WO2019038683A1

WO2019038683A1 - Compounds targeting tandem brct domains of brca1, compositions and methods thereof

Info

Publication number: WO2019038683A1
Application number: PCT/IB2018/056344
Authority: WO
Inventors: Kavitha BHARATHAM; Vadiraj KURDEKAR; Vijay Potluri; Ashok R VENKITARAMAN
Original assignee: Institute For Stem Cell Biology And Regenerative Medicine
Priority date: 2017-08-24
Filing date: 2018-08-22
Publication date: 2019-02-28

Abstract

The present invention is in the field of medicinal/pharmaceutical sciences. The present disclosure relates to compounds, compositions, methods, and uses for diagnosis and treatment of disease or conditions responsive to BRCA1 modulation, and/or the modulation of other proteins that contain BRCT domains. In particular, the invention relates to compound of formula I, corresponding compositions and methods for inhibiting BRCA1 activity and thereby DNA damage response (DDR) in cells, mediated via ATM, ATR, CDKs, DNA-PK, BRCA1, BRCA2, PALB2, RAD51 or CHEK1, as well as other molecules. Said modulation of steps in the DDR results in treatment or management of proliferative disorders including cancer.

Description

COMPOUNDS TARGETING TANDEM BRCT DOMAINS OF BRCAl, COMPOSITIONS

AND METHODS THEREOF

RELATED APPLICATION

This application is related to and takes priority from Indian Application No. 201741030084 filed on August 24, 2017 and is incorporated herein in its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds, compositions, methods, and applications in the treatment of cancer or other diseases. In particular, the invention relates to compounds, compositions and methods for inhibiting the interaction of breast cancer gene 1 (BRCAl) tandem carboxyl (C)-terminal (BRCT) domains with phosphorylated substrates including BTB Domain and CNC Homolog 1 (BACH1) helicase. The compounds of the present invention are useful in treating diseases or conditions responsive to or requiring the inhibition of ATM, ATR, DNA-PK, BRCAl, BRC A2, PALB2, RAD51 or CHEK1 and/or other BRCT- domain containing proteins.

BACKGROUND OF THE DISCLOSURE

Selective modulation of intracellular signalling pathways is a major challenge impeding deeper understanding of the biology of human diseases, as well as their therapy using small- molecule drugs. Thus far, efforts in academia and the pharmaceutical industry have focused largely on the inhibition of enzymes such as protein kinases using ATP-competitive

inhibitors(Nat. Rev. Drug Discov. 16, 19-34, 2017). However, these approaches suffer from the lack of chemical and biological selectivity. Chemically, majority of ATP competitive inhibitors exhibit off-target binding owing to structural similarities between the ATP binding catalytic fold of many protein kinases. Biologically, inhibition of proximal catalytic steps in signal transduction leads to a wide variety of phenotypic effects.

Alternative approaches for the modulation of intracellular signallingpathways are therefore being sought to overcome these problems. Signal propagation in pathways initiated by protein kinases occurs through the molecular recognition of site-specific protein phosphorylation by

phosphopeptide recognizing domains. Over 10 different structural mechanisms for such recognition have been identified through distinct protein domains that bind to pSer, pThr or pTyr residues in proteins. Inhibition of phosphopeptide substrate recognition by these domains using small molecule drugs is an attractive approach to selectively modulate intracellular signalling(Cell Chem. Biol. 24, 1-12, 2017). The BRCT (BRCA1 C-terminal) domain represents one member of a family of

phosphopeptide recognizing domains. BRCT domains were originally identified in Breast cancer associated 1 (BRCA1) protein but exist in many proteins from prokaryotes to eukaryotes. The BRCT domain typically consists of repeats containing approximately -90-

100 amino acids. Each BRCT repeat adopts a characterized fold with a central, parallel four- stranded β -sheet, along with a pair of a -helices packed against one face and a single a -helix packed against the opposite face of the sheet. The arrangement of the a 1 , a 3 and the central β-sheet is conserved in all repeats as a number of key hydrophobic residues maintain the packing of the BRCT fold. The two BRCT repeats in BRCA1 interact in a head-to-tail manner. In this arrangement, the N-terminal half of the one BRCT domain forms a pocket for pSer as the C-terminal half of the same domain generates a hydrophobic pocket for Phe. The tandem BRCT (tBRCT) domain pair in BRCA1 recognizes the phosphorylated peptide motif pS-P-T-F in various protein partners such as BRC A 1 -associated C-terminal helicase protein (BACH1), CtlPand Abraxas/Coiled-coil domain-containing protein and the ability of BRCA1 to recognize different binding partners in DDR signalling regulates BRCA1 recruitment and function(Science 302, 636-639, 2003; J. biol. chem. 278, 52914- 52918,2003). Crystal structures of the BRCAltBRCTdomainbound to their respective phosphopeptides reveal a conserved bipartite recognition involving two distinct pockets: a pS/pT binding pocket in the N-terminal BRCT and a secondary specificity pocket at the BRCT-BRCT interface that generally provides selectivity for a hydrophobic residue at the +3 position in the

phosphopeptide with respect to the pS.

The tBRCT domain of BRCA1 is critical forthe cellular DNA damage response

(DDR)through the recognition of phosphorylated proteins that have been modified by protein kinases activated by DNA damage, including but not limited to CDKs, ATM, ATR and DNA- PK. The DDR is proposed to constitute an early barrier to tumorigenesis and current cancer therapy regimens, including but not limited to radiation therapy exploit weaknesses in this system to selectively kill cancer cells. Thus, the establishment of a platform for the identification of chemical compounds that inhibit the interaction of the BRCA1 tBRCT domains with their phosphopeptide substrates will lead to the discovery of potential sensitizers to cancer therapyand should accelerate the development of new treatment strategies. Small-molecule chemical tools that target aforesaid interactions could offer an advanced therapeutic approach for the selective modulation of intracellular signalling pathways. As noted earlier, BRCA1 activity through phosphopeptide recognition by its tBRCT domain selectively propagates intracellular signals downstream of protein kinases like ATM, ATR or DNA-PK. However, synthesizing improved and advantageous small molecules for selective modulation of intracellular signalling pathways via phosphopeptide recognition or other protein-protein interactions has been difficult in the prior art.

The present disclosure addresses the aforesaid needs of the prior art by providing novel small molecule selective modulators of intracellular signalling pathways which are useful in

managing diseases/conditions requiring such modulation, including cancer.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I

or its prodrugs, tautomeric forms, stereoisomers, optical isomers, pharmaceutically acceptable salts, solvates or polymorphs thereof, wherein

Rl, R2 and R3 are independently selected from a group consisting of H, C1-C6 alkyl, C6-C10 aryl and wherein each of them is unsubstituted or substituted;

Q is N or C and wherein each of them is unsubstituted or substituted;

L and M are independently selected froma group consisting of a bond, H, C1-C10 alkyl, C1-C10 alkoxyl, Carbonyl (C=0), Sulfonyl (S0₂), Methylene (CH₂), Carboxyl(C0₂), Carbamide (0=C-

N), Hydroxyl (OH), C6-C10 aryl and wherein each of them is unsubstituted or substituted; and

R4 and R5 are selected from a group consisting of phenyl, 5-10 membered heteroaryl, 5-10 membered bicyclic heteroaryland wherein each of them is unsubstituted or substituted.

In one aspect of the invention, Rl is H, methyl, S-Methyl, R-Methyl,isopropyl, S-Isopropyl, benzyl, R-Isopropyl, S-benzyl or R-benzyl.

In another aspect, R2 and R3 are independently H or Methyl.

In yet another aspect, L and M are linkers independently selected from 

Wherein n = 0 to 6 and R9 is-H, -CH₃, -CH₂-CN, -OCH₃, -OCH₂CN, -OCH₂CH₂OH,

OCH₂CH₂OCH₃, -OCH₂COOH, -OS0₂CH₃, -S0₂CH₃, -N(CH₂CH₂OH)2, - HCH₃ or N(CH₃)₂. R5 is

Wherein RIO is F, CI, Br, I, CN, OH, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkylthio, arylthio, nitro, azido, hydrazino, carboxyl acid and carboxylic acid ester.

R5 is also provided as

The compounds of the invention are provided (from 1 to 129) in Table I.

Further, the invention provides a method of inhibiting phosphopeptide recognition by the human BRCA1 (t)BRCT domain by using the compounds of the invention encompassed by Formula I along with its substitutions described above.

The invention also provides a method of inhibiting the function of BRCA1 by using the compounds of the invention encompassed by Formula I along with its substitutions described above.

Furthermore, the invention presents a method of inhibiting cell cycle arrest induced by DNA damage by using the compounds of the invention encompassed by Formula I along with its substitutions described above. In another aspect, the invention provides a method of inhibiting the recruitment of cellular proteins essential for G2 arrest and DNA repair by homologous DNA recombination by using the compounds of the invention encompassed by Formula I along with its substitutions described above.

The invention also provides a method of sensitizing cancer cells to the cytostatic or cytotoxic effects of radiation or DNA damaging agents by using the compounds of the invention encompassed by Formula I along with its substitutions described above and the said DNA damaging agents are cisplatin, carboplatin, doxorubicin, toposide, topotecan, irinotecan or mitomycin C, inhibitors of poly-ADP ribose polymerase (PARP) enzymes, inhibitors of telomerase or inhibitors of polymerase theta or any combination thereof.

The compounds of the invention formulated into pharmaceutical composition comprising at least one pharmaceutical excipient are useful in the treatment of diseases responsive to inhibition of ATM, ATR, DNA-PK, BRCA1, BRCA2, PALB2, RAD51 or CHEK1

The compounds of the invention formulated into pharmaceutical composition comprising at least one pharmaceutical excipient are useful in the treatment of cancer, proliferative disorders (for example: rheumatoid arthritis, idiopathic pulmonary fibrosis and psoriasis), inflammatory disorders associated with cell proliferation or Fanconi Anemia.

The invention also provides a combination of the compounds of invention along with at least one additional active therapeutic agent wherein the said active therapeutic agent is an anti-cancer, immune modulatory, cytostatic, cytotoxic, anti-hyperproliferative, anti-inflammatory and chemotherapeutic agents

BRIEF DESCRIPTION OF FIGURES

Figure 1 shows the direct binding assay for Compound 6 by Micro Scale Thermophoresis (MST).

Figure 2 shows the competitive binding assay for selected compounds by Micro Scale

Thermophoresis (MST).

Figure 3 shows target engagement studies for Compound 6 using FRET sensitized emission and acceptor photobleaching measurement methodologies.

Figure 4 shows inhibition of endogenous recruitment of BRCA1 foci by selected compounds.

Figure 5 shows inhibition of endogenous recruitment of RAD 1 foci by Compound 6.

Figure6 shows cell cycle and G2 checkpoint regulation studies using selected compounds of the invention. Figure 7 showssynergistic effect of Compound 6 with Olaparib under steady state conditions in HEK293 cells.

Figure 8 shows decreased cell survival in the presence of Compound 6 in different cancer cell lines as indicated in the Figure.

Figure 9 shows cellular proliferation and radiation sensitivity studies by Compound 6. DESCRIPTION OF THE INVENTION

The present disclosure relates to compounds and compositions as modulators of intracellular signalling pathways. Corresponding methods of treating/managingdiseases or conditions responsive to said modulation are also disclosed. As used in the present disclosure, modulation comprises inhibition, activation or a combination thereof. In an exemplary embodiment, compounds and compositions of the present disclosure are inhibitors of proteins including BRCA1 involved in intracellular signallingpathwaysresponsible for DNA damage response (DDR) in cells.

The present disclosure providescompounds of general formula I:

formula I

wherein:

Rl, R2, R3 are independently selected from a group consisting of H, C1-C6 alkyl and C6-C10 aryl, and wherein each of them is unsubstituted or substituted;

Q isNor C, and wherein each of them is unsubstituted or substituted;

L and M are independently selected from a group consisting of a bond, H, CI -C IO alkyl, Cl- C10 alkoxyl, Carbonyl (C=0), Sulfonyl (S0₂), Methylene (CH₂), Carboxyl(C0₂)and Carbamide (0=C-N), Hydroxyl (OH), C6-C10 aryland wherein each of them is unsubstituted or substituted; and

R4 and R5 are independently selected from a group consisting of phenyl, 5-10 membered heteroaryl, 5-10 membered bicyclic heteroaryland wherein each of them is unsubstituted or substituted; and salt, derivative, tautomeric form, isomer, polymorph, solvate and intermediates thereof of the above compound.

In a non-limiting embodiment of the present disclosure, Rl in the compound of formula I is selected from a group comprising Hydrogen, Methyl, S-methyl, R-methyl,isopropyl, S- isopropyl, R-isopropyl, Benzyl, S-benzyl and R-benzyl.

In a non-limiting embodiment of the present disclosure, R2 and R3 in the compound of formula I are either Hydrogen or Methyl. In a preferred embodiment, R2 in the compound of formula I is hydrogen and R3 is methyl.

In an embodiment of the present disclosure, L and M of formula I are linker moieties. In another non-limiting embodiment of the present disclosure, L and M of the compound of formula I are linkers independently selected from

, wherein n is 0 to 6.

In yet another non-limiting embodiment of the present disclosure, R4 of the compound of formula I is selected from a group comprising

wherein R6 is H or Carboxylic acid (COOH) and R8 is -H, -CH₃ -CH₂-CH₂-OH or -CH₂- CH₂-CN and R7 is

9— <^' 0 N-

HO C

and wherein n = 0 to 6 and R9 is -H, -CH₃, -CH₂-CN, -OCH₃, -OCH₂CN, -OCH₂CH₂OH, OCH₂CH₂OCH₃, -OCH₂COOH, -OS0₂CH₃, -S0₂CH₃, -N(CH₂CH₂OH)2, -NHCH₃ or N(CH₃)₂. In a non-limiting embodiment of the present disclosure, R5 of the compound of formula I is

wherein RIO is selected from a group consisting of F, CI, Br, I, CN, OH, alkyl, alkenyl, alkynyl, alkoxy, aryoxy, alkylthio, arylthio, nitro, azido, hydrazino, carboxyl acid

andcarboxylic acid ester.

In another non-limiting embodiment of the present disclosure, R5 of formula I is:

The present disclosure further provides com ounds of general formula II:

formula II

wherein Rl, R2, R3, R4, L and Q are as defined in general formula I. The present disclosure also provides com ounds of general formula ΠΙ:

formula III

wherein Rl, R2, R3, R7 and Q are as defined in general formula I.

The present disclosure provides com ounds of general formula IV:

formula IV wherein Rl, R2, R3, R9 and Q are as defined in general formula I.

Exemplary compounds of Formula I, II, III and IV are provided in Table 1 below:

Table 1: Exemplary compounds of the present invention

Comp

-ound Structure

LCMS and Ή NMR data numb IUPAC Name

-er

F LCMS: (M+H⁺): 382.34; ¾ NMR (DMSO-d₆

400 MHz) δ ppm 1 1.914 (s, 1H), 8.059 (s, 2H), 7.476 (s, 1H), 7.439-7.405 (t, J = 7.2 Hz, 1H),

1 7.353-7.305 (m, 1H), 7.200-7.148 (m, 3H), o 3.503-3.404 (m, 3H), 2.423 (s, 3H).

(4-(2-fluorobenzyl)piperazin-l-yl)(lH- indol-6-yl)methanone

Ό LCMS: (M+H⁺): 382.34; Ή NMR (DMSO-d₆

2 7.353-7.305 (m, 1H), 7.200-7.148 (m, 3H),

H n 3.503-3.404 (m, 3H), 2.423 (s, 3H).

0

6-(4-(2-fluorobenzyl)piperazine- 1 - carbonyl)-lH-indole-3-carboxylic acid

LCMS: (M+H⁺): 335.23; ^l NMR (DMSO-d₆ 400 MHz) δ ppm 12.683 (s, 1H), 7.508-7.522 (t, J = 9.6 Hz, 2H), 7.240-7.219 (d, J = 8.4 Hz,

3 1H), 7.183 -7.133 (q, J = 5.2 Hz, 2H), 7.048-

0 7.029 (d, J = 7.6 Hz, 1H), 6.994-6 957 (t, J =

12, 1H) , 3.672 (br, 4H), 2.854 (s, 4H), 2.521-

(2-methyl-lH-benzo[d]imidazol-5-yl)(4- 2.505 (s, 3H), 2.273 (s, 3H).

(o-tolyl)piperazin- 1 -yl)methanone

LCMS: (M+H⁺): 389.5; ^:H NMR (DMSO-d₆ 400 MHz) δ ppm 12.748 (s, 1H), 7.799 (s, 1H), 7.654-7.672 (d, J = 1.2 Hz, 1H), 7.458-7.478 (d, J = 8 Hz, 1H), 7.287-7.305 (d, J = 7.2 Hz, 2H),

4

7.086-7.141 (dd, J = 8.4 Hz, 2H), 3.499 (br, 2H), 2.853 (br, 4H), 2.552 (s,3H) , 2.442 (br,

5-((4-(2-fluorobenzyl)piperazin- 1 - 4H).

yl)sulfonyl)-2-methyl-lH- benzo[d]imidazole

LCMS: (M+H⁺): 445.23; ¾ NMR (DMSO-d₆ 400 MHz) δ ppm 2.888 (s, 1H), 7.572 (br, 2H),

5 7.429 (br, 1H), 7.343-7.303 (t, 3H), 7.208-7.189

o (br, 3H), 7.101-7.081 (d, 2H), 6.998-6.961 (t,

1H), 5.344 (s, 2H), 3.573 (br, 5H), 2.428 (br,

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2- 3H). (phenoxymethyl)-lH-benzo[d]imidazol- 6-yl)methanone

F LCMS: (M+H⁺): 415.3; ^lU NMR (DMSO-d₆ 400 MHz) δ ppm 13.132 (s, 1H), 8.198-8.180 (d, J = 7.2 Hz, 2H), 7.708-7.667 (m, 1H), 7.586-7.726 (m, 4H), 7.446-7.412 (t, J = 6.8 Hz, 1H), 7.341-

0 7.324 (d, J = 6 8 Hz, 1H), 3.581 (s, 3H), 2.442

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2- (s,lH), 1.225 (s,lH).

phenyl-lH-benzo[d]imidazol-6- yl)methanone

LCMS: (M+H⁺): 381.40; ¾ NMR (DMSO-d₆ 400 MHz) δ ppm 12.434 (s, NH), 7.516-7.495 (d, J = 8.4 Hz, 2H), 7.465-7.429 (t, J = 7.2 Hz, 1H) 7.363-7.349 (d, J = 5.6 Hz, 1H), 6.556 (s,

0 1H), 3.214-3.110 (m, lH), 2.544 (s, 2H), 1.355-

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2- 1.338 (d, J = 6.8 Hz, 6H).

isopropyl-lH-benzo[d]imidazol-6- yl)methanone

LCMS: (M+H⁺): 741.22; ¾ NMR (CD₃OD 400 MHz) δ ppm 7.725-7.655 (br, 2H), 7.474-7.433 (td, J = 1 6 Hz, 1H), 7.365-7 302 (m, J = 2 Hz, 4H), 7.199 -7.159 (m, J = 0.8 Hz, 1H), 7.182-

— ° 0 7.028 (m, J = 8.4 Hz, 1H), 6.682-6.671 (t, J = 2,

(2-(3,5-dimethoxyphenyl)-lH- 1H) , 3.909 (s, 5H), 3.810 (s, 2H), 3.685-3.661 benzo[d]imidazol-6-yl)(4-(2- (d, J = 9.6 Hz, 2H), 3.588 (br, 2H), 2.603-2.542 fluorobenzyl)piperazin- 1 -yl)methanone (br, 4H), 1.356-1.306 (m, J = 13.2 Hz, 1H).

LCMS: (M+H⁺): 437.22_; ^JH NMR (DMSO-d₆, 400 MHz) δ ppm 12.387 (Br, 1H), 7.484-7.464 (d, J = 8Hz, 2H), 7.263-7.223 (t, / = 8Hz, 1H), o 7.155-7.134 (d, J = 8.4Hz 1H), 6.932-6.913 (d, J

= 8Hz, 1H), 6.822-6.802 (d, J = 8Hz 1H), 6.559 ethyl 2-(3-((4-(2-methyl-lH (s, 1H), 4.761 (s, 2H), 4.187-4.134 (dd, J = benzo[d]imidazole-6- 7.2Hz, 2H), 3.504 (br, 5H), 2.406 (br, 3H), carbonyl)piperazin- 1 - 1.221-1.185 (t, J = 14.4Hz, 3H).

yl)methyl)phenoxy)acetate

LCMS: (M+H⁺): 409.22_; *H NMR (DMSO-d₆, 400 MHz) δ ppm 12.957 (Br, 1H), 7.465 (s, 2H), 7.178-7.1 13 (q, J = 8.2 Hz, 2H), 6.802 (s, 2H), 6.725-6.705 (d, J = 8, 1H), 4.136 (s, 2H), 3.520

0 (Br, 2H), 3.373 (s, 3H), 2.509-2.487 (d, J = 16

2-(3-((4-(2-methyl-lH- Hz, 2H), 2.380 (s, 3H).

benzo[d]imidazole-6- carbonyl)piperazin- 1 - yl)methyl)phenoxy)acetic acid

LCMS: (M+H⁺): 349.2; *H NMR (DMSO-d₆ 400 MHz) δ ppm 12.424 (s, 1H), 7.521-7.449 (m, 7H), 7.199-7.180 (s, 1H), 3.564 (s, 7H), 2.077 (s, 1H).

0

(4-benzoylpiperazin- 1 -yl)(2-methyl-lH- benzo[d]imidazol-6-yl)methanone

LCMS: (M+H⁺): 378.46; *H NMR (DMSO-d₆ 400 MHz) δ ppm 12.441 (s, NH), 9 842 (s, NH), 7.642-7.623 (d, 2H), 7.505-7.485 (t, 2H), 7.328- 7.289 (t, 2H), 7.184-7.160 (dd, IH), 7.078-7.041 o (t, IH), 3.603 (bs, 4H), 3.255 (s, 2H), 2.614 (s,

2-(4-(2-methyl-lH-benzo[d]imidazole- 4H).

6-carbonyl)piperazin-l-yl)-N- phenylacetamide

LCMS: (M+H⁺): 408.22; ¾ NMR (DMSO-d₆, 400 MHz) δ ppm 12.369 (br, IH), 7.539 (s, IH) 7.486-7.467 (d, J = 7.6Hz, 2H), 7.268-7.230 (t, J = 7.6Hz, IH), 7.138-7.135 (d, J = 1.2Hz, IH),

0

6.929-6.908 (d, 8.4Hz, 2H), 4 40

2-(3-((4-(2-methyl-lH- J = 6 (s, 2H),

3.507 (s, 5H), 2.417 (s, 3H)

benzo[d]imidazole-6- carbonyl)piperazin- 1 - yl)methyl)phenoxy)acetamide

LCMS: (M+H⁺): 381.2; ^:H NMR (MeOD 400 MHz) δ ppm 7.580 (s, 2H), 7.498-7.464 (t, J = 12 Hz, IH), 7.299-7.275 (dd, J = 1.2 Hz, 2H), 7.145 (s, IH), 7.072-7.028 (t, J = 8.4 Hz, IH),

0 3.478 (s, IH) , 3.639 (s, 3H), 3.368-3.350 (d,

(4-(2-fluorobenzyl)-3,3- IH), 2.609 (s, 4H), 2.538 (s, IH), 1.179-1.353 dimethylpiperazin- 1 -yl)(2-methyl- 1H- (q, J = 6.0 Hz 4H), 1.066 (s, 3H).

benzo[d]imidazol-5-yl)methanone

° ^ΟΗ LCMS: (M+H⁺): 424.3; ¾ NMR (DMSO-de 400

MHz) δ ppm 11.898 (s, IH), 8.075-7.024 (m, 2H), 7.430 (s, 2H), 7.331-7.315 (d, IH), 7.183- 7.114 (m, 3H), 4.220 (bs, IH), 3.525-3.297 (m, 7H), 2.946-2.856 (d. 2H), 2.691 (s, IH), 2.406 (s, IH), 1.998 (s, IH), 1.229 (s, IH), 0.898-0.835

(S)-6-(4-(2-fluorobenzyl)-2- (br, 4H), 0.664 (s, IH), 0.504 (s, IH).

isopropylpiperazine- 1 -carbonyl)- 1H- indole-3-carboxylic acid

LCMS: (M+H⁺): 377.27, ¾ NMR (DMSO-d₆, 400 MHz) δ ppm 13.131 (s, NH), 7.585-7.550 (m, 2H), 7.255-7.235 (d, IH), 7.184-7.166 (d, IH), 7.090 (s, IH), 7.013-6.979 (t, IH), 4.382 (s, IH), 2.289 (s, 3H), 1.008 (br, 3H), 0.763 (br,

(S)-(2-isopropyl-4-(o-tolyl)pip uerazin- 1 - 2H).

yl)(2-methy 1- 1 H-benzo [d] imidazol - 5 - yl)methanone

LCMS: (M+H⁺): 487.22; ¾ NMR (DMSO-d₆ 400 MHz) δ ppm 12.875 (s, IH), 7.346-7.307 (t,3H), 7.104-7.084 (d, 2H), 7.000-6.964 (t, IH), 5.345 (s,2H), 3.3479 (s, lH), 2.973-2.943 (br d, 2H), 2.406 (s, lH), 0.909-0.824 (br, 4H), 0.654 (br, IH), 0.501 (br, IH).

F

LCMS: (M+H⁺): 320.3; ^lH NMR (DMSO-d₆,

X) 400 MHz) δ ppm 11.308 (s, IH), 7.606-7.585 (d,

J = 8.4 Hz, IH), 7.498 (s, IH), 7.478-7.466 (t, J = 2.4/4.8 Hz, IH), 7.184-7.154 (t, J = 7.2 Hz,

H 0 IH), 7.135 (s, IH), 7.091-7.071 (d, J = 8 Hz,

0 IH), 7.047-7.028 (d, J = 7.6 Hz, IH), 6.994-

( 1 H-indol-6-yl)(4-(o-tolyl)piperazin- 1 - 6.958 (t, J = 7.2/14.4 Hz, IH), 6 488 (s, IH), yl)methanone 3.686 (br, 4H), 2.853 (br, 4H), 2.276 (s, 3H).

LCMS: (M+H⁺): 307.2; ^lH NMR (DMSO-d₆ 400 MHz) δ ppm 12 631 (s, IH), 8.329 (s, IH), 7.661 (br s, 2H), 7.294 (m, IH), 7.252-7.213 (q, J = 1.2 Hz, 2H), 6.975-6.955 (d, J = 8 Hz, 2H) ,

0 6.831-6.795 (t, J = 7.2 Hz, IH), 3.669 (br s, 4H),

(lH-benzo[d]imidazol-6-yl)(4- 3.117-3.164 (d, J = 5.2 Hz, 4H).

phenylpiperazin- 1 -yl)methanone

LCMS: (M+H⁺): 429.5. ^LH NMR (DMSO-d₆ 400 MHz) δ ppm 12.598 (s, IH), 8.292 (s, IH), 7.482-7.445 (t, / = 7.6 Hz, 2H), 7.370-7.355 (d, J = 6.0 Hz, IH), 7.217-7.131 (br, 8H), 6.653 (br, 2H), 3.639-3.606 (d, J = 13.2Hz, IH) , 3.460- 3.427 (d, J = 13.2 Hz, 2H), 2.971 (br, 3H), o 2.077-2.051 (d, J = 10.4 Hz, 2H).

(S)-(lH-benzo[d]imidazol-6-yl)(2- benzyl-4-(2-fluorobenzyl)piperazin- 1 - yl)methanone

LCMS: (Μ+Ή⁺): 382.3; ¾ NMR CD30D 400 MHz) δ ppm 15-16 (br, IH), 7.965-7.944 (d, IH, J = 8.4), 7.882 (s, IH), 7.433-7.375 (m, 2H), 7.336-7.298 (m, IH), 7.202-7.150 (m, 2H), 4.339-4.206 (m, IH), 3.623-3.470 (m, 2H),

0 3.407-3.266 (m, 2H), 2.984-2.955 (m, 2H),

(S)-(lH-benzo[d][l,2,3]triazol-6-yl)(4- 2.408 (br s, IH), 2.058-2.008 (t, IH, J = 9.6), (2-fluorobenzyl)-2-isopropylpiperazin- 0.928-0.828 (m, 4H), 0.666-0.653 (br s, IH), l-yl)methanone 0.498-0.486 (br s, IH).

F LCMS: (M+H⁺): 350.40; ^:H NMR (DMSO-d₆

400 MHz) δ ppm 8.971-8.965 (d, J = 2.4 Hz, IH), 8.440-8.420 (d, J = 8 Hz, IH), 8.077-8.056 (d, J = 8.4 Hz, 1H),7.977 (s, IH), 7.623-7.592

0 (m, 2H), 7.435 (s, IH), 7.334 (s, IH), 7.191 (s,

(4-(2-fluorobenzyl)piperazin- 1 - 2H), 3.682-3.345 (m, 4H), 2.411 (s, 2H).

yl)(quinolin-7-yl)methanone

LCMS: (M+H⁺): 350.40; ^lH NMR (DMSO-d₆ 400 MHz) δ ppm 8.928 (s, 2H), 8.208-8.146 (m, 2H), 7.843-7.823 (d, J = 8 Hz, IH), 7.466-7.431 (t, J = 6.8 Hz, IH), 7.339-7.322 (d, J = 6.8 Hz,

F IH), 7.195-7.158 (t, J = 7.2 Hz, IH), 7.114-

6-(4-(2-fluorobenzyl)piperazine- 1 - 7.069 (t, J = 8.8 Hz, IH), 3.956 (s, 2H), 3.797 (s, carbonyl)-lH-indole-3-carboxylic acid 2H), 3.606 (s, 2H), 2.766-2.623 (m, 4H).

carbonyl)piperazine- 1 -carboxylate

LCMS: (M+H⁺): 441.2; *H NMR (DMSO-d₆ 400 MHz) δ ppm 13.151 (s, IH), 8.205-8.187 (d, J = 8.4Hz, 2H), 7.690-7.506 (m, 5H), 7.383-7.272 (m, 6H) , 5.112 (s, 2H), 3.501 (br s, 7H).

^H o benzyl4-(2 -phenyl- 1H- benzo[d]imidazole-6- carbonyl)piperazine- 1 -carboxylate

LCMS: (M+H⁺): 364.24; ¾ NMR (DMSO-d₆, 400 MHz) δ ppm 11.316 (s, IH), 7.644-7.640 (t, J = 0.81.6 Hz, IH), δ ppm 7.444-7.425 (q, J = 2, 4.8,7.6, 2H), δ ppm 7.382-7.354 (t, J = 4.4, 11.2 Hz, 4H), δ ppm 7.343-7.332 (t, J = 2.8, 4.4 Hz,

IH), 7.169-7.144 (dt, J = 1.6 Hz, 8.4 Hz, IH), δ benzyl4-(lH-indole-5- ppm 6.505-6.493 (m, IH), δ ppm 3.533-3.473 carbonyl)piperazine- 1 -carboxylate (br, 8H).

LCMS: (M+H⁺): 303.47; ^lU NMR (DMSO-d₆ 400 MHz) δ ppm 12.968 (bs, IH), 8.414 (s, IH), 7.667-7.645 (d, J = 8.8 Hz, 2H), 7.293-7.269 (dd, J = 1.2 Hz, J = 8 Hz, 2H), 7.085 (s, IH), o 4.087 (m, 2H), 3.607 (bs, 3H), 1.206-1.171 (t, ethy 14-( 1 H-b enzo [d]imi dazol e-6- 3H).

carbonyl)piperazine- 1 -carboxylate

0 LCMS: (M+H⁺): 362.34; ^:H NMR (DMSO-d₆

400 MHz) δ ppm 11.317 (s, IH), 7.594-7.573 (d, J = 8.4 Hz, IH), 7.480-7.465 (m, 2H), 7.296- 7.237 (m, 4H), 7.197-7.164 (t, J = 6.8 Hz, IH), 7.055-7.031 (dd, J = 9.6 Hz, J = 8.4 Hz, IH), 6.484 (s, IH), 3.480 (s, 7H), 2.840-2.801 (t, J = l-(4-(lH-indole-6-carbonyl)piperazin-l- 7.6 Hz, 2H), 2.666-2.646 (d, J = 8Hz, 2H). yl)-3 -phenylpropan- 1 -one

0 LCMS: (M+H⁺): 364.29; ¾ NMR (DMSO-d₆,

400 MHz) δ ppm 11.330 (s, IH), 7.601-7.581 (d, J = 8.0 Hz, IH), 7.486 (s, 2H), 7.302-7.264 (t, J = 7.6 Hz, 2H), 7.078-7.058 (d, J = 8.0 Hz, IH),

O 6.960-6.920 (t, J = 8.0 Hz, 3H), 6.488 (s, IH), l-(4-(lH-indole-6-carbonyl)piperazin-l- 4.850 (s, 2H), 3.531 (brs, 8H).

yl)-2-phenoxyethan-l-one

LCMS: (M+H⁺): 364.24; ¾ NMR (DMSO-d₆, 400 MHz) δ ppm 11.291 (s, lH), 7.586-7.566 (d, J = 8 Hz, IH), 7.471-7.457 (t, J = 2.8/5.6, IH), 7.441 (s, IH), 7.298-7.258 (td, 2H), 7.035-7.011 (dd, J = 1.2/8/9.6, IH), 6.949-6.904 (m, 3H),

(lH-indol-6-yl)(4-(2- 6.483-6.473 (q, J = Mill A Hz, IH), 4.101- phenoxyethyl)piperazin- 1 -yl)methanone 4.072 (t, J = 5.6, 11 6 Hz, 2H), 3.534 (br, 4H),

2.760-2.732 (t, J = 5.6, 11.2 Hz, 2H)

3.701 (br, 2H), 3.498 (s, 3H), 2.409 (br, 4H),

1.192-1.227 (t, J = 7.7Hz, 3H).

LCMS: (M+H⁺): 471.22; ¾ NMR (DMSO-d₆, 400 MHz) δ ppm 13.441 (Br, 2H), 8.199-8.219 (t, J = 1.2 Hz, 2H), 7.626-7.644 (d, J = 7.2 Hz,

0 2H), 7.498-7.587 (m, 3H), 7.198-7.245 (m, 2H),

2-(3-((4-(2-phenyl- 6.850-6.882 (t, J = 8 Hz, 2H), 6.756-6.782 (dd, J lHbenzo[d]imidazole-5- = 2 Hz, 1H), 4.546 (s, 2H), 3.507 (s, 4H), 2.418 carbonyl)piperazin- 1 - (s, 3H).

yl)methyl)phenoxy)acetic acid

LCMS: (M+H⁺): 416.5; ¾ NMR (DMSO-d₆ 400 MHz) δ ppm 9.361 (s, 1H), 8.702-8.714 (m, 1H), 8.516 (d, J=8.0 Hz, 1H), 7.771-7.757 (m, 1H) 7.571-7.634 (m, 2H), 7.434 (t, J=7.2 Hz, 1H), 7.160-7.364 (m, 4H), 3.490-3.630 (m, 6H), 2.380-2.510 (m, 4H).

F

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2-

(pyridin-3-yl)-lH-benzo[d]imidazol-5- yl)methanone

LCMS: (M+H⁺): 416.3; ¾ NMR (DMSO-d₆ 400 MHz) δ ppm 13.512 (s, 1H), 8.786 (d, J=5.2 Hz, 2H), 8.117 (d, J=5.2 Hz, 2H), 7.592-7.786 (m, 2H), 7.433 (t, J=7.2 Hz, 1H), 7.159-7.380 (m, 4H), 3.410-3.810 (m, 6H), 2.350-2.510 (m, 4H).

F

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2-

(pyridin-4-yl)-lH-benzo[d]imidazol-5- yl)methanone

F LCMS: (M+H⁺): 417.4; ¾ NMR (DMSO-d₆ 400 MHz) δ ppm 13.384 (br s, 1H), 9.373 (dd, J= 1.6 Hz, 5.2 Hz, 1H), 8.530 (dd, J= 1.6 Hz, 8.4 Hz, 1H), 7 920-7.954 (m, 1H), 7.510-7.512 (m, 2H),

0 7.413-7.455 (m, 1H), 7.308-7.360 (m, 2H),

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2- 7.190-7.204 (m, 2H), 3.422-3.710 (m, 6H),

(pyridazin-3-yl)-lH-benzo[d]imidazol- 2.380-2.490 (m, 4H).

6-yl)methanone

LCMS: (M+H⁺): 424.45; ¾ NMR (DMSO-d₆ 400 MHz) δ ppm 11.799 (br, s, 1H), 7.410-7.480 (m, 1H), 7.310-7.390 (m, 1H), 7.165-7.243 (m, 4H), 7 003-7 022 (d, J= 7.2 Hz 1H), 3.718-3 741 (m, 4H), 3.349-3.650 (m, 12 H), 2.381-2.500 (m, 4H).

F

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2- morpholino-lH-benzo[d]imidazol-5- yl)methanone LCMS: (M+H⁺): 437.5; *H NMR (DMSO-d₆ 400

MHz) δ ppm 11.575 (m, 1H), 7.404-7.446 (m, 1H), 7.305-7.362 (m, 1H), 7.154-7.204 (m, 4H), 6.939- 7.021 (m, 1H), 3.570 (s, 2H), 3.440-3.560 (m, 8H), 2.370-2.470 (m, 8H), 2.224 (s, 3H).

F

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2-(4- methylpiperazin- 1 -yl)- 1H- benzo[d]imidazol-5-yl)methanone

LCMS: (M+H⁺): 454.5; ^lU NMR (DMSO-d₆ 400 MHz) δ ppm 13.224 (s, 1H), 8.234 (s, 1H), 8.131 (d, J=8.0 Hz, 1H), 7.687-7.727 (m, 1H), 7.489- 7.628 (m, 3H), 7.436 (t, J= 6.8 Hz, 1H), 7.159- 7.364 (m, 4H), 4.200 (s, 2H), 3.410-3.680 (m, 6H), 2.400-2.500 (m, 4H).

2-(3-(5-(4-(2-fluorobenzyl)piperazine-l- carbonyl)- 1 H-benzo [d] imidazol -2- yl)phenyl)acetonitrile

F LCMS: (M+H⁺): 431.5; *H NMR (CD₃OD 400 MHz) δ ppm 7.971 (d, J=8.8 Hz, 2H), 7.610- 7.680 (m, 2H), 7.450 (t, J=7.2 Hz, 1H), 7.301- 7.353 (m, 2H), 7.177 (t, J=7.2 Hz, 1H), 7.102 (t,

0 J=10 Hz, 1H), 6.965 (d, J=8.8 Hz, 2H), 3.510-

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2-(4- 3.780 (m, 6H), 2.470-2.680 (m, 4H).

hydroxyphenyl)-lH-benzo[d]imidazol-6- yl)methanone

LCMS: (M+H⁺): 405.45; ¾ NMR (DMSO-d₆ 400 MHz) δ ppm 13.204 (br s, 2H), 7.880-7.942 (m, 1H), 7.510-7.600 (m, 2H), 7.433 (t, J=6.8 Hz NH 1H), 7.312-7.361 (m, lH ), 7.165-7.250 (m, 3H),

6.904 (d, J=2, 1H), 3.450-3.610 (m, 6H), 2.410- 2.510 (m 4H).

F

(2-(lH-pyrazol-5-yl)-lH- benzo[d]imidazol-5-yl)(4-(2- fluorobenzyl)piperazin- 1 -yl)methanone

LCMS: (M+H⁺): 445.5; ¾ NMR (CD₃0D 400 MHz) δ ppm 8.048-8.077 (m, 2H), 7.620-7.690 (m, 2H), 7.732-7.7.447 (m, 1H), 7.303-7.359 (m, 2H), 7.104-7.199 (m, 4H), 3.909 (s, 3H), 3.570- 3.870 (m, 6H), 2.491-2.680 (m, 4H).

F

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2-(4- methoxy phenyl)- 1 H-b enzo [d] imidazol - 5-yl)methanone LCMS: (M+H⁺): 397.6; ¾ NMR (DMSO-d₆ 400

MHz) δ ppm 13.124 (s, 1H), 8.193 (d, J=6.8 Hz, 1H), 7.675-7.712 (m, 1H), 7.507-7.595 (m, 4H),

0 7.316-7.360 (m, 4H), 7.213-7.276 (m, 2H),

(4-benzylpiperazin- 1 -yl)(2-phenyl- 1 H- 3.480-3.590 (m, 6H), 2.375-2.450 (m, 4H). benzo[d]imidazol-6-yl)methanone

LCMS: (M+H⁺): 436.5; ^lU NMR (DMSO-d₆ 400 MHz) δ ppm 13.128 (s, 1H), 8.193 (d, J=7.2 Hz,

0 2H), 7.681-7.741 (m, 1H), 7.508-7.591 (m, 4H),

2-(3-((4-(2-phenyl-lH-benzo[d]imidazole- 7.217-7.386 (m, 5H), 4.052 (s, 2H), 3.440-3.660 6-carbonyl)piperazin- 1 - (m, 6H), 2.370-2.500 (m, 4H).

yl)methyl)phenyl)acetonitrile

N LCMS: (M+H⁺): 422.4; ¾ NMR (DMSO-d₆,

1 1 400 MHz) δ ppm 3.134 (s, 1H), 8.195 (d, J=8.4 Hz, 2H), 7.836 (d, J=6.8 Hz, 1H), 7.677-7.717 (m, 2H), 7.469-7.622 (m, 6H), 7.224 -7.294 (m, 1H), 3.706 (s, 2H), 3.491-3.620 (m, 4H), 2.460-

O 2- 2.510 (m, 4H).

((4-(2-phenyl-lH-benzo[d]imidazole-6- carbonyl)piperazin- 1

yl)methyl)benzonitrile

LCMS: (M+H^): 427.5 ^:H NMR (DMSO-d₆, 400 MHz) δ ppm 13.122 (s, 1H), 8.193 (d, J=8.4 Hz, 2H), 7.673-7.713 (m, 1H), 7.508-7.591 (m, 4H), 7.330 (d,J=7.2, 1H), 7.209-7.279 (m, 2H),

O 6.911-6.994 (m, 2H), 3.778 (s, 3H), 3.510-3.610

(4-(2-methoxybenzyl)piperazin-l-yl)(2- (m, 6H), 2.410-2.490 (m, 4H).

phenyl-lH-benzo[d]imidazol-6- yl)methanone

LCMS: (M+H⁺): 398.4; ¾ NMR (MeOD 400 MHz) δ ppm 8.490-8.505 (,m, 2H), 8.112-8.143 (m, 2H), 7.640-7.780 (m , 2H), 7.562-7.617 (m,

0 3H), 7.499 (d, J=6.0 Hz, 2H), 7.381 (d, J=8.0

(2-phenyl-lH-benzo[d]imidazol-5-yl)(4- Hz , 1H), 3.55-3.95 (m, 6H), 2.430-2.680 (pyridin-4-ylmethyl)piperazin- 1 - (m, 4H).

yl)methanone

LCMS: (M+H⁺): 411.5; ¾ NMR (DMSO-de 400 MHz) (80°C)

δ ppm 9.610 (br s, 1H), 8.188-8.212 (m, 2H), 7.756 (s, 1H), 7.687 (d, J=8.4 Hz, 1H), 7.555- 7.615 (m, 3H), 7.357-7.394 (m, 3H), 7.291-

0 7.312 (m, 2H), 4.100-4.400 (m, 4H), 3.200-

(4-phenethylpiperazin- 1 -yl)(2-phenyl- 3.700 (m , 6H), 3.033-3.075 (m, 2H).

lH-benzo[d]imidazol-6-yl)methanone

LCMS: (M+H⁺): 414.5; ¾ NMR (DMSO-de 400 MHz) δ ppm 13.075 (br s, 1H), 8.194 (d, J=6.8 Hz, 2H), 7.506-7.595 (m, 5H), 7.235-7.309 (m, 3H), 7.117-7.170 (m, 2H), 4.450-4.520 (m, 1H), o 3.620-3.810 (m , 1H), 2.720-2.890 (m, 2H)

(4-(2-fluorobenzyl)piperidin-l-yl)(2- 2.605 (d, J=7.2 Hz, 2H), 1.500-1.890 (m, 3H),

y met anone LCMS: (M+H⁺): 41 1.27; ^lH NMR (DMSO-d₆,

400 MHz) δ ppm 13.18 (br s, IH), 8.194 (d, J=7.2 Hz, 2H), 7.496-7.638 (m, 5H), 7.190-

0 7.241 (m, 3H), 7.120-7.150 (m, 2H), 3.470-

(4-(4-methylbenzyl)piperazin-l-yl)(2- 3.620 (m, 4H), 3.468(s, 2H), 2.320-2.445 (m, phenyl-lH-benzo[d]imidazol-5- 4H), 2.281 (s, 3H).

yl)methanone

LCMS: (M+H⁺): 428.3.

¾ NMR (CD₃OD 400 MHz) δ ppm 8.778 (d, J=5.6 Hz , 2H), 8.124 (d, J=6.0 Hz, 2H), 7.700- 7.890 (m, 2H), 7.414- 7.435 (m, IH), 7.290- 7.352 (m, 2H), 6.936-7.021 (m ,2H), 3.550-

0 3.920 (m, 9H), 2.550-2.780 (m, 4H).

(4-(2-methoxybenzyl)piperazin-l-yl)(2-

(pyridin-4-yl)-lH-benzo[d]imidazol-5- yl)methanone

LCMS: (M+H⁺): 457.2; ¾ NMR (DMSO-d₆, 400 MHz) δ ppm 13. 12 (s, IH), 8.192 (d, J=6.8 Hz, 2H), 7.505-7.593 (m, 5H), 7.246 (d, J=8.0 Hz, IH), 7.013-7.052 (m, IH), 6.926-6.956 (m,

0 2H), 7.793 (s, 3H), 3.727 (s, 3H), 3.475-3.620

(4-(2,3 -dimethoxybenzyl)piperazin- 1 - (m, 6H), 2.375-2.475 (m, 4H).

yl)(2-phenyl-lH-benzo[d]imidazol-5- yl)methanone

LCMS: (M+H⁺): 388.53; Ή NMR (DMSO-d₆ 400 MHz) δ ppm 13.480 (s, IH), 12.617 (s, IH), 8.786(d, J=4.4 Hz, 2H), 8.1 1 1 (d, J=4.0 Hz, 2H), 7.584-7.785 (m, 3H), 7.248-7.332 (m, IH), o

6. 161 ( s, IH), 3.345-3.710 (m, 6H), 2.350 -

(4-((lH-pyrazol-5-yl)methyl)piperazin- 2.710 (m, 4H).

l-yl)(2-(pyridin-4-yl)-lH- benzo[dlimidazol-5-yl)methanone

LCMS: (M+H⁺): 475.2; ¾ NMR (CD₃OD, 400 MHz) δ ppm 7.550-7.680 (m, 3H), 7.285 (d, J=8.0 Hz, IH), 6.750-6.880 (m, 4H), 6.321

0

(s, lH), 4.01 l (t, J=1 1.0 Hz , 2H), 3.500-3.900

(4-((lH-pyrazol-5-yl)methyl)piperazin- (m, 9H), 3.121 (t, J=7.6 Hz, 2H), 2.420-2.650 1 -yl)(2-(3 -(4-methoxyphenoxy)propyl)- (m, 4H), 2.280-2.330 (m, 2H).

lH-benzo[d]imidazol-5-yl)methanone

LCMS: (M+H⁺): 515.1 ; ¾ NMR CD₃OD, 400 MHz) δ ppm 7.50-7.610 (m, 2H), 7.264-7.336 (m, 3H), 7.921 -7.001 (m, 2H), 6.777-6.824(m,

0 4H), 4.017 (t, J=6.0 Hz, 2H), 3.843 (s, 3H),

(4-(2-methoxybenzyl)piperazin-l-yl)(2- 3.732 (s, 3H), 3.676 (s, 2H), 3.510-3.610 (m,

(3-(4-methoxyphenoxy)propyl)-lH- 4H), 3.132 (t, J=9.0 Hz, 2H, 2.490-2.690 (m, benzo[d]imidazol-5-yl)methanone 4H), 2.274-2.341 (m, 2H).

LCMS: (M+H⁺): 503.23; ¾ NMR CD3OD, 400 MHz) δ ppm 7.578-7.595 (m, 2H), 7.435-7.469 (m, IH), 7.285-7.365 (m, 2H), 7.183 (t, J=6.8

0 Hz, IH), 7.108 (t, J=9.6 Hz, IH), 6.770-6.850

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2-(3 - (m, 4H), 4.018 (t, J= 6.0 Hz, 2H), 3.50-3.90 (m, (4-methoxyphenoxy)propyl)-lH- 9H), 3.130 (t, J= 7.6 Hz, 2H), 2.500-2.700 (m, benzo[d]imidazol-5-yl)methanone 4H), 2.292-2.328 (m, 2H).

LCMS: (M+H⁺): 417.64; ^l NMR CD₃OD 400 MHz) δ ppm 8.065 (d, J=8.8 Hz, 2H), 7.601- 7.658 (m, 3H), 7 323(dd, J=1.6 Hz, 8 4 Hz, 1H), o 7.126 (d, J=8.8 Hz, 2H), 6.329 (s, 1H), 3.906 (s,

(4-((lH-pyrazol-5-yl)methyl)piperazin-l- 3H), 3.565-3.816 (m, 6H), 2.490-2.660 (m, 4H). yl)(2-(4-methoxyphenyl)-lH- benzo[d]imidazol-5-yl)methanone

LCMS: (M+H⁺): 473.68; ¾ NMR CD3OD, 400 MHz) δ ppm 7.540-7.630 (m, 2H), 7.427-7.468 (m, 1H), 7.157-7.339 (m, 5H), 7.080-7.126 (m, 1H), 6.848-6.921 (m, 3H), 4.076 (t, J= 6.0 Hz,

0

(4-(2-fluorobenzyl)piperazin-l-yl)(2-(3- 2H), 3.50-3.900 (m, 6H), 3.140 (t, J=7.2, 2H), phenoxypropyl)-lH-benzo[d]imidazol-5- 2.430-2.680 (m, 4H), 2.304-2.371(m, 2H).

yl)methanone

LCMS: (M+H⁺):437.2; ¾ NMR CD₃OD 400 MHz) δ ppm 8.054-8.091 (m, 2H), 7.659-7.698 (m, 2H), 7.360 (dd, J=1.2 Hz, 8Hz, 1H), 7.113- 7.150 (m, 2H), 3.910 (s, 3H), 3.400-3.850 (m,

0

8H), 1.493 (s, 9H).

tert-butyl 4-(2-(4-methoxyphenyl)- 1H- benzo[d]imidazole-5- carbonyl)piperazine- 1 -carboxylate

LCMS: (M+H⁺): 529.6, ¾ NMR (DMSO-d₆, 400 MHz) δ ppm 12.876 (br s, 1H), 7.610-680

0

(m, 1H), 7.480-7.570 (m, 1H), 7.346-7.306 (m, 2H), 7.241 (t, J=7.6 HZ, 2H), 7.060-120 (m,

0 2H), 6.983 (t, J=7.2 Hz, 1H), 6.920 (d, J=7.6Hz,

Ethyl2-(3 -((4-(2-(phenoxymethyl)- 1H- 1H), 6.875 (s, 1H), 6.760-6.819 (m, 1H), 5.344 benzo[d]imidazole-5 carbonyl)piperazin- (s, 2H), 4.760 (s, 2H), 4.172 (q, J=6.8 HZ, 14 l-yl)methyl)phenoxy)acetate Hz, 2H), 3.410-3.510 (m, 6H), 2.31-2.450 (m,

4H), 1.206 (t, J=7.2 Hz, 3H).

O LCMS: (M+H⁺): 364.34; ^!H NMR (CDC1₃ 400

MHz)) δ ppmppm 8.200 (s, 1H), 7.855 (s, 1H), 7.664-7.685 (d, J = 8.4 Hz, 1H), 7.488-7.513 (dd, J = 1.6 Hz, J = 8.4 Hz, 1H), 7.304-7.341 (m, 2H), 7.299-7.258 (m, 3H), 3.456-3.654 (bd, 9H), l-(4-(benzo[d]oxazole-5- 2.996-3.034 (t, J = 8 Hz, 2H), 2.681 (s, 2H). carbonyl)piperazin- 1 -yl)-3 - phenylpropan- 1 -one

LCMS: (M+H⁺): 287.45. ¾ NMR: DMSO 400 MHz δ 12.371 (s, 1H), 7.429 (bs, 2H), 7.095-

Y-N NH 7.076 (d, J = 7.6 Hz, 1H), 4.096 (s, 1H), 3.076

(bs, 2H), 2.733 (bs, 1H), 2.674-2.605 (m, 3H), 2.408 (bs, 4H), 0.916-0.861 (d, J = 22 Hz, 4H), 0.676 (bs, 2H).

(S)-(2-isopropylpiperazin- 1 -yl)(2- methyl-lH-benzo[d]imidazol-6- yl)methanone

LCMS: (M+H⁺): 301.45. ¾ NMR: DMSO 400 MHz δ 12.361 (s, IH), 7.492-7.472 (d, J = 8 Hz, y-N N— IH), 7.412 (s, IH), 7.112-7.089 (dd, J = 1.2 Hz,

J = 8.4 Hz, IH), 4.243 (bs, IH), 3.447 (s, IH), 3.281-3.176(m, IH), 2.922-2.892 (m, 2H), 2.545 (s, 3H), 2.379-2.363 (m, IH), 2.206 (bs, 3H),

(S)-(2-isopropyl-4-methylpiperazin- 1 - 2.100-1.756 (m, 2H), 0.991-0.910 (bd, J = 32.4 yl)(2-methyl-lH-benzo[d]imidazol-6- Hz, 4H), 0.672 (s, 2H).

yl)methanone

LCMS: (M+H⁺): 329.45. ¾ NMR: DMSO 400 MHz δ 12.393 (s, IH), 7.496-7.418 (m, 2H), 7.131 (s, IH), 4 604-4.487 (m, IH), 4.300 (bs, IH), 3.949-3.891 (m, IH), 3.687-3.660 (d, J = 10.8 Hz, IH), 3.499-3.466 (m, 2H), 3.233 (bs, IH), 3.046 (bs, IH), 2.891 (bs, IH), 2.732-2.674

(S)-l-(3-isopropyl-4-(2-methyl-lH- (m, IH), 2.080 (s, IH), 2.002 (s, 3H), 1.075- benzo[d]imidazole-6- 1.024 (d, J = 20.4 Hz, 2H), 0.900 (s, 2H), 0.692 carbonyl)piperazin- 1 -yl)ethan- 1 -one (s, 2H).

LCMS: (M+H⁺): 307.50. ¾ NMR: DMSO 400 MHz δ 13.120 (s, IH), 8.208-8.187 (m, 2H), 7.666 (bs, IH), 7.599-7.507 (m, 4H), 7.242 (bs, IH), 3.466-3.340 (m, 4H), 2.756-2.678 (m, 4H).

0

(2-phenyl-lH-benzo[d]imidazol-5- yl)(piperazin- 1 -yl)methanone

LCMS: (M+H⁺): 363.40. ¾ NMR: DMSO 400 MHz δ 13.127 (s, IH), 8.202-8.183 (d, J = 7.6 Hz, 2H), 7.713-7.673 (t, J = 8 Hz, 2H), 7.592- 7.504 (m, 4H), 7.277-7.211 (dd, J = 8 Hz, J= 18

0 Hz, IH), 3.508 (bs, 4H), 2.362-2.332 (m, 4H),

(4-isobutylpiperazm-l-yl)(2-phenyl-lH- 2.077-2.063 (d, J = 5.6 Hz, 2H), 1.793-1.777 (m, benzo[d]imidazol-5-yl)methanone IH), 0.871-0.861 (d, J= 6.4 Hz, 6H).

LCMS: (M+H⁺): 321.42. ¾ NMR: DMSO 400 MHz δ 13.137 (s, IH), 8.203-8.185 (d, J = 7.2 Hz, 2H), 7.716-7.675 (t, J = 8 Hz, 2H), 7.594-

0 7.523 (m, 4H), 7.277-7.207 (m, IH), 3.533 (bs,

(4-methylpiperazin-l-yl)(2-phenyl-lH- 4H), 2.337 (bs, 4H), 2.210 (s, 3H).

benzo[d]imidazol-5-yl)methanone

LCMS: (M+H⁺): 363.14. ¾ NMR: DMSO 400 MHz δ 13.138-13.103 (d, J = 14 Hz, IH), 8.197- 8.179 (d, J = 7.2 Hz, 2H), 7.719-7.698 (d, J = 8.4 Hz, IH), 7.613-7.505 (m, 4H), 7.229-7.166 (m, IH), 4.241 (s, IH), 3.495 (bs, IH), 2.962- o

2.873 (m, 2H), 2.674-2.607 (m, IH), 2.445-

(S)-(2-isopropyl-4-methylpiperazin- 1 - 2.332 (m, IH), 2.165 (s, 3H), 1.991-1.911 (bs, yl)(2-phenyl-lH-benzo[d]imidazol-5- IH), 1.678 (bs, IH), 0.998-0.859 (m, 4H), 0.698 yl)methanone

(s, 2H).

yl)methoxy)phenyl)- 1H- 2H), 3.937-3.576 (m, 6H), 2.811-2.704 (m, 4H). benzo[d]imidazol-5-yl)(4-(2- fluorobenzyl)piperazin- 1 -yl)methanone

LCMS: (M+H⁺): 429.20. ¾ NMR: DMSO 400 MHz δ 13.122-13.1 10 (d, J= 4.8 Hz, IH), 8.203-8.182 (m, 2H), 7.712-7.637 (m, IH), 7.593-7.439 (m, 5H), 7.339-7.305 (m, IH), o 7.241-7.155 (m, 3H), 3.891 (bs, IH), 3.561 (s,

(S)-(4-(2-fluorobenzyl)-2- 2H), 3.245-3.181 (m, IH), 2.804-2.791 (m, IH), methylpiperazin- 1 -yl)(2 -phenyl- 1H- 2.682-2.673 (m, IH), 2.214-2.186 (m, IH), benzo[d]imidazol-5-yl)methanone 2.092-2.063 (m, IH), 1.296-1.239 (m, 4H)

LCMS:(M+H⁺): 433.15 ¾ NMR: CDC13 400 MHz δ 8.111 (bs, 2H), 7.612 (bs, IH), 7.458 (bs, 4H), 7.359-7.340 (m, IH), 7.248-7.227 (m, IH), 6.886-6.830 (m, 2H), 3.837 (bs, 2H), 3.603-

0 3.496 (m, 4H), 2.646-2.448 (m, 4H).

(4-(2,4-difluorobenzyl)piperazin-l- yl)(2-phenyl-lH-benzo[d]imidazol-5- yl)methanone

LCMS:(M+H⁺): 411.20.^IH NMR: DMSO 400 MHz

δ 13.141 (s, IH), 8.206-8.186 (m, 2H), 7.647- o 7.523 (m, 5H), 7.257-7.239 (d, J = 7.2 Hz, 2H),

(4-(2-methylbenzyl)piperazin-l-yl)(2- 7.170-7.126 (m, 3H), 3.475-3.349 (m, 6H), phenyl-lH-benzo[d]imidazol-5- 2.548 (s, 2H), 2.424 (bs, 2H) , 2.342 (s, 3H). yl)methanone

LCMS: (M+H⁺): 427.10. H NMR: DMSO 400 MHz δ 13.129-13.123 (d, J = 2.4Hz IH), 8.201- 8.181 (d, J = 8 Hz, 2H), 7.710-7 667 (m, IH),

0 7.594-7.508 (m, 4H), 7.274-7.204 (m, 3H),

(4-(4-methoxybenzyl)piperazin- 1 -yl)(2- 6.901-6.879 (d, J = 8.8 Hz, 2H), 3.736 (s, 3H) pheny 1 - 1 H-b enzo [d]imi dazol -5 - 3.554-3.448 (m, 6H) 2.387 (bs, 4H).

yl)methanone

LCMS: (M+H⁺): 403.30. ^!H NMR: MeOD 400 MHz δ 8.160-8.137 (m, 3H), 7.791-7.771 (m, IH), 7.685 (bs, IH), 7.623-7.551 (m, 3H), 7.492-

0 7.458 (m, IH), 7.346-7.294 (m, IH), 7.164-

N-(2-((2- 7.080 (m, 2H), 3.775 (s, 2H), 3.659-3.627 (t, J = fluorobenzyl)(methyl)amino)ethyl)-2- 6.4 Hz, 2H), 2.794-2.762 (t, J = 6.4 Hz, 2H), phenyl-lH-benzo[d]imidazole-5- 2.401 (s, 3H).

carboxamide

LCMS: (M+H⁺): 416.22. Ή NMR: CDC1₃ 400 MHz δ 12.738 (bs, IH), 8.967 (s, IH), 8.242- 8.224 (m, 2H), 8.045 (s, IH), 7.512-7.499 (m, 3H), 7.413-7.376 (m, IH), 7.171-7.022 (m, 3H),

0 3.919 (bs, 4H), 3.670 (s, 2H), 2.685-2.563 (m,

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2- 4H).

pheny 1 -3 H-imi dazo[4, 5 -c]py ri din-6- yl)methanone LCMS: (M+H⁺): 416.22. ^!H NMR: CDC13 400

MHz δ 8.758-8.752 (m, IH), 8.315-8.290 (m, 2H), 7.805-7.803 (d, J = 0.8 Hz, IH), 7.782- 7.592 (m, IH), 7.573-7.511 (m, 3H), 7.400-

0 7.363 (m, IH), 7.173-7.031 (m, 3H), 3.680-

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2- 3.623 (m, 6H), 2.587 (bs, 4H).

phenyl-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6- yl)methanone

LCMS: (M+H⁺): 429.20. Ή NMR: DMSO 400 MHz δ 7.885-7.860 (m, 2H), 7.703-7.683 (m, 2H), 7.606-7.589 (m, 3H), 7.459-7.416 (m, IH), 7.366-7.309 (m, 2H), 7.210-7.159 (m, 2H),

0 3.908 (s, 3H), 3.584 (bs, 6H), 2.517-2.446 (m,

(4-(2-fluorobenzyl)piperazin- 1 -yl)(l - 4H).

methyl-2-phenyl-lH-benzo[d]imidazol-

5-yl)methanone

F LCMS (M+H⁺): 369.15. ¾ NMR: DMSO 400 MHz δ 12.528 (s, IH), 7.520-7.498 (m, 2H), 7.441-7.406 (t, / = 7 Hz, IH), 7.341-7.309 (m, IH), 7.201-7.153 (m, 3H), 5.776-5.747 (t, J = 6

0 Hz, IH), 4.706-4.692 (d, J = 5.6 Hz, 2H), 3.581

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2- (bs, 3H), 3.345 (bs, 3H), 2.444 (bs, 4H).

(hydroxymethyl)-lH-benzo[d]imidazol-

5-yl)methanone

LCMS: (M+H⁺): 444.16. ¾ NMR: DMSO 400 MHz δ 11.645 (s, IH), 7.811-7.789 (d, J = 8.8 Hz, 2H), 7.534 (s, IH), 7.443-7.405 (m, 2H), 7.397-7.305 (m, IH), 7.201-7.150 (m, 2H),

0 7.104-7.032 (m, 3H), 6.832-6.829 (d, J = 1.2 Hz,

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2-(4- IH), 3.806 (s, 3H), 3.571-3.525 (m, 6H), 2.423 methoxy phenyl)- 1 H-indol -5 - (bs, 4H).

yl)methanone

LCMS: (M+H⁺): 462.20. ¾ NMR: DMSO 400 MHz δ 12.349 (s, IH), 7.457 (bs, IH), 7.393 (bs, IH), 7.185-7.146 (t, J = 8 Hz, IH), 7.078 (bs, IH) 6.886 (s, IH), 6.832-6.753 (dd, J = 8 Hz, J = o 24 Hz, 2H), 4.263-4.188 (m, IH), 3.733-3.711 (t,

(S)-(2-isopropyl-4-(3- J=4.4 Hz, 4H), 3.548-3.462 (m, 3H), 3.260 (s, morpholinobenzyl)piperazin- 1 -yl)(2- 3H), 2.918 (bs, 2H), 2.756-2.666 (m, 2H), 2.080- methyl-lH-benzo[d]imidazol-5- 2.071 (m, IH), 1.901 (bs, 2H), 1.227 (s, IH), yl)methanone 0 895-0.833 (m, 4H), 0.651-0 496 (m, 3H).

LCMS: (M+H⁺): 391.10 Ή NMR: MeOD 400 MHz δ 7.574-7.537 (m, 2H), 7.285-7.153 (m, 6H), 4.438-4.275 (m, IH), 3.624-3.589 (m, IH), 3.419 (bs, IH), 3.141 (bs, IH), 3.137-3.079 (m,

0 IH), 2.845-2.806 (m, 3H), 2.603 (s, 3H), 2.449-

(S)-(2-isopropyl-4-phenethylpiperazin- 2.440 (bs, IH), 2.337-2.164 (m, 2H), 2.117- l-yl)(2-methyl-lH-benzo[d]imidazol-5- 2.045 (m, IH), 1.039-0.958 (m, 4H), 0.801- yl)methanone 0.784 (m, 2H).

y met anone

yl)benzyl)piperazin-l -yl)(2-phenyl-lH- 9.2 Hz, 4H), 2.410-2.510 (m, 4H).

benzo[d]imidazol-5-yl)methanone

The present disclosure also provides salts, derivatives, tautomers, isomers, polymorphs, solvates and intermediates thereof of the above compounds of Table 1.

Method of Preparation

The present disclosure provides a general method for preparing compound of formula I as

G = prelecting group ¹

wherein Q, Rl, R2, R3, R4, R5, L and M are as defined in compound of Formula I. The protecting group PG as provided here is selected from a group comprising BOC, Fmoc,

CbzBn, Ac and combinations thereof.

In an embodiment, the present disclosure provides the following method for preparing compound of formula I

Q Coupling J Q R5 deprotection Q R5 Coupling y Q R

R3 R3 R3 R3 G = protecting group * wherein Q, Rl, R2, R3, R4, R5, L and M are as defined in compound of general Formula I. Coupling reaction for preparing compound of formula I is carried out in the presence of coupling reagentselected from a group consisting K₂C0₃/DMF, HATU DIPEA, EDC/HOBt and combinations thereof.

Deprotection step for preparing compound of formula I is carried out in presence of deprotecting reagent

selected from a group consisting of Pd/C, TFA/DCM, HC1/DCM, Aq NaOH and

combinations thereof.

The present disclosure provides a general method for preparing compound of formula II as follows:

PG = protecting group ^!l wherein Q, Rl, R2, R3, L and M are as defined in compound of general Formula I or compound of Formula II.

Coupling reaction for preparing compound of formula II is carried out in presence of coupling reagentselected from a group comprising K₂C0₃/DMF, HATU DIPEA, EDC/HOBt and combinations thereof.

Deprotection reaction for preparing compound of formula II is carried out in presence of deprotecting reagentselected from a group comprising Pd/C, HCl DCM, TFA/DCM, Aq. NaOH and combinations thereof.

The present disclosure also provides the following method for preparing compound of formula

wherein Q, Rl, R2, R3, L and M are as defined in compound of general Formula I or compound of Formula II.

The present disclosure provides a general method for preparing compound of formula III as follows:

wherein R7 is as defined in compound of general formula I or compound of formula III.

In another embodiment, the present disclosure provides the following method for preparing compound of formula ΙΠ

The present disclosure provides a general method for preparing compound of formula IV as follows:

IV wherein Rl, R2, R3, R9 and Q are as defined in compound of general formula I or compound of formula IV.

In an embodiment, the present disclosure provides the following method for preparing

Furthermore, the invention also encompassespharmaceutically acceptable salts of the compound of formula I-IV which is selected from a group consisting of sodium, potassium, calcium, magnesium, ammonium and combinations thereof.

The present invention also provides isomers of compounds of formula I-IV or the compounds described above which is selected from a group consisting of positional isomers, geometric isomers, optical isomers, tautomers, enantiomers and their pharmaceutically acceptable salt thereof.

The present disclosure further provides a pharmaceutical composition comprising compound of formula I-IV as defined above, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, optionally along with at least one pharmaceutically acceptable excipient.

In a non-limiting embodiment of the present disclosure, the pharmaceutical composition further comprises one or more additional active agents/drugs.

The present disclosure provides a method for preparing pharmaceutical composition comprising compound of formula I-IV as defined above, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, optionally along with at least one pharmaceutically acceptable excipient.

Route of Administration

The compounds of the present invention are delivered to the subjects by forms suitable for each administration route. For example, the compounds are administered as tablets, capsules, injection, drops, inhaler, ointment, foams suppository. In a preferred embodiment, the route of administration is oral (buccal or sublingual), parenteral, rectal, vaginal, or topical. The route of administration may further include transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, local administration, intralesional administration. Parenteral administration include but not restricted to intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration, or any combination thereof. Topical or transdermal administration include powders, sprays, ointments, pastes creams, lotions, gels, solutions, patches and inhalants.

Formulation

In a non-limiting embodiment of the present disclosure, the pharmaceutical composition defined above is formulated into forms selected from a group comprising, but not limited to, solution, aqueous suspension, capsule, tablet, injection, cream, gel, ointment, lotion, solutions, dispersions, emulsion, foam, troche, lozenge, oily suspension, powders, sprays, suppositories, patch, dentifrice, spray, drops, dispersible powder or granule, syrup, elixir, food stuff, and any combination of forms thereof. In an embodiment of the present disclosure, the excipient in the pharmaceutical composition/formulation defined above is selected from a group comprising, but not limited to, carrier, diluent, pH modifier, sweetening agent, bulking agent, granulating agent, binding agent, lubricating agent, disintegrating agent, sweetening agent, glidant, anti -adherent, anti- static agent, surfactant, anti-oxidant, gum, coating agent, coloring agent, flavouring agent, coating agent, plasticizer, preservative, suspending agent, emulsifying agent, plant cellulosic material, spheronization agents and combinations thereof.

In a non-limiting embodiment of the present disclosure, the compound of Formula I-IV defined above, or salt, derivative, tautomeric form, isomer, polymorph, solvate or

intermediates thereof is formulated and administered in a prodrug form.

Uses of the Compounds of the invention

The compounds of the invention selectively inhibit the interaction of BRCAl with multiple partner proteins that contain phosphopeptide motifs recognized by the BRCAl tBRCT domain.

These interactions are essential for the cellular DNA damage response (DDR), which involves the activation by DNA damage of protein kinases including ATM, ATR or DNA-PK. Proper execution of the DDR enforces cell cycle checkpoints that arrest cell division at different phases of the cell cycle, enables the efficient repair of DNA damage by different mechanisms, and promotes cell survival. Proper execution of the DDR also suppresses the occurrence of abnormal DNA intermediates that may cause genomic DNA mutations, impede accurate gene expression, or activate the innate or adaptive immune response. It is therefore well accepted that failure or inhibition of the DDR can lead to multiple effects, including (a) increased sensitivity of cells including cancer cells to DNA damage caused by agents such as radiation or chemotherapeutic drugs, (b) increased sensitivity of cells including cancer cells to targeted inhibitors (for example, inhibitors of poly-ADP ribose polymerase (PARP) enzymes), or (c) enhanced responsiveness of cancers to immune checkpoint inhibitors (for example, therapeutic antibodies or drugs that block signalling via PD-1, PD-L1 or CTLA4) Compounds of the invention are expected to suppress the DDR by inhibiting the interactions of BRCAl with multiple partner proteins via the BRCl tBRCT domain. In particular, BRCAl has been implicated during the DDR as an essential factor in several processes including: cell cycle checkpoint activation following DNA damage, and the repair of DNA double-strand breaks by homologous DNA recombination (HR). BRCAl inactivation is associated with the increased responsiveness of cancer cells to immune checkpoint blockade (for example, to antibodies against CTLA4). Compounds of the invention are expected to affect such processes by inhibiting the interactions of BRCAl with multiple partner proteins via the BRC1 tBRCT domain.

Furthermore, BRCAl has been implicated as a key modulator of cellular processes including: (a) RNA processing after DNA damage, (b) mitotic progression including centrosome function or cytokinesis, (c) maintenance of heterochromatin and the repression of satellite RNA expression, (d) X-chromosome inactivation, (e) DNA replication (f) telomere maintenance and (g) prevention of chromosomal lesions, micronuclei formation and immune activation. Compounds of the invention will affect such processes by inhibiting the interactions of BRCAl with multiple partner proteins via the BRC1 tBRCT domain.

Thus, compounds of the invention or compositions thereof of present invention are usefulalone or in combination with other agents in the treatment of cancer or other diseases (a) to inhibit the growth or viability of diseased cells such as cancer cells, (b) to sensitize diseased cells to the effects of radiation or chemotherapy, (c) to sensitize diseased cells to targeted inhibitors of poly-

ADP ribose polymerase (PARP) enzymes, (d) to sensitizediseased cells to inhibitors of DNA repair enzymes including polymerase theta or (e) to enhance the sensitivity of diseased cells to agents that modulate the immune response. By 'sensitize', it is meant that the diseased cells are 'prepared' or 'primed' to act in a modified way as mentioned here. By 'diseased cell' it is meant that the cell is not normal and does not act normally and has undergone changes leading to its diseased state.

Particularly, the small molecule inhibitors described as compounds of formula I-IV are useful for the treatment of cancers of specific molecular types which may exhibit characteristic patterns of genome instability detected by next-generation sequencing of tumor DNA followed by bio- informatic analysis to identify said patterns of genome instability. Furthermore, the compounds of present invention are used for treatment of any disease responsive to the inhibition of genes ATM, ATR, CDKs, DNA-PK, BRCAl, BRCA2, PALB2, RAD51 or CHEK1 or diseases or conditions related to inhibition of ATM, ATR, DNA-PK, BRCAl, BRCA2, PALB2, RAD51 or CHEK1.

In addition, the compounds of Formula I-IV as defined above, are useful for the treatment or management of conditions including but not limited to cancer, proliferative disorders

including rheumatoid arthritis, idiopathic pulmonary fibrosis or psoriasis, inflammatory disorders associated with cell proliferation such as rheumatoid arthritis, Fanconi Anemia, or any disease responsive to or requiring the inhibition of B CA1 activity, or any combination thereof.

As used in the present disclosure, the term 'managing' or 'management' includes preventing a disease or disorder from occurring in a subject, decreasing the risk of death due to a disease or disorder, delaying the onset of a disease or disorder,inhibiting the progression of a disease or disorder, partial or complete cure of a disease or disorder and/or adverse effect attributable to the said disease or disorder, obtaining a desired pharmacologic and/or physiologic effect (the effect may be prophylactic in terms of completely or partially preventing a disorder or disease or condition, or a symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease or disorder and/or adverse effect attributable to the disease or disorder), relieving a disease or disorder (i.e. causing regression of the disease or disorder).

The present disclosure further provides a kit comprising compound of formula I-IV, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, optionally along with at least one pharmaceutically acceptable excipient as described above.

In a non-limiting embodiment of the present disclosure, the kit comprises: a) the

pharmaceutical composition of compound of formula I-IV, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, optionally along with at least one pharmaceutically acceptable excipient as described above; and b) instructions for use.

Combination Therapy

Inhibition of the DDR can lead to multiple effects, including (a) increased sensitivity of cells including cancer cells to DNA damage caused by agents such as radiation or chemotherapeutic drugs, (b) increased sensitivity of cells including cancer cells to targeted inhibitors (for example, inhibitors of poly-ADP ribose polymerase (PARP) enzymes), or (c) enhanced responsiveness of cancers to immune checkpoint inhibitors (for example, therapeutic antibodies or drugs that block signalling via PD-1, PD-Ll or CTLA4). Compounds of the invention are expected to suppress the DDR by inhibiting the interactions of BRCA1 with multiple partner proteins via the BRC1 tBRCT domain.

In a non-limiting embodiment of the present disclosure, the kit further comprises one additional active agents/drugs. The additional active agents are selected from a group consisting of anti-hyperproliferative, anti-cancer, cytostatic, cytotoxic, anti-inflammatory and chemotherapeutic agents.

Inhibition of the DDR can increase the sensitivity of cells including cancer cells to DNA damage caused by chemotherapeutic drugs. In yet another non-limiting embodiment of the present disclosure, the additional active agents are selected from the group essentially consisting of cisplatin, carboplatin, doxorubicin, paclitaxel (including albumin-bound formulations), docetaxel, etoposide, topotecan, irinotecan or mitomycin C, targeted inhibitors including inhibitors of poly- ADP ribose polymerase (PARP) enzymes, inhibitors of telomerase and inhibitors of polymerase theta or any combination thereof.

Inhibition of the DDR can increase the sensitivity of cells including cancer cells to targeted inhibitors of DNA damage responses or DNA repair. In yet another non-limiting embodiment of the present disclosure, the additional active agents are selected from the group essentially consisting of inhibitors of poly-ADP ribose polymerase (PARP) enzymes, inhibitors of telomerase, inhibitors of polymerase theta, or any combination thereof.

Inhibition of the DDR can lead to the enhanced responsiveness of cancers to immune

checkpoint inhibitors (for example, therapeutic antibodies or drugs that block signalling via PD-1, PD-L1 or CTLA4). In yet another non-limiting embodiment of the present disclosure, the additional active agents are therapeutic antibodies that target immune checkpoints selected from the group essentially consisting of anti-CTLA4, anti-PDl, anti-PD-Ll, or any

combination thereof. The present disclosure further provides a method for combination therapy for treating or managing cancer, other proliferative disorder including rheumatoid arthritis, idiopathic pulmonary fibrosis or psoriasis, inflammatory disorder associated with cell proliferation such as rheumatoid arthritis, Fanconi Anemia , any disease responsive to the inhibition of BRCA1 activity or any combination thereof, comprising administering a therapeutically effective amount of compound(s) of formula I-IVor a composition as described above along with anti- hyperproliferative, anti-cancer, cytostatic, cytotoxic, anti-inflammatory or chemotherapeutic agents selected from the group essentially consisting of cisplatin, carboplatin, doxorubicin, paclitaxel (including albumin-bound formulations), docetaxel, etoposide, topotecan, irinotecan or mitomycin C, or any combination thereof. A method of using compounds of current invention as inhibitors of the DNA damage response to enhance therapeutic sensitivity or prevent therapeutic resistance to radiation therapy is provided. Inhibition of the DDR can increase the sensitivity of cells including cancer cells to DNA damage caused by radiation. Furthermore, the compounds of the present invention can be employed in combination treatment strategies with therapeutic radiation.

A method of using compounds of current invention as inhibitors of the DNA damage response to enhance therapeutic sensitivity or prevent therapeutic resistance to chemotherapeutic agents that induce DNA damage is provided. Inhibition of the DDR can increase the sensitivity of cells including cancer cells to DNA damage caused by such agents. In a non-limiting embodiment, compounds of the present invention can be employed in combination treatment strategies with agents including but not limited to radiomimetic drugs, platinum compounds, and inhibitors of topoisomerase I or II such as etoposide, topotecan, irinotecan or doxorubicin.

The present disclosure provides use of compound of formula I-IV as described above, or salt,derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, or composition as described above for selective disruption of homologous DNA recombination mediated by RAD51, thereby suppressing DNA repair or the response to replication stress. In a specific embodiment of the present disclosure, the compounds or compositions described above inhibit homologous DNA recombination by inhibiting BRCAl tBRCT signalling and suppressing the recruitment and assembly of RAD51 at sites of DNA damage or replication stress. The present disclosure further provides methods or use of compounds or compositions as

BRCAl modulators. In particular, thecompounds or compositions as described above are used as inhibitors of BRCAl or in methods of inhibiting BRCAl or more particularly selectively degrading BRCAl by adding tags like Proteolysis Targeting Chimerics (PROTACs). The present disclosure also provides a method for inhibiting the interaction between

BRCAltBRCT and phosphorylated BACH1 helicase comprising administering the compounds or compositions described above. The present disclosure also provides a method or use of compound of formula I-IV, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, or composition described above to treat a disease responsive to or requiring the inhibition of RAD51 assembly at sites of DNA damage or replication stress. BRCA1 co-localizes with RAD51 at sites of DNA damage or replication stress and activates RAD51 -mediated homologous recombination repair of DNA double-strand breaks. Thus, inhibition of BRCA1 supresses translocation of RAD51 to site of DNA damage.

In another aspect, the compounds of formula I-IV of the present invention provides a method of stabilizing proteins for X-ray crystallography and structural elucidation.

The present disclosure provides a method or use of compound of formula I-IV, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, as biomarkers for prognosis of cancer, stratification of cancer, or a combination thereof. In an exemplary embodiment, the compounds or compositions of the present disclosure are used for predicting the likelihood of a response to exposure to BRCA1 tBRCT modulator as a method of cancer treatment. The method for predicting the likelihood of a response to exposure to BRCA1 tBRCT modulator comprises administering the BRCAltBRCT modulator and collecting biological samples and measuring the cellular localization and level of one or more biomarkers selected from a group comprising BRCA1, RAD51, CTIP, BARDl or

combinations thereof. The biological sample for such purpose is a tissue sample comprising cancer cells which is fixed, paraffin-embedded, fresh, or frozen, or any combination thereof. Biological samples may also include any other sample from a human subject in which

RAD51, CTIP, BARDl can be detected.

The present disclosure also provides a method or use of compound of formula I-IV, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, or their compositions as described above, as biomarkers for prognosis of a proliferative disorder, inflammatory disorder associated with cell proliferation, Fanconi Anemia or a disease responsive to the inhibition of BRCA1 activity

The present disclosure provides a method or use of compound of formula I-IV or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, or their compositions as described above for killing or inhibiting cancer cells. The present disclosure provides a method or use of compound of Formula I-IV, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, or their compositions as described above for a method of monitoring response in patients after administration of above compound or composition, and obtain sample from patients to measure molecular response in patient by measuring nuclear levels of BRCAl, RAD51 and/or

CTIP followed by prediction of likely response in subject.

As used in the present disclosure, the subject/patient refers to a mammal including human. In a preferred embodiment of the present disclosure, the subject/patient is human.

A method for treating malignancy or cancer in a patient in need thereof is provided which comprises use of compounds or compositions of the present disclosure in combination with radiation therapy, drug therapy or both.

A method for treating malignancy or cancer in a patient in need thereof is provided which comprises administering to said patient a first amount of compound of formula I-IV, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, or their compositions in a first treatment procedure, and a second amount of radiation in a second treatment procedure wherein, the first and second amounts together comprise a therapeutically effective amount.

A method for treating malignancy or cancer in a patient in need thereof is provided which comprises administering to said patient a first amount of compound of formula I-IV or, salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, or their compositions in a first treatment procedure, and a second amount of other active agent/drug in a second treatment procedure wherein, the first and second amounts together comprise a therapeutically effective amount.

A method for treating malignancy or cancer in a patient in need thereof is provided which comprises administering to said patient a first amount of compound of formula I-IV, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, or their compositions in a first treatment procedure, a second amount of radiation in a second treatment procedure wherein, and a third amount of other active agent/drug in a second treatment procedure the first, second and third amounts together comprise a therapeutically effective amount. The present disclosure provides a method or use of compound of formula I-IV, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, or their compositionsas described above for imaging. Compounds of present disclosure selectively bind to BRCAl protein in normal cellsor tumor tissues when coupled to a signal agent, and are thereby useful as bioimaging agent/molecular probe. These molecular probes are used for early disease detection, characterization, and real-time monitoring of therapeutic responses, as well as for investigating drug efficacy. The present disclosure also provides a method or use of compound of formula I-IV, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, or their compositions as described above for treating viral infections by inhibiting for protein-protein interaction critical for viral proliferation. BRCAl plays an important role in viral transcription and cells that lack BRCAl activity show resistance to viral infection. Tat protein, a viral protein that play an important role in viral transcription forms complex with BRCAl to initiate viral protein transcription. Thus, inhibition of interaction of Tat protein and BRCAl using the present compounds/small molecule inhibitors are potentially used as antiviral therapy. The present disclosure additionally provides a method or use of compound of formula I-IV, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, or their compositions as described aboveas radiosensitizers in clinical settings during cancer therapy to avoid possible disease relapse. Additional embodiments and features of the present disclosure will be apparent to one of ordinary skill in art based upon description provided herein. The disclosure is further illustrated with the following Examples and Figures. These Examples are for better understanding of the invention and should not be construed to limit the scope of the invention in any way. Examples

Example 1: Direct binding assay by Micro Scale Thermophoresis (MST)

Micro Scale Thermophoresis (MST) was used to elucidate the interaction of compounds to BRCAl tBRCTdomain. This assay was carried out to test the binding of Compound 6to the target, and to evaluate its potential as BRCAl modulator, more particularly, inhibitorof

BRCAl activity as shown in Figure l(Methods 59, 301-315, 2013; Cell Chem. Biol. 21, 677- 90, 2018).

Example 2: Competitive binding assay by Micro Scale Thermophoresis (MST)

Competitive binding assay by MST (Reference provided in Example 1) was used to elucidate the capacity of the compound to displace peptides derived from binding partner of BRCAltBRCT domain in a competitive manner. The activity of selected compounds as depicted in Figure 2 span from two digit nanoMolar to single digit microMolar with compound 96 as the negative control representing a structure activity relationship for the compound series.

Table 2: IC50 (μΜ) value for compounds of the present disclosure

A < 1 μΜ, B = 1 μΜ to < 10 μΜ, C = 10 μΜ to 100 μΜ, D > 100 to 200 μΜ, E = >200 μΜ, NS = Insoluble in DMSO

Competitive binding assay by MST was used to measure the binding properties of compounds with different structural analogues to tBRCT domain of BRCAl protein and the data were expressed as IC50 value in μΜ (Table 2). The compounds were broadly categorized as compounds with varying degree of potency such as those with less than 1 μΜ A, 1-10 uM as B, 10-100 μΜ as C, compounds with 100-250 μΜ potency as D and compounds with potency of >250 μΜ as E. The activity of selected compounds including Compound 6 has been depicted in Figure 2. Example 3: Target engagement using FRET studies

A unimolecular FRET construct is designed in order to demonstrate direct target engagement in the cellular milieu. The assay elucidates whether the compound directly inhibits the recognition of a pSer substrate by the BRCA1 tBRCT domain following substrate phosphorylation induced by DNA damage-activated protein kinases including CDKs, ATM, ATR or DNA-PK(Cell Chem. Biol. 21, 677-90, 2018).

Conclusions: Compounds of the present disclosure such as Compound 6 were tested and confirmed using two independent FRET measurement methodologies - sensitized emission (SE) and acceptor photobleaching. Results were compared with genetic benchmarking by over-expressing BRCA1 tBRCT domain, leading to dominant negative effect and loss of

FRET activity. Figure 3 indicates that Compound 6 disrupts FRET activity, indicating that the compound directly engages its target and selectively disrupts phosphopeptide substrate recognition by the BRCA1 tBRCT domain in the cellular milieu. These results indicate the utility of compounds of the present disclosure to inhibit intracellular signalling by DNA damage-activated protein kinases including CDKs, ATM, ATR or DNA-PK.

Example 4: Recruitment of DNA damage response (DDR) proteins to sites of DNA damage The cellular DNA damage response (DDR) enforces cell cycle checkpoints that arrest cell division at different phases of the cell cycle, enables the efficient repair of DNA damage by different mechanisms, and promotes cell survival. BRCA1 is essential for the DDR. It interacts via the BRCA1 tBRCT domain with multiple protein partners like Claspin, CtIP, CHK1/CHK2, BACHl, RAD51 and so on to mediate G2 checkpoint control, to enable DNA repair, and to promote cell survival after DNA damage. Several of these protein partners are recruited to sites of DNA damage via their interaction with the BRCA1 tBRCT domain.

Accordingly, the ability of compounds of the present disclosure to modulate the recruitment of such DDR proteins to sites of DNA damage induced by radiation was tested using the phenotypic foci formation assays as described in Periasamy, J. et. al. 2018 (Cell Chem. Biol. 21, 677-90, 2018). Conclusions: Compounds of the present disclosure selectively abrogate the recruitment of BRCA1 to nuclear foci formed at sites of DNA damage (Figure4). Cells treated with Compound 6 selectively abrogate the recruitment of the DNA damage response protein RAD51 essential for the repair of DNA breaks by homologous DNA recombination

(Figure 5). These results indicate that treatment with compounds of the present disclosure inhibits the function of BRCA1 in the cellular DDR activated at sites of DNA breakage, by suppressing the recruitment of DDR factors to such sites. Furthermore, these results indicate that compounds of the present disclosure inhibit DNA repair by homologous recombination by suppressing RAD51 recruitment to DNA damage sites. These results also indicate the utility of compounds of the present disclosure to inhibit steps in

intracellular signalling by DNA damage-activated protein kinases including ATM, ATR or DNA-PK that normally lead to the recruitment of RAD51 to sites of DNA damage, mediated by BRCA1, BRCA2, PALB2 and other proteins.

Example 5: Cell cycle and G2 checkpoint regulation

The cellular DNA damage response (DDR) enforces cell cycle checkpoints that arrest cell division at different phases of the cell cycle, enables the efficient repair of DNA damage by different mechanisms, and promotes cell survival. BRCA1 is essential for the DDR. It interacts via the BRCA1 tBRCT domain with multiple protein partners like Claspin, CtIP,

CHK1/CHK2, BACHl, RAD51 and so on to mediate G2 checkpoint control, to enable DNA repair, and to promote cell survival after DNA damage.

Accordingly, the ability of compounds of the present disclosure to modulate cell cycle arrest at the G2 phase of the cell cycle after exposure to radiation was enumerated as detailed in Periasamy, J. et. al., 2018 (Cell Chem. Biol. 21, 677-90, 2018).

Conclusions: Treatment of cells with compounds of the present disclosure abrogates cell cycle arrest at the G2 checkpoint after DNA damage (Figure 6)indicating that the compounds inhibit the function of BRCA1 in this process. Since G2 arrest is a result of the activation by DNA damage of protein kinases including ATM, ATR or DNA-PK, compounds of the present disclosure are said to selectively inhibit certain steps in intracellular signalling by these kinases after DNA damage, mediated by BRCA1, Claspin, CHEK1 and other DDR factors. Example 6:

(a) Cellular proliferation and radiation sensitivity

The cellular DNA damage response (DDR) enforces cell cycle checkpoints that arrest cell division at different phases of the cell cycle, enables the efficient repair of DNA damage by different mechanisms, and promotes cell survival. BRCA1 is essential for the DDR. It interacts via the BRCA1 tBRCT domain with multiple protein partners like Claspin, CtIP, CHK1/CHK2, BACHl, RAD51 etc. tomediate G2 checkpoint control, to enable DNA repair, and to promote cell survival after DNA damage. Accordingly, the ability of compounds of the present disclosure to affect survival after DNA damage was measured. The assay below measures the survival curve (Dose Response Curve; DRC)reporting the relationship between the dose of radiationadministered, and the fraction of cells retaining their ability to survive or divide. Overexpression of the BRCA1 tBRCT domain was used as a genetic tool to benchmark the assays as provided in Periasamy, J. et. al., 2018 (Cell Chem. Biol. 21, 677-90, 2018).

(b) Synergistic Effect of Combination therapy

Synergistic effects were seen with Compound 6 and Olaparib, a chemothrapeutic agent, under steady state conditions in HEK293 cells (Figure 7). Also, Compound 6 has been tested in the absence of DNA damage in different cancer cell lines for its ability to induce cell death as indicated in Figure8.

Conclusions: Treatment of cells with Compound 6 significantly sensitizes several different cancer cell lines to cell death and/or growth inhibition induced by irradiation (Figure 9). The results also indicate the utility of compounds of the present disclosure in combination with radiation or chemotherapy to induce the death or inhibit the growth of cancer cells (Figure 9).

The Examples illustrated herein also enable the compounds of invention and establish their role in treatment of a disease responsive to inhibition of protein kinases including ATM, ATR or DNA-PK, and DDR factors including BRCA1, BRCA2, PALB2, RAD51 or CHEK1.

Claims

CLAIMS We Claim:

1.A compound of formula I:

Q is N or C and wherein each of them is unsubstituted or substituted;

L and M are independently selected froma group consisting of a bond, H, C1-C10 alkyl, Cl- C10 alkoxyl, Carbonyl (C=0), Sulfonyl (S0₂), Methylene (CH₂), Carboxyl(C0₂), Carbamide (0=C-N), Hydroxyl (OH), C6-C10 aryl and wherein each of them is unsubstituted or substituted; and

R4 and R5 are selected from a group consisting of phenyl, 5-10 membered heteroaryl, 5-10 membered bicyclic heteroaryl and wherein each is unsubstituted or substituted.

2. The compound according to claim 1, wherein Rl is H, methyl, S-Methyl, R-Methyl, isopropyl, S-Isopropyl, benzyl, R-Isopropyl, S-benzyl or -benzyl.

3. The compound according to claim 1, wherein R2 and R3 are independently H or Methyl.

4. The compound according to claim 1, wherein L and M are linkers independently selected from

wherein n is 0 to 6.

5. The compound according to claim 1, wherein R4 is selected from a group consisting of

wherein R6 is H or COOH; R8 is -H, -CH₃ -CH₂-CH₂-OH or -CH₂-CH₂-CN and R7 is

Wherein n = 0 to 6 and R9 is-H, -CH₃, -CH₂-CN, -OCH₃, -OCH₂CN, -OCH₂CH₂OH, OCH₂CH₂OCH₃, -OCH₂COOH, -OS0₂CH₃, -S0₂CH₃, -N(CH₂CH₂OH)2, -NHCH₃ or N(C¾)₂.

6. The compound according to claim 1, wherein R5 is

7. The compound according to claim 1, wherein R5 is

8. The compound according to claim 1, wherein the compound is

(4-(2-fluorobenzyl)piperazin- 1 -yl)(lH-indol-6-yl)methanone;

6-(4-(2-fluorobenzyl)piperazine-l-carbonyl)-lH-indole-3-carboxylic acid; (2-methyl-lH-benzo[d]imidazol-5-yl)(4-(o-tolyl)piperazin-l-yl)methanone; 5-((4-(2-fluorobenzyl)piperazin-l-yl)sulfonyl)-2-methyl-lH- benzo[d]imidazole;

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2-(phenoxymethyl)- lH-benzo[d]imidazol-6- yl)methanone;

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2-phenyl- lH-benzo[d]imidazol-6- yl)methanone;

(4-(2-fluorobenzyl)piperazin-l-yl)(2-isopropyl-lH-benzo[d]imidazol-6- yl)methanone; (2-(3,5-dimethoxyphenyl)-lH-benzo[d]imidazol-6-yl)(4-(2- fluorobenzyl)piperazin-l-yl)methanone;

ethyl 2-(3-((4-(2 -methyl- lH4oenzo[d]imidazole-6-carbonyl)piperazin- 1- yl)methyl)phenoxy)acetate;

2-(3-((4-(2-methyl-lH-benzo[d]imidazole-6-carbonyl)piperazin-l- yl)methyl)phenoxy)acetic acid;

(4-benzoylpiperazin-l-yl)(2-methyl-lH-benzo[d]imidazol-6-yl)methanone; 2-(4-(2-methyl- lH-benzo[d]imidazole-6-carbonyl)piperazin- 1 -yl)-N- phenylacetamide;

2-(3-((4-(2-methyl-lH-benzo[d]imidazole-6-carbonyl)piperazin-l- yl)methyl)phenoxy)acetamide;

(4-(2-fluorobenzyl)-3,3-dimethylpiperazin-l-yl)(2-methyl-lH- benzo[d]imidazol-5-yl)methanone;

(S)-6-(4-(2-fluorobenzyl)-2-isopropylpiperazine-l-carbonyl)-lH-indole-3- carboxylic acid;

(S)-(2-isopropyl-4-(o-tolyl)piperazin-l-yl)(2-methyl-lH-benzo[d]imidazol-5- yl)methanone;

(S)-(4-(2-fluorobenzyl)-2-isopropylpiperazin-l-yl)(2-(phenoxymethyl)-lH- benzo[d]imidazol-6-yl)methanone;

(S)-(2-(3,5-dimethoxyphenyl)-lH-benzo[d]imidazol-6-yl)(4-(2-fluorobenzyl)- 2-isopropylpiperazin-l-yl)methanone;

ethyl (S)-2-(3-((3-isopropyl-4-(2-methyl-lH-benzo[d]imidazole-6- carbonyl)piperazin- 1 -yl)m ethyl )phenoxy)acetate;

(S)-2-(3-((3-isopropyl-4-(2-methyl-lH-benzo[d]imidazole-6- carbonyl)piperazin- 1 -yl)methyl)phenoxy)acetic acid;

benzyl 4-(lH-indole-6-carbonyl)piperazine-l-carboxylate;

(2-methyl-lH-benzo[d]imidazol-6-yl)(4-(pyridin-3-yl)piperazin-l- yl)methanone;

benzyl 4-(lH-benzo[d]imidazole-6-carbonyl)piperazine-l-carboxylate; benzyl l-(lH-indole-6-earbonyl)piperidine-4-carboxylate;

benzyl 4-(2 -methyl- lH-benzo[d]imidazole-6-carbonyl)piperazine-l- carboxylate;

benzyl (S)-4-(lH-indole-6-carbonyl)-3-isopropylpiperazine-l-carboxylate;

4-((4-(lH-benzo[d]imidazole-6-carbonyl)piperazin-l-yl)methyl)benzonitrile;

(S)-(4-(2-fluorobenzyl)-2-isopropylpiperazin-l-yl)(lH-indol-6-yl)methanone

(lH-indol-6-yl)(4-(o-tolyl)piperazin-l-yl)methanone,

(lH-benzo[d]imidazol-6-yl)(4-phenylpiperazin-l-yl)methanone,

(S)-(lH-benzo[d]imidazol-6-yl)(2-benzyl-4-(2-fluorobenzyl)piperazin-l- yl)methanone;

(S)-(lH-benzo[d][l,2,3]triazol-6-yl)(4-(2-fluorobenzyl)-2-isopropylpiperazin- 1 -yl)methanone;

(4-(2-fluorobenzyl)piperazin- 1 -yl)(quinolin-7-yl)methanone;

6-(4-(2-fluorobenzyl)piperazine-l-carbonyl)-lH-indole-3-carboxylic acid; (S)-(4-(2-fluorobenzyl)-2-isopropylpiperazin- 1 -yl)(2-phenyl- 1 H- benzo[d]imidazol-5-yl)methanone;

l-(4-(lH-benzo[d]imidazole-6-carbonyl)piperazin-l-yl)-3-phenylpropan-l-one; (S)-l-(4-(lH-benzo[d]imidazole-6-carbonyl)-3-isopropylpiperazin-l-yl)-2- phenoxy ethan- 1 -one ;

benzyl (S)-4-(lH-benzo[d]imidazole-6-carbonyl)-3-isopropylpiperazine-l- carboxylate,

(lH-benzo[d]imidazol-6-yl)(4-(2-phenoxyethyl)piperazin-l-yl)methanone; tert-butyl 4-(lH-benzo[d]imidazole-6-carbonyl)piperazine-l-carboxylate; benzyl 4-(2 -phenyl- lH-benzo[d]imidazole-6-carbonyl)piperazine- 1- carboxylate,

b enzyl 4-( 1 H-indol e- 5 -carb ony l)piperazine- 1 -carb oxyl te ;

ethyl 4-(lH-benzo[d]imidazole-6-carbonyl)piperazine-l-carboxylate;

1 -(4-(lH-indole-6-carbonyl)piperazin- 1 -yl)-3 -phenylpropan-1 -one;

1 -(4-(lH-indole-6-carbonyl)piperazin- 1 -yl)-2-phenoxy ethan- 1 -one; (lH-indol-6-yl)(4-(2-phenoxyethyl)piperazin-l-yl)methanone;

benzyl 4-((lH-indol-6-yl)methyl)piperazine-l-carboxylate;

benzyl 4-(3 -(methylamino)benzoyl)piperazine- 1 -carboxylate;

(S)-(2-(3,5-dimethoxyphenyl)-l-(2 -hydroxy ethyl)-lH-benzo[d]imidazol-5- yl)(4-(2-fluorobenzyl)-2-isopropylpiperazin-l-yl)methanone;

(S)-(4-(2-fluorobenzyl)-2-isopropylpiperazin-l-yl)(q inoxalin-6-yl)methanone;

(S)-(4-(2-fluorobenzyl)-2-isopropylpiperazin-l-yl)(2-(4-methoxyphenyl)-lH- benzo[d]imidazol-5-yl)methanone;

(S)-(4-(2-fluorobenzyl)-2-isopropylpiperazin-l-yl)(2-(hydroxymethyl)-lH- benzo[d]imidazol-5-yl)methanone;

(S)-2-(5-(4-(2-fluorobenzyl)-2-isopropylpiperazine-l-carbonyl)-lH- benzo[d]imidazol-2-yl)acetonitrile;

(S)-(4-(2-fluorobenzyl)-2-isopropylpiperazin-l-yl)(2-(3-(4- methoxyphenoxy)propyl)-lH-benzo[d]imidazol-5-yl)methanone;

5-((4-(2-fluorobenzyl)piperazin-l-yl)sulfonyl)-2-phenyl-lH- benzo[d]imidazole;

ethyl 2-(3-((4-(2-phenyl-lH-benzo[d]imidazole-5-carbonyl)piperazin-l- yl)methyl)phenoxy)acetate;

2-(3-((4-(2-phenyl-lH-benzo[d]imidazole-5-carbonyl)piperazin-l- yl)methyl)phenoxy)acetic acid;

(4-(2-fluorobenzyl)piperazin-l-yl)(2-(pyridin-3-yl)-lH-benzo[d]imidazol-5- yl)methanone;

(4-(2-fluorobenzyl)piperazin-l-yl)(2-(pyridin-4-yl)-lH-benzo[d]imidazol-5- yl)methanone;

(4-(2-fluorobenzyl)piperazin-l-yl)(2-(pyridazin-3-yl)-lH-benzo[d]imidazol-6- yl)methanone;

(4-(2-fluorobenzyl)piperazin-l-yl)(2-morpholino-lH-benzo[d]imidazol-5- yl)methanone;

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2-(4-methylpiperazin- 1 -yl)- 1H- benzo[d]imidazol-5-yl)methanone;

2-(3-(5-(4-(2-fluorobenzyl)piperazine-l-carbonyl)-lH-benzo[d]imidazol-2- yl)phenyl)acetonitrile;

(4-(2-fluorobenzyl)piperazin-l-yl)(2-(4-hydroxyphenyl)-lH-benzo[d]imidazol- 6-yl)methanone;

(2-(lH-pyrazol-5-yl)-lH-benzo[d]imidazol-5-yl)(4-(2-fluorobenzyl)piperazin- 1 -yl)methanone;

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2-(4-methoxyphenyl)- lH4jenzo[d]imidazol- 5-yl)methanone,

(4-benzylpiperazin-l-yl)(2-phenyl-lH-benzo[d]imidazol-6-yl)methanone;

2-(3-((4-(2-phenyl-lH-benzo[d]imidazole-6-carbonyl)piperazin-l- yl)methyl)phenyl)acetonitrile;

2-((4-(2-phenyl-lH-benzo[d]imidazole-6-carbonyl)piperazin-l- yl)methyl)benzonitrile;

(4-(2-methoxybenzyl)piperazin- 1 -yl)(2-phenyl- lH-benzo[d]imidazol-6- yl)raethanone,

(2-phenyl- lH-benzo[d]imidazol-5-yl)(4-(pyridin-4-ylmethyl)piperazin- 1 - yl)methanone;

(4-phenethylpiperazin- 1 -y l)(2-phenyl - 1 H-b enzo [d]imi dazol -6-yl)methanone;

(4-(2-fluorobenzyl)piperidin-l-yl)(2-phenyl-lH-benzo[d]imidazol-6- yl)methanone;

(4-(benzo[d] [ 1 ,3 ]dioxol-5-ylmethyl)piperazin- 1 -yl)(2-phenyl- 1H- benzo[d]imidazol-6-yl)methanone;

(4-(3-morpholinobenzyl)piperazin-l-yl)(2-phenyl-lH-benzo[d]imidazol-6- yl)methanone;

(4-((lH-pyrazol-5-yl)methyl)piperazin-l-yl)(2-phenyl-lH-benzo[d]imidazol-6- yl)methanone;

2-(4-(5-(4-(2-fluorobenzyl)piperazine-l-carbonyl)-lH-benzo[d]imidazol-2- yl)phenoxy)acetonitrile; 2-(5-(4-(2-fluorobenzyl)piperazine-l-carbonyl)-lH4jenzo[d]imidazol-2- yl)acetonitrile;

(4-(4-hydroxybenzyl)piperazin-l-yl)(2-phenyl-lH-benzo[d]imidazol-5- yl)methanone;

(4-(4-methylbenzyl)piperazin- 1 -yl)(2-phenyl- lH-benzo[d]imidazol-5- yl)methanone;

(4-(2-methoxybenzyl)piperazin-l-yl)(2-(pyridin-4-yl)-lH-benzo[d]imidazol-5- yl)methanone;

(4-(2,3 -dimethoxyb enzyl)piperazin- 1 -yl)(2-phenyl - 1 H-b enzo[d]imidazol- 5 - yl)methanone;

(4-((lH-pyrazol-5-yl)methyl)piperazin-l-yl)(2-(pyridin-4-yl)-lH- benzo[d]imidazol-5-yl)methanone;

(4-((lH-pyrazol-5-yl)methyl)piperazin-l-yl)(2-(3-(4-methoxyphenoxy)propyl)- lH-benzo[d]imidazol-5-yl)methanone;

(4-(2-methoxybenzyl)piperazin- 1 -yl)(2-(3-(4-methoxyphenoxy)propyl)- 1H- benzo[d]imidazol-5-yl)methanone;

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2-(3-(4-methoxyphenoxy)propyl)- 1 H- benzo[d]imidazol-5-yl)methanone;

(4-((lH-pyrazol-5-yl)methyl)piperazin-l-yl)(2-(4-methoxyphenyl)-lH- benzo[d]imidazol-5-yl)methanone;

(4-(2-fluorobenzyl)piperazin-l-yl)(2-(3-phenoxypropyl)-lH-benzo[d]imidazol- 5-yl)methanone;

tert-butyl 4-(2-(4-methoxyphenyl)-lH-benzo[d]imidazole-5- carbonyl)piperazine- 1 -carboxylate;

ethyl 2-(3 -((4-(2-(phenoxymethyl)- 1 H-benzo [d]imi dazol e- 5 - carbonyl)piperazin-l-yl)methyl)phenoxy)acetate;

l-(4-(benzo[d]oxazole-5-carbonyl)piperazin-l-yl)-3-phenylpropan-l-one;

(S)-(2-isopropylpiperazin-l-yl)(2-methyl-lH-benzo[d]imidazol-6- yl)methanone; (S)-(2-isopropyl-4-methylpiperazin-l-yl)(2-methyl-lH-benzo[d]imidazol-6- yl)methanone;

(S)-l-(3-isopropyl-4-(2-methyl-lH-benzo[d]imidazole-6-carbonyl)piperazin-l- yl)ethan-l-one;

(2-phenyl-lH4jenzo[d]imidazol-5-yl)(piperazin-l-yl)methanone;

(4-i sobutylpiperazin- 1 -y l)(2-phenyl - 1 H-benzo [d] imi dazol-5 -yl)methanone;

(4-methylpiperazin-l-yl)(2 -phenyl- lH-benzo[d]imidazol-5-yl)methanone;

(S)-(2-isopropyl-4-methylpiperazin-l-yl)(2-phenyl-lH-benzo[d]imidazol-5- yl)methanone;

(4-(2-fluorobenzyl)piperazin- 1 -yl)(phenyl)methanone;

1- (4-(2-fluorobenzyl)piperazin-l-yl)ethan-l-one;

(4-(2-fluorobenzyl)piperazin-l-yl)(2-(4-(2-hydroxyethoxy)phenyl)-lH- benzo[d]imidazol-5-yl)methanone;

2- (4-(5-(4-(2-fluorobenzyl)piperazine-l-carbonyl)-lH-benzo[d]imidazol-2- yl)phenoxy)acetic acid;

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2-(4-(methylsulfonyl)phenyl)- 1H- benzo[d]imidazol-5-yl)methanone;

4-(5-(4-(2-fluorobenzyl)piperazine-l-carbonyl)-lH-benzo[d]imidazol-2- yl)phenyl methanesulfonate;

(2-(4-((lH-tetrazol-5-yl)methoxy)phenyl)-lH-benzo[d]imidazol-5-yl)(4-(2- fluorobenzyl)piperazin-l-yl)methanone;

(S)-(4-(2-fluorobenzyl)-2-methylpiperazin- 1 -yl)(2-phenyl - 1 H- benzo[d]imidazol-5-yl)methanone;

(4-(2,4-difluorobenzyl)piperazin-l-yl)(2-phenyl-lH-benzo[d]imidazol-5- yl)methanone;

(4-(2-methylbenzyl)piperazin- 1 -yl)(2-phenyl- lH-benzo[d]imidazol-5- yl)methanone;

(4-(4-methoxybenzyl)piperazin-l-yl)(2-phenyl-lH-benzo[d]imidazol-5- yl)methanone; N-(2-((2-fluorobenzyl)(methyl)amino)ethyl)-2-phenyl-lH-benzo[d]imidazole- 5-carboxamide;

(4-(2-fluorobenzyl)piperazin-l-yl)(2-phenyl-3H-imidazo[4,5-c]pyridin-6- yl)methanone;

(4-(2-fluorobenzyl)piperazin-l-yl)(2-phenyl-[l,2,4]triazolo[l,5-a]pyridin-6- yl)methanone;

(4-(2-fluorobenzyl)piperazin-l-yl)(l-methyl-2-phenyl-lH-benzo[d]imidazol-5- yl)methanone;

(4-(2-fluorobenzyl)piperazin-l-yi)(2-(hydroxymethyl)-lH-benzo[d]imidazol-5- yl)methanone;

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2-(4-methoxyphenyl)- lH-indol-5- yl)methanone

(S)-(2-isopropyl-4-(3-morpholinobenzyl)piperazin-l-yl)(2-methyl-lH- benzo[d]imidazol-5-yl)methanone;

(S)-(2-isopropyl-4-phenethylpiperazin-l-yl)(2-methyl-lH-benzo[d]imidazol-5- yl)methanone;

(S)-(2-isopropyl-4-(4-methylbenzyl)piperazin-l-yl)(2-methyl-lH- benzo[d]imidazol-5-yl)met anone;

(2-phenyl-lH-benzo[d]imidazol-5-yl)(4-(3-thiomoφholinobenzyl)piperazin-l- yl)methanone,

(4-(2-fluorobenzyl)piperazin-l-yl)(2-(thiophen-2-yl)-lH-benzo[d]imidazol-5- yl)methanone;

(4-(2-fluorobenzyl)piperazin-l-yl)(2-(thiophen-3-yl)-lH-benzo[d]imidazol-5- yl)methanone,

(4-(2-fluorobenzyl)piperazin-l-yl)(2-phenylbenzo[d]oxazol-5-yl)methanone;

(4-(2-fluorobenzyl)-4-hydroxypiperidin-l-yl)(2-phenyl-lH-benzo[d]imidazol-

5-yl)methanone;

(S)-(4-(2-methoxybenzyl)-2-methylpiperazin-l-yl)(2-methyl-lH- benzo[d]imidazol-5-yl)methanone; (S)-(2-methyl- lH-benzo[d]imidazol-5-yl)(2-methyl-4-phenethylpiperazin- 1 - yl)methanone;

(S)-(2-methyl-lH-benzo[d]imidazol-5-yl)(2-methyl-4-(4- methylbenzyl)piperazin- 1 -yl)methanone;

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2-(4-(2-(2-(2- hydroxyethoxy)ethoxy)ethoxy)phenyl)-lH-benzo[d]imidazol-5-yl)methanone;

(4-(2-fluorobenzyl)piperazin- 1 -yl)(2-(4-(2-(2-(2-(2- hydroxyethoxy)ethoxy)ethoxy)ethoxy)phenyl)-lH-benzo[d]imidazol-5- yl)methanone;and

(4-(3 -( 1 ,4-oxazepan-4-yl)benzyl)piperazin- 1 -yl)(2 -phenyl- 1H- benzo[d]imidazol-5-yl)methanone.

9. A method of inhibiting phosphopeptide recognition by the human BRCAl (t)BRCT domain wherein the said method comprises using a compound according to claims 1 to 8, or a pharmaceutically acceptable salt of compound according to claims 1 to 8 along with at least one pharmaceutically acceptable excipient

10. A method of inhibiting the function of BRCAl wherein the said method comprises using a compound according to claims 1 to 8 or a pharmaceutically acceptable salt of compound according to claims 1 to 8 along with at least one pharmaceutically acceptable excipient.

1 1. A method of inhibiting cell cycle arrest induced by DNA damage wherein the said method comprises using a compound according to claims 1 to 8 or a pharmaceutically acceptable salt of compound according to claims 1 to 8 along with at least one pharmaceutically acceptable excipient.

12. A method of inhibiting the recruitment of cellular proteins essential for G2 arrest and DNA repair by homologous DNA recombination wherein the said method comprises a compound according to claims 1 to 8 or a pharmaceutically acceptable salt of compound according to claims 1 to 8 along with at least one pharmaceutically acceptable excipient.

13. A method of sensitizing cancer cells to the cytostatic or cytotoxic effects of radiation or DNA damaging agents wherein the said method comprises using a compound according to claims 1 to 8 or pharmaceutically acceptable salt of compound according to compound 1 to 8 along with at least one pharmaceutically acceptable excipient.

14 The method of sensitizing cancer cells to the cytostatic or cytotoxic effects of radiation or DNA damaging agents according to claim 13 wherein the said DNA damaging agents are selected from a group consisting of cisplatin, carboplatin, doxorubicin, toposide, topotecan, irinotecan or mitomycin C, inhibitors of poly-ADP ribose polymerase (PARP) enzymes, inhibitors of telomerase and inhibitors of polymerase theta or any combination thereof.

15. A pharmaceutical composition comprising compounds according to claims 1 to 8 for use in the treatment of diseases responsive to inhibition of ATM, ATR, DNA-PK, BRCA1, BRCA2, PALB2, RAD51 or CHEK1.

16. A pharmaceutical composition comprising compounds according to claims 1 to 8 for use in the treatment of cancer, proliferative disorders, inflammatory disorders associated with cell proliferation or Fanconi Anemia.

17. The pharmaceutical composition for use in treatment of proliferative disorders according to claim 16, wherein the said proliferative disorders are selected from a group consisting of rheumatoid arthritis, idiopathic pulmonary fibrosis and psoriasis.

18. A pharmaceutical composition comprising compounds according to claims 1 to 8 and at least one additional active therapeutic agent wherein the said active therapeutic agent is selected from the group consisting of anti-cancer, immune modulatory, cytostatic, cytotoxic, anti-hyperproliferative, anti-inflammatory and chemotherapeutic agents.

19. A pharmaceutical formulation comprising compounds according to claims 1 to 8 and at least one additional pharmaceutical excipient.