx Pharma), US20120219615(Ventirx Pharma), US20140066432(Ventirx rma), US 000085 (Ventirx Pharma), US Pharma 02767 (US Pharma 51302513025148), US 2015167516729 (US 2014), US 46593929, US2014 patent application nos. 2014 593929 and US patent application nos. 2014.

Examples of TLR9 modulators include BB-001, BB-006, CYT-003, IMO-2055, IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200, atorvastatin (agotolimod), DIMS-9054, DV-1079, DV-1179, AZD-1419, rifflemod (leftolomod) (MGN-1703), ritummod (litenimod), and CYT-003-QbG 10.

Examples of TLR7, TLR8, and TLR9 modulators include the compounds disclosed in: WO2017047769 (TeikaSeyaku), WO2015014815(Janssen), WO2018045150(Gilead Sciences Inc), WO2018045144(Gilead Sciences Inc), WO2015162075(Roche), WO2017034986(University of Kansas), WO2018095426(Jiangsu Hengrui Medicine Co Ltd), WO2016091698(Roche), WO 7575752015661 (GlaxoSmithKline Biologicals), WO 20180743,20189695 (Roche), WO2018089695(Dynavax Technologies), WO2016055553(ROche), WO 1682015279 (Novartis), WO 201620162016536 (wash Discovery), WO2018086593 (Livo), (Shanghai) Pharmacologne, WO 201067120120120120120140278), WO 20120120120120120120120120120120140297 (WO 20120170779), WO 20170059 (WO 20170059), WO 20170059 (WO 20170059), WO 201wo 201700570059), WO 201wo 20170059 (WO 70059), WO 201wo 20170059 (WO 20170059), WO 70059) and WO 201wo 200201wo 201wo 200201wo 201wo 200201wo 20020170469 (WO 20070469) and WO 20070059 (WO 20070059), WO 20070469), WO 201wo 20170059), WO 201wo 200201wo 201wo 20070059 (WO 20020170059) and WO 200201wo 201wo 200201wo 201wo 200201wo 20070469 (WO 20070059) and WO 20070059 (WO 20070059) and WO200, WO2017202704(Roche), WO2018026620(Bristol Myers Squibb), WO2016029077(Janus Biothereutics), WO201803143(Merck), WO2016096778(Roche), WO2017190669(Shanghai De Novo Pharmatech), US09884866(University of Minnesota), WO2017219931(Sichuan Kelun Biotech Biopharmaceutica), WO2018002319(Janssen Sciences), WO2017216054(Roche), WO2017202703(Roche), WO 2018484735 (IFMTherepeutics), WO2017184746(IFM Therapeutics), WO2015088045 (Takedarmaceutica), WO 707038909 (Takeda Pharmaceutica), WO 2015780 (Unissica of Uninasticus).

Interferon alpha receptor ligands

Examples of interferon α receptor ligands include interferon α -2b (INTRON)) Pegylated interferon α -2aPegylated interferon α -1b and interferon α 1bVeldona, infrapure, Roferon-A, YPEG-interferon α -2a (YPEG-rhIFN α -2a), P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co (recombinant super Compound interferon), Ypeg interferon α -2b (YPEG-rhIFN α -2b), MOR-22, peg interferon α -2bBioferon、Novaferon、Inmutag(Inferon)、Interferon α -n1Interferon β -1aShaferon, interferon α -2B (axxo), Alfaferone, interferon α -2B (BioGeneric Pharma), interferon- α (CJ), Laferon, VIPEG, BLAUFERON-A, BLAUFERON-B, Intermax α, Realdiron, Lansion, Pegaferon, PDferon-B PDferon-B, interferon α -2B (IFN, Laboratorias bioprorma), α 3 interferon 2B, Kalferon, Pegnano, Feronsure, Pegihep, interferon α B (Zydus-Cadila), interferon α a, Optipeg A, Realfa 2B, Reliferon, interferon α -2B (Amega), interferon 5967-2B Virchhog interferon 2B (axxo-2B), interferon 2-3-2B, interferon 2-27-35-23-interferon, interferon 23-2B-23-interferon, interferon 2B-2B, interferon-2B-3-interferon 2B, (HSA-3-9-3-Haffron, HSA-B, HSA-B-2B, HSA-2-9-2B, interferon-3-2B, interferon, HSA, interferon-2-3-2B, interferon-3-2, HSA, interferon-2, interferon-9, interferon-9-2B, interferon-9-2, interferon-2BAnderferon, Shanferon, Layferenon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai (Fukangtai), Pegstat, rHSA-IFN α -2b, SFR-9216, and Interapo (Interapa).

Hyaluronic acid enzyme inhibitor

Examples of the hyaluronidase inhibitor include aspermide (astodimer).

Hepatitis B surface antigen (HBsAg) inhibitors

Examples of the HBsAg inhibitor include HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139-Ca, REP-2165, REP-2055, REP-2163, REP-2165, REP-2053, REP-2031 and REP-006 and REP-9 AC'.

Examples of HBsAg secretion inhibitors include BM 601.

Cytotoxic T lymphocyte-associated protein 4(ipi4) inhibitors

Examples of cytotoxic T lymphocyte-associated protein 4(ipi4) inhibitors include AGEN-2041, AGEN-1884, ipilimumab (ipilimumab), belicept (belitacept), PSI-001, PRS-010, Probody mAb, tremelimumab (tremelimumab), and JHL-1155.

Cyclophilin inhibitors

Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175, and the compounds disclosed in US8513184(Gilead Sciences), US20140030221(Gileadsciences), US20130344030(Gilead Sciences), and US20130344029(Gilead Sciences).

HBV virus invasion inhibitor

Examples of HBV viral entry inhibitors include Myrcludex B.

Antisense oligonucleotides targeted to viral mRNA

Examples of antisense oligonucleotides targeting viral mRNA include ISIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, RG-6004.

Short interfering RNA (siRNA) and ddRNAi

Examples of siRNA include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, and ARC-520, ARC-521, ARB-1740, ARB-1467.

An example of DNA directed RNA interference (ddRNAi) includes BB-HB-331.

Endonuclease modulators

Examples of endonuclease modulators include PGN-514.

Ribonucleotide reductase inhibitors

Examples of ribonucleotide reductase inhibitors include Trimidox.

HBV E antigen inhibitors

Examples of HBV E antigen inhibitors include wogonin (wogonin).

Covalently closed circular DNA (cccDNA) inhibitors

Examples of cccDNA inhibitors include BSBI-25 and CHR-101.

Farnesoid X receptor agonists

Examples of farnesoid X receptor agonists are such as EYP-001, GS-9674, EDP-305, MET-409, Tropifexor, AKN-083, RDX-023, BWD-100, LMB-763, INV-3, NTX-023-1, EP-024297 and GS-8670.

HBV antibodies

Examples of HBV antibodies targeting the surface antigen of hepatitis B virus include GC-1102, XTL-17, XTL-19, KN-003, IV Hepabulin SN and fully human monoclonal antibody therapy (hepatitis B virus infection, Humabs BioMed).

Examples of HBV antibodies including monoclonal and polyclonal antibodies include Zutetra, Shangsheng Gan Di, Uman Big (hepatitis B hyperimmunity), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGamB, igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4, HBV infection, Shanghai RAASblood Products) and Fovepta (BT-088).

Fully human monoclonal antibodies include HBC-34.

CCR2 chemokine antagonists

Examples of CCR2 chemokine antagonists include propaggrium (propagermanium).

Thymosin agonists

Examples of thymosin agonists include Thymalfasin (Thymalfasin), recombinant thymosin alpha 1 (GeneScience).

Cytokine

Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24, and cembreukin (celmoleukin).

Nuclear protein modulators

The nucleoprotein modulator may be an HBV core or capsid protein inhibitor. Examples of nucleoprotein modulators include GS-4882, AB-423, AT-130, GLS4, NVR-1221, NVR-3778, AL-3778, BAY 41-4109, moxidectin mesylate (morpholinone mesylate), ARB-168786, ARB-880, JNJ-379, RG-7907, HEC-72702, AB-506, ABI-H0731, JNJ-440, ABI-H2158, and DVR-23.

Examples of capsid inhibitors include the compounds disclosed in: US20140275167(Novira therapeutics), US20130251673(Novira therapeutics), US20140343032(Roche), WO2014037480(Roche), US20130267517(Roche), WO2014131847 (janssesen), WO2014033176 (janssesen), WO2014033170 (janssesen), WO2014033167 (janssesen), WO2015/059212 (janssesen), WO 20152015118057 (janssesen), WO 2015011011281 (janssesen), WO2014184365 (janssesen), WO2014184350 (janssesen), WO 161888 (janssense 20151612015), WO 20196744 (Novira), US 2015535355 (Novira), US 0178337(Novira), US 51515159 (Novira), WO 0193 (Novira 019), WO 20130962015 201201201201201201201201201201201722012012017283 (WO 201201201201722017283), WO 201201201201201201201201722017283 (WO 2012017220172201722017295), WO 201201201201201201201722012012017295 (WO 2017220120172201722017283), WO 201201201201201201201201201201201607295), WO 2012012012012016072714226 (WO 20120120120120120120120160729), WO 20160722012012016072201607295), WO 20120120160722016072201607295 (WO 201201201201201607295), WO 20120160722012012012016072201607295), WO 2012012016072201607290 (WO 201201201201201201201201201201201201201607220160722016072201607283), WO 201607295), WO 201201201201201604235 (WO 201201201201201201201201201201201201201201201201607220120120160722016072201201201201201607283), WO 20160722012012016072201604235 (WO 2012012012012012012012012012012016072201607295), WO 2012012012012012016072201201201607283), WO 2016060606060489 (WO 201607295), WO 201201201201606060606072201607220160606060606060606072201607295), WO 201201, US20170121328(Novira), US20170121329 (Novira).

Examples of transcription inhibitors include the compounds disclosed in: WO2017013046(Roche), WO2017016960(Roche), WO2017017042(Roche), WO2017017043(Roche), WO2017061466(Toyoma chemicals), WO2016177655(Roche), WO2016161268(Enanta), WO2017001853(Redex Pharma), WO2017211791(Roche), WO2017216685(Novartis), WO2017216686(Novartis), WO2018019297(Ginkgo Pharma), WO2018022282(Newave Pharma), US20180030053(Novartis), WO2018045911(zhejian Pharma).

Retinoic acid inducible gene 1 stimulators

Examples of retinoic acid inducible gene 1 stimulators include SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198 and ORI-7170, RGT-100.

NOD2 stimulant

Examples of NOD2 stimulants include SB-9200.

Phosphatidylinositol 3-kinase (PI3K) inhibitors

Examples of PI3K inhibitors include idenexib (idelalisib), ACP-319, AZD-8186, AZD-8835, bupariib (buparlisib), CDZ-173, CLR-457, picrolib (pictilisb), neratinib (neratinib), regoraib (rigosertib), regoraib sodium, EN-3342, TGR-1202, epenib (alpelisib), duvexib (duvelisib), IPI-549, UCB-5857, taselib (taselisib), XL-765, gedatulisib (gedatolisib), ME-401, VS-sys 84, bapalissib (copulisib), CAI, perlifatinine (perifosine), RG-7666, GSK-2636771, Pipalexib-7423, VS-5583, PQbalsamib-64309, PQValencib-3683, PQValencib-64309, PQWIB-3655, Pykurlicib, PyK-3655, Pykob, Pykolide (Pykob-3655, Pykob-1082439, Pykob-b-3655, Pykob, Py, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, Sonoxib (sonolisib), LY-3023414, SAR-260301, TAK-117, HMPL-689, Tennessib (tenalisib), Wotaxib (voxtalisib) and CLR-1401. Indoleamine-2, 3-dioxygenase (IDO) pathway inhibitors

Examples of IDO inhibitors include ipastat (INCB24360), dominostat (4SC-201), indomethadone (indoximod), F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028, GBV-1012, NKTR-218, and US20100015178(Incyte), US2016137652(Flexus Biosciences, Inc 2014.), WO 073738(Flexus Biosciences, Inc.), and WO2015188085(Flexus Biosciences, Inc.).

PD-1 inhibitors

Examples of PD-1 inhibitors include gemipizumab (cemipilimumab), nivolumab (nivolumab), pericentrab (pembrolizumab), pidilizumab (pidilizumab), BGB-108, STI-A1014, SHR-1210, PDR-001, PF-06801591, IBI-308, GB-226, STI-1110, JNJ-63723283, CA-170, Dewar mab (durvalumab), alezumab (atezolizumab) and mDX-400, JS-001, Canlizumab (Camrelizumab), Spriluzumab (Sintillimumab), Stilumab, Stilzumab (tillizumab), BCD-100, BGB-A333, JNJ-63723283, GLS-010 (WBP-1485), PD-305072, AGEN-784, GNS-780 (GNELlizumab), BCD-100, TGF-P-A333, TGF-203J-63723283, TGF-010 (TGF-P-1485), TGF-305072, AGEN-780, TGF-receptor antagonist (GNS-2, TGF-beta-fusion protein, and TGF-2, Jennuzumab (Genolimzumab), BMS-936559.

PD-L1 inhibitors

Examples of PD-L1 inhibitors include astuzumab, avizumab (avelumab), AMP-224, MEDI-0680, RG-7446, GX-P2, Devolumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, GS-4224, CX-072, and BMS-936559.

Examples of PD-1 inhibitors include the compounds disclosed in: WO2017112730(Incyte Corp), WO2017087777(Incyte Corp), WO2017017624, WO2014151634(Bristol Myers Squibb Co), WO201317322(Bristol Myers Squibb Co), WO2018119286(Incyte Corp), WO2018119266(Incyte Corp), WO2018119263(Incyte Corp), WO2018119236(Incyte Corp), WO2018119221(Incyte Corp), WO 201811888118848 (Bristol Myers Squibb Co), WO20161266460(Bristol Myers Squibb Co), WO2017087678(Bristol Myers Squibb Co 2015), WO 20120162015 2015, WO 149351(Bristol My Squibb Co), WO 201033 WO 20196200201033, WO 201nyls Hetero Squib Hetero WO 201672015 Squib WO 2012002012002012002016731, WO 201nylch Tokyi Squib WO 20120020120020120020167201, WO 201nylch Heterophyll WO 20120020120020120020 (Oscil Heterophyll Tokyi, WO2018073754 (Austogen Discoverytechnologies Ltd), WO2016077518(Bristol Myers Squibb Co), WO2016057624(Bristol Myers Squibb Co), WO2018044783(Incyte Corp), WO2016100608(Bristol Myers Squibb Co), WO2016100285(Bristol Myers Squibb Co), WO 20160397649 (Bristol Myers Squibb Co), WO 2015019019019019019019 (Cambridge Enterprise Ltd), WO 142894 (Austogen Discoverytechnologies Ltds Totd), WO 1342015605 (Australir Squibb Co 20152012015), WO 201805120151201512015 (Austogen DiscoyZones) WO 20120120120120120120120120120144284), WO 201technyL tdemter WO 2012012012012012012012012012012012012012012012012012017120197254 (Australine DiscoyZone WO 20120120120120120120120120120120120120120120120120120120120120120120120120120120120120120120120171201201201201201201201201201201712012012012017120120120120120120120120120199), WO 201201201201201201201201201201201201201201201201201201201712012012012012012012012012012012017120199 (Australine WO 2012012012012012012012012012012012012012012012012012012012012012012012012012012012012012012012012012012017120120120120120171201712012012012012017120120120120120199).

Recombinant thymosin alpha-1

Examples of recombinant thymosin alpha 1 include NL-004 and pegylated thymosin alpha 1.

Inhibitors of Bruton's Tyrosine Kinase (BTK)

Examples of BTK inhibitors include ABBV-105, acampritinib (ACP-196), ARQ-531, BMS-986142, dasatinib (dasatinib), ibrutinib (ibrutinib), GDC-0853, PRN-1008, SNS-062, ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058, RG-7845, sbertinib (spibrutinib), TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7536, M-2951, TAK-020, AC-0025, and 20140330010015 (Ono Pharmaceutical), US20130079327(Ono Pharmaceutical), and US 30217880(Ono Pharmaceutical).

KDM inhibitors

Examples of KDM5 inhibitors include the compounds disclosed in: WO2016057924(Genentech/Constellation Pharmaceuticals), US20140275092(Genentech/Constellation Pharmaceuticals), US20140371195(Epitherapeutics) and US20140371214(Epitherapeutics), US20160102096(Epitherapeutics), US20140194469(Quanticel), US20140171432, US 20143502191 (Quanticel), US20160039808(Quanticel), US20140275084(Quanticel), WO2014164708 (Quanticel).

Examples of KDM1 inhibitors include the compounds disclosed in US9186337B2(Oryzon Genomics), GSK-2879552 and RG-6016.

STING agonists

Examples of STING agonists include SB-11285, AdVCA0848, STING vax and the compounds disclosed in: WO 2018065360(Biolog Life Science Institute Forschungslabor und Biochemica-Vertrieb GmbH, Germany), WO 2018009466(Aduro Biotech), WO 2017186711(InvivoGen), WO 2017161349(Immune Sensor), WO 2017106740(Aduro Biotech), US 20170158724(Glaxo Smithkiline), WO 2017075477(Aduro Biotech), US 20170044206(Merck), WO 179760(University of California), WO2018098203(Janssn), WO2018118665(Merck), WO2018118664(Merck), WO2018100558(Takeda), WO2018067423(Merck), WO2018060323 (Boehringer).

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Examples of NNRTIs include the compounds disclosed in: WO2018118826(Merck), WO2018080903(Merck), WO2018119013(Merck), WO2017100108(Idenix), WO2017027434(Merck), WO2017007701(Merck), WO2008005555 (Gilead).

Inhibitors of HBV replication

Examples of inhibitors of hepatitis B virus replication include isothiafludine (isothiafludine), IQP-HBV, RM-5038, and Xilinganie.

Spermidase inhibitors

Examples of spermidase inhibitors include CB-1158, C-201 and lenomastat.

Gene therapy and cell therapy

Gene therapy and cell therapy include gene modifications for silencing genes; genetic methods for direct killing of infected cells; an infusion of immune cells designed to replace the majority of the patient's autoimmune system to enhance the immune response to infected cells or to activate the patient's autoimmune system to kill infected cells or to seek out and kill infected cells; genetic methods for modifying cellular activity to further alter the endogenous immune response to infection.

Gene editing agent

Examples of genome editing systems include CRISPR/Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems, and meganuclease systems; such as cccDNA elimination via targeted cleavage, and altering one or more of the Hepatitis B Virus (HBV) viral genes. Altering (e.g., gene knockout and/or blocking of gene expression) the PreC, C, X, PreSI, PreS2, S, P, or SP gene refers to (1) reducing or eliminating the expression of the PreC, C, X, PreSI, PreS2, S, P, or SP gene, (2) interfering with the Precore (Precore), Core protein (Core), X protein, long surface protein, middle surface protein, S protein (also known as HBs antigen and HBsAg), polymerase protein, and/or hepatitis B splice protein function (HBe, HBc, HBx, PreS1, PreS2, S, Pol, and/or HBSP), or (3) reducing or eliminating the intracellular, serum, and/or brain parenchymal content of HBe, HBc, HBx, LHBs, MHBs, SHBs, Pol, and/or HBSP protein. Gene expression blocking of one or more of the PreC, C, X, PreSI, PreS2, S, P, and/or SP genes is performed by targeting genes within HBV cccDNA and/or integrated HBV DNA.

CAR-T cell therapy

CAR T cell therapy includes a population of immune effector cells engineered to express a Chimeric Antigen Receptor (CAR), wherein the CAR comprises an HBV antigen binding domain. The immune effector cell is a T cell or an NK cell. In some embodiments, the T cell is a CD4+ T cell, a CD8+ T cell, or a combination thereof. The cells may be autologous or allogeneic.

TCR-T cell therapy

TCR T cell therapy includes T cells expressing HBV-specific T cell receptors. TCR-T cells are engineered to target HBV-derived peptides on the surface of virus-infected cells. In some embodiments, the T cells express HBV surface antigen (HBsAg) -specific TCR. Examples of TCR-T therapies for the treatment of HBV include LTCR-H2-1.

In another particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is in combination with: HBV DNA polymerase inhibitors; one or two additional therapeutic agents selected from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies (including HBV antibodies and bispecific antibodies targeting the surface antigen of hepatitis B virus), and "antibody-like" therapeutic proteins (such as Fab derivatives or TCR-like antibodies), cyclophilin inhibitors, retinoic acid inducible gene 1 stimulators, RIG-I like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, and NOD2 stimulators; and one or two additional therapeutic agents selected from the group consisting of: HBV virus invasion inhibitor, NTCP inhibitor, HBx inhibitor, cccDNA inhibitor, HBV antibody targeting surface antigen of hepatitis B virus, siRNA, miRNA gene therapy agent, sshRNA, KDM5 inhibitor, and nucleoprotein modulator (HBV core or capsid)Protein modulators).

In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least one second additional therapeutic agent selected from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies (including HBV antibodies and bispecific antibodies targeting the surface antigen of hepatitis B virus), and "antibody-like" therapeutic proteins (such asFab derivatives or TCR-like antibodies), cyclophilin inhibitors, retinoic acid inducible gene 1 stimulators, RIG-I like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, and NOD2 stimulators.

In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor and at least one second additional therapeutic agent selected from the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting the surface antigen of hepatitis B virus, siRNA, miRNA gene therapeutics, sshRNA, KDM5 inhibitors, and nucleoprotein modulators (HBV core or capsid protein inhibitors).

In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with: compounds such as US 2010/0143301 (Gilead Sciences), US 2011/0098248 (Gilead Sciences), US 2009/0047249 (Gilead Sciences), US 8722054 (Gilead Sciences), US 2014/0045849 (Janssen), US 2014/0073642 (Janssen), WO2014/056953(Janssen), WO2014/076221(Janssen), WO2014/128189(Janssen), US 2014/0350031 (Janssen), WO2014/023813(Janssen), US 2008/0234251 (Aray Biopharma), US 2008/0306050 (Aray Pharma), US 2010/0029585 (Ventirx), US 2011/0092485 (US irxPxpP), US Phantx 0118235 (Ventx 0118235), US 2011irx 2012/0082658 (America), US 2011irx 596 (Janssen), U.S. publication No. 2014/0066432 (Ventirx Pharma), U.S. publication No. 2014/0088085 (Ventirx Pharma), U.S. publication No. 2014/0275167 (Novira Therapeutics), U.S. publication No. 2013/0251673 (Novira Therapeutics), U.S. patent No. 8513184(Gilead Sciences), U.S. publication No. 2014/0030221 (Gilead Sciences), U.S. publication No. 2013/0344030 (Gilead Sciences), U.S. publication No. 2013/0344029 (Gilead Sciences), US 20145102767 (Novira Therapeutics), US20130251673(Novira Therapeutics), U.S. publication No. 2014/0343032 (Roche), WO 20140320152015201520152015201580 (Roche 201520152015201520152015201520152015), U.S. publication No. 2013/0267517 (Roche), WO 847 (jansenson), WO 2014176 (Janssen 2014), WO 019170 (jansx Pharma), WO2014 019 2015 032015 2015, 2014 2015, 2014 967 (2014 967 (2014 46967), WO 2014) and 2014033 2014 967 (2014) 4 (2014, US20150259324, (Novira), US20150132258(Novira), US9181288(Novira), WO2014184350(Janssen), WO2013144129(Roche), US20100015178(Incyte), US2016137652(Flexus Biosciences, Inc.), WO2014073738(Flexus Biosciences, Inc.), WO2015188085(Flexus Biosciences, Inc.), US publication 2014/0330015 (Ono Pharmaceutical), US publication 2013/0079327 (OnoPharmaceutical), US publication 2013/0217880 (Ono Pharmaceutical), WO 57924 (genente/conjugation Pharmaceutical), US 02792 (Genentech/conjugation Pharmaceutical 20160710320160195), US 0275076 (Genentech/20160710371195), US 0275076 (american quaternatant 71032014), US 201471032014 (03505076), US 20146 (american quaternatant 712014), HBV 2014 032014 7108), and other drugs for treatment (quant).

Combination cancer therapy

In one embodiment, the compounds of the present invention may be used with other therapeutic methods for the treatment of cancer. Preferably, combination therapies with chemotherapeutic agents, hormones, antibodies, surgery and/or radiation therapy are contemplated.

In some embodiments, the other anti-cancer therapy is surgery and/or radiation therapy.

In some embodiments, the additional anti-cancer therapy is at least one additional cancer agent.

In some embodiments, a combination is provided comprising a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc), or a pharmaceutically acceptable salt thereof, and at least one other cancer agent.

In some embodiments, there is provided a combination comprising the use of a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc), or a pharmaceutically acceptable salt thereof, and at least one other cancer agent, for use in therapy.

In some embodiments, there is provided a use of a combination comprising a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc), or a pharmaceutically acceptable salt thereof, and at least one cancer agent for the manufacture of a medicament for treating cancer.

Examples of other cancer agents include intercalating agents such as anthracyclines (anthracyclines), doxorubicin (doxorubicin), idarubicin (idarubicin), epirubicin (epirubicin), and daunorubicin (daunorubicin); topoisomerase inhibitors such as irinotecan (irinotecan), topotecan (topotecan), camptothecin (camptothecin), lamellarin d (lamellarin d), etoposide (etoposide), teniposide (teniposide), mitoxantrone (mitoxantrone), amsacrine (amsacrine), ellipticine (elliticines) and aurintricarboxylic acid (aurintricarboxylic acid); nitrosourea compounds such as carmustine (carmustine) (BCNU), lomustine (lomustine) (CCNU) and streptozotocin (streptozocin); nitrogen mustards such as cyclophosphamide, mechlorethamine, uramustine, bendamustine, melphalan, chlorambucil, macphosphoramide, trofosfamide, and ifosfamide; alkyl sulfonates such as busulfan and troosufan; alkylating agents, such as procarbazine (procarbazin), dacarbazine (dacrbazin), temozolomide (temozolomid) and thiotepa (thiotepa); platinum analogs such as cisplatin (cissplatin), carboplatin (carboplatin), nedaplatin (nedaplatin), oxaliplatin (oxaliplatin), satraplatin (satraplatin) and triplatin tetranitrate (triplatin tetranitrate); microtubule-disrupting drugs such as vinblastine (vinblastine), colchicide (colcemid), and nocodazole (nocodazole); antifolates such as methotrexate, aminopterin, dichloromethotrexate, pemetrexed, raltitrexed and pralatrexate: purine analogs such as azathioprine (azathioprine), mercaptopurine (mercaptoprine), thioguanine (thioguanine), fludarabine (fludarabine), fludarabine phosphate, pentostatin (pentostatin), and cladribine (cladribine); pyrimidine analogs such as 5-fluorouracil (5-fluorouricil), floxuridine (floxuridine), cytarabine (cytarabine), 6-azauracil, gemcitabine (gemcitabine); steroids such as gemetazine (getagene), andersyn (andragene), glucocorticoids (glucocorticoids), dexamethasone (dexamethasone), prednisolone (prednisone), and prednisone (prednisone); anti-cancer antibodies such as monoclonal antibodies, e.g., alemtuzumab (alemtuzumab), aprezumab (apilizumab), cetuximab (cetuximab), epratuzumab (epratuzumab), galiximab (galiximab), gemtuzumab (gemtuzumab), ipilimumab (ipilimumab), labuzumab (labetuzumab), panitumumab (panitumumab), rituximab (rituximab), trastuzumab (trastuzumab), nimotuzumab (nimotuzumab), mapatuzumab (mapatuzumab), matuzumab (matuzumab), rhMab ICR62 and pertuzumab (pertuzumab), radiolabeled antibodies and antibody-conjugates; anti-cancer peptides, such as radiolabeled peptides and peptide-drug conjugates; and taxanes (taxanes) and taxane analogs such as paclitaxel (paclitaxel) and docetaxel (docetaxel).

In certain embodiments, there is provided a method for treating or preventing a hyperproliferative disorder or cancer in a human or animal suffering from, or at risk of suffering from, the hyperproliferative disorder or cancer, comprising administering to the human or animal a therapeutically effective amount of a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc), as disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two or one to three) other therapeutic agents. In one embodiment, there is provided a method for treating a hyperproliferative disorder or cancer in a human or animal suffering from, or at risk of suffering from, the hyperproliferative disorder or cancer, comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two or one to three) other therapeutic agents.

In certain embodiments, the present invention provides a method for treating a hyperproliferative disorder or cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more other therapeutic combinations useful for treating a hyperproliferative disorder or cancer.

The compounds described herein may be used or combined with one or more of the following: chemotherapeutic agents, anti-cancer agents, anti-angiogenic agents, anti-fibrotic agents, immunotherapeutic agents, therapeutic antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins (such as Fab derivatives), antibody-drug bindingAn Agent (ADC), a radiotherapeutic agent, an antineoplastic agent, an antiproliferative agent, an oncolytic virus, a gene modification or editing agent (such as CRISPR/Cas9, zinc finger nucleases or synthetic nucleases, TALENs), a CAR (chimeric antigen receptor) T cell immunotherapeutic, an engineered T cell receptor (TCR-T), or any combination thereof. These therapeutic agents may be in the form of compounds, antibodies, polypeptides, or polynucleotides. In one embodiment, the invention provides a product comprising a compound described herein and other therapeutic agents in a combined preparation for simultaneous, separate or sequential use in therapy.

The one or more therapeutic agents include, but are not limited to, inhibitors, agonists, antagonists, ligands, modulators, stimulators, blockers, activators or inhibitors of genes, ligands, receptors, proteins or factors. Non-limiting examples of other therapeutic agents include: the Abelson (Abelson) murine leukemia virus oncogene homolog 1 gene (ABL, such as ABL1), acetyl-CoA carboxylase (such as ACC1/2), activated CDC kinase (ACK, such as ACK1), adenosine deaminase, adenosine receptors (such as A2B, A2a, A3), adenylate cyclase, ADP ribosyl cyclase-1, adrenocorticotropic hormone receptor (ACTH), Aerolysin (Aerolysin), AKT1 gene, Alk-5 protein kinase, alkaline phosphatase, alpha 1 adrenergic receptor, alpha 2 adrenergic receptor, alpha-ketoglutarate dehydrogenase (KGDH), aminopeptidase N, AMP activated protein kinase, thymopoietic lymphoma kinase (Alk, such as Alk1), angiogenin (androgen receptors such as ligand-1, ligand-2), Angiotensinogen (AGT) gene, murine tumor virus oncogene homolog 1(AKT), Protein kinases (such as AKT1, AKT2, AKT3), apolipoprotein a-I (APOA1) gene, apoptosis-inducing factor, apoptotic proteins (such as 1, 2), apoptosis signal-regulating kinase (ASK, such as ASK1), arginase (I), arginase deiminase, aromatase, astroglobulin 1(ASTE1) gene, ataxia telangiectasia and Rad 3-Associated (ATR) serine/threonine protein kinase, aurora protein kinase (such as 1, 2), Axl tyrosine kinase receptor, baculovirus IAP repeat containing gene No. 5 (BIRC5), basic immunoglobulin (Basigin), B-cell lymphoma 2(BCL2) gene, BCL2 binding component 3, BCL2 protein, BCL2L11 gene, BCR (breakpoint region) protein and gene, beta-adrenalin receptor, beta-catenin, B-lymphocyte antigen CD19, B-lymphocyte antigen 20, CD20, B-lymphocyte cell adhesion molecules, B-lymphocyte stimulator ligands, bone morphogenic protein-10 ligands, bone morphogenic protein-9 ligand modulators, brachyury proteins, bradykinin receptors, B-Raf protooncogene (BRAF), Brc-Abl tyrosine kinase, bromodomains and the outer domain (BET), bromodomain-containing proteins (such as BRD2, BRD3, BRD4), Bruton's Tyrosine Kinase (BTK), calmodulin-dependent protein kinase (CaMK, such as CAMKII), cancer testis antigen 2, cancer testis antigen NY-ESO-1, cancer/testis antigen 1B (CTAG1) gene, cannabinoid receptors (such as CB 1, CB2), carbonic anhydrase, casein kinase (CK, such as CKI, CKII), caspases (such as Caspase-3), Caspase-7, caspase-9), caspase 8 apoptosis-related cysteaminopeptidase CASP 8-FADD-like modulators, caspase-recruiting domain protein-15, cathepsin G, CCR5 gene, CDK-activated kinase (CAK), checkpoint kinases (such as CHK1, CHK2), chemokine (C-C major structure) receptors (such as CCR2, CCR4, CCR5), chemokine (C-X-C major structure) receptors (such as CXCR4, CXCR1, and CXCR2), chemokine CC21 ligand, cholecystokinin CCK2 receptor, chorionic gonadotropin, C-Kit (tyrosine-protein kinase set or CD117), tight junction proteins (such as 6, 18), differentiation Clusters (CD), such as CD4, CD 465, CD29, CD30, CD33, CD37, CD40, CD40 ligand, CD2 ligand, CD 56 gene, CD 8640 gene, CD 86 44, CD 868446 gene, CD45 ligand, CD 21 ligand, cholecystokinin CCK2 receptor, CCK, and CD2, CD47, CD49b, CD51, CD52, CD55, CD58, CD66e, CD70 gene, CD74, CD79, CD79b, CD79B gene, CD80, CD95, CD99, CD117, CD122, CDw123, CD134, CDw137, CD158a, CD158b1, CD158b2, CD223, CD276 antigen; clusterin (CLU) gene, clusterin, C-Met (hepatocyte growth factor receptor (HGFR)), complement C3, connective tissue growth factor, COP9 signalsome subunit 5, CSF-1 (colony stimulating factor 1 receptor), CSF2 gene, CTLA-4 (cytotoxic T-lymphocyte protein 4) receptor, cyclin D1, cyclin G1, cyclin-dependent kinase (CDK, such as CDK1, CDK1B, CDK2-9), cyclooxygenase (such as 1, 2), CYP2B1 gene, porcine cysteine palmitoyl transferase, cytochrome P45011B 2, cytochrome P45017A1, cytochrome P4502D 6, cytochrome P4503A 4, cytochrome P450 reductase, cytokine signal transduction-1, cytokine signal transduction-3, cytoplasmic isocitrate dehydrogenase, cytosine deaminase, cytosine DNA methyltransferase, Cytotoxic T lymphocyte globulin-4, DDR2 gene, like protein ligands (such as 3, 4), deoxyribonuclease, Dickkopf-1 ligand, dihydrofolate reductase (DHFR), dihydropyrimidine dehydrogenase, dipeptidyl peptidase IV, discoid domain receptors (DDR, such as DDR1), DNA binding proteins (such as HU-beta), DNA dependent protein kinase, DNA gyrase, DNA methyltransferase, DNA polymerase (such as alpha), DNA primase, dUTP pyrophosphatase, L-dopachrome tautomerase, echinoderm tubulin 4, EGFR tyrosine kinase receptor, elastase, elongation factor 1 alpha 2, elongation factor 2, endoglin, endonucleases, reticulin, endosialin, endostatin, endothelin (such as ET-A, ET-B), enhancer of zeste homolog 2 (EZH2), Ephrin (EpH) tyrosine kinases (such as Epha3, Ephb4), Ephrin B2 ligand, Epidermal Growth Factor Receptor (EGFR) gene, epigenetic factor (Epigen), epithelial cell adhesion molecule (EpCAM), Erb-2 (v-Erb-B2 avian erythrocytic leukemia virus oncogene homolog 2) tyrosine kinase receptor, Erb-B3 tyrosine kinase receptor, Erb-B4 tyrosine kinase receptor, E-selectin, estradiol 17 β dehydrogenase, estrogen receptor (such as α, β), estrogen-related receptor, eukaryotic initiation factor 5A (F5A) gene, Exportin 1(Exportin1), extracellular signal-related kinases (such as 1, 2), extracellular signal-regulating kinases (ERK), factors (such as Xa, VIIa), Farnesol X Receptor (FXR) (. X) FX, Fas ligand, Fatty Acid Synthase (FASN), ferritin, FGF-2 ligand, FGF-5 ligand, fibroblast growth factor (FGF, such as FGF1, FGF2, FGF4), fibronectin, Fms-related tyrosine kinase 3(Flt3), focal adhesion kinase (FAK, such as FAK2), folate hydroxylase prostate specific membrane antigen 1(FOLH1), folate receptor (such as alpha), folate transporter 1, FYN tyrosine kinase, paired basic amino acid lyase (FURIN), beta-glucuronidase, galactosyltransferase, galectin-3, ganglioside GD2, glucocorticoid-induced TNFR-related protein GITR receptor, glutamic acid carboxypeptidase II, glutaminase, glutathione S-transferase P, hepatic glucose synthase kinase (GSK, such as 3-beta), Glypican 3(GPC3), gonadotropin releasing hormone (GNRH), granulocyte macrophage colony stimulating factor (GM-CSF) receptor, Granulocyte Colony Stimulating Factor (GCSF) ligand, growth factor receptor binding protein 2(GRB2), Grp78(78kDa glucose regulating protein) calcium binding protein, molecular associated protein groEL2 gene, heat shock proteins (such as 27, 70, 90 alpha, beta), heat shock protein gene, heat stable enterotoxin receptor, hedgehog protein, heparinase, hepatocyte growth factor, HERV-HLTR-related protein 2, hexokinase, histamine H2 receptor, histone methyltransferase (DOT1L), histone deacetylase (HDAC's) such as 1,2,3, 6, 10, 11, histone H1, histone H3, HLA class I antigen (A-2 alpha), HLA class II antigen (HLA A-2 alpha), HLA class II antigen, HLA, Homeobox proteins NANOG, HSPB1 gene, Human Leukocyte Antigen (HLA), human papilloma virus (such as E6, E7) protein, hyaluronic acid, hyaluronidase, hypoxia inducible factor-1 alpha (HIF1 alpha), imprinted maternal expression transcript (H19) gene, mitogen-activated protein kinase 1(MAP4K1), tyrosine kinase HCK, I-kappa-B kinase (IKK, such as IKKbe), IL-1 alpha, IL-1 beta, IL-12 gene, IL-15, IL-17, IL-2 gene, IL-2 receptor alpha subunit, IL-2, IL-3 receptor, IL-4, IL-6, IL-7, IL-8, immunoglobulin (such as G, G1, G2, K, M), immunoglobulin Fc receptor, immunoglobulin gamma Fc receptor (such as I, gamma Fc receptor, G6, E7), III, IIIA), indoleamine 2, 3-dioxygenase (IDO, such as IDO1), indoleamine pyrrole 2, 3-dioxygenase 1 inhibitors, insulin receptors, insulin-like growth factors (such as 1, 2), integrin alpha-4/beta-1, integrin alpha-4/beta-7, integrin alpha-5/beta-1, integrin alpha-V/beta-3, integrin alpha-V/beta-5, integrin alpha-V/beta-6, intercellular adhesion molecule 1(ICAM-1), interferons (such as alpha, alpha 2, beta, gamma), interferon inducible protein not present in melanoma 2 (AIM2), type I interferon receptor, interleukin 1 ligand, interleukin 13 receptor alpha 2, interleukin 2 ligand, IL-1 receptor-associated kinase 4(IRAK4), IL-2, IL-29 ligand, isocitrate dehydrogenase (such as IDH1, IDH2), Janus kinase (Janus kinase; JAK, such as JAK1, JAK2), Jun N-terminal kinase, kallikrein-associated peptidase 3(KLK3) gene, killer cell Ig-like receptor, kinase insert domain receptor (KDR), kinesin-like protein KIF11, Kirsten rat sarcoma virus oncogene homolog (KRAS) gene, Kisspeptin (Kisspeptin) (KiSS-1) receptor, KIT gene, v-KIT Hardy-Zuckerman 4 feline sarcoma virus oncogene homolog (KIT), tyrosine kinase, lactoferrin, lanosterol-14 demethylase, LDL receptor-associated protein-1, leukotriene A lytic 4, Listeria hydroxylase (Listeriolysin), L-selective cytokine receptor, luteinizing receptor, Resolvase, lymphocyte activation gene 3 protein (LAG-3), lymphocyte antigen 75, lymphocyte functional antigen-3 receptor, lymphocyte specific protein tyrosine kinase (LCK), lymphocyte chemotactic factor, Lyn (novel Lck/Yes) tyrosine kinase, lysine demethylase (such as KDM1, KDM2, KDM4, KDM5, KDM6, A/B/C/D), lysophosphatidic acid-1 receptor, lysosome-associated membrane protein family (LAMP) gene, aminoacylase homolog 2, aminoacylase protein (LOX), aminoacylase-like protein (LOXL, such as LOXL2), hematopoietic progenitor kinase 1(HPK1), hepatocyte growth factor receptor (MET) gene, macrophage stimulating factor (MCSF) ligand, macrophage migration inhibitory factor, MAGEC1 gene, MAGEC2 gene, macrophage migration inhibitory factor, macrophage activating gene, Lymphocyte Activating Gene (LAG) 3, lymphocyte chemotactic factor, and lymphocyte activating gene, Large nuclear apical proteins, MAPK-activated protein kinases (such as MK2), Mas-associated G protein-coupled receptors, matrix metalloproteinases (MMPs, such as MMP2, MMP9), Mcl-1 differentiation proteins, Mdm2 p53 binding proteins, Mdm4 proteins, Melan-a (MART-1) melanoma antigen, melanocyte protein Pmel 17, melanocyte stimulating hormone ligands, melanoma antigen family a3(MAGEA3) genes, melanoma-associated antigens (such as 1,2,3, 6), membrane cuprammino oxidase, mesothelin, MET tyrosine kinase, metabolic glutamic acid receptor 1, metal reductase STEAP1 (prostate six transmembrane epithelial antigen 1), metastatins, methionine aminopeptidase-2, methyltransferases, mitochondrial 3 ketoacyl CoA thiolases, mitogen-activated protein kinases (MAPK), mitogen-activated protein kinases (MEK), such as MEK1, MEK2), mTOR (a mechanistic target of rapamycin/threonine kinase), mTOR complexes (such as 1, 2), mucins (such as 1, 5A, 16), mut T homologs (MTH, such as MTH1), Myc proto-oncogene proteins, myeloid cell leukemia 1(MCL1) genes, myristoylated alanine-rich protein kinase C receptor (MARCKS) protein, NAD ADP ribosyltransferase, natriuretic peptide receptor C, neuroblastic adhesion molecule 1, neurokinin 1(NK1) receptor, neurokinin receptor, neuromedin 2, NF-. kappa.B activating protein, NIMA-related kinase 9(NEK9), nitric oxide synthase, NK cell receptor, NK3 receptor, NKG2A B activating NK receptor, norepinephrine transporter, ch (such as Notch-2 receptor, Notch-3 receptor, Notch-4 receptor), Nuclear erythrocyte 2-associated factor 2, Nuclear Factor (NF) κ B, nucleolin phosphate-polymorphic lymphoma kinase (NPM-ALK), 2-oxoglutarate dehydrogenase, 2, 5-oligoadenylate synthetase, O-methylguanine DNA methyltransferase, opioid receptors (such as, ornithine decarboxylase, orotate phosphoribosyltransferase, orphan nuclear hormone receptor NR4A1, osteocalcin, osteoclast differentiation factor, osteopontin, OX-40 (tumor necrosis factor receptor superfamily member 4; TNFRSF4, or CD134) receptor, P3 protein, P38 kinase, P38 MAP kinase, P53 tumor suppressor protein, parathyroid hormone ligand, peroxisome proliferator-activated receptors (PPAR, such as α, γ), P-glycoprotein (such as 1), Phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), phosphoinositide-3 kinase (PI3K, such as α, γ), Phosphorylase Kinase (PK), PKN3 gene, placental growth factor, platelet-derived growth factor (PDGF, such as α, β), pleiotropic drug resistant transporter, Plexin B1, PLK1 gene, Polo-like kinase (PLK), Polo-like kinase 1, poly ADP ribose polymerase (PARP, such as PARP1, 2 and 3), antigen preferentially expressed in melanoma (PRAME) gene, pentenyl binding protein (PrPB), probable transcription factor PML, progesterone receptor, programmed cell death 1(PD-1), programmed cell death ligand 1 inhibitor (PD-L1), sphingolipid activator pro-P (PSAP) gene, phosphoinositide (PSAP) gene, and the like, Prostaglandin receptor (EP4), prostate specific antigen, prostatic acid phosphatase, proteasome, protein E7, protein farnesyl transferase, protein kinase (PK, such as A, B, C), protein tyrosine kinase, protein tyrosine phosphatase beta, proto-oncogene serine/threonine-protein kinase (PIM, such as PIM-1, PIM-2, PIM-3), P-selectin, purine nucleoside phosphorylase, purine receptor P2X ligand-gated ion channel 7(P2X7), Pyruvate Dehydrogenase (PDH), pyruvate dehydrogenase kinase, pyruvate kinase (PYK), 5-alpha-reductase, Raf protein kinase (such as 1, B), RAF1 gene, Ras gtpase, RET gene, RET tyrosine kinase receptor, retinoblastoma-related protein, retinoic acid receptor (such as gamma), Retinoid X receptor, Rheb (Ras homolog rich in brain) GTPase, Rho (Ras homolog) related protein kinase 2, ribonuclease, ribonucleotide reductase (such as M2 subunit), ribosomal protein S6 kinase, RNA polymerase (such as I, II), Ron (receptor D' Origine Nantias) tyrosine kinase, ROS1(ROS proto-oncogene 1, receptor tyrosine kinase) gene, Ros1 tyrosine kinase, Runt-related transcription factor 3, gamma-secretase, S100 calcium binding protein A9, Sarco endoplasmic reticulum calcium ATPase, second mitochondria-derived caspase activator of cysteine (SMAC) protein, secreted frizzled-related protein-2, signal protein-4D, serine protease, serine/threonine kinase (STK), serine/threonine-protein kinase (TBK, such as TBK1), signal transduction and transcription (STAT, such as STAT-1, STAT-3, STAT-5), the signal transduction lymphocyte activating molecule (SLAM) family member 7, the Six Transmembrane Epithelial Antigen (STEAP) gene of the prostate, SL cytokine ligands, the Smooth (SMO) receptor, sodium iodide co-transporter, sodium phosphate co-transporter 2B, somatostatin receptors (such as 1,2,3,4, 5), sonic hedgehog protein, guanine nucleoside exchange factor (Son of seven; SOS), specific protein 1(Sp1) transcription factor, sphingomyelin synthase, sphingosine kinase (such as 1, 2), sphingosine-1-phosphate receptor-1, splenic tyrosine kinase (SYK), SRC gene, SRC tyrosine kinase, STAT3 gene, steroid sulfatase, interferon gene Stimulator (STING) receptor, interferon gene protein stimulator, stromal cell-derived factor 1 ligand, SUMO (small ubiquitin-like modulator), superoxide dismutase, survivin protein, synapsin 3, syndecan-1, synuclein alpha, T cell surface glycoprotein CD28, trough-binding kinase (TBK), TATA box-binding protein-related factor RNA polymerase I subunit B (TAF1B) gene T cell CD3 glycoprotein zeta chain, T cell differentiation antigen CD6, T cell-containing immunoglobulin and mucin domain-3 (TIM-3), and, T cell surface glycoprotein CD8, Tec protein tyrosine kinase, Tek tyrosine kinase receptor, telomerase reverse transcriptase (TERT) gene, tenascin, TGF beta 2 ligand, thrombopoietin receptor, thymidine kinase, thymidine phosphorylase, thymidylate synthase, thymosin (such as alpha 1), thyroid hormone receptor, thyroid stimulating hormone receptor, tissue factor, TNF-related apoptosis-inducing ligand, TNFR 1-related death domain protein, TNF-related apoptosis-inducing ligand (TRAIL) receptor, TNFSF11 gene, TNFSF9 gene, Toll-like receptor (TLR, such as 1-13), topoisomerase (such as I, II, III), transcription factor, transferase, iron transfer protein, transforming growth factor (TGF, such as beta) kinase, transforming growth factor TGF-beta receptor kinase, transglutaminase, translocation-related protein, Transmembrane glycoprotein NMB, Trop-2 calcium signal transducer, trophoblastic glycoprotein (TPBG) gene, trophoblastic glycoprotein, myo-spinosin receptor kinase (Trk) receptor (such as TrkA, TrkB, TrkC), tryptophan 5-hydroxylase, tubulin, tumor necrosis factor (TNF, such as alpha, beta), tumor necrosis factor 13C receptor, tumor progression locus 2(TPL2), tumor protein 53(TP53) gene, tumor inhibitor candidate 2(TUSC2) gene, tyrosinase, tyrosine hydroxylase, Tyrosine Kinase (TK), tyrosine kinase receptor, Tyrosine Kinase (TK) receptor having immunoglobulin-like and EGF-like domains, tyrosine protein kinase L1 inhibitor, ubiquitin carboxy hydroxylase isozyme L5, ubiquitin thioesterase-14, ubiquitin thioesterase E2I (UBE2I, UBC9), urease, urokinase plasminogen activator, Uteroglobin, vanilloid VR1, vascular cell adhesion protein 1, Vascular Endothelial Growth Factor Receptor (VEGFR), T cell activation V domain Ig inhibitor (VISTA), VEGF-1 receptor, VEGF-2 receptor, VEGF-3 receptor, VEGF-A, VEGF-B, vimentin, vitamin D3 receptor, proto-oncogene tyrosine-protein kinase Yes, Wee-1 protein kinase, Wilms ' tumor antigen 1(Wilms ' tumor 1), Wilms ' tumor protein, X-linked inhibitor of apoptotic proteins, zinc finger protein transcription factor, or any combination thereof.

Non-limiting examples of other therapeutic agents may be classified by their mechanism of action into, for example, the following groups:

antimetabolites/anticancer agents, such as the pyrimidine analogues floxuridine, capecitabine, cytarabine, CPX-351 (liposomal cytarabine, daunorubicin), TAS-118;

purine analogs, folic acid antagonists such as pralatrexate (pralatrexate), and related inhibitors;

antiproliferative/antimitotic agents, including natural products such as vinca alkaloids (vinblastine, vincristine) and microtubule-disrupting agents such as taxanes (paclitaxel, docetaxel), vinblastine, nocodazole (nocodazole), epothilones (epothilone), vinorelbineAnd epipodophyllotoxins (etoposide, teniposide);

DNA damaging agents, such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamideActinomycin D, daunomycin, doxorubicin, epirubicin, ifosfamide, melphalan, mechlorethamine, mitomycin C, mitoxantrone, nitrosourea, procarbazine, paclitaxel, anticancer drug (Taxotere), teniposide, etoposide, and triethylenethiophosphoramide;

DNA hypomethylating agents such as guadaroxetine (guadectiadine) (SGI-110), ASTX 727;

antibiotics such as actinomycin D, daunomycin, doxorubicin, idarubicin, anthracycline, mitoxantrone, bleomycin (bleomycin), plicamycin (plicamycin) (mithramycin);

enzymes such as L-asparaginase which metabolises L-asparagine systemically and deprives cells which do not have the ability to synthesize their own asparagine;

-an antiplatelet agent;

-a Bcl-2 targeted DNAi oligonucleotide, such as PNT 2258;

-agents that activate or reactivate potential Human Immunodeficiency Virus (HIV), such as parbinotal and romidepsin;

asparaginase stimulators, such as kriptase (crisantapase)And GRASPA (ERY-001, ERY-ASP), pegylated caralase (calasapagase pegol);

pan-Trk, ROS1 and ALK inhibitors such as entrectinib (entrectinib), TPX-0005;

-polymorphic lymphoma kinase (ALK) inhibitors such as elotinib (aletinib), ceritinib (ceritinib);

antiproliferative/antimitotic alkylating agents, such as nitrogen mustard cyclophosphamide and analogues (melphalan, chlorambucil phenylbutyric acid, hexamethylmelamine (hexamethylmellemamine) and thiotepa), alkyl nitrosoureas (carmustine) and analogues, streptozotocin and triazenes (dacarbazine);

-antiproliferative/antimitotic antimetabolites such as folic acid analogues (methotrexate);

-platinum coordination complexes (cisplatin, oxaliplatin (oxiloplatinim) and carboplatin), procarbazine, hydroxyurea, mitotane and gluten (aminoglutethimide);

-hormones, hormone analogues (oestrogen, tamoxifen, goserelin, bicalutamide and nilutamide) and aromatase inhibitors (letrozole and anastrozole);

anticoagulants, such as heparin, synthetic heparin salts and other inhibitors of thrombin;

fibrinolytic agents such as tissue plasminogen activator, streptokinase, urokinase, aspirin (aspirin), dipyridamole (dipyridamole), ticlopidine (ticlopidine) and clopidogrel (clopidogrel);

-an anti-migration agent;

-antisecretory agents (breveldin);

immunosuppressants such as tacrolimus (tacrolimus), sirolimus (sirolimus), azathioprine and mycophenolate mofetil;

-growth factor inhibitors, and vascular endothelial growth factor inhibitors;

-inhibitors of fibroblast growth factor, such as FPA 14;

anti-VEGFR antibodies such as IMC-3C5, GNR-011, tanibizumab (tanibirumab);

anti-VEGF/DDL 4 antibodies, such as ABT-165;

anti-cadherin antibodies, such as HKT-288;

anti-CD 70 antibodies, such as AMG-172; antibodies No. 15 (LRRC15) containing anti-leucine rich repeats, such as ABBV-085. ARGX-110;

-a vasoconstrictor receptor blocker, a nitric oxide donor;

antisense oligonucleotides such as AEG35156, IONIS-KRAS-2.5Rx, EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (prexigebersen), IONIS-STAT3-2.5 Rx;

DNA interfering oligonucleotides such as PNT2258, AZD-9150;

anti-ANG-2 antibodies such as MEDI3617 and LY 3127804;

anti-ANG-1/ANG-2 antibodies, such as AMG-780;

anti-MET/EGFR antibodies such as LY 3164530;

anti-EGFR antibodies such as ABT-414, AMG-595, lecitumumab (necitumumab), ABBV-221, maprotigotine pertuzumab (ABT-414), tolytuximab (tomotuximab), ABT-806, vembix (vectib), mototuximab (modotuximab), RM-1929;

anti-CSF 1R antibodies, such as ematuzumab (emactuzumab), LY3022855, AMG-820, FPA-008 (cabeprizumab));

anti-CD 40 antibodies, such as RG7876, SEA-CD40, APX-005M, ABBV-428;

anti-endoglin antibodies, such as TRC105 (cetuximab);

anti-CD 45 antibodies, such as 131I-BC8 (lomab-B);

anti-HER 3 antibodies, such as LJM716, GSK 2849330;

anti-HER 2 antibodies, such as margemtuximab (margetuximab), MEDI4276, BAT-8001;

anti-HLA-DR antibodies such as IMMU-114;

anti-IL-3 antibodies, such as JNJ-56022473;

anti-OX 40 antibodies such as MEDI6469, MEDI6383, MEDI0562 (Tavoxilumab)), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368;

anti-EphA 3 antibodies, such as KB-004;

anti-CD 20 antibodies, such as obinutuzumab (obinutuzumab), IGN-002;

anti-CD 20/CD3 antibodies, such as RG 7828;

anti-CD 37 antibodies, such as AGS67E, ottertuzumab (otlertuzumab) (TRU-016);

-anti-ENPP 3 antibodies, such as AGS-16C 3F;

anti-FGFR-3 antibodies such as LY3076226, B-701;

anti-FGFR-2 antibodies such as GAL-F2;

anti-C5 antibodies, such as ALXN-1210;

anti-CD 27 antibodies, such as varolimumab (CDX-1127);

anti-TROP-2 antibodies, such as IMMU-132;

anti-NKG 2a antibodies, such as monlizumab;

anti-VISTA antibodies such as HMBD-002;

anti-PVRIG antibodies, such as COM-701;

anti-EpCAM antibodies, such as VB 4-845;

anti-BCMA antibodies, such as GSK-2857916;

anti-CEA antibodies, such as RG-7813;

anti-differentiating cluster 3(CD3) antibodies, such as MGD 015;

anti-folate receptor alpha antibodies, such as IMGN 853;

-MCL-1 inhibitors such as AMG-176, S-64315 and AZD-5991, 483-LM, a-1210477, UMI-77, JKY-5-037;

-epha2 inhibitors, such as MM-310;

anti-LAG-3 antibodies, such as Rilatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767;

-RAF kinase/VEGFR inhibitors such as RAF-265;

-inhibitors of polyhive protein (EED), such as MAK 683;

anti-Fibroblast Activation Protein (FAP)/IL-2R antibodies, such as RG 7461;

anti-Fibroblast Activation Protein (FAP)/TRAIL-R2 antibodies, such as RG 7386;

anti-fucoidan-GM 1 antibody, such as BMS-986012;

-p38 MAP kinase inhibitors such as nalitinib (ralimetinib);

-PRMT1 inhibitors, such as MS 203;

-inhibitors of sphingosine kinase 2(SK2), such as opanib (opaganib);

-FLT3-ITD inhibitors, such as BCI-332;

-a nuclear red blood cell 2-associated factor 2 stimulating agent such as omavirolone (omavelolone) (RTA-408);

-inhibitors of myo-actin receptor kinase (TRK), such as LOXO-195, ONO-7579;

anti-ICOS antibodies such as JTX-2011, GSK 3359609;

anti-DR 5(TRAIL2) antibodies, such as DS-8273;

-anti-GD 2 antibodies, such as APN-301;

anti-interleukin-17 (IL-17) antibodies, such as CJM-112;

anti-carbonic anhydrase IX antibodies, such as TX-250;

anti-CD38 artantin (anti-CD 38-attentukine), such as TAK 573;

anti-mucin 1 antibodies, such as gaddilizumab (gatipotuzumab);

-mucin 1 inhibitors such as GO-203-2C;

-MARCKS protein inhibitors such as BIO-11006;

folic acid antagonists such as aforeline (arfolitixorin);

-galectin-3 inhibitors such as GR-MD-02;

-inhibitors of phosphorylated P68, such as RX-5902;

CD95/TNF modulators, such as Oxvoraba (offenergen obadenovec);

-PI3K/Akt/mTOR inhibitors, such as ABTL-0812;

pan-PIM kinase inhibitors, such as INCB-053914;

IL-12 gene stimulators, such as EGEN-001, Tavokines telseplasmid;

heat shock protein HSP90 inhibitors such as TAS-116, PEN-866;

-VEGF/HGF antagonists, such as MP-0250;

-SYK tyrosine kinase/FLT 3 tyrosine kinase inhibitors such as TAK-659;

-SYK tyrosine kinase/JAK tyrosine kinase inhibitors such as ASN-002;

-FLT3 tyrosine kinase inhibitors such as FF-10101;

-FLT3 tyrosine kinase agonists such as CDX-301;

-FLT3/MEK1 inhibitors, such as E-6201;

-IL-24 antagonists such as AD-IL 24;

-RIG-I agonists such as RGT-100;

-an aerolysin stimulant such as topsin (toplysin);

-P-glycoprotein 1 inhibitors such as HM-30181A;

-CSF-1 antagonists such as ARRY-382, BLZ-945;

anti-mesothelin antibodies, such as SEL-403;

thymidine kinase stimulants such as alogliptin (agoverine besadenovec);

-Polo-like kinase 1 inhibitors such as PCM-075;

TLR-7 agonists such as TMX-101 (imiquimod);

-NEDD8 inhibitors such as pevoritat (MLN-4924), TAS-4464;

-pleiotropic pathway modulators, such as adadimide (avadomide) (CC-122);

-FoxM1 inhibitors, such as streptomyces thioparus (thiostrepton);

anti-MUC 1 antibodies, such as Mab-AR-20.5;

anti-CD38 antibodies, such as iximab (isatuximab), MOR-202;

-UBA1 inhibitors, such as TAK-243;

src tyrosine kinase inhibitors, such as VAL-201;

-VDAC/HK inhibitors such as VDA-1102;

-BRAF/PI3K inhibitors, such as ASN-003;

-Elf4a inhibitors such as roxitib (rohinitib), eFT 226;

-TP53 gene stimulators, such as ad-p 53;

-PD-L1/EGFR inhibitors such as GNS-1480;

-retinoic acid receptor alpha (RAR α) inhibitors such as SY-1425;

-SIRT3 inhibitors such as YC 8-02;

-inhibitors of stromal cell-derived factor 1 ligands, such as pegylated olanexide (NOX-a 12);

-IL-4 receptor modulators, such as MDNA-55;

spermidase-I stimulants such as peralase (pegzilarginase);

-topoisomerase I inhibitors/hypoxia inducible factor-1 α inhibitors, such as PEG-SN38 (pegylated non-canam (fistecan pegol));

hypoxia inducible factor-1 α inhibitors such as PT-2977, PT-2385;

-CD122 agonists such as NKTR-214;

-p53 tumor suppressor protein stimulants such as clavine (kevatrin);

-Mdm4/Mdm2 p53 binding protein inhibitors such as ALRN-6924;

-kinesin axis protein (KSP) inhibitors such as finasterib (arinesib) (ARRY-520);

-CD80-fc fusion protein inhibitors, such as FPT-155;

-multiple endocrine adenoma proteins and Mixed Lineage Leukemia (MLL) inhibitors such as KO-539;

-liver x receptor agonists such as RGX-104;

-IL-10 agonists such as AM-0010;

-EGFR/ErbB-2 inhibitors such as varlitinib (varlitinib);

-VEGFR/PDGFR inhibitors such as voranib (vorolanib);

-IRAK4 inhibitors, such as CA-4948;

anti-TLR-2 antibodies such as OPN-305;

calmodulin modulators, such as CBP-501;

-glucocorticoid receptor antagonists such as relarant (realorilan) (CORT-125134);

-a second mitochondrially-derived activator of caspase (SMAC) protein inhibitor, such as BI-891065;

-lactoferrin modulators, such as LTX-315;

-Kit tyrosine kinase/PDGF receptor alpha antagonists such as DCC-2618;

-KIT inhibitors such as PLX-9486;

-Exportin 1 inhibitors such as eltanix (eltanexor);

-EGFR/ErbB2/Ephb4 inhibitors such as tegafatinib (tesevatinib);

anti-CD 33 antibodies, such as IMGN-779;

anti-KMA antibodies, such as MDX-1097;

anti-TIM-3 antibodies such as TSR-022, LY-3321367, MBG-453;

anti-CD 55 antibodies, such as PAT-SC 1;

anti-PSMA antibodies, such as ATL-101;

anti-CD 100 antibodies, such as VX-15;

anti-EPHA 3 antibodies, such as non-pauzumab (fibatuzumab);

anti-Erbb antibodies such as CDX-3379, HLX-02, Seribandromab (seribanumab);

anti-APRIL antibodies, such as BION-1301;

anti-Tigit antibodies such as BMS-986207, RG-6058;

-CHST15 gene inhibitors such as STNM-01;

-RAS inhibitors such as NEO-100;

somatostatin receptor antagonists such as OPS-201;

-CEBPA gene stimulators such as MTL-501;

DKK3 gene modulators, such as MTG-201;

-p70s6k inhibitors, such as MSC 2363318A;

-methionine aminopeptidase 2(MetAP2) inhibitors such as M8891, APL-1202;

-inhibitors of arginine N-methyltransferase 5, such as GSK-3326595;

anti-programmed cell death protein 1 (anti-PD-1) antibodies, such as nivolumab: (a)BMS-936558, MDX-1106), palivizumab (MK-3477, SCH-900475, Lalizumab (lambrolizumab), CAS registry number 1374853-91-4), Pilizumab, PF-06801591, BGB-A317, GLS-010(WBP-3055), AK-103 (K-K (K-HX-008), MGA-012, BI-754091, REGN-2810 (gemipimab (cemipimab)), AGEN-2034, JS-001, JNJ-63723283, genilizumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, BAT-1306, and an anti-programmed death ligand 1 (anti-PD-L1) antibody, such as BMS-936559, Attributab (MPDL3280A), Devolumab (MEDI4736), Avermemab, CK-301(MSB0010718C), MEDI0680, CX-072, CBT-502, PDR-001 (Spartalizumab), TSR-042 (dostilimab), JTX-4014, BGB-A333, SHR-1316, CS-1001(WBP-3155, KN-035, IBI-308, FAZ-053, and MDX 1105-01);

-PD-L1/VISTA antagonists such as CA-170;

anti-PD-L1/TGF β antibodies, such as M7824;

anti-transferrin antibodies, such as CX-2029;

anti-IL-8 (interleukin-8) antibodies, such as HuMax-Inflam;

ATM (ataxia telangiectasia) inhibitors such as AZD 0156;

CHK1 inhibitors such as GDC-0575, LY2606368 (prexasertib), SRA737, RG7741(CHK 1/2);

-CXCR4 antagonists such as BL-8040, LY2510924, bulisafrfor (TG-0054), X4P-002, X4P-001-IO;

-inhibitors of EXH2, such as GSK 2816126;

-HER2 inhibitors such as neratinib (neratinib), cartainib (tucatenib) (ONT-380);

-KDM1 inhibitors such as ary-1001, IMG-7289, INCB-59872, GSK-2879552;

-CXCR2 antagonists such as AZD-5069;

-GM-CSF antibodies such as langzilumab (lentilizumab);

DNA-dependent protein kinase inhibitors such as MSC2490484A (Nethertib), VX-984, AsiDNA (DT-01);

-protein kinase c (pkc) inhibitors such as LXS-196, sotastarin (sotastaurin);

-selective estrogen receptorConditioning (SERD), such as fulvestrantRG6046, RG6047, Elamestrant (RAD-1901), and AZD 9496;

-Selective Estrogen Receptor Covalent Antagonists (SERCA), such as H3B-6545;

-Selective Androgen Receptor Modulators (SARMs), such as GTX-024, darownamide (darolutamide);

-transforming growth factor-beta (TGF- β) kinase antagonists such as homotopib (galinisertib);

anti-transforming growth factor-beta (TGF- β) antibodies such as LY3022859, NIS793, XOMA 089;

bispecific antibodies such as MM-141(IGF-1/ErbB3), MM-111(Erb2/Erb3), JNJ-64052781(CD19/CD3), PRS-343(CD-137/HER2), AFM26(BCMA/CD16A), JNJ-61186372(EGFR/cMet), AMG-211(CEA/CD3), RG7802(CEA/CD3), ERY-974(CD3/GPC3), vanzezumab (vancizumab) (angiopoietin/VEGF), PF-06671008 (cadherin/CD 3), AFM-13(CD16/CD30), APVO (CD123/CD3), fuzumab (flotetuzumab) (CD123/CD3), REV-1979 (CD 3/CD3), CD-LA-117 (CD3/CLEC 3612), MCLA-3 (MCHER-753672), JNJ/3 (HER-3), JNJ-3664/3 (heme), AMG-757(DLL3-CD3), MGD-013(PD-1/LAG-3), AK-104(CTLA-4/PD-1), AMG-330(CD33/CD3), AMG-420(BCMA/CD3), BI-836880(VEFG/ANG2), JNJ-63709178(CD123/CD3), MGD-007(CD3/gpA33), MGD-009(CD3/B7H 3);

mutant selective EGFR inhibitors such as PF-06747775, EGF816 (azartinib), ASP8273, ACEA-0010, BI-1482694;

anti-GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) antibodies, such as MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323;

anti-like protein ligand 3(DDL3) antibodies such as pivotuzumab (pivalozumab);

anti-clusterin antibodies, such as AB-16B 5;

anti-aprepilin-a 4(EFNA4) antibodies, such as PF-06647263;

anti-RANKL antibodies, such as denosumab (denosumab);

anti-mesothelin antibodies such as BMS-986148, anti-MSLN-MMAE;

anti-sodium phosphate cotransporter 2B (NaP2B) antibodies, such as livatuzumab (lifastuzumab);

anti-c-Met antibodies such as ABBV-399;

adenosine A2A receptor antagonists such as CPI-444, AZD-4635, Preledina (preladenant), PBF-509;

- α -ketoglutarate dehydrogenase (KGDH) inhibitors such as CPI-613;

-XPO1 inhibitors such as penicillin russia (selinexor) (KPT-330);

-inhibitors of isocitrate dehydrogenase 2(IDH2), such as enalaprib (enasidib) (AG-221);

IDH1 inhibitors such as AG-120 and AG-881(IDH1 and IDH2), IDH-305, BAY-1436032;

-interleukin-3 receptor (IL-3R) modulators, such as SL-401;

-argininase stimulators, such as polyethylene glycol arginase (ADI-PEG-20);

-antibody-drug conjugates such as MLN0264 (anti-GCC, guanylate cyclase C), T-DM1 (trastuzumab emtansine), Kadcycla, milatuzumab (matuzumab) -doxorubicin (hCD74-DOX), bertuzumab vedotti (brentuximab vedotti), DCDT2980S, borlizumab vedotti (polatuzumab vedotti), SGN-CD70A, SGN-CD19A, influzumab (ovozogamycin), lovastatin (lovastatin mertansine), SAR3419, satuzumab (actituzumab peguaceva), inflatazumab (inflixataveb), lutetium (asotuzumab) mertansine (lutetuzumab mertansine), lutuzumab (sar341177), lutuzumab (lututab) (asttuzumab), lutuzumab (ritukutam), ritukutam-ct (r), ritukutam-C) (g-15-luctuzumab-g-36177), lutuzumab (lutetuzumab-C-g-80-d 36177), lutuzumab (lutetuzumab-C) and luytuzumab (rituc) incorporated) Tesovizumab vidotti (tisotuzumab vedotti), Annetuzumab lafaxine (anetumavavtannine), CX-2009, SAR-566658, W-0101, Baonalizumab vedotti (polatuzumab vedotti), ABBV-085;

-a claudin-18 inhibitor, such as clevidimab (claudiximab);

-beta-catenin inhibitors such as CWP-291;

anti-CD 73 antibodies, such as MEDI-9447 (olelumab), CPX-006, IPH-53, BMS-986179;

-CD73 antagonists such as AB-680, PSB-12379, PSB-12441, PSB-12425;

-CD39/CD73 antagonists, such as PBF-1662;

-chemokine receptor 2(CCR) inhibitors such as PF-04136309, CCX-872, BMS-813160(CCR2/CCR 5);

thymidylate synthase inhibitors such as ONX-0801;

-ALK/ROS1 inhibitors such as loratinib (loratinib);

telomerase inhibitors such as G007-LK;

-Mdm 2p 53-binding protein inhibitors such as CMG-097, HDM-201;

-c-PIM inhibitors such as PIM 447;

BRAF inhibitors such as dabrafenib (dabrafenib), vemurafenib (vemurafenib), encorafenib (LGX818), PLX 8394;

inhibitors of sphingosine kinase-2 (SK2), such as(ABC294640)；

Cell cycle inhibitors such as semetinib (selumetinib) (MEK1/2), and sapacitabine (sapacitabine);

-AKT inhibitors such as MK-2206, ibatilib (iptasertib), afurticib (afurertib), AZD5363 and ARQ-092, kavasertib (capivastrib), triciribine (triciribine);

anti-CTLA-4 (cytotoxic T-lymphocyte globulin-4) inhibitors, such as tremelimumab (tremelimumab), age-1884, BMS-986218;

-c-MET inhibitors such as AMG-337, savotinib (savolitinib), tivatinib (tivatinib) (ARQ-197), cappuccinib (caplatinb) and tepatinib (tepotinib), ABT-700, AG213, AMG-208, JNJ-38877618(OMO-1), merletinib (merletitinib), HQP-8361;

-c-Met/VEGFR inhibitors such as BMS-817378, TAS-115;

-c-Met/RON inhibitors such as BMS-777607;

-BRAF/EGFR inhibitors such as BGB-283;

-bcr/abl inhibitors such as Ribes nigrib (rebastinib), Acini-b (asciminib);

-MNK1/MNK2 inhibitors such as eFT-508;

-mTOR inhibitors/cytochrome P4503 a4 stimulators, such as TYME-88;

-lysine-specific demethylase-1 (LSD1) inhibitors, such as CC-90011;

pan RAF inhibitors such as LY3009120, LXH254, TAK-580;

-Raf/MEK inhibitors such as RG 7304;

-CSF1R/KIT and FLT3 inhibitors such as pexidinib (PLX 3397);

kinase inhibitors such as vandetanib (vandetanib);

-E-selectin antagonists such as GMI-1271;

-differentiation inducing agents such as tretinoin (tretinoin);

-Epidermal Growth Factor Receptor (EGFR) inhibitors such as oxitinib (osimertinib) (AZD-9291);

-topoisomerase inhibitors such as doxorubicin, daunomycin, actinomycin D, enicoside (eniposide), epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pyranthrone (pixantrone), sobuzolne (sobuzoxane), topotecan, irinotecan, MM-398 (liposomal irinotecan), voraxacin (vosaroxin) and GPX-150, idoxine (aldoxorubicin), AR-67, maverinib (maveliniib), AST-2818, avitinib (avitinib) (ACEA-0010), ifosfil (irofiln) (MGI-114);

corticosteroids such as cortisone (cortisone), dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone;

-growth factor signal transduction kinase inhibitors;

nucleoside analogues such as DFP-10917;

-Axl inhibitors such as BGB-324 (besitinib), SLC-0211;

BET inhibitors, such as INCB-054329, INCB057643, TEN-010, AZD-5153, ABT-767, BMS-986158, CC-90010, GSK525762 (molibresib), NHWD-870, ODM-207, GSK-2820151, GSK-1210151A, ZBC246, ZBC260, ZEN3694, FT-1101, RG-6146, CC-90010, mivebresib (mivebressib), BI-894999, PLX-2853, PLX-51107, CPI-0610, GS-5829;

PARP inhibitors such as olaparib (rucaparib), such as carboparib (rucaparib), veliparib (veliparib), talaroparib (talazoparib), ABT-767, BGB-290;

proteasome inhibitors, such as ixazomi (ixazomib), carfilzomib (carfilzomib)Marizumi (marizomib);

-inhibitors of glutaminase, such as CB-839;

vaccines, such as the peptide vaccines TG-01(RAS), GALE-301, GALE-302, Leneparstat-S (nelipepimut-S), SurVaxM, DSP-7888, TPIV-200, PVX-410, VXL-100, DPX-E7, ISA-101, 6MHP, OSE-2101, Galnepiprat-S (galinpimut-S), SVN53-67/M57-KLH, IMU-131; bacterial vector vaccines such as CRS-207/GVAX, Alimo gold filolisbac (ADXS 11-001); adenoviral vector vaccines, such as nadofagente fiadienovic; autologous Gp96 vaccine; dendritic cell vaccines such as CVactm, Starcel-T (Stapuldencel-T), Idelacel-T (eltrapuldencel-T), SL-701, BSK01TM, Rockadecel-T (rocapudencel-T) (AGS-003), DCVAC, CVac^tmStazel-T, itazel-T, SL-701, BSK01^TMADXS 31-142; oncolytic diseaseSeedlings, such as Talimonellaevick (talimogenielaherparpvec), Pexatimogyne devaciprepvec, GL-ONC1, MG1-MA3, parvovirus H-1, ProstAtak, Ennahsei (enadenotricirev), MG1MA3, ASN-002 (TG-1042); therapeutic vaccines, such as CVAC-301, CMP-001, PF-06753512, VBI-1901, TG-4010, ProscaVax^TM(ii) a Tumor cell vaccines, such as(IND-14205), Oncoquest-L vaccine; live, killed, recombinant, serotype 1 poliovirus vaccine, such as PVS-RIPO; adapalexine (Adagloxad simolenin); MEDI-0457; DPV-001, a tumor-derived autophagosome enriched cancer vaccine; RNA vaccines such as CV-9209, LV-305; DNA vaccines such as MEDI-0457, MVI-816, INO-5401; a modified vaccinia virus Ankara (vaccinia virus Ankara) vaccine expressing p53, such as MVA-p 53; DPX-Survivac; BriaVax^TM；GI-6301；GI-6207；GI-4000；

anti-DLL 4 (ligand 4-like) antibodies, such as daclizumab (demcizumab);

-STAT-3 inhibitors such as napabusin (BBI-608);

-ATPase p97 inhibitors such as CB-5083;

inhibitors of Smoothing (SMO) receptors, such as(Sonidegib (sonidegib), formerly LDE-225), LEQ506, vismodegib (vismodegib) (GDC-0449), BMS-833923, Glaedegib (glasedgib) (PF-04449913), LY2940680, and itraconazole (itraconazole);

interferon alpha ligand modulators, such as Interferon alpha-2 b, Interferon alpha-2A biosimilars (biogeomics), Ropeter Interferon alpha-2 b (AOP-2014, P-1101, PEG IFN alpha-2 b), Mutiraferon (Multiferon) (Alfanative), Viragon (Viragen)), Interferon alpha 1b, Rosterferon-A (Roferon-A) (Caneron, Ro-25-3036), Interferon alpha-2A successor (Biosidus) (Inmutag, Inter 2A), Interferon alpha-2 b successor (Biosidus) -Bioferon (Beziron), Citophereron, Ganapar (Ga-Gajga), Bejjon-2 b successor biologicals (Bioferon), and Biotechnol-1-interferon alpha-2 b (Bioferon), and interferon alpha-2 b successor, Subsequent biological preparation of pegylated interferon alpha-2 b (Amerga), recombinant human interferon alpha-1 b, recombinant human interferon alpha-2 a, recombinant human interferon alpha-2 b, Vituzumab (veltuzumab) -IFN alpha 2b conjugate, Dynavax (SD-101) and interferon alpha-n 1 (Homomolon (Humoferon), SM-10500, Sumiferon (Sumiferon));

-interferon gamma ligand modulators, such as interferon gamma (OH-6000, ogema 100(Ogamma 100));

IL-6 receptor modulators, such AS tositumumab (tocilizumab), situximab (siltuximab), AS-101(CB-06-02, IVX-Q-101);

-telomerase modulators such as tetomotide (tertomotide) (GV-1001, HR-2802, Riavax) and imestat (imetelstat) (GRN-163, JNJ-63935937);

DNA methyltransferase inhibitors such as temozolomide (temozolomide) (CCRG-81045), decitabine (decitabine), citrulline (guadectiadine) (S-110, SGI-110), KRX-0402, RX-3117, RRx-001 and azacitidine (azacitidine);

DNA gyrase inhibitors such as pyranthrone (pixantrone) and sobuzoxane (sobuzoxane);

-Bcl-2 family protein inhibitors such as ABT-263, Venetocclax (ABT-199), ABT-737 and AT-101;

notch inhibitors such as LY3039478 (crenistat), tarexituzumab (tarextumab) (anti-Notch 2/3), BMS-906024;

anti-myostatin inhibitors, such as landomab (landogrozumab);

-a hyaluronidase stimulator, such as PEGPH-20;

-Wnt pathway inhibitors such as SM-04755, PRI-724, Wnt-974;

-gamma-secretase inhibitors such as PF-03084014, MK-0752, RO-4929097;

-inhibitors of Grb-2 (growth factor receptor binding protein-2), such as BP 1001;

-TRAIL pathway inducing compounds such as ONC201, ABBV-621;

focal adhesion kinase inhibitors such as VS-4718, difatinib (defactinb), GSK 2256098;

hedgehog inhibitors such as saridegib (saridegib), sonetybigb (sonidegib) (LDE225), glargib (glasdegib) and vismodegib (vismodegib);

aurora kinase inhibitors such as alisertib (MLN-8237) and AZD-2811, AMG-900, Barceltinib (barasertib), ENMD-2076;

HSPB1 modulators (heat shock protein 27, HSP27), such as brivudine (brivudine), apatosen (apatosen);

ATR inhibitors such as BAY-937, AZD6738, AZD6783, VX-803, VX-970 (berzosertib), and VX-970;

mTOR inhibitors such as cyprotetib (sapaniertib) and visertib (vistuertib) (AZD2014), ME-344;

mTOR/PI3K inhibitors, such as gedatolisib, GSK2141795, omissib, RG 6114;

-Hsp90 inhibitors such as AUY922, onalles (onalespib) (AT13387), SNX-2112, SNX 5422;

murine double minute (mdm2) oncogene inhibitors such as DS-3032b, RG7775, AMG-232, HDM201 and idarubinin (RG 7388);

-CD137 agonists such as ulirubizumab (urelumab), ugamumab (utomobilab) (PF-05082566);

-STING agonists such as ADU-S100(MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291;

-FGFR inhibitors such as FGF-401, INCB-054828, BAY-1163877, AZD4547, JNJ-42756493, LY2874455, Debio-1347;

-Fatty Acid Synthase (FASN) inhibitors, such as TVB-2640;

anti-KIR monoclonal antibodies, such as lirilumab (IPH-2102), IPH-4102;

-antigen CD19 inhibitors such as MOR208, MEDI-551, AFM-11, neiblizumab (inelizumab);

-CD44 binding agents such as a 6;

-inhibitors of protein phosphatase 2A (PP2A), such as LB-100;

-CYP17 inhibitors such as sevieronel (VT-464), ASN-001, ODM-204, CFG920, abiraterone acetate;

-RXR agonists such as IRX 4204;

hedgehog/smoothing (hh/Smo) antagonists such as taraggib (taladegib), patidegib (patidegib);

complement C3 modulators, such as nepadam pgg (imprime pgg);

IL-15 agonists such as ALT-803, NKTR-255 and hetIL-15;

-EZH2 (enhancer of zeste homolog 2) inhibitors such as tasett (tazemetostat), CPI-1205, GSK-2816126;

oncolytic viruses such as parylene (pelareorecep), CG-0070, MV-NIS therapy, HSV-1716, DS-1647, VCN-01, ONCOS-102, TBI-1401, Tasaxabere (tasadeoturev) (DNX-2401), Waxijin amitriptvec (vocagene aminoretrvec), RP-1, CVA21, Celyvir, LOAd-703, OBP-301;

-DOT1L (histone methyltransferase) inhibitors such as pinometstat (EPZ-5676);

toxins such as Cholera toxin (Cholera toxin), ricin, pseudomonas exotoxin (pseudomonas exotoxin), Bordetella pertussis (Bordetella pertussis) adenylate cyclase toxin, diphtheria toxin and caspase activators;

-DNA plastids such as BC-819;

PLK inhibitors of PLK1, 2 and 3, such as voralartib (PLK 1);

-WEE1 inhibitors, such as AZD1775 (adavisertib);

rho kinase (ROCK) inhibitors such as AT13148, KD 025;

-ERK inhibitors such as GDC-0994, LY3214996, MK-8353;

IAP inhibitors such as ASTX660, debio-1143, dipyridamole (birinapagt), APG-1387, LCL-161;

RNA polymerase inhibitors such as lurnitidine (Lurbineedin) (PM-1183), CX-5461;

tubulin inhibitors such as PM-184, BAL-101553 (lisavanbulin) and OXI-4503, Flappaxin (fluapacin) (AC-0001), Pulabulin (plinabulin);

toll-like receptor 4(TL4) agonists such as G100, GSK1795091 and PEPA-10;

-elongation factor 1 α 2 inhibitors such as protidesin (plipidepsin);

-CD95 inhibitors such as APG-101, APO-010, asunapol (asunercept);

-WT1 inhibitors, such as DSP-7888;

-splicing factor 3B subunit 1(SF3B 1) inhibitors such as H3B-8800;

PDGFR α/KIT mutant specific inhibitors such as BLU-285;

-SHP-2 inhibitors such as TNO155(SHP-099), RMC-4550; and

retinoid Z receptor gamma (ROR γ) agonists, such as LYC-55716.

In some embodiments, provided herein is a method of treating or preventing a hyperproliferative disorder or cancer in a human or animal suffering from or at risk of suffering from the hyperproliferative disorder or cancer, comprising administering to the human or animal a therapeutically effective amount of a compound of formula (J), (I), (Ia), (IIa), (IIIa), (IIIb), (IIIc), (IVa), (IVb), and/or (IVc) as disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two or one to three) additional therapeutic agents selected from the group consisting of: apoptosis signal-regulating kinase (ASK) inhibitors; inhibitors of Bruton's Tyrosine Kinase (BTK); inhibitors of cluster of differentiation 47(CD 47); inhibitors of cyclin-dependent kinases (CDKs); discoidin Domain Receptor (DDR) inhibitors; (ii) a Histone Deacetylase (HDAC) inhibitor; indoleamine-pyrrole-2, 3-dioxygenase (IDO1) inhibitors; janus kinase (JAK) inhibitors; inhibitors of the amidooxidase-like protein (LOXL); matrix Metalloproteinase (MMP) inhibitors; inhibitors of mitogen-activated protein kinase (MEK); phosphatidylinositol 3-kinase (PI3K) inhibitors; spleen tyrosine kinase (SYK) inhibitors; toll-like receptor 8(TLR8) inhibitors; toll-like receptor 9(TLR9) inhibitors; a Tyrosine Kinase Inhibitor (TKI) and any combination thereof or a pharmaceutically acceptable salt thereof. Non-limiting examples include:

-inhibitors of apoptosis signal-regulating kinase (ASK): ASK inhibitors include ASK1 inhibitors. Examples of ASK1 inhibitors include, but are not limited to, the inhibitors described in WO 2011/008709(Gilead Sciences) and WO 2013/112741 (GileadSciences);

-inhibitors of Bruton's Tyrosine Kinase (BTK): examples of BTK inhibitors include, but are not limited to, (S) -6-amino-9- (1- (but-2-alkynoyl) pyrrolidin-3-yl) -7- (4-phenoxyphenyl) -7H-purin-8 (9H) -one, acarbatinib (acarbatinib) (ACP-196), BGB-3111, CB988, HM71224, ibrutinib, M-2951 (evalutinib), M7583, tiratinib (tiratinib) (ONO-4059), PRN-1008, sibirib (spebrutinib) (CC-292), TAK-020, vicarinib (cabbrutinib), ARQ-531, SHR-1459, DTMWS-12, TAS-53XH15;

-inhibitors of the differentiation cluster 47(CD 47): examples of CD47 inhibitors include, but are not limited to, anti-CD 47mAb (Vx-1004), anti-human CD47mAb (CNTO-7108), CC-90002-ST-001, humanized anti-CD 47 antibody (Hu5F9-G4), NI-1701, NI-1801, RCT-1938, and TTI-621;

-inhibitors of cyclin-dependent kinases (CDKs): CDK inhibitors include inhibitors of CDK 1,2, 3,4, 6,7 and 9, such as abbelib (abemaciclib), alvocidib (HMR-1275, flaperoxopiridol), AT-7519, danasinib (dinaciclib), ibolan (ibrance), FLX-925, LEE001, palbociclib (palbociclib), ribicicli (ribociclib), regoraib (rigosetib), rusalexin (selinexor), UCN-01, SY1365, CT-7001, SY-1365, G1T38, micicinib (milciib), tracicilib (trilicib) and TG-02-TG;

-Discoidin Domain Receptor (DDR) inhibitors: DDR inhibitors include inhibitors of DDR1 and/or DDR 2. Examples of DDR inhibitors include, but are not limited to, the inhibitors disclosed in WO 2014/047624(Gilead Sciences), US 2009-0142345(Takeda Pharmaceuticals), US 2011-0287011(Oncomed Pharmaceuticals), WO 2013/027802(Chugai Pharmaceuticals) and WO 2013/034933(Imperial Innovations);

-inhibitors of Histone Deacetylase (HDAC): examples of HDAC inhibitors include, but are not limited to, abenostat (abexinostat), ACY-241, AR-42, BEBT-908, belinostat (belinostat), CKD-581, CS-055(HBI-8000), CUDC-907 (non-miltostat (fimepinostat)), entinostat (entinostat), gibeprinostat (givinostat), moxetat (mocetinostat), paminostat (panobinostat), pracinostat (pracinostat), quininostat (quisinostat) (JNJ-26485), minostat (remininostat), Ricinuostat (ricinostat), SHP-141, valproic acid (VAL-001), vorinostat (vorinostat), teinostat (teinostatinine), raninostat (reinnostat), retenostat (entinostat), and enrinostat (enrinostat);

-inhibitors of indoleamine-pyrrole-2, 3-dioxygenase (IDO 1): examples of IDO1 inhibitors include, but are not limited to, BLV-0801, Eparstat, F-001287, GBV-1012, GBV-1028, GDC-0919, indomethamide (indoximod), NKTR-218, NLG-919 based vaccines, PF-06840003, pipamanaphthaquinone derivatives (SN-35837), Reminostat (reminostat), SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916;

-Janus kinase (JAK) inhibitors: JAK inhibitors inhibit JAK1, JAK2, and/or JAK 3. Examples of JAK inhibitors include, but are not limited to, AT9283, AZD1480, baricitinib (baricitinib), BMS-911543, fidatinib (fedratinib), fergolinib (filgoninib) (GLPG0634), gandotinib (gandottinib) (LY2784544), INCB039110 (itatinib), lestaurtinib (lestaurtinib), molominib (mometatinib) (CYT0387), NS-018, palitinib (pacitinib) (SB 1518), dermatinib (peicitinib) (ASP015K), rucolinib (ruxolitinib), tofacitinib (tofacitinib) (formerly), inc (tasocinib), XL 793 and 019052;

-inhibitors of the amidooxidase-like protein (LOXL): LOXL inhibitors include inhibitors of LOXL1, LOXL2, LOXL3, LOXL4, and/or LOXL 5. Examples of LOXL inhibitors include, but are not limited to, antibodies described in WO 2009/017833 (aristobiosciences). Examples of LOXL2 inhibitors include, but are not limited to, antibodies described in WO 2009/017833(Arresto Biosciences), WO 2009/035791(Arresto Biosciences), and WO 2011/097513(Gilead Biologics);

-inhibitors of Matrix Metalloproteinases (MMPs): MMP inhibitors include inhibitors of MMPs 1 through 10. Examples of MMP9 inhibitors include, but are not limited to, inhibitors described in marimastat (marimastat) (BB-2516), cimestat (cipemastat) (Ro 32-3555), GS-5745 (andrexizumab (andrecaliximab)), and WO 2012/027721(Gilead Biologics);

-inhibitors of mitogen-activated protein kinase (MEK): MEK inhibitors include azaquinol (antroquinol), binetitinib (binimetinib), cobimetinib (cobimetinib) (GDC-0973, XL-518), MT-144, semetinib (selumetinib) (AZD6244), sorafenib (sorafenib), trametinib (trametinib) (GSK1120212), arsetiib (uprosertib) + trametinib (trametinib), PD-0325901, pimasertib (pimasertib), LTT462, AS703988, CC-90003, rifametinib (refametinib);

inhibitors of phosphatidylinositol 3-kinase (PI3K) PI3K including inhibitors of PI3K γ, PI3K, PI3K β, PI3K α and/or pan PI3K examples of PI3K inhibitors include, but are not limited to, ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY 10824391, BEZ235, buparlix (buparlisib) (BKM120), BYL719 (empiriib)), CH5132799, Cobamixib (Copalisib) (BAY 80-6946), Duvelisib (duvelisib), GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, Adesb (Aielisib)INCB50465、IPI-145. IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, regoralbum (rigosertib), RP5090, RP6530, SRX3177, Taselisib (taselisib), TG100115, TGR-1202 (Winbuxib), TGX221, WX-037, X-339, X-414, XL (SAR 2454408), XL499, XL756, wortmannin (wortmannin), ZSTK474 and WO 2005/113556(ICOS), WO 2013/052699 (Gileadcalidacaloga), WO 2013/116562 (Gileadacalisd calligoga), WO 2014/100765(Gilead calligoga), WO 2014/100767(Gilead calligoga) and WO 2014/201409 (Gilles);

-inhibitors of spleen tyrosine kinase (SYK): examples of SYK inhibitors include, but are not limited to, 6- (1H-indazol-6-yl) -N- (4- (N-morpholinyl) phenyl) imidazo [1,2-a ] pyrazin-8-amine, BAY-61-3606, nerdulotinib (PRT-062607), entustinib (entospletinib), fostatinib (R788), HMPL-523, NVP-QAB 205AA, R112, R343, tamatinib (R406), and the inhibitors described in US8450321(Gilead Connecticut) and the inhibitors described in u.s.s.2015/0175616;

-Toll-like receptor 8(TLR8) inhibitors: examples of TLR8 inhibitors include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, VTX-1463, and VTX-763;

-Toll-like receptor 9(TLR9) inhibitors: examples of TLR9 inhibitors include, but are not limited to, AST-008, IMO-2055, IMO-2125, Leftitolimod (lefitolimod), Littemozolod (litenimod), MGN-1601, and PUL-042; and

tyrosine Kinase Inhibitors (TKI): TKI can target Epidermal Growth Factor Receptor (EGFR) as well as receptors for Fibroblast Growth Factor (FGF), platelet-derived growth factor (PDGF), and Vascular Endothelial Growth Factor (VEGF). Examples of TKIs include, but are not limited to, Afatinib (afatinib), ARQ-087 (deazantinib), ASP5878, AZD3759, AZD4547, bosutinib (bosutinib), bugatinib (brigitinib), cabozantinib (cabozantinib), cediranib (cediranib), cronilb (crenolanib), dacomitinib (dacomitinib), dasatinib (dasatinib), doratinib (dovitinib), E-6201, erdasatinib (erdasatinib), erlotinib (erlotinib), gefitinib (gefitinib), giberetinib (gilteritinib) (ASP-5), FP-1039, HM 713, critinib (otatinib), imatinib (ibrinib), erlotinib (391 (Kvaninib), erlotinib (ODm-9225), erlotinib (olatinib) (Osteinib 92203), erlotinib (Kvaninib) (ASP-2219, getinib (Kvaninib) (ODm-22125), getinib (ovatinib), erlotinib) (Osteinib (Kylinib), erlotinib) (Osteinib) (ODm-22125), Ib (Klinitinib), Ib (Kylinib) (Osteinib) (I-22125), Ib), Ipomib (Tab), Ipomib), Ib (Tatinib, Quinatinib (quizartinib), ladostinib (raditinib), rocitinib (rociletinib), sufantinib (sunitinib) (HMPL-012), sunitinib (sunitinib), tifanib (tivonib), TH-4000, MEDI-575 (anti-PDGFR antibody).

As used herein, the term "chemotherapeutic agent" or "chemotherapy" (or "chemotherapy" in the context of treatment with a chemotherapeutic agent) is intended to encompass any non-proteinaceous (i.e., non-peptide) compound suitable for treating cancer. Examples of chemotherapeutic agents include (but are not limited to): alkylating agents, such as thiotepa and cyclophosphamideAlkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodepa, carboquone, meturedepa, and uredepa; ethyleneimine and methyl melamine including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimetholomelamine; polyacetylenes (acetogenins), in particular bullatacin (bullatacin) and bullatacin (bullatacinone); camptothecin, including the synthetic analog topotecan; bryostatin, marine chalone (callystatin); CC-1065, including the synthetic analogs of adozelesin, carzelesin, and bizelesin; cryptophycins, in particular cremophin 1(cryptophycin 1) and cremophin 8; dolastatin (dolastatin); duocarmycin (duocarmycin), including the synthetic analogs KW-2189 andCBI-TMI; eiscosahol (eleutherobin); 5-azacytidine; discostatin (pancratistatin); sarcandra glabra alcohol (sarcodictyin); spongistatin (spongistatin); nitrogen mustards such as chlorambucil (chlorambucil), cyclophosphamide, glufosfamide (glufosfamide), avotame (evofosfamide), bendamustine (bendamustine), estramustine (estramustine), ifosfamide (ifosfamide), mechlorethamine (mechlorethamine), oxydichloroethylmethylamine hydrochloride, melphalan (melphalan), neomustard (novembichin), benzene mustard cholesterol (pheresterestine), prednimustine (prednimustine), triamcinolone (trofosfamide), and uracil mustard; nitrosoureas such as carmustine (carmustine), chlorozotocin (chlorozotocin), fotemustine (formustine), lomustine (lomustine), nimustine (nimustine) and ramustine (ranimustine); antibiotics, such as enediyne antibiotics (e.g. calicheamicin), especially calicheamicin gamma II and calicheamicin) Damycin (dynemicin) (including damycin a), bisphosphonates (such as clodronate), esperamicin (esperamicin), neocanostatin chromophores and related chromoprotein enediyne antibiotic chromophores, aclacinomycin (aclacinomycin), actinomycin (aurramycin), azoserine, bleomycin (bleomycin), actinomycin C, carabicin (carabicin), carinamicin (carninomycin), carcinomycin (carzinophilin), chromomycin (chromomycins), actinomycin D, daunomycin, ditocin (detoribicin), 6-orubin-5-lateral oxy-L-norleucine, doxorubicin (including (N-morpholinyl) -doxorubicin, cyano (N-deoxymorpholinyl) -doxorubicin, 2-pyrrolinyl-doxorubicin and epirubicin), doxorubicin (isorubicin), doxorubicin (doxycycline-rubicin), and doxorubicin (doxycycline) Idarubicin (idarubicin), marijumicin (marcellomycin), mitomycin (such as mitomycin C), mycophenolic acid, nogomycin (nogalamycin), olivomycin (olivomycin), pelomycin (polyplomycin), porfiromycin (porfiromycin), puromycin (puromycin), quinomycin (quelamycin), and rodobicin (ro)dorubicin), streptonigrin (streptonigrin), streptozotocin (streptozocin), tubercidin, ubenimex (ubenimex), restatin (zinostatin), and levorubicin (zorubicin); antimetabolites such as methotrexate and 5-fluorouracil; folic acid analogs such as dimulin (demopterin), methotrexate, pteropterin (pteropterin), and trimetrexate (trimetrexate); purine analogs such as fludarabine (fludarabine), 6-mercaptopurine, thiamiprine (thiamiprine), and thioguanine; pyrimidine analogs such as ancitabine (ancitabine), azacitidine, 6-azauridine, carmofur (carmofur), cytarabine (cytarabine), dideoxyuridine (dideoxyuridine), deoxyfluorouridine (doxifluridine), enocitabine (enocitabine), and floxuridine (floxuridine); androgens such as carotinone (calusterone), dromostanolone propionate, epitioandrostanol (epitiostanol), mepiquitane (mepiquitane), and testolactone; anti-adrenaline such as amikacin (aminoglutethimide), mitotane (mitotane) and trilostane (trilostane); folic acid replenisher such as folinic acid; radiotherapeutic agents, such as radium-223; trichothecenes, especially T-2 toxin, vernacrine A (verracutinin A), tuberculin A (roridin A), and aminocephaline (anguidine); taxanes (taxoids), such as paclitaxelAbiraxan (abraxane), docetaxel (docetaxel)Carbazitaxel (cabazitaxel), BIND-014, tesetaxel (tesetaxel); platinum analogs such as cisplatin and carboplatin, NC-6004 neplatinum (nanoplatin); acetyl glucuronate (acegultone); (ii) an aldophosphamide glycoside; aminolevulinic acid (aminolevulinic acid); eniluracil (eniluracil); amsacrine (amsacrine); hebrschil (hestrabucil); bisantrene; edatrexed (edatraxate); delphamide (defofamine); dimecorsine (demecolcine); diazaquinone (diaziqutone); efaxin (elformmint); illicium acetate (ellitinium aceta)te); epothilones (epothilones); etoglut (etoglucid); gallium nitrate; a hydroxyurea; lentinan (lentinan); leucovorin (leucovorin); lonidamine (lonidamine); maytansinoids (maytansinoids), such as maytansine and ansamitocins (ansamitocins); propiguanylhydrazone (mitoguzone); mitoxantrone (mitoxantrone); mopidamol (mopidamol); diamine nitracridine (nitrarine); pentostatin (pentostatin); vannamine (phenamett); pirarubicin (pirarubicin); losoxantrone (losoxantrone); fluoropyrimidines; an aldehyde folic acid; podophyllinic acid (podophyllic acid); 2-ethyl hydrazide; procarbazine polysaccharide-k (psk); razoxane (rizoxane); rhizoxin (rhizoxin); sisofilan (sizofiran); helical germanium; tenuazonic acid (tenuazonic acid); trabectedin, triimiquiquinone (triaziquone); 2,2 ', 2 "-terlomitamine (2, 2', 2" -tricuorotriviamine); a carbamate; vindesine (vindesine); dacarbazine (dacarbazine); mannitol mustard (mannomustine); dibromomannitol (mitobronitol); dibromodulcitol (mitolactol); pipobromane (pipobroman); gatifloxacin (gacytosine); arabinoside ("Ara-C"); cyclophosphamide; a thiopeta (thiopeta); chlorambucil; gemcitabine (gemcitabine)6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbineMitoxantrone; (ii) teniposide; edatrexate (edatrexate); daunorubicin (daunomycin); aminopterin (aminopterin); (xioloda); ibandronate (ibandronate); CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine acid (DFMO); retinoids, such as retinoic acid; capecitabine (capecitabine); NUC-1031; FOLFIRI (fluorouracil, leucovorin (leucovorin), and irinotecan); and a pharmaceutically acceptable salt, acid or derivative of any of the above.

The definition of "chemotherapeutic agent" also includes anti-hormonal agents such as anti-estrogen and Selective Estrogen Receptor Modulators (SERMs) for modulating or inhibiting hormonal effects on tumors, aromatase inhibitors, anti-androgens and pharmaceutically acceptable salts, acids or derivatives of any of the above.

Anti-hormonal agents

Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEX)^TM) Raynaoxifene (raloxifene), traloxifene (droloxifene), 4-hydroxyttamoxifen, triptoxifene (trioxifene), raloxifene (keoxifene), LY117018, onapristone (onapristone), and toremifene (toremifene)

Aromatase inhibitors modulate estrogen production in the adrenal gland. Examples include 4(5) -imidazole, amin gluten, megestrol acetateExemestane (exemestane), formestane (formestane), fadrozole (fadrozole), vorozole (vorozole)Letrozole (letrozole)And anastrozole (anastrozole)

Examples of antiandrogens include alprenolomide (apalcutamine), abiraterone (abiraterone), enzalutamide (enzalutamide), flutamide (flutamide), galitolone (galeterone), nilutamide (nilutamide), bicalutamide (bicalutamide), leuprolide (leuprolide), goserelin, ODM-201, APC-100, ODM-204.

Examples of progesterone receptor antagonists include onapristone.

Anti-angiogenic agents

Anti-angiogenic agents include, but are not limited to, retinoids and derivatives thereof, 2-methoxyestradiol,Regorafenib, nicandraba (necoparanib), suramin (suramin), squalamine (squalamine), tissue inhibitors of metalloproteinase-1, tissue inhibitors of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage derived inhibitors, paclitaxel (albumin bound paclitaxel), platelet factor 4, protamine sulfate (menhaden), sulfated chitin derivatives (prepared from crab shell), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, matrix metabolism regulators (including amino acid analogs such as l-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d, I-3, 4-dehydroprolide, thioprolide), α' -bipyridyl, β -aminopropionitrile fumarate, 4-propyl-5- (4-pyridyl) -2 (3-disoproxil) -2 (heparin-2), heparin-aminopterin inhibitor (VEGF-5), heparin-2-aminopterin inhibitor (e.g), heparin-2- α -kinase inhibitor, heparin-2 inhibitor, heparin- α -2, heparin-2- α -2, heparin- α -2- α -2, heparin- α -2- α -2, heparin- α (e, heparin- α -2- α -2- α -2, heparin- α -2- α -2- α -.

Anti-fibrotic agents

Anti-fibrotic agents include, but are not limited to, compounds such as beta-aminopropionitrile (BAPN), as well as compounds disclosed in US 4965288 related to inhibitors of ionoxygenases and their use in treating diseases and conditions associated with abnormal deposition of collagen, and compounds disclosed in US 4997854 related to compounds that inhibit LOX to treat various pathological fibrotic conditions, which applications are incorporated herein by reference. Other exemplary inhibitors are described in US 4943593 relating to compounds such as 2-isobutyl-3-fluoro-allylamine, 2-isobutyl-3-chloro-allylamine, or 2-isobutyl-3-bromo-allylamine; US 5021456, US 5059714, US 5120764, US 5182297, US 5252608 related to 2- (1-naphthyloxymethyl) -3-fluoroallylamine; and US 2004-.

Exemplary anti-fibrotic agents also include primary amines that react with a carbonyl group off the active site of the aminoacyloxidase, and more particularly primary amines that generate resonance stabilization products upon binding of the carbonyl group, such as the following primary amines: ethylenediamine (ethylene imine), hydrazine, phenylhydrazine and derivatives thereof; amine ureas and urea derivatives; aminonitriles such as BAPN or 2-nitroacetamine; unsaturated or saturated haloamines such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halophenylmethylamine; and seleno homocysteine lactone.

Other anti-fibrotic agents are copper chelators that are permeable or impermeable to cells. Exemplary compounds include indirect inhibitors that block aldehyde derivatives derived from the oxidation de-amination of the ionomido and hydroxyionomido residues by ionomido oxidase. Examples include thiolamines (especially D-penicillamine) and their analogues such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3- ((2-acetamidoethyl) disulfide) butyric acid, p-2-amino-3-methyl-3- ((2-aminoethyldisulfide) butyric acid, sodium sulfide-4- ((p-1-dimethyl-2-amino-2-carboxyethyl) disulfide) butane, 2-acetamidoethyl-2-acetamidoenethiol sulfonate and sodium-4-mercaptobutanesulfinate trihydrate.

Immunotherapeutic agent

Immunotherapeutics include, but are not limited to, therapeutic antibodies suitable for treating a subject. Some examples of therapeutic antibodies include abamectin (abagovacab), ABP-980, adalimumab (adecatumum)ab, aftuzumab (afutuzumab), alemtuzumab (alemtuzumab), alemtuzumab (aleumumab), amamicumab (amatuximab), nummulumab (anatuomab), alemtuzumab (arctumomab), bavituximab (bavituximab), betuzumab (bectmomab), bevacizumab (bevacizumab), bivatuzumab (bivatuzumab), brenmumab (blinatumumab), bevatuzumab (brentum), tocytuzumab (cantuzumab), catuoximab (catamaxb), CC49, cetuximab (cetuximab), cetuximab (cettuzumab), cetuximab (cetuximab), cetuximab (rituximab), afuzumab (clavumab), alexituzumab (rituximab (seditumab), rituximab (seditumab (sedatuzumab), rituximab (seduttatuguex (sedatuzumab), rituximab (sedatuzumab), image (sed, Eimeria-pertuzumab (emibetuzumab), enzitumumab (ensituximab), estummomab (ertumaxomab), edazumab (etaracizumab), valtuzumab (farletuzumab), felatuzumab (ficlatuzumab), non-gemumab (figitumumab), flantezumab (flinvitumumab), pumicitumab (futuximab), ganitumab (ganitumumab), gemtuzumab (gemtuzumab), gemtuzumab ozolomide (glimbatuzumab), isometrizumab (ibritumomab), goitumomab (igomomab), immungitumumab (immitumumab), induzumab (induzumab), itumomab (inmotuzumab), intuzumab (intrigitumomab), rituximab (igomozumab), golimumab (igoimab), immitumumab (immitumumab), rituzumab (infliximab), etc. (indiumumab)MDX-010, BMS-734016, and MDX-101), itumumab (iratuzumab), rabepredumab (labeuzumab), lesinumab (lexatuzumab), lintuzumab (lintuzumab), lovastatin (lorvotuzumab), lucatumumab (lucatumab), mapatumumab (mapatumumab), matuzumab (matuzumab), miralizumab, minremoumab (minretumumab), mitumumab (mitumomab), and mogulizumab (mog)amulizumab, moxidermumab (moxetumumab), namomab (naptuzumab), nanatumumab (narnatumamab), lesitumumab (necitumumab), nimotuzumab (nimotuzumab), norfitumab (nofetumumab), obit-833, obinutuzumab (obinutuzumab), ocattlumab (ocartuzumab), ofatumumab (ofatumumab), olanzumab (olabrazumab), olanzumab (olatsumacumab), olanzumab (olanzumab), onartumab (onartuzumab), oportuzumab (oportuzumab), origomtuzumab (oredomomab), panitumumab (panitumumab), pacakazumab (sapartuzumab), pantuzumab (panitumumab), pantuzumab (sapuzumab), pantuotuzumab (sapatuzumab), pantuotuzumab (pantuotuzumab), pantuotuzumab (raputamtuzumab), pantuzumab (raputab), brauzumab (raputamtuzumab), pantuzumab (raputab), brauzumab (raputab), brauzumab), brazzumab (raputab), brazzumab (rapatuzumab), brazzumab), or brazzumab (rapatuzumab), or brazzumab)Riluzumab (rilotuzumab), rituximab (rituximab), rituximab (robitumumab), sibutrumab (robitumumab), semuximab (situximab), solituzumab (solituzumab), samuzumab (satumomab), sibutrumab (sibutrumab), situzumab (stauthuzumab), tapentaumab (tapetum umab), teprotitumumab (teprotuzumab), tikazumab (tigatuzumab), tositumomab (tositumomab), trastuzumab (trastuzumab), tuzumab (tuzumab), wutuzumab (tuzumab), wuxituzumab (ulituzumab), veveluzumab (tuzumab), trastuzumab (trastuzumab), wauzumab (tuzumab), wutuzumab (rituxuzumab), wurtuzumab (wutuzumab), wutuzumab (wurtutuzumab), and (8). Rituximab is useful in the treatment of indolent B cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. Rituximab is particularly effective in combination with chemotherapeutic agents.

Exemplary therapeutic antibodies may be further labeled with or combined with radioisotope particles, such as indium-111, yttrium-90 (90Y-pivatumab), or iodine-131.

Cancer gene therapy and cell therapy

Cancer gene therapy and cell therapy include insertion of normal genes into cancer cells to replace mutated or altered genes; genetic modification for silencing a mutant gene; genetic methods for direct killing of cancer cells; an infusion of immune cells designed to replace a majority of the subject's autoimmune system to enhance the immune response to cancer cells or to activate the subject's autoimmune system to kill cancer cells or to seek out and kill cancer cells; genetic methods for modifying cellular activity to further alter endogenous immune responses against cancer.

Gene editing agent

Examples of genome editing systems include CRISPR/Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems, and meganuclease systems.

CAR-T cell therapy and TCR-T cell therapy

CAR-T cell therapy includes a population of immune effector cells engineered to express a Chimeric Antigen Receptor (CAR), wherein the CAR comprises a tumor antigen binding domain. The immune effector cell is a T cell or an NK cell. TCR-T cell therapies include TCR-T cells engineered to target tumor-derived peptides on the surface of tumor cells. The cells may be autologous or allogeneic.

In some embodiments, the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain.

In some embodiments, the intracellular domain comprises a primary signaling domain, a costimulatory domain, or both a primary signaling domain and a costimulatory domain.

In some embodiments, the primary signaling domain comprises one or more functional signaling domains of a protein selected from the group consisting of: CD3 ζ, CD3 γ, CD3, CD3, common FcR γ (fcrig), fcrβ (FcRlb), CD79a, CD79b, Fc γ RIIa, DAP10, and DAP 12.

In some embodiments, the co-stimulatory domain comprises one or more functional domains of a protein selected from the group consisting of: CD, 4-1BB (CD137), OX, CD, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD, LIGHT, NKG2, B-H, a ligand that specifically binds to CD, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHT TR), SLAMF, KLRF, CD160, CD alpha, CD beta, IL2 gamma, IL7 alpha, ITGA, VLA, CD49, ITGA, IA, CD49, ITGA, VLA-6, CD49, ITGAD, CD11, ITGAE, CD103, ITGAL, CD11, LFA-1, ITGAM, CD11, ITGAX, CD11, ITGB, CD, LFA-1, ITGB, TNFR, CD103, CD160, SLAMM-160, ACAM 2, CD150, TAAMF-100, TAAMF-1, CD-100, TAAMF, CD-1, CD-6, CD-ITGA, CD49, ITGAD, ITGAE, CD103, ITGAE, CD-7, ITGAL, NKRF, CD-6, CD-7, ITGAL, BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, NKp44, NKp30, NKp46, and NKG 2D.

In some embodiments, the transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of: CD, GITR, CD, BAFFR, HVEM (LIGHT TR), SLAMF, NKp (KLRF), CD160, CD, IL2 beta, IL2 gamma, IL7 mu, ITGA, VLA, CD49, ITGA, IA, CD49, ITGA, VLA-6, CD49, ITGAD, CD11, ITGAE, CD103, ITDNA, CD11, ITGAL-1, ITGAM, CD11, ITGAX, CD11, ITGB, CD, LFA-1, ITGB, TNFR, GALM (226), SLAMF, LFA-1, CD, LFA-1, CD-150, TAAMGL, CD-1, CD-60, CD-1, CD-150, TAAMBR, TAAMF (TAAMBR), CD-1, CD-60, CD-150, CD-CD, NKp44, NKp30, NKp46, NKG2D and NKG 2C.

In some embodiments, the antigen binding domain binds to a tumor antigen.

In some embodiments, the tumor antigen is selected from the group consisting of: CD 19; CD 123; CD 22; CD 30; CD 171; CS-1 (also known as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A 24); c-type lectin-like molecule-1 (CLL-1 or CLECLI); CD 33; epidermal growth factor receptor variant iii (egfrvlll); ganglioside G2(GD 2); ganglioside GD3(aNeuSAc (2-8) aNeuSAc (2-3) bDGaip (1-4) bDGIcp (1-1) Cer); TNF receptor family member B Cell Maturation (BCMA); tn antigen ((Tn Ag) or (GaINAcu-Ser/Thr)); prostate Specific Membrane Antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (RORI); fms-like tyrosine kinase 3(FLT 3); tumor associated glycoprotein 72(TAG 72); CD 38; CD44v 6; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3(CD 276); KIT (CD 117); interleukin-13 receptor subunit alpha-2 (IL-13Ra2 or CD213A 2); mesothelin; interleukin 11 receptor alpha (IL-11 Ra); prostate Stem Cell Antigen (PSCA); protease serine 21 (testosterone or PRSS 21); vascular endothelial growth factor receptor 2(VEGFR 2); a lewis (Y) antigen; CD 24; platelet-derived growth factor receptor beta (PDGFR-beta); stage-specific embryonic antigen-4 (SSEA-4); CD 20; sample 3(DLL 3); a folate receptor alpha; receptor tyrosine-protein kinase ERBB2(Her 2/neu); cell surface associated mucin 1(MUC 1); epidermal Growth Factor Receptor (EGFR); neuronal Cell Adhesion Molecule (NCAM); prostasin; prostatic Acid Phosphatase (PAP); mutant elongation factor 2(ELF 2M); aprepilin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-I receptor), carbonic anhydrase ix (caix); proteasome (precursor, megalin) subunit, beta form, 9(LMP 2); glycoprotein 100(gp 100); an oncogene fusion protein (BCR-Abl) consisting of a Breakpoint Cluster Region (BCR) and the homolog 1(Abl) of the Abelson murine leukemia virus oncogene; tyraminidase; eprinolin type a receptor 2(EphA 2); fucoidan-based GM 1; a sialyl lewis adhesion molecule (sLe); ganglioside GM3(aNeuSAc (2-3) bDGalp (1-4) bDGlcp (1-1) Cer); transglutaminase 5(TGS 5); high Molecular Weight Melanoma Associated Antigen (HMWMAA); o-acetyl-GD 2 ganglioside (OAcGD 2); folate receptor beta; tumor endothelial marker 1(TEM1/CD 248); related tumor endothelial marker 7(TEM 7R); prostate six transmembrane epithelial antigen I (STEAP 1); claudin 6(CLDN 6); thyroid Stimulating Hormone Receptor (TSHR); class C G protein-coupled receptors, group 5, member d (gprcsd); x chromosome open reading frame 61(CXORF 61); CD 97; CD179 a; polymorphic lymphoma kinase (ALK); polysialic acid; placenta-specific 1(PLAC 1); the hexasaccharide moiety of a globoH glycosylceramide (globoH); mammary differentiation antigen (NY-BR-1); urosoluble protein 2(UPK 2); hepatitis a virus cell receptor 1(HAVCR 1); adrenergic receptor β 3(ADRB 3); ubiquitin 3(PANX 3); g protein-coupled receptor 20(GPR 20); lymphocyte antigen 6 complex, locus K9 (LY 6K); olfactry receptor 51E2(ORS IE 2); TCR γ alternative reading frame protein (TARP); wilms tumor protein (Wilms tumor; WT 1); cancer/testis antigen 1 (NY-ESO-1); cancer/testis antigen 2 (LAGE-la); melanoma-associated antigen 1(MAGE-a 1); ETS translocation variant 6, located on chromosome 12p (ETV 6-AML); sperm protein 17(SPA 17); the X antigen family, member 1A (XAGE 1); angiogenin binds to cell surface receptor 2(Tie 2); melanoma cancer testis antigen-1 (MADCT-1); melanoma cancer testis antigen-2 (MAD-CT-2); fos-related antigen 1; tumor protein p53(p 53); a p53 mutant; prostate protein; survivin; a telomerase; prostate cancer tumor antigen-1 (PCTA-1 or galectin 8), melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); a sarcoma translocation breakpoint; melanoma apoptosis inhibitors (ML-IAP); ERG (transmembrane protease, serine 2(TMPRSS2) ETS fusion gene); n-acetylglucosaminyltransferase V (NA 17); paired-box protein Pax-3(PAX 3); an androgen receptor; cyclin B1; v-myc avian myelomatosis virus oncogene neuroblastoma-derived homolog (MYCN); ras homolog family member c (rhoc); tyraminidase-related protein 2 (TRP-2); cytochrome P4501B 1 (CYPIBI); CCCTC binding factor (zinc finger protein) like (BORIS or Brother of modulators of imprinted sites), squamous cell carcinoma antigen recognized by T cells 3(SART 3); paired-box protein Pax-5(PAX 5); the anterior vertex voxel binding protein sp32(OY-TES I); lymphocyte specific protein tyrosine kinase (LCK); a kinase anchor protein 4 (AKAP-4); synovial sarcoma, X breakpoint 2(SSX 2); receptors for advanced glycation end products (RAGE-I); renal ubiquitin 1 (RUI); renal ubiquitin 2(RU 2); legumain; human papilloma virus E6(HPV E6); human papilloma virus E7(HPV E7); an intestinal carboxylesterase; mutant heat shock protein 70-2(mut hsp 70-2); CD79 a; CD79 b; CD 72; leukocyte-associated immunoglobulin-like receptor 1 (LAIRI); an Fc fragment of IgA receptor (FCAR or CD 89); leukocyte immunoglobulin-like receptor subfamily a member 2(LILRA 2); CD300 molecular-like family member f (CD300 LF); c-type lectin domain family 12 member a (CLEC 12A); bone marrow stromal cell antigen 2(BST 2); EGF-like module 2(EMR2) containing mucin-like hormone receptors; lymphocyte antigen 75(LY 75); phosphoinositide proteoglycan-3 (GPC 3); fc-like receptor 5(FCRL 5); and immunoglobulin lambda-like polypeptide 1(IGLL 1).

In some embodiments, the tumor antigen is selected from the group consisting of CD150, 5T4, ActRIIA, B7, BMCA, CA-125, CCNA 7, CD123, CD126, CD138, CD7, CD148, CD7, CD200, CD7, CD261, CD262, CD 7-D, CD7, CE7, CS-1, CSPG 7, CSPG-B fiber binding protein, EGFR, EGFP-2, EGFP-4, EGFP-7, EGFP-72, EGFP-7, EGFP-72, EGFP-7, EGHER-72, EGFP-72, EGHER-7, EGHER-72, EGHER-HBr-72, EGHER-3-7, EGHER-HBr-3-7, EGHER-HBr-7, EGB-36, IL-2, IL-22R-alpha, IL-6R, Ia, Ii, L1-CAM, L1 cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-Rl (DR4), TRAIL-R2(DR5), VEGF, VEGFR2, WT-I, G protein-coupled receptor, Alpha Fetoprotein (AFP), angiogenic factor, exogenous homologous binding molecule (ExoCBM), oncogene product, anti-receptor, c-Met, carcinoembryonic antigen (CEA), cyclin (D1), ephrin B2, epithelial antigen receptor, acetylcholine receptor, gp100, and the like, Hepatitis B surface antigen, kappa chain, kappa light chain, kdr, lambda chain, livin, melanoma-associated antigen, mesothelin, mouse double mini 2 homolog (MDM2), mucin 16(MUC16), mutant P53, mutant ras, necrotic antigen, carcinoembryonic antigen, ROR2, progesterone receptor, prostate specific antigen, tfegfr, tenascin, P2-microglobulin, Fc-like receptor 5(FcRL 5).

Non-limiting examples of cell therapies include algenpancreatcel-L, Sipuleucel-T, (BPX-501) Rivogenlecule US9089520, WO2016100236, AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, Imileckeuelel-T, Batareel-T (Bataleuceuelel-T), PNK-007, UCCS ART 1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, FT-1050 treated bone marrow stem cell therapy, CD4CARNK-92 cells, CryoStim, allo Stim, slow transduced huCART-22 cells, CAR/BBT-19-28-19/GRT-19/19-7/19-GREFZ-3612/539, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, CSG-005.

In some embodiments, the tumor targeting antigen comprises: alpha-fetoproteins such as ET-1402 and AFP-TCR; coalignal toxin receptor 1, such as anti-TEM 8 CAR T cell therapy; b Cell Maturation Antigens (BCMA) such as BB-2121, UCART-BCMA, ET-140, KITE-585, MCM-998, LCAR-B38M, CART-BCMA, SEA-BCMA, BB212, UCART-BCMA, ET-140, P-BCMA-101, AUTO-2 (APRIL-CAR); anti-CLL-1 antibodies, such as-796; b7 homolog 6, such as CAR-NKp30 and CAR-B7H 6; b-lymphocyte antigens CD19 such as TBI-1501, CTL-119huCART-19T cells, JCAR-015US7446190, JCAR-014, JCAR-017, WO2016196388, WO2016033570, WO2015157386), Cicaducil (axicabagene ciloleucel) (KTE-C19), US7741465, US6319494, UCART-19, EBV-CTL, Titsangelnokui-T (T tisagenglelecuceuelel-T) (CTL019), WO 2019000, WO2017049166, CD 19-CD 28-CD3 zeta-EGF expressing T cells, CD19/4-1BBL armored T cell therapy, C-CAR-011, CIK-CAR.19, CD 19-zeta 28-CDT cells, PCCAR-019, MatchCAR, DSCAR-01-BCAR 19; b-lymphocyte antigens CD20, such as ATTCK-20; b-lymphocyte cell adherents such as UCART-22, JCAR-018WO 2016090190; NY-ESO-1, such as GSK-3377794, TBI-1301; carbonic anhydrases such as DC-Ad-GMCAIX; caspase 9 suicide genes such as CaspaciDe DLI, BPX-501; CCR5, such as SB-728; CDw123 such as MB-102, UCART-123; CD20m, such as CBM-C20.1; CD4, such as ICG-122; CD30, such as CART30 (CBM-C30.1; CD33, such as CIK-CAR CD33; CD38, such as T-007, UCART-38; CD40 ligands, such as BPX-201; CEACAM protein 4 modulators, such as MG 7-CART; claudin 6, such as CSG-002; targeting EBV, such as CMD-003; EGFR, such as autologous 4H11-28 z/fIL-12/GREFT cells; endonucleases, such as PGN-514, PGN-201; Epstein-Barr virus (Epstein-Barrvirus) specific T lymphocytes, such as TT-10; Erbb2, such as CICAR-102; ganglioside (DeGD 2), such as SCA R-GD 2; aminopeptidase II, such as CIK-CAR, RDT-CAR, PSMA-101-beta-TGF-3; PSMA-3; phosphoinositide-GPC protein), such as TT-16, GLYCAR; hemoglobin, such as PGN-236; hepatocyte growth factor receptors, such as anti-cMet RNA CAR T; human papilloma virus E7 proteins, such as KITE-439; immunoglobulin γ Fc receptor III, such as ACTR 087; IL-12, such as DC-RTS-IL-12; IL-12 agonist/mucin 16, such as JCAR-020; IL-13 α 2, such as MB-101; IL-2, such as CST-101; K-Ras GTPase, such as anti-KRAS G12V mTCR cell therapy; a neuronal cell adhesion molecule L1L 1CAM (CD171), such as JCAR-023; latent membrane protein 1/latent membrane protein 2, autologous dendritic cells transduced with Ad5f35-LMPd 1-2; melanoma-associated antigen 10, such as MAGE-a10C796TMAGE-a10 TCR; melanoma-associated antigen 3/melanoma-associated antigen 6(MAGE A3/a6), such as kit-718; mesothelins such as CSG-MESO, TC-210; NKG2D, such as NKR-2; ntrkr1 tyrosine kinase receptors, such as JCAR-024; t cell receptors such as BPX-701, IMCgp 100; t lymphocytes such as TT-12; tumor-infiltrating lymphocytes such as LN-144, LN-145; and Wilms tumor proteins such as JTCR-016, WT 1-CTL.

Lymphoma or leukemia combination therapy

In some embodiments, the additional therapeutic agent is suitable for treating a lymphoma or leukemia. These agents include aldesleukin, aldibodib, amifostine trihydrate, aminocamptothecin (amin)ocamptothecin), antineoplaston A10(antineoplaston A10), anti-neoplaton AS2-1, anti-thymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, β alicine (betaalethine), BMS-345541, bortezomib (bortezomib)Bortezomib (b)PS-341), bryodin 1, Buschufan (buckulfan), kaposi-1H (campath-1H), carboplatin, carfilzomib (carfilzomib)Carmustine, caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide, adriamycin, vincristine and prednisone), cisplatin, cladribine, clofarabine, curcumin, CVP (cyclophosphamide, vincristine and prednisone), cyclophosphamide, cyclosporine, cytarabine, dilleukin diftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicin hydrochloride, DT-PACE (dexamethasone, thalidomide, cisplatin, adriamycin, cyclophosphamide and etoposide), enzastarin (zaestaurin), epoetin (epoetin alfa), etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide and tolteroxantrone), FCR (fludarabine, cyclophosphamide and ritinib), etoposide (irinotecan), etoposide (valvimentine), doxorubine (APR, doxorubine, doxycycline hydrochloride), dexrazine (cisplatin), doxycycline hydrochloride, cisplatin, rituximab (E), dexrazine (ibandrographofirpoint-E), doxycycline (E) and doxycycline (cisplatin), dexrazine (ibamide), dexrazine (ibandrocine (E), dexrazine), doxycycline (E, doxycycline (E, doxycyclineCC-5013), lymphomedium-activated killersThe composition comprises a cell, MCP (mitoxantrone, chlorambucil and polamonylon), melphalan, mesna (mesna), methotrexate, mitoxantrone hydrochloride, motoxafen gadolinium, mycophenolate mofetil (mycophenolate mofetil), nelarabine (nelarabine), obacara (obaclax) (GX15-070), oblimersen (oblimersen), octreotide acetate (octreotide acetate), omega-3 fatty acid, Omr-IgG-am (WNIG, orix), oxaliplatin, paclitaxel, paleociclib (Palbociclib) (PD 2903391), peggefitinib (pegvistin), pegylated liposome doxorubicin hydrochloride, pefuricin (perifossin), polonilone, prednisone, recombinant mevinolin 3, interferon, phytonciclovir, phytoncine (CVR-12), vincristine citrate-IV), vincristine (HCR-N), vincristine-D-E), vincristine (HCI), vincristine-E), vincristine (HCI), vincristine (HCI-E), vincristine (HCI), vincristine (HCI-E), vincristine (HCI-E), vincristine (HCI-E), vincristine (HCI-E), vincristine (HCI-E-L-E), vincristine (HCI-L-E), vincristine (HCI-E-L-E-L-E-L-202), vincristine (HCI-E), vincristine (HCI-L-E), vincristine (HCI-L), vincVenetork (ABT-199).

An improved method is radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles, such as indium-111, yttrium-90 and iodine-131. Examples of combination therapies include, but are not limited to, iodine-131 tositumomabYttrium-90 ibritumomab tiuxetanAndand CHOP.

The above therapies may be supplemented with or combined with stem cell transplantation or treatment. Therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biologic therapy, enzyme inhibitor therapy, systemic irradiation, stem cell infusion, bone marrow ablation with stem cell support, peripheral blood stem cell transplantation by ex vivo treatment, umbilical cord blood transplantation, immunoenzyme technology, low LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

Non-hodgkin's lymphoma combination therapy

In some embodiments, other therapeutic agents are useful for treating non-hodgkin's lymphoma (NHL), particularly non-hodgkin's lymphoma of B-cell origin, including monoclonal antibodies, standard chemotherapy methods (e.g., CHOP, CVP, FCM, MCP, and the like), radioimmunotherapy, and combinations thereof, particularly combinations of antibody therapy and chemotherapy.

Examples of unbound monoclonal antibodies for use in the treatment of NHL/B cell cancers include rituximab, alemtuzumab, human or humanized anti-CD 20 antibody, lumiximab (lumiiximab), anti-TNF-related apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD 74.

Examples of experimental antibody agents for the treatment of NHL/B cell cancer include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumizezumab, aprezumab, milnaclizumab, and bevacizumab.

Examples of standard regimens for chemotherapy of NHL/B cell cancers include CHOP, FCM, CVP, MCP, R-CHOP, R-FCM, R-CVP, and R-MCP.

Example packages for radioimmunotherapy for NHL/B cell cancersIncluding yttrium-90 Bluemerumab tezetan (ibritumomab tiuxetan)And iodine-131 tositumomabCombined therapy for mantle cell lymphoma

In some embodiments, the other therapeutic agent is suitable for treating Mantle Cell Lymphoma (MCL), which includes combination chemotherapy such as CHOP, hyperCVAD, and FCM. These regimens may also be supplemented with the monoclonal antibody rituximab to form combination therapies R-CHOP, hyperCVAD-R and R-FCM. Any of the above therapies may be combined with stem cell transplantation or ICE to treat MCL.

Other examples of therapeutic agents suitable for treating MCL include:

immunotherapy, such as monoclonal antibodies (e.g. rituximab) and cancer vaccines, such as GTOP-99, based on the genetic composition of the tumor of the individual subject;

radioimmunotherapy, in which monoclonal antibodies are combined with radioisotope particles, such as iodine-131 tositumomabYttrium-90 ibritumomab tiuxetanAndsequentially with CHOP for treatment;

autologous stem cell transplantation coupled with high-dose chemotherapy, administration of proteasome inhibitors such as bortezomib (bOr PS-341), or administering an anti-angiogenic agent, such as thalidomide, especially in combination with rituximab;

-drugs that cause Bcl-2 proteolysis and increase cancer cell sensitivity to chemotherapy, such as olymerson, in combination with other chemotherapeutic agents;

mTOR inhibitors, which can cause inhibition of cell growth and even cell death. Non-limiting examples are sirolimus, temsirolimus (A)CCI-779), CC-115, CC-223, SF-1126, PQR-309 (bimiralisib), Woltasib (voxtalisib), GSK-2126458 and temsirolimusOr a combination of other chemotherapeutic agents;

other agents, such as flazapine, paleocoxib (PD0332991), R-rosuvastatin (CYC 202), styryl sulfone, olbazole (GX15-070), TRAIL, anti-TRAIL death receptors DR4 and DR5 antibodies, temsirolimus (R: (R) (R))CCl-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (R) ((R)CC-5013) and geldanamycin (17-AAG).

Combination therapy for Waldenstrom's Macroglobulinemia in some embodiments, these other therapeutic agents are suitable for use in the treatment of Waldenstrom's Macroglobulinemia (WM), including aldesleukin, alemtuzumab, axidibu, amifostine trihydrate, aminocamptothecin, anti-neopralatone A10, anti-neopralatone AS2-1, anti-thymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitors ABT-263, β aricin, BortezomibBryodin 1, busulfan, caspasi-1H, carboplatin, carmustine, caspofungin acetateCC-5103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, dinicointerleukin, dexamethasone, docetaxel, dolastatin 10, doxorubicin hydrochloride, DT-PACE, enzastalin, alfacacetin, epratuzumab (hLL 2-anti-CD 22 humanized antibody), etoposide, everolimus, feitinib, filgrastim, fludarabine, ifosfamide, indium-111 monoclonal antibody MN-14, iodo-131 tositumomab, human irinotecan hydrochloride, ixabepilone, lymphomedium-activated killer cells, melphalan, mesna, methotrexate, mitoxantrone hydrochloride, monoclonal antibody CD19 (such as tesselinu-T, CART-19, CTL-019), monoclonal antibody CD20, motroxafine, gadolinium mycophenolate ethyl ester, nelarabine, ormin, olmersin, octreotide acetate, omega-3 fatty acid, oxaliplatin, paclitaxel, pegaptanide, pegapterin hydrochloride, recombinant pegapterin, pegvisfatin form 7, pegapterin hydrochloride, recombinant pegvisfatin formSimvastatin, sirolimus, tacrolimus, temspiramycin, thalidomide, therapeutic allogenic lymphocytes, thiotepa, tipifarnib, tositumomab, vetotuzumab, vincristine sulfate, vinorelbine bitartrate, vorinostat, WT 1126-134 peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomab, yttrium-90 humanized epratuzumab, and any combination thereof.

Other examples of therapeutic procedures for treating WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, systemic irradiation, stem cell infusion, bone marrow ablation with stem cell support, ex vivo treated peripheral blood stem cell transplantation, cord blood transplantation, immunoenzyme technology, low LET cobalt-60 gamma ray therapy, bleomycin, routine surgery, radiation therapy and non-myeloablative allogeneic hematopoietic stem cell transplantation.

Combination therapy for diffuse large B cell lymphoma

In some embodiments, the other therapeutic agent is suitable for the treatment of diffuse large B-cell lymphoma (DLBCL), including cyclophosphamide, doxorubicin, vincristine, prednisone, an anti-CD 20 monoclonal antibody, etoposide, bleomycin, many of the agents listed for WM, and any combination thereof, such as ICE and R-ICE.

Chronic lymphocytic leukemia combination therapy

In some embodiments, other therapeutic agents are suitable for the treatment of Chronic Lymphocytic Leukemia (CLL), including chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin, vincristine, prednisone, prednnon, alemtuzumab, many of the agents listed for WM, as well as combination chemotherapies and chemoimmunotherapies, including the following common combination regimens: CVP, R-CVP, ICE, R-ICE, FCR, and FR.

Myelofibrosis combination therapy

In some embodiments, the additional therapeutic agent is suitable for treating myelofibrosis, and includes a hedgehog inhibitor, a Histone Deacetylase (HDAC) inhibitor, and a tyrosine kinase inhibitor. Non-limiting examples of hedgehog inhibitors are saredgie and vismodegib.

Examples of HDAC inhibitors include, but are not limited to, pranopotal and paribinotal.

Non-limiting examples of tyrosine kinase inhibitors are lestaurtinib, bosutinib, imatinib, giltinib, ladostitinib and cabozantinib.

Combination therapy for hyperproliferative diseases

In some embodiments, the additional therapeutic agent is suitable for treating a hyperproliferative disease, which includes gemcitabine, albumin-bound paclitaxel, and gemcitabine/albumin-bound paclitaxel with a JAK inhibitor and/or PI3K inhibitor.

Bladder cancer combination therapy

In some embodiments, the additional therapeutic agent is suitable for treating bladder cancer, which includes alemtuzumab, carboplatin, cisplatin, docetaxel, doxorubicin, fluorouracil (5-FU), gemcitabine, idomide (idosfamide), interferon alpha-2 b, methotrexate, mitomycin, albumin-bound paclitaxel, pemetrexed, thiotepa, vinblastine, and any combination thereof.

Combination therapy for breast cancer

In some embodiments, the additional therapeutic agent is suitable for treating breast cancer, which includes albumin-bound paclitaxel, anastrozole, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, epirubicin, everolimus, exemestane, fluorouracil, fulvestrant, gemcitabine, ixabepilone, lapatinib, letrozole, methotrexate, mitoxantrone, paclitaxel, pegylated liposomal doxorubicin, pertuzumab tamoxifen, toremifene, trastuzumab, vinorelbine, and any combination thereof.

Triple negative breast cancer combination therapy

In some embodiments, the additional therapeutic agent is suitable for treating triple negative breast cancer, which includes cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof.

Combination therapy for colorectal cancer

In some embodiments, the other therapeutic agent is suitable for treating colorectal cancer, which includes bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, aflibercept, and any combination thereof.

Castration resistant prostate cancer combination therapy

In some embodiments, the additional therapeutic agent is suitable for treating castration-resistant prostate cancer, which includes abiraterone, cabazitaxel, docetaxel, enzalutamide, prednisone, ciplenete-T, and any combination thereof.

Combined therapy for esophagus and esophagus-stomach junction cancer

In some embodiments, the additional therapeutic agent is suitable for treating cancers of the esophagus and esophageal-gastric junction, including capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof.

Combination therapy for gastric cancer

In some embodiments, the other therapeutic agent is suitable for treating gastric cancer, which includes capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof.

Head and neck cancer combination therapy

In some embodiments, the additional therapeutic agent is suitable for treating a cancer of the head and neck, comprising afatinib, bleomycin, capecitabine, carboplatin, cetuximab, cisplatin, docetaxel, fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab, paclitaxel, parizumab, vinorelbine, and any combination thereof.

Combination therapy for hepatobiliary cancer

In some embodiments, the additional therapeutic agent is suitable for treating hepatobiliary cancer, which includes capecitabine, cisplatin, fluoropyrimidine, 5-fluorouracil, gemetabine (gemecitabine), oxaliplatin, sorafenib, and any combination thereof.

Combination therapy for hepatocellular carcinoma

In some embodiments, the other therapeutic agent is suitable for the treatment of hepatocellular carcinoma, which includes capecitabine, doxorubicin, gemcitabine, sorafenib, and any combination thereof.

Combination therapy for non-small cell lung cancer

In some embodiments, the other therapeutic agent is suitable for treating non-small cell lung cancer (NSCLC), which includes afatinib, albumin-bound paclitaxel, oletinib, bevacizumab, cabozantinib, carboplatin, cisplatin, crizotinib, darafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, parilizumab, pemetrexed, ramucirumab, tremelimumab, trastuzumab, vandetanib, verrofenib, vinblastine, vinorelbine, and any combination thereof.

Combination therapy for small cell lung cancer

In some embodiments, the other therapeutic agent is suitable for treating Small Cell Lung Cancer (SCLC), including bentamil (bendamustine), carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, gemcitabine, ipilimumab (ipilimumab), irinotecan, nivolumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combination thereof.

Melanoma combination therapy

In some embodiments, the additional therapeutic agent is suitable for treating melanoma, which includes albumin-bound paclitaxel, carboplatin, cisplatin, cobicistinib (cobiemotiib), dabrafenib, dabrasazine (dacrbazine), IL-2, imatinib, interferon alpha-2 b, ipulimab, nitrosourea, nivolumab, paclitaxel, parilizumab, pidimumab (pilimumab), temozolomide, tremetinib, verofibrib, vinblastine, and any combination thereof.

Combination therapy for ovarian cancer

In some embodiments, the additional therapeutic agent is suitable for treating ovarian cancer, comprising 5-fluorouracil, albumin-bound paclitaxel, altretamine, anastrozole, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, exemestane, gemcitabine (gemcibabine), ifosfamide, irinotecan, letrozole, leuprolide acetate, liposomal doxorubicin, megestrol acetate, melphalan, olaparib, oxaliplatin, paclitaxel, palozolomide, pemetrexed, tamoxifen, topotecan, vinorelbine, and any combination thereof.

Pancreatic cancer combination therapy

In some embodiments, the other therapeutic agent is suitable for treating pancreatic cancer, which includes 5-fluorouracil, albumin-bound paclitaxel, capecitabine, cisplatin, docetaxel, erlotinib, fluoropyrimidine, gemcitabine, irinotecan, leucovorin, oxaliplatin, paclitaxel, and any combination thereof.

Renal cell carcinoma combination therapy

In some embodiments, the additional therapeutic agent is suitable for treating renal cell carcinoma, which includes axitinib, bevacizumab, cabozantinib, erlotinib, everolimus, levavitinib (levantinib), nivolumab, palozopanib, sorafenib, sunitinib, temsirolimus, and any combination thereof.

VIII. set

The present invention provides a kit comprising a compound of the invention or a pharmaceutically acceptable salt thereof. The kit may further comprise instructions for use, e.g., for treating a viral infection. The instructions are typically written instructions, but electronic storage media (e.g., magnetic or optical disks) containing the instructions are also acceptable.

The invention also provides a pharmaceutical kit comprising one or more containers comprising a compound of the invention, or a pharmaceutically acceptable salt thereof. Optionally associated with these containers may be a notice in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the manufacturing, use or sale agency for human administration. The various components (if more than one component is present) may be packaged in separate containers, or some components may be combined in one container, as cross-reactivity and shelf-life permits. The kit may be in unit dosage form, in bulk packaging (e.g., multi-dose packaging), or in sub-unit doses. The kit may also include a plurality of unit doses of the compound and instructions for use, and are packaged in sufficient quantity for storage and use in pharmacy, such as hospital pharmacies and compounding pharmacies.

Also provided are articles of manufacture comprising a unit dose of a compound of the invention, or a pharmaceutically acceptable salt thereof, suitable for packaging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, jars, flexible packaging and the like. The article may be further sterilized and/or sealed.

IX. example