1,2,4-oxadiazole and 1 ,2,4-thiadiazole compounds of formula (I):

ONE EXAMPLE

 

OR

1,3,4-oxadiazole and 1 ,3,4-thiadiazole compounds of formula (I):

EXAMPLES

PREDICTED AUPM 170, CA 170, AUPM-170, CA-170

Synthesis coming………….

WATCH THIS SPACE

 

Aurigene Discovery Technologies Limited INNOVATOR

Curis with the option to exclusively license Aurigene’s orally-available small molecule antagonist of programmed death ligand-1 (PD-L1) in the immuno-oncology field

Addressing immune checkpoint pathways is a well validated strategy to treat human cancers and the ability to target PD-1/PD-L1 and other immune checkpoints with orally available small molecule drugs has the potential to be a distinct and major advancement for patients.

Through its collaboration with Aurigene, Curis is now engaged in the discovery and development of the first ever orally bioavailable, small molecule antagonists that target immune checkpoint receptor-ligand interactions, including PD-1/PD-L1 interactions.  In the first half of 2016, Curis expects to file an IND application with the U.S. FDA to initiate clinical testing of CA-170, the first small molecule immune checkpoint antagonist targeting PD-L1 and VISTA.  The multi-year collaboration with Aurigene is focused on generation of small molecule antagonists targeting additional checkpoint receptor-ligand interactions and Curis expects to advance additional drug candidates for clinical testing in the coming years. The next immuno-oncology program in the collaboration is currently targeting the immune checkpoints PD-L1 and TIM3.

 

(Oral Small Molecule PD-L1/VISTAAntagonist)

Certain human cancers express a ligand on their cell surface referred to as Programmed-death Ligand 1, or PD-L1, which binds to its cognate receptor, Programmed-death 1, or PD-1, present on the surface of the immune system’s T cells.  Cell surface interactions between tumor cells and T cells through PD-L1/PD-1 molecules result in T cell inactivation and hence the inability of the body to mount an effective immune response against the tumor.  It has been previously shown that modulation of the PD-1 mediated inhibition of T cells by either anti-PD1 antibodies or anti-PD-L1 antibodies can lead to activation of T cells that result in the observed anti-tumor effects in the tumor tissues.  Therapeutic monoclonal antibodies targeting the PD-1/PD-L1 interactions have now been approved by the U.S. FDA for the treatment of certain cancers, and multiple therapeutic monoclonal antibodies targeting PD-1 or PD-L1 are currently in development.

In addition to PD-1/PD-L1 immune regulators, there are several other checkpoint molecules that are involved in the modulation of immune responses to tumor cells¹.  One such regulator is V-domain Ig suppressor of T-cell activation or VISTA that shares structural homology with PD-L1 and is also a potent suppressor of T cell functions.  However, the expression of VISTA is different from that of PD-L1, and appears to be limited to the hematopoietic compartment in tissues such as spleen, lymph nodes and blood as well as in myeloid hematopoietic cells within the tumor microenvironment.  Recent animal studies have demonstrated that combined targeting/ blockade of PD-1/PD-L1 interactions and VISTA result in improved anti-tumor responses in certain tumor models, highlighting their distinct and non-redundant functions in regulating the immune response to tumors².

As part of the collaboration with Aurigene, in October 2015 Curis licensed a first-in-class oral, small molecule antagonist designated as CA-170 that selectively targets PD-L1 and VISTA, both of which function as negative checkpoint regulators of immune activation.  CA-170 was selected from the broad PD-1 pathway antagonist program that the companies have been engaged in since the collaboration was established in January 2015.  Preclinical data demonstrate that CA-170 can induce effective proliferation and IFN-γ (Interferon-gamma) production (a cytokine that is produced by activated T cells and is a marker of T cell activation) by T cells that are specifically suppressed by PD-L1 or VISTA in culture.  In addition, CA-170 also appears to have anti-tumor effects similar to anti-PD-1 or anti-VISTA antibodies in multiple in vivo tumor models and appears to have a good in vivo safety profile.  Curis expects to file an IND and initiate clinical testing of CA-170 in patients with advanced tumors during the first half of 2016.

 

POSTER

 

WO2011161699, WO2012/168944, WO2013144704 and WO2013132317 report peptides or peptidomimetic compounds which are capable of suppressing and/or inhibiting the programmed cell death 1 (PD1) signaling pathway.

PATENT

WO 2015033299

Example 5: Synthesis of

The compound was synthesised using similar procedure as depicted in Example 4 (compound 4) using D-amino acids are linked up in reverse order. Boc-D-Thr(‘Bu)-OH was used in place of Boc-Ser(‘Bu)-OH, Fmoc-D-Asn(trt)-OH in place of Fmoc-Asn(trt)-OH and H-D-Ser(‘Bu)-0’Bu was used in place of H-Thr^Bu^O’Bu to yield 0.3 g crude material of the title compound. The cmde solid material was purified using preparative HPLC described under experimental conditions. LCMS: 361.3 (M+H)⁺. HPLC: t_R = 13.58 min.

Example 8: Synthesis of

The compound was synthesised using similar procedure as depicted in Example 2 (compound 2) using Fmoc-Glu(0’Bu)-OH instead of Fmoc-Asn(Trt)-OH to get 0.4 g crude material of the title compound. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 362.1 (M+H)⁺. HPLC: t_{R =} 13.27 min.

 

PATENT

WO2015033301

Example 3: Synthesis of compound 3

Step 3a:

3a

Lawesson’s reagent (2.85 g, 7.03 mmol) was added to a solution of compound 2e (4 g, 4.68 mmol) in THF (40 mL) and stirred at 75°C for 4 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced

pressure and the obtained residue was partitioned between ice water and ethyl acetate. The organic layer was washed with NaHCC>3 solution followed brine solution. The organic layer was dried over Na₂S0₄, filtered and evaporated under reduced pressure to get residue which was further purified by silica gel column chromatography (eluent: 0-5% ethyl acetate in hexane) to afford 2.7 g of compound 3a (Yield: 67.66%). LCMS: 852.3 (M+H)⁺,

Step 3

3a 3b

Fmoc group on compound 3a was deprotected by adding diethylamine (3.8 mL) to the solution of compound 3a (1 g, 1.17 mmol) in CH₂CI₂ (3.8 mL). The reaction mixture was stirred at room temperature for 30 min. The resulting solution was concentrated in vacuum to get a thick gummy residue. The crude compound was purified by neutral alumina column chromatography (eluent: 0-50% ethyl acetate in hexane then 0-5% methanol in chloroform) to attain 0.62 g of compound 3b. LCMS: 630.5 (M+H)⁺.

Step 3c

To a solution of compound 3b (0.6 g) in CH₂CI₂ (7.5 mL), trifluoroacetic acid (2.5 mL) and catalytic amount of triisopropylsilane were added and stirred at room temperature for 3 h. The resulting solution was concentrated in vacuum to get 0.13 g of compound 3 which was purified by preparative HPLC method described under experimental conditions. LCMS: 232.3 (M+H)⁺.

Example 1: Synthesis of compound 1

Step la:

Potassium carbonate (7.9 g, 57.39 mmol) and Methyl iodide (1.3 mL, 21.04 mmol) were added to a solution of compound la (5.0 g, 19.13 mmol) in DMF (35 mL) and stirred at room temperature for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was partitioned between water and ethyl acetate. Organic layer was washed with water, brine, dried over Na₂S0₄ and evaporated under reduced pressure to get 5.0 g of compound lb (Yield: 96.1%). LCMS: 176.1 (M-Boc)⁺.

Step lb:

Hydrazine hydrate (7.2 mL) was added to a solution of compound lb (5.0 g, 18.16 mmol) in methanol (30 mL) and stirred at room temperature for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure, the residue obtained was partitioned between water and ethyl acetate. Organic layer was washed with water, brine, dried over Na₂S0₄ and evaporated under reduced pressure to get 4.0 g of compound lc (Yield: 80.0%). LCMS: 276.3 (M+H)⁺. Step lc:

NMM (0.67 ml, 6.52 mmol) was slowly added to a stirred solution of lc (1.2 g, 4.35 mmol), Id (1.43 g, 4.35 mmol), HOBt (0.7 g, 5.22 mmol) and EDC.HC1 (0.99 g, 5.22 mmol) in DMF (15 mL) at 0°C. The reaction mixture was stirred at room temperature for 12 h. The completeness of the reaction was confirmed by TLC analysis. The reaction was quenched with ice and the solid precipitated was filtered and dried under vacuum to obtain 2.0 g of pure product le (Yield: 83.3%). LCMS: 591.5 (M+Na)⁺.

St

1 e

1f

To a stirred solution of le (1.5 g, 2.63 mmol) in dry THF (15.0 mL) and DMF (5.0 mL) triphenylphosphine (1.38 g, 5.27 mmol) and iodine (1.33 g, 5.27 mmol) were added at 0°C. After the iodine was completely dissolved, Et3N (1.52 mL, 10.54 mmol) was added to this reaction mixture at ice cold temperature. Reaction mixture was allowed to attain room temperature and stirred for 4 h. The completeness of the reaction was confirmed by TLC analysis. The reaction was quenched with ice water and extracted with ethyl acetate. Organic layer was washed with saturated sodium thiosulphate and brine solution.

The separated Organic layer was dried over Na₂SC>4 and evaporated under reduced pressure to get residue, which was further purified by silica gel column chromatography (eluent: 30% ethyl acetate in hexane) to afford 0.8 g of compound If (Yield: 55%). LCMS: 551.3 (M+H)⁺.

Step le:

1f i g

Fmoc group was deprotected by the addition of diethylamine (20.0 mL) to a solution of compound If (0.8 g, 1.45 mmol) in CH₂CI₂ (20.0 mL) at 0°C. The reaction was stirred at room temperature for 2 h. The resulting solution was concentrated in vacuum to get a thick gummy residue. The crude compound was purified by neutral alumina column chromatography (eluent: 2% methanol in chloroform) to afford 0.38 g of compound lg (Yield: 80.0%): LCMS: 329.4 (M+H)⁺.

Step If:

ig ^{1 i}

Compound lg (0.38 g, 1.16 mmol), TEA (0.33 mL, 2.32 mmol) dissolved in DMF (10 mL) were added drop wise to a solution of lh (0.55 g, 1.39 mmol) at 0°C for urea bond formation and the mixture was stirred at room temperature for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction was quenched with ice water, the solid precipitated was filtered and dried under vacuum to get crude compound, which was further purified by silica gel column chromatography (eluent: 0-35% ethyl acetate in hexane) to get 0.4 g of product li (Yield: 59.7%). LCMS: 586.4 (M+H)⁺.

Step lg:

BocHN’ IJ, H _LT Y^~™

1

To a solution of compound li (0.4 g, 0.68 mmol) in CH₂CI₂ (5 m L), trifluoro acetic acid (5 mL) and catalytic amount of triisopropylsilane were added and stirred at room temperature for 3 h to remove the acid sensitive protecting groups. The resulting solution was concentrated under nitrogen and the solid material was purified by preparative HPLC method as described under experimental conditions (Yield: 0.05 g). LCMS: 318.0 (M+H)⁺; HPLC: t_R= 10.96 min.

Synthesis of compound lh (N0₂-C₆H4-OCO-Thr(tBu)- 0¾u):

To a solution of 4-nitrophenylchloroformate (4.79 g, 23.77 mmol) in DCM (25.0 mL) was added a solution of H-Thr(tBu)-OtBu (5.0 g, 21.61 mmol) TEA (6.2 mL, 43.22 mmol) in CH₂CI₂ (25 mL) slowly at 0°C and allowed to stir for 30 min. The completion of the reaction was confirmed by TLC analysis. After completion of reaction it was diluted with DCM and washed with 1.0 M of citric acid followed by 1.0 M sodium carbonate solution. The organic layer was dried over Na₂S0₄ and evaporated under reduced pressure to afford crude compound 1 h, which was further purified by silica gel column chromatography (eluent: 0-5% ethyl acetate in hexane) to get 3.0 g of product lh. ^jH NMR (CDCI₃, 400 MHz): £1.17 (s, 9H), 1 .28 (d, 3H), .50 (s, 9H), 4.11 (m, 1 H), 4.28 (m, 1H , 5.89 (d, 1H), 7.37 (d, 2H), 8.26 (d, 2H).

 

Brahma Reddy V, Thomas Antony, Murali Ramachandra, Venkateshwar Rao G, Wesley Roy Balasubramanian, Kishore Narayanan, Samiulla DS, Aravind AB, and Shekar Chelur.

REFERENCES

US20150073024

WO2011161699A2	27 Jun 2011	29 Dec 2011	Aurigene Discovery Technologies Limited	Immunosuppression modulating compounds
WO2012168944A1	21 Dec 2011	13 Dec 2012	Aurigene Discovery Technologies Limited	Therapeutic compounds for immunomodulation
WO2013132317A1	4 Mar 2013	12 Sep 2013	Aurigene Discovery Technologies Limited	Peptidomimetic compounds as immunomodulators
WO2013144704A1	28 Mar 2013	3 Oct 2013	Aurigene Discovery Technologies Limited	Immunomodulating cyclic compounds from the bc loop of human pd1

http://www.curis.com/images/stories/pdfs/posters/Aurigene_PD-L1_VISTA_AACR-NCI-EORTC_2015.pdf

////////Curis and Aurigene,  AUPM 170, CA 170, AUPM-170, CA-170, PD-L1, VISTA antagonist