MACROCYCLIC COMPOUNDS AS STING AGONISTS AND METHODS AND

USES THEREOF CROSS REFERENCE TO THE RELATED APPLICATIONS

[0001] This PCT application claims the benefit of Indian Provisional Patent Application Nos.201921029556, filed July 22, 2019; 201921051086, filed December 10, 2019, and 202021003961, filed January 29, 2020, the disclosure of each of which are incorporated herein by reference in their entirety for all purposes.

FIELD OF THE INVENTION

[0002] The invention relates to macrocyclic compounds having the general Formula (I) and their tautomeric forms, stereoisomers, pharmaceutically acceptable salts, and their combination with suitable medicament, corresponding processes for the synthesis and pharmaceutical compositions and uses of compounds containing the invention.

INCORPORATION BY REFERENCE

[0003] All U.S. patents, U.S. patent application publications, foreign patents, foreign and PCT published applications, articles and other documents, references and publications noted herein, and all those listed as References Cited in any patent or patents that issue herefrom, are hereby incorporated by reference in their entirety. The information incorporated is as much a part of this application as if all the text and other content was repeated in this application, and will be treated as part of the text and content of this application as filed.

BACKGROUND xy THE INVENTION

[0004] The following includes information that may be useful in understanding the invention. It is not an admission that any of the information, publications or documents specifically or implicitly referenced herein is prior art, or essential, to the presently described or claimed invention.

[0005] Stimulator of interferon genes (STING, also known as transmembrane protein 173/ TMEM173/MPYS/MITA/ERIS) is a signalling molecule that in humans is encoded by TMEM173 gene. STING is protein with 379 amino acids, consisting of several transmembrane regions. STING protein is expressed in several endothelial and epithelial cell types, as well as in haematopoietic lineage, which can include or exclude: T cells, dendritic cells (DCs) including plasmacytoid dendritic cells (pDCs) and macrophages. STING is associated with endoplasmic reticulum (ER) in the cell and has a major role in controlling the transcription of numerous host defence genes, including type I interferons (IFNs) and pro-inflammatory cytokines.

[0006] Recognition of aberrant DNA species or cyclic dinucleotides (CDNs) in the cytosol of the cell leads to the activation of STING. Cytosolic DNA species can activate STING signalling following binding to cyclic GMP–AMP synthase (cGAS). Binding of cytosolic DNA to cGAS catalyses the production of a type of CDN known as cGAMP (cyclic GMP–AMP), which contains one 2ʹ,5ʹ-phosphodiester linkage and a canonical 3ʹ,5ʹ linkage (c[G(2ʹ,5ʹ)pA(3ʹ,5ʹ)p]). The binding of cGAMP and other bacterial CDNs induce changes in the conformation of STING protein and facilitates the binding of TANK-binding kinase 1 (TBK1). STING-TBK1 complex, further transposes to perinuclear regions of the cell to transport TBK1 to endolysosomal compartments where it phosphorylates the transcription factors like, interferon regulatory factor 3 (IRF3). Similarly, STAT6 and nuclear factor-kB (NF-kB) also get activated downstream to STING activation. These transcription factors then translocate into the nucleus to initiate innate immune gene transcription and production of type I IFN and other cytokines. STING is then rapidly degraded, an event that may avoid problems associated with sustained cytokine production. (Nature Reviews Immunol, 2015, 15:760-770; Cell Reports, 2015, 11:1018–1030).

[0007] Studies in mice have shown that type I IFN signalling plays an important role in tumour-initiated T cell priming and tumour control (J. Exp. Med.2011, 208, 1989– 2003). Mice lacking the IFN-a/b receptor in DCs failed to reject immunogenic tumours, and CD8a+ DCs from these mice are defective in antigen cross-presentation to CD8+ T

cells. Additionally, transcriptional profiling analyses of melanoma patients has publicised that tumours containing infiltrating activated T cells are characterized by a type I IFN transcriptional signature (Cancer Res. 2009, 69:3077–3085.). Thus, STING activation may play a role in tumour control.

[0008] PCT International Application Publications Nos. WO2017/011920, WO2017/175147, WO2017/175156, WO2018/234805, WO2018/234807, WO2018/234808, WO2019/023635, WO2019/027857, WO2019/027858, and Nature (2018), 564 (7736):439-443, discloses STING modulators.

SUMMARY OF THE INVENTION

[0009] The invention described and claimed herein has many attributes and embodiments including, but not limited to, those set forth or described or referenced in this Summary. It is not intended to be all-inclusive and the invention described and claimed herein is not limited to or by the features or embodiments identified in this introduction, which is included for purposes of illustration only and not restriction.

[0010] It is an object of the invention to provide compounds, compositions, formulations, kits and methods for the modulation of a STING protein and/or STING protein complex, and/or for the treatment of disorders that will benefit from modulation of a STING protein and/or STING protein complex. In some embodiments, the modulation of a STING protein and/or STING protein complex is the activation of said STING protein and/or STING protein complex. Thus, in one aspect, the invention relates to compounds and methods for the modulation of a STING protein and/or STING protein complex, and particularly, but not exclusively, to methods for the treatment of disorders for which modulation of a STING protein and/or STING protein complex, may be of benefit, the methods comprising administering a STING protein and/or STING protein complex modulator, for example, compounds of formula I or formula II, and/or one or more analogue or prodrug of any of the foregoing compounds thereof.

[0011] The compounds of invention having STING protein and/or STING protein complex modulator activity are described herein.

[0012] The invention relates to compounds of general Formula (I), and their tautomeric forms, stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof.

wherein,

G1 is independently selected from -CH2- or
;

G2 is -CH=CH-;

ring A is optionally substituted heterocyclyl, and optionally substituted heteroaryl;

ring B is aromatic ring;

ring C is optionally substituted five membered heteroaryl;

R1 is independently selected from optionally substituted heteroaryl, - CONHSO2R3a, and -CON(R3)2;

R2 is independently selected from hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted C3-C5 monocyclic cycloalkyl;

R3 is independently selected from hydrogen, substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally

substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, optionally substituted arylalkyl, and

wherein when R1 substitution on both ring B are - CON(R3)2, then at least for one R1 substitution, both R3 substitutions cannot be hydrogen at the same time;

R3a is independently selected from optionally substituted alkyl, and optionally substituted cycloalkyl;

R3b is independently selected from hydrogen or optionally substituted alkyl;

m is 1;

n is 0;

o is 1;

p is selected from 0, 1, or 2;

when‘alkyl’ group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, oxo (=O), alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -N(R4)2, -C(=O)OH, -N(H)-SO2-alkyl, and -OR4;

when‘carbocycle’ or‘cycloalkyl’ group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, alkyl, perhaloalkyl, heteroaryl, heterocyclyl, -N(R4)2, -C(=O)OH, and -OR4;

when‘heterocycle’ or‘heterocyclyl’ group is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, cyano, alkyl, perhaloalkyl, heterocyclyl, -OR4, -OP(O)(OR4)2, -P(O)(OR4)2, -P(O)(OR4)R4a, - SO2R4a, -C(=O)OH, -C(=O)N(H)R4, -C(=O)N(alkyl)R4, -N(H)C(=O)R4a, -N(H)- SO2-alkyl, -N(H)R4, and -N(alkyl)R4;

when the‘aryl’ group is substituted, it is substituted with 1 to 4 substituents selected from halogen, cyano, alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, -O- alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -SO2-alkyl, - N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, -SO2N(alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -OP(O)(OR4)2, - P(O)(OR4)2, -P(O)(OR4)R4a, and -C(=O)OH;

when the‘heteroaryl’ group is substituted, it is substituted with 1 to 4 substituents selected from halogen, cyano, alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, -O- alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -SO2-alkyl, - N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, -SO2N(alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -OP(O)(OR4)2, - P(O)(OR4)2, -P(O)(OR4)R4a, and -C(=O)OH;

each R4 is independently selected from hydrogen, alkyl, and cycloalkyl;

each R4a is independently selected from alkyl, and cycloalkyl.

[0013] The invention relates to compounds of general Formula (I), and their tautomeric forms, stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof.

wherein,

G1 is independently selected from -CH2- or
G2 is -CH=CH-;

ring A is optionally substituted heterocyclyl, and optionally substituted heteroaryl;

ring B is aromatic ring;

ring C is optionally substituted five membered heteroaryl;

R1 is -CON(R3)2;

R2 is independently selected from hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted C3-C5 monocyclic cycloalkyl;

R3 is independently selected from hydrogen, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl, wherein at least for one R1 substitution, both R3 substitutions cannot be hydrogen at the same time;

m is 1;

n is 0;

o is 1;

p is selected from 0, 1, or 2;

when‘alkyl’ group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, oxo (=O), alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -N(R4)2, -C(=O)OH, -N(H)-SO2-alkyl, and -OR4;

when‘carbocycle’ or‘cycloalkyl’ group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, alkyl, perhaloalkyl, heteroaryl, heterocyclyl, -N(R4)2, -C(=O)OH, and -OR4;

when‘heterocycle’ or‘heterocyclyl’ group is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, cyano, alkyl, perhaloalkyl, heterocyclyl, -OR4, -OP(O)(OR4)2, -P(O)(OR4)2, -P(O)(OR4)R4a, - SO2R4a, -C(=O)OH, -C(=O)N(H)R4, -C(=O)N(alkyl)R4, -N(H)C(=O)R4a, -N(H)- SO2-alkyl, -N(H)R4, and -N(alkyl)R4;

when the‘aryl’ group is substituted, it is substituted with 1 to 4 substituents selected from halogen, cyano, alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, -O- alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -SO2-alkyl, - N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, -SO2N(alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -OP(O)(OR4)2, - P(O)(OR4)2, -P(O)(OR4)R4a, and -C(=O)OH;

when the‘heteroaryl’ group is substituted, it is substituted with 1 to 4 substituents selected from halogen, cyano, alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, -O- alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -SO2-alkyl, - N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, -SO2N(alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -OP(O)(OR4)2, - P(O)(OR4)2, -P(O)(OR4)R4a, and -C(=O)OH;

each R4 is independently selected from hydrogen, alkyl, and cycloalkyl;

each R4a is independently selected from alkyl, and cycloalkyl.

[0014] In some embodiments, the invention provides a compound of general Formula (II), and their tautomeric forms, stereoisomers, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof,

wherein,

R3m is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl;

G1 is independently selected from -CH2- or

ring A is optionally substituted heterocyclyl, and optionally substituted heteroaryl;

R2a , R2b, R2c, and R2d are independently selected from hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted C3-C5 monocyclic cycloalkyl.

[0015] According to some embodiments, the invention relates the compound of Formula (I), Formula (II), its tautomeric form, its stereoisomer, its pharmaceutically

acceptable salt, its hydrate, its solvate or its prodrug, wherein, G1 is -CH2- or

[0016] According to some embodiments, the invention relates the compound of Formula (I), Formula (II), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, its solvate or its prodrug, wherein, G1 is -CH2.

[0017] According to some embodiments, the invention relates the compound of Formula (I), Formula (II), its tautomeric form, its stereoisomer, its pharmaceutically

acceptable salt, its hydrate, its solvate or its prodrug, wherein, G1 is
[0018] According to some embodiments, the invention relates the compound of Formula (I), Formula (II), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, its solvate or its prodrug, wherein, ring A is optionally substituted heterocyclyl or optionally substituted heteroaryl.

[0019] According to some embodiments, the invention relates the compound of Formula (I), Formula (II), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, its solvate or its prodrug, wherein, ring A is selected from the group consisting of:

[0020] According to some embodiments, the invention relates the compound of Formula (I), Formula (II), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, its solvate or its prodrug, wherein R2a , R2b, R2c, and R2d are independently selected from methyl or ethyl.

[0021] According to some embodiments, the invention relates the compound of Formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, its solvate or its prodrug, wherein, R1 is -CON(R3)2,wherein R3 is independently selected from hydrogen, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl, wherein at least for one R1 substitution, both R3 substitutions cannot be hydrogen at the same time.

[0022] According to some embodiments, the invention relates the compound of Formula (II), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, its solvate, or its prodrug, wherein R3m is selected from the group consisting of:

[0023] According to some embodiments, the invention relates the compound of Formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, its solvate, or its prodrug, wherein R2a , R2b, R2c, and R2d are independently selected from optionally substituted C1-C6 alkyl ; G2 is -CH=CH-; ring C is pyrazole; ring

B is aromatic ring; n is 0; m is 1;p is 1 or 2; o is 1; G1 is -CH2- or
wherein ring A is optionally substituted heterocyclyl or optionally substituted heteroaryl, and R1 is -CON(R3)2, wherein in R3 hydrogen, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl, wherein at least for one R1 substitution, both R3 substitutions cannot be hydrogen at the same time.

[0024] In some embodiments, the invention provides a compound of Formula (I), their tautomeric forms, and their all possible geometrical isomers, including, but not limiting to Formula (A), Formula (B), Formula (C), Formula (D), and Formula (E) as represented below:

[0025] In some aspects, any R group described herein can include or exclude the recited options.

[0026] In some embodiments, the invention provides a compound of Formula (I), and Formula (II) and their tautomeric forms, its pharmaceutically acceptable salt, its hydrate, its solvate, or its prodrug, wherein the compound is selected from a compound set forth in Table 1 below.

Table 1. Exemplary Compounds of the Invention

yl-3- 19-

-

yl-3- 19-

-

1- -

- -

19- acid

xyl)- ,2,1-

yl)- ,2,1-

19-

thyl-

ic

- H-

- - 7H-

l-3- 19-

l-3- 19-

,15-

,2,1-

,15-

,2,1-

-oxa- hyl- 6,19-

-oxa- hyl- 6,19-

tan- yl-

tan- yl-

,15-

,2,1-

3- l-3- 19-

xyl)- -

,2,1-

3- 1H- ro-

xyl)-

1- -8- oxa-

yl-3-

oxa-

oxa-

yl)-

- ,19-

l-1H- ro-

zole- 0- ,2,1-

hyl-

-

ro-

zole- 0- ,2,1-

yl-

ne

- azin- ioxa-

-

,2,1-

- ,19-

-

xa-

- -

e-5-

xa-

e-5-

xa-

- yl)-

- idin- ioxa-

)-

,2,1-

l-3- 19-

)-

,2,1-

(1- -

19-

-

- ridin- ioxa-

,15-

,2,1-

l-1H- ro-

-

-3-

yl-3- 19-

yl-3- 19-

thyl-

ylic

19-

acid

19-

acid

an-

ro-

[0027] In some embodiments, the invention provides a compound of Formula (I), Formula (II), and their tautomeric forms, stereoisomers, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, wherein the compound is selected from:

(1R,4R)-4-((E)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4- carboxamido)cyclohexane-1-carboxylic acid (Compound 2);

(E)-N-((1R,4R)-4-(1H-tetrazol-5-yl)cyclohexyl)-1,15-bis(1-ethyl-3-methyl-1H- pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 6);

(E)-1-(3-(12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)propyl)- 1H-pyrazole-4-carboxylic acid (Compound 8);

(8S,E)-N4-((1R,4S)-4-(1H-tetrazol-5-yl)cyclohexyl)-8-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 12); and

(1S,4R)-4-((8S,E)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-12-carbamoyl-1,15- bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H- 6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene- 4-carboxamido)cyclohexane-1-carboxylic acid (Compound 14).

[0028] In some embodiments, the invention provides a pharmaceutical composition comprising a compound of Formula (I), Formula (II), or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and at least one or more pharmaceutically acceptable excipient.

[0029] In some embodiments, the invention provides a compound of Formula (I), Formula (II), or a prodrug thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or condition in which activation of STING is beneficial.

[0030] In some embodiments, the invention provides the use of a compound or pharmaceutical composition of Formula (I), Formula (II), or a prodrug thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or condition in which activation of STING is beneficial.

[0031] In some embodiments, the invention provides a method of treating a disease or condition in which activation of STING is beneficial in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the invention provides a method of treating cancer or one or more infectious diseases in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (II), or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, the invention provides a method of treating cancer, wherein cancer can be one or more solid tumors, one or more leukemias, one or more lymphomas, or a combination thereof.

[0034] In some embodiments, the invention provides a method of treating one or more infectious diseases, wherein the infectious diseases can include or exclude: viral infection, bacterial infection, or a combination thereof.

[0035] In some embodiments, the invention provides a composition comprising a compound of Formula (I), Formula (II), or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and one or more additional therapies.

[0036] In some embodiments, the invention provides a composition comprising a compound of Formula (I), Formula (II), or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and one or more additional therapies which can include or exclude: chemotherapy, immunotherapy, radiotherapy or a combination thereof.

[0037] In some embodiments, the invention provides a vaccine adjuvant comprising a compound of Formula (I), Formula (II), or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the invention provides a composition comprising (i) a compound of Formula (I), Formula (II), or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and (ii) one or more antigens, one or more antigen compositions, or a combination thereof.

[0039] In some embodiments, the invention provides a vaccine composition comprising (i) a compound of Formula (I), Formula (II), or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and (ii) one or more antigens, one or more antigen compositions, or a combination thereof.

BRIEF DESCRIPTION OF THE FIGURES

[0040] The accompanying drawings, which are incorporated herein and form a part of the specification, illustrate the aspects of the present disclosure and, together with the description, further serve to explain the principles of the aspects and to enable a person skilled in the pertinent art to make and use the aspects. The drawings are for illustration purposes only, show exemplary non-limiting embodiments, and are not necessarily drawn to scale.

[0041] Figure 1A shows the effect of a representative compound of the invention, Compound 2, in CT26 Ectopic Allograft BALB/c Mice Model, on tumor volume reduction, indicating that Compound 2 reduces tumor volume, with 7 out of 9 subjects exhibiting complete tumor regression. Compound 2 was administered to the subjects (n=9) at the indicated dose at days 1, 4, and 8.

[0042] Figure 1B shows the effect of Compound 2 in CT26 Ectopic Allograft BALB/c Mice Model on body weight change on the same subjects in Figure 1A.

[0043] Figure 2A shows the effect of a representative compound of the invention, Compound 6, in CT26 Ectopic Allograft BALB/c Mice Model, on tumor volume reduction, indicating that Compound 6 reduces tumor volume, with 7 out of 9 subjects exhibiting complete tumor regression. Compound 6 was administered to the subjects (n=9) at the indicated dose at days 1, 4, and 8.

[0044] Figure 2B shows the effect of Compound 6 in CT26 Ectopic Allograft BALB/c Mice Model on body weight change on the same subjects in Figure 2A.

[0045] Figure 3A shows the effect of a representative compound of the invention, Compound 8, in CT26 Ectopic Allograft BALB/c Mice Model, on tumor volume reduction, indicating that Compound 8 reduces tumor volume, with 5 out of 9 subjects exhibiting complete tumor regression. Compound 8 was administered to the subjects (n=9) at the indicated dose at days 1, 4, and 8.

[0046] Figure 3B shows the effect of Compound 8 in CT26 Ectopic Allograft BALB/c Mice Model on body weight change on the same subjects in Figure 3A.

[0047] Figure 4A shows the effect of a representative compound of the invention, Compound 12, in CT26 Ectopic Allograft BALB/c Mice Model, on tumor volume reduction, indicating that Compound 12 reduces tumor volume, with 8 out of 10 subjects exhibiting complete tumor regression. Compound 12 was administered to the subjects (n=10) at the indicated dose at days 1, 4, and 8.

[0048] Figure 4B shows the effect of Compound 12 in CT26 Ectopic Allograft BALB/c Mice Model on body weight change on the same subjects in Figure 4A.

[0049] Figure 5A shows the effect of a representative compound of the invention, Compound 14, in CT26 Ectopic Allograft BALB/c Mice Model on tumor volume reduction, indicating that Compound 14 reduces tumor volume, with 6 out of 9 subjects exhibiting complete tumor regression. Compound 14 was administered to the subjects (n=9) at the indicated dose at days 1, 4, and 8.

[0050] Figure 5B shows the effect of Compound 14 in CT26 Ectopic Allograft BALB/c Mice Model on body weight change on the same subjects in Figure 5A.

[0051] Figure 6 shows the effect of Compound 2 at high dose in CT26 Ectopic Allograft BALB/c Mice Model wherein Compound 2 at two different doses reduces tumor volume (the plot lines for the two doses of Compound 2 overlap). Compound 2 was administered to the subjects (n=10) at the indicated dose at days 1, 4, and 8.

[0052] Figure 7A shows a flow cytometry plot of the percentage of CD3+CD8+ T cells infiltration in the tumor 96h post treatment with vehicle.

[0053] Figure 7B shows representative data of a flow cytometry plot of the percentage of CD3+CD8+ T cells infiltration in the tumor 96h post treatment with a representative compound of the invention, Compound 2, indicating a higher percentage of T cell infiltration over that of vehicle control.

DETAILED DESCRIPTION OF THE INVENTION

[0054] This description of the exemplary embodiments is intended to be read in connection with the accompanying drawings, which are to be considered part of the entire written description. Additionally, the section headings used herein are for organizational purposes only, and are not to be construed as limiting the subject matter described.

[0055] General terms used in formula can be defined as follows; however, the meaning stated should not be interpreted as limiting the scope of the term per se.

[0056] The term“alkyl” as used herein refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has from one to six carbon atoms, and is attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1- dimethylethyl (t-butyl) and the like. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

[0057] The term“perhaloalkyl,” as used herein, refers to an alkyl group as defined hereinabove wherein all the hydrogen atoms of the said alkyl group are substituted with halogen. The perhaloalkyl group is exemplified by trifluoromethyl, pentafluoroethyl, and the like.
Claims:

1. A compound of general Formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, its solvate or its prodrug thereof.

wherein,

G1 is independently selected from -CH2- or

G2 is -CH=CH-;

ring A is optionally substituted heterocyclyl, and optionally substituted heteroaryl;

ring B is aromatic ring;

ring C is optionally substituted five membered heteroaryl;

R1 is independently selected from optionally substituted heteroaryl, -CONHSO2R3a, and -CON(R3)2;

R2 is independently selected from hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted C3-C5 monocyclic cycloalkyl;

R3 is independently selected from hydrogen, substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, optionally

substituted arylalkyl, and
wherein when R1 substitution on both ring B are CON(R3)2, then at least for one R1 substitution, both R3 substitutions cannot be hydrogen at the same time;

R3a is independently selected from optionally substituted alkyl, and optionally substituted cycloalkyl;

R3b is independently selected from hydrogen or optionally substituted alkyl;

m is 1;

n is 0;

o is 1;

p is selected from 0, 1, or 2;

when‘alkyl’ group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, oxo (=O), alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -N(R4)2, -C(=O)OH, -N(H)-SO2-alkyl, and -OR4;

when‘carbocycle’ or‘cycloalkyl’ group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, alkyl, perhaloalkyl, heteroaryl, heterocyclyl, -N(R4)2, -C(=O)OH, and -OR4;

when‘heterocycle’ or‘heterocyclyl’ group is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, cyano, alkyl, perhaloalkyl, heterocyclyl, -OR4, -OP(O)(OR4)2, -P(O)(OR4)2, -P(O)(OR4)R4a, -SO2R4a, -C(=O)OH, -C(=O)N(H)R4, -C(=O)N(alkyl)R4, -N(H)C(=O)R4a, -N(H)-SO2-alkyl, -N(H)R4, and -N(alkyl)R4;

when the‘aryl’ group is substituted, it is substituted with 1 to 4 substituents selected from halogen, cyano, alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, -O-alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -SO2-alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, -SO2N(alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -OP(O)(OR4)2, -P(O)(OR4)2, -P(O)(OR4)R4a, and -C(=O)OH;

when the‘heteroaryl’ group is substituted, it is substituted with 1 to 4 substituents selected from halogen, cyano, alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, -O-alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -SO2-alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, -SO2N(alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -OP(O)(OR4)2, -P(O)(OR4)2, -P(O)(OR4)R4a, and -C(=O)OH;

each R4 is independently selected from hydrogen, alkyl, and cycloalkyl;

each R4a is independently selected from alkyl, and cycloalkyl.

2. A compound of general Formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, its solvate or its prodrug thereof

wherein,
G1 is independently selected from -CH2- or

G2 is -CH=CH-;

ring A is optionally substituted heterocyclyl, and optionally substituted heteroaryl;

ring B is aromatic ring;

ring C is optionally substituted five membered heteroaryl;

R1 is -CON(R3)2;

R2 is independently selected from hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted C3-C5 monocyclic cycloalkyl;

R3 is independently selected from hydrogen, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl, wherein at least for one R1 substitution, both R3 substitutions cannot be hydrogen at the same time;

m is 1;

n is 0;

o is 1;

p is selected from 0, 1, or 2;

when‘alkyl’ group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, oxo (=O), alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -N(R4)2, -C(=O)OH, -N(H)-SO2-alkyl, and -OR4; when‘carbocycle’ or‘cycloalkyl’ group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, alkyl, perhaloalkyl, heteroaryl, heterocyclyl, -N(R4)2, -C(=O)OH, and -OR4;

when‘heterocycle’ or‘heterocyclyl’ group is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, cyano, alkyl, perhaloalkyl, heterocyclyl, -OR4, -OP(O)(OR4)2, -P(O)(OR4)2, -P(O)(OR4)R4a, - SO2R4a, -C(=O)OH, -C(=O)N(H)R4, -C(=O)N(alkyl)R4, -N(H)C(=O)R4a, -N(H)- SO2-alkyl, -N(H)R4, and -N(alkyl)R4;

when the‘aryl’ group is substituted, it is substituted with 1 to 4 substituents selected from halogen, cyano, alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, -O- alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -SO2-alkyl, - N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, -SO2N(alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -OP(O)(OR4)2, - P(O)(OR4)2, -P(O)(OR4)R4a, and -C(=O)OH;

when the‘heteroaryl’ group is substituted, it is substituted with 1 to 4 substituents selected from halogen, cyano, alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, -O- alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -SO2-alkyl, - N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, -SO2N(alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -OP(O)(OR4)2, - P(O)(OR4)2, -P(O)(OR4)R4a, and -C(=O)OH;

each R4 is independently selected from hydrogen, alkyl, and cycloalkyl;

each R4a is independently selected from alkyl, and cycloalkyl.

3. A compound of general Formula (II), and its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, its hydrate, its solvate or its prodrug thereof,

wherein,

R3m is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl;

G1 is independently selected from -CH2- or

ring A is optionally substituted heterocyclyl, and optionally substituted heteroaryl;

R2a , R2b , R2c , and R2d are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, and optionally substituted C3-C5 monocyclic cycloalkyl;when ‘alkyl’ group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, oxo (=O), alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -N(R4)2, -C(=O)OH, -N(H)-SO2-alkyl, and -OR4;

when‘carbocycle’ or‘cycloalkyl’ group is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, alkyl, perhaloalkyl, heteroaryl, heterocyclyl, -N(R4)2, -C(=O)OH, and -OR4;

when‘heterocycle’ or‘heterocyclyl’ group is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, cyano, alkyl, perhaloalkyl, heterocyclyl, -OR4, -OP(O)(OR4)2, -P(O)(OR4)2, -P(O)(OR4)R4a, -SO2R4a, -C(=O)OH, -

C(=O)N(H)R4, -C(=O)N(alkyl)R4, -N(H)C(=O)R4a, -N(H)-SO2-alkyl, -N(H)R4, and - N(alkyl)R4;

when the‘aryl’ group is substituted, it is substituted with 1 to 4 substituents selected from halogen, cyano, alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, -O-alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -SO2-alkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, - C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, -SO2N(alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -OP(O)(OR4)2, -P(O)(OR4)2, -P(O)(OR4)R4a, and -C(=O)OH;

when the‘heteroaryl’ group is substituted, it is substituted with 1 to 4 substituents selected from halogen, cyano, alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, -O-alkyl, -O- perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -SO2-alkyl, -N(alkyl)C(=O)alkyl, - N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, - SO2N(alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -OP(O)(OR4)2, -P(O)(OR4)2, - P(O)(OR4)R4a, and -C(=O)OH;

each R4 is independently selected from hydrogen, alkyl, and cycloalkyl;

each R4a is independently selected from alkyl, and cycloalkyl.

4. The compound according to any one of claims 1to 3, wherein G1 is -CH2.

5. The compound according to any one claims 1 to 3, wherein G1 is

6. The compound according to any one claims 1 to 3, wherein ring A is optionally substituted heterocyclyl or optionally substituted heteroaryl.

7. The compound according to claim 6, wherein ring A is

8. The compound according to claim 1 or 2, wherein R2 is methyl or ethyl.

9. The compound according to claim 1 or 2, wherein R1 is -CON(R3)2,wherein R3 is independently selected from hydrogen, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl, wherein at least for one R1 substitution, both R3 substitutions cannot be hydrogen at the same time.

10. The compound according to claim 3, wherein R3m is

11. The compound according to claim 1 or 2, wherein R2 is optionally substituted C1-C6 alkyl; G2 is -CH=CH-; ring C is pyrazole; ring B is aromatic ring; n is 0; m is 1;p is 1

or 2; o is 1; G1 is -CH2- or
, wherein ring A is optionally substituted heterocyclyl or optionally substituted heteroaryl, and R1 is -CON(R3)2, wherein R3 is hydrogen, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted heteroarylalkyl, and optionally substituted arylalkyl, wherein at least for one R1 substitution, both R3 substitutions cannot be hydrogen at the same time.

12. The compound according to claim 1, wherein the compound is selected from:

(1S,4S)-4-((E)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4- carboxamido)cyclohexane-1-carboxylic acid (Compound 1);

(1R,4R)-4-((E)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-

tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)cyclohexane-1-carboxylic acid (Compound 2);

(E)-N-(3-(1H-tetrazol-5-yl)propyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 3);

(E)-N-(2-(1H-tetrazol-5-yl)ethyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 4);

(E)-2-(2-(12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)ethyl)benzoic acid (Compound 5);

(E)-N-((1R,4R)-4-(1H-tetrazol-5-yl)cyclohexyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 6);

(E)-N-((1S,4S)-4-(1H-tetrazol-5-yl)cyclohexyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 7);

(E)-1-(3-(12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)propyl)-1H-pyrazole-4-carboxylic acid (Compound 8);

(E)-2-((12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)methyl)nicotinic acid (Compound 9); (E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-N-(3-(5-oxo-4,5-dihydro-1H-tetrazol-1-yl)propyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide(Compound 10);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-N-(3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 11);

(8S,E)-N4-((1R,4S)-4-(1H-tetrazol-5-yl)cyclohexyl)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 12);

(8R,E)-N4-((1R,4R)-4-(1H-tetrazol-5-yl)cyclohexyl)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 13);

(1S,4R)-4-((8S,E)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)cyclohexane-1-carboxylic acid (Compound 14);

(1R,4R)-4-((8R,E)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)cyclohexane-1-carboxylic acid (Compound 15);

(8S,E)-N4-(3-(1H-tetrazol-5-yl)propyl)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 16);

(8R,E)-N4-(3-(1H-tetrazol-5-yl)propyl)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 17);

1-(3-((8S,E)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)propyl)-1H-pyrazole-4-carboxylic acid(Compound 18);

1-(3-((8R,E)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)propyl)-1H-pyrazole-4-carboxylic acid (Compound 19);

(1R,4R)-4-((E)-8-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)cyclohexane-1-carboxylic acid (Compound 20);

(E)-N-(3-(1H-tetrazol-5-yl)propyl)-8-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 21);

(E)-N-((1R,4R)-4-(1H-tetrazol-5-yl)cyclohexyl)-8-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 22);

(E)-1-(3-(8-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)propyl)-1H-pyrazole-4-carboxylic acid (Compound 23);

(E)-N-((1R,4R)-4-(1H-tetrazol-5-yl)cyclohexyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-morpholino-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide(Compound 24);

(E)-N-(3-(1H-tetrazol-5-yl)propyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-morpholino-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 25);

(1R,4R)-4-((E)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-morpholino-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)cyclohexane-1-carboxylic acid (Compound 26);

(E)-1-(3-(12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-morpholino-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)propyl)-1H-pyrazole-4-carboxylic acid (Compound 27);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-N-(2-morpholinoethyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 28);

(E)-(12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4-carbonyl)glycine (Compound 29);

(E)-N-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)ethyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 30);

(E)-3-(12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4-carboxamido)propanoic acid (Compound 31);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-N-(3-morpholinopropyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 32);

(E)-N-(3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)propyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 33);

(E)-N-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)butyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 34);

(E)-(2-(4-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-12-carboxamido)ethyl)-L-proline (Compound 35);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-N-(3-(4-(methylsulfonyl)piperazin-1-yl)propyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 36);

(E)-N-(3-(4,4-difluoropiperidin-1-yl)propyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 37);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-N-(4-morpholinobutyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 38);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-N-(3-(4-fluoropiperidin-1-yl)propyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 39);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-N-(methylsulfonyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 40);

(R,E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-N-(3-(3-fluoropyrrolidin-1-yl)propyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 41);

(S,E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-N-(3-(3-fluoropyrrolidin-1-yl)propyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 42);;

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-N-(2-(methylsulfonamido)ethyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 43);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-N-(3-(4-(methylsulfonyl)piperidin-1-yl)propyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 44);

E)-N-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 45);

(E)-N-(3-((2R,6S)-2,6-dimethylmorpholino)propyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 46);

(E)-N-(3-(1,1-dioxidothiomorpholino)propyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 47);

(E)-N-(3-(1H-imidazol-1-yl)propyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 48);

(S,E)-2-(12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4-carboxamido)-3-(dimethylamino)propanoic acid (Compound 49);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-N-(3-(pyridin-2-yl)propyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 50);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-N-(3-(4-(trifluoromethyl)piperidin-1-yl)propyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 51);

(E)-N-(3-(3,3-dimethylmorpholino)propyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12-dicarboxamide (Compound 52);

(E)-(12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4-carbonyl)glycyl-L-valine (Compound 53);

(E)-N,N'-(12-carbamoyl-4-(1H-tetrazol-5-yl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-1,15-diyl)bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide (Compound 54);

(1S,3S)-3-((E)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4-carboxamido)cyclobutane-1-carboxylic acid (Compound 55);

(1R,3R)-3-((E)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4-carboxamido)cyclobutane-1-carboxylic acid (Compound 56);

(E)-1-((12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4-carboxamido)methyl)cyclopropane-1-carboxylic acid (Compound 57);

(E)-2-(2-(12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-

tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4- carboxamido)ethyl)nicotinic acid (Compound 58);

(E)-2-(3-(12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4- carboxamido)propyl)benzoic acid (Compound 59);

(E)-N-(3-(4-ethoxy-4-oxido-1,4-azaphosphinan-1-yl)propyl)-1,15-bis(1-ethyl-3- methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa- 2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c'd']diindene-4,12- dicarboxamide (Compound 60).

13. The compound according to any one of claims 1 to 11, wherein the compound is selected from:

(1S,4S)-4-((E)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4- carboxamido)cyclohexane-1-carboxylic acid (Compound 1);

(1R,4R)-4-((E)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4- carboxamido)cyclohexane-1-carboxylic acid (Compound 2);

(E)-N-(3-(1H-tetrazol-5-yl)propyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 3);

(E)-N-(2-(1H-tetrazol-5-yl)ethyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 4);

(E)-2-(2-(12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4- carboxamido)ethyl)benzoic acid (Compound 5);

(E)-N-((1R,4R)-4-(1H-tetrazol-5-yl)cyclohexyl)-1,15-bis(1-ethyl-3-methyl-1H- pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 6);

(E)-N-((1S,4S)-4-(1H-tetrazol-5-yl)cyclohexyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 7);

(E)-1-(3-(12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)propyl)-1H-pyrazole-4-carboxylic acid (Compound 8);

(E)-2-((12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)methyl)nicotinic acid (Compound 9); (E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-N-(3-(5-oxo-4,5-dihydro-1H-tetrazol-1-yl)propyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide(Compound 10);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-N-(3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 11);

(8S,E)-N4-((1R,4S)-4-(1H-tetrazol-5-yl)cyclohexyl)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 12);

(8R,E)-N4-((1R,4R)-4-(1H-tetrazol-5-yl)cyclohexyl)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 13);

(1S,4R)-4-((8S,E)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)cyclohexane-1-carboxylic acid (Compound 14);

(1R,4R)-4-((8R,E)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)cyclohexane-1-carboxylic acid (Compound 15);

(8S,E)-N4-(3-(1H-tetrazol-5-yl)propyl)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 16);

(8R,E)-N4-(3-(1H-tetrazol-5-yl)propyl)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 17);

1-(3-((8S,E)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)propyl)-1H-pyrazole-4-carboxylic acid(Compound 18);

1-(3-((8R,E)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)propyl)-1H-pyrazole-4-carboxylic acid (Compound 19);

(1R,4R)-4-((E)-8-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)cyclohexane-1-carboxylic acid (Compound 20);

(E)-N-(3-(1H-tetrazol-5-yl)propyl)-8-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 21);

(E)-N-((1R,4R)-4-(1H-tetrazol-5-yl)cyclohexyl)-8-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 22);

(E)-1-(3-(8-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)propyl)-1H-pyrazole-4-carboxylic acid (Compound 23);

(E)-N-((1R,4R)-4-(1H-tetrazol-5-yl)cyclohexyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-morpholino-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide(Compound 24);

(E)-N-(3-(1H-tetrazol-5-yl)propyl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-8-morpholino-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 25);

(1R,4R)-4-((E)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-8-morpholino-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4- carboxamido)cyclohexane-1-carboxylic acid (Compound 26);

(E)-1-(3-(12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-8-morpholino-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)propyl)- 1H-pyrazole-4-carboxylic acid (Compound 27).

14. The compound according to any one of claims 1 to 11, wherein the compound is selected from:

(1R,4R)-4-((E)-12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4- carboxamido)cyclohexane-1-carboxylic acid (Compound 2);

(E)-N-((1R,4R)-4-(1H-tetrazol-5-yl)cyclohexyl)-1,15-bis(1-ethyl-3-methyl-1H- pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 6);

(E)-1-(3-(12-carbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4-carboxamido)propyl)- 1H-pyrazole-4-carboxylic acid (Compound 8);

(8S,E)-N4-((1R,4S)-4-(1H-tetrazol-5-yl)cyclohexyl)-8-(3-oxa-8- azabicyclo[3.2.1]octan-8-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5- carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a,19a- tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene-4,12-dicarboxamide (Compound 12);

(1S,4R)-4-((8S,E)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-12-carbamoyl-1,15- bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H- 6,10-dioxa-2,14,15a,19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c’d’]diindene- 4-carboxamido)cyclohexane-1-carboxylic acid (Compound 14).

15. A pharmaceutical composition comprising a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 14 and at least one or more pharmaceutically acceptable excipients.

16. Use of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 14 for the manufacture of a medicament for the treatment of a disease or condition in which activation of STING is beneficial.

17. A method of treating a disease or condition in which activation of STING is beneficial in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 14.

18. The method according to claim 17, wherein the disease or condition is cancer or one or more infectious diseases.

19. The method according to claim 17, wherein the disease or condition is cancer, and wherein the cancer is one or more solid tumors, leukemia, lymphoma, or a combination thereof.

20. The method according to claim 17, wherein the disease or condition is one or more infectious diseases, wherein infectious diseases is viral infection, bacterial infection, or a combination thereof.

21. The method according to claim 18 or 19, wherein the cancer is selected from brain cancer, renal cancer, testicular cancer, cancer of urethra, rectal cancer, cancer of fallopian tubes, penile cancer, vaginal cancer, stomach cancer, skin cancer, liver cancer, gastrointestinal stromal tumors, urothelial cancer, thyroid cancer, parathyroid gland cancer, adrenal cancer, bone cancer, oral cancer, ovarian cancer, uterine cancer, head and neck sqamous cell carcinoma, endometrial cancer, gall bladder cancer, renal cancer, bladder cancer, orophyrangeal cancer, lymph node cancer, gliobalstoma, astrocytoma, glioblastoma multiforme or sarcomas of soft tissue, fibrosarcoma, chondrosarcoma, hemangioma, teratoma, lipoma, myxoma, fibroma, rhabdomyoma, teratoma,

cholangiocarcinoma, myeloma, Ewing’s sarcoma, myeloma, Hodgkin’s disease, non-Hodgkin’s lymphoma, follicular lymphoma, mantle cell lymphoma, Burkitt’s lymphoma, lymphoblastic T-cell lymphoma, marginal zone lymphoma, cutaneous T cell lymphoma, CNS lymphoma, small lymphocytic lymphoma, lymphoplasmacytic lymphoma, diffuse large cell lymphoma (DLBCL), peripheral T-cell lymphoma, anaplastic large cell lymphoma, primary mediastinal lymphoma, mycosis fungoides, small non- cleaved cell lymphoma, lymphoblastic lymphoma, immunoblastic lymphoma, primary effusion lymphoma, HIV associated (or AIDS related) lymphomas, lymphoblastic T cell leukemia, chronic myelogenous leukemia, acute lymphoblastic T cell leukemia, lymphoblastic T cell leukemia, acute myelobastic leukemia, hairy-cell leukemia, chronic neutrophilic leukemia, mantle cell leukemia, acute megakaryocytic leukemia, multiple myeloma, megakaryoblastic leukemia, erythroleukemia, plasmacytoma, promyelocytic leukemia, chronic myelomonocytic leukemia, myelodysplastic syndrome, myelofibrosis, chronic myelogenous leukemia, polycythemia vera, thrombocythemia, chronic lymphocytic leukemia, prolymphocytic leukemia, hairy cell leukemia, Waldenstrom’s macroglobulinemia, Castleman’s disease, chronic neutrophilic leukemia, immunoblastic large cell leukemia and plasmacytoma.

22. The method according to claim 18 or 20, wherein the disease or condition is HIV, HPV, HCV, HBV, alphavirus, rotavirus or influenza infection.

23. A method according to claim 17, further comprising administering to the subject, one or more additional therapies.

24. A method according to claim 23, wherein the additional therapies is chemotherapy, immunotherapy, radiotherapy, or a combination thereof.

25. The compound according to any one of claims 1 to 14, for use as a vaccine adjuvant.

26. A composition comprising (i) a compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 14, and {ii}one or more antigens, one or more antigen compositions, or a combination thereof.