CA2942761A1

CA2942761A1 - Novel 3-indol substituted derivatives, pharmaceutical compositions and methods for use

Info

Publication number: CA2942761A1
Application number: CA2942761A
Authority: CA
Inventors: Sandra CAUWENBERGHS; Stefano Crosignani; Gregory DRIESSENS; Frederik Deroose
Original assignee: Iteos Therapeutics SA
Current assignee: Iteos Therapeutics SA
Priority date: 2014-03-18
Filing date: 2015-03-17
Publication date: 2015-09-24
Also published as: JP2017507983A; WO2015140717A9; WO2015140717A1; EP3119763A1

Abstract

The present invention relates to compound of Formula (I) or pharmaceutically acceptable enantiomers, salts or solvates thereof. The invention further relates to the use of the compounds of Formula I as TDO2 inhibitors. The invention also relates to the use of the compounds of Formula I for the treatment and/or HIV, depression, and obesity. The invention also relates to a process for manufacturing compounds of Formula (I).

Description

NOVEL 3-INDOL SUBSTITUED DERIVATIVES, PHARMACEUTICAL COMPOSITIONS
AND METHODS FOR USE
FIELD OF INVENTION
The present invention relates to novel 3-(indo1-3-y1)-pyridine derivatives, including pharmaceutically acceptable enantiomers, salts and solvates thereof. Compounds of the invention are inhibitors of TD02 (tryptophan 2,3-dioxygenase) and are useful as therapeutic compounds, particularly in the treatment and/or prevention of cancers.
BACKGROUND OF INVENTION
Two decades after the importance of tryptophan catabolism for maintaining the immune privilege of the placenta was discovered (Munn, D.H. et al., Science, 1998, 281, 1191-1193), increasing evidence is extending its biological relevance beyond immune tolerance to non-self. According to the generally accepted concept, tryptophan, an essential amino acid, is catabolized in the local microenvironment of tumors, immune-privileged sites, or sites of inflammation (Mellor AL and Munn DH., Nat Rev Immunol, 2008, 8, 74-80). In these tissues, cancer cells, immune cells, or specialized epithelial cells (e.g., syncytiotrophoblasts in the placenta) create an immunosuppressive environment in tumors that shuts down antitumor immune responses in tumors and in tumor-draining lymph nodes by inducing T-cell anergy and apoptosis through depletion of tryptophan and accumulation of immunosuppressive tryptophan catabolites (Munn DH et al., J Exp Med., 1999, 189, 1363-1372; Fallarino F et al., Cell Death Differ., 2002, 9, 1069-1077).
It has recently been discovered that a key enzyme in tryptophan catabolism, tryptophan

2,3-dioxygenase (TD02), which is considered responsible for regulating systemic tryptophan levels in the liver, is constitutively expressed in a wide variety of cancers, such as for example in bladder carcinoma, hepatocarcinoma, melanoma, mesothelioma, neuroblastoma, sarcoma, breast carcinoma, leukemia, renal cell carcinoma, colorectal carcinoma, head and neck carcinoma, lung carcinoma, brain tumor, glioblastoma, astrocytoma, myeloma, and pancreatic carcinoma (Pilotte L et al., Proc Natl Acad Sci U
5 A, 2012, 109(7), 2497-502). TD02 expression in tumor cells prevents tumor surveillance by the immune system and thus prevents tumor rejection by locally degrading tryptophan (Opitz CA et al., Nature, 2011, 478(7368), 197-203). The first evidence for this was provided through inhibition of TD02 by a small molecule which inhibited tumor growth in a P815 mastocytoma tumor model with a prophylactic vaccination approach (Pilotte Let al., Proc Natl Acad Sci U S A, 2012, 109(7), 502). P815mTD02 expressing tumors were rejected less in comparison to P815 tumors transfected with an empty vector, clearly demonstrating a growth benefit for expressing tumors. Inhibition with a TD02 inhibitor strongly decreased tumor growth in P815mTD02 implanted tumors. Anti-tumor activity with the TD02 inhibitor was equally observed in the P815 control implanted tumors negative for TD02, thus providing evidence for an effect of TD02 expressed in the immune system of the animal.
These experiments for the first time provided clear evidence for a role of TD02 in regulating tumor growth through expression in the cancer cell as well as immune compartment.
In line with its expression profile in liver, TD02 was found predominantly in hepatocellular carcinoma (HCC) (Pilotte Let al., Proc Natl Acad Sci U S A, 2012, 109(7), 2497-502). Inhibition of tryptophan catabolism and thus restoration of tryptophan concentration and decreased production of downstream metabolites could prove beneficial in the context of liver disease progressing to the stage of liver carcinoma.
More particularly: (i) several reports have shown evidence that increased availability of tryptophan through supplementation is beneficial for example, cirrhotic livers, allowing the direct use of tryptophan for protein synthesis (Ohta et al., Amino Acids, 1996, 10(4), 369-78); (ii) there is a correlation between increased downstream serum tryptophan metabolites, such as quinolinic acid, and hepatic dysfunction in patients with liver cirrhosis (Lahdou et al., Hum Immunol, 2013, 74(1), 60-6) and (iii) increased secretion of another tryptophan metabolite, indole-3-lactic acid, has been associated with alcohol-induced liver disease in mice (Manna et al., J Proteome Res, 2011, 10(9), 4120-33). In the context of liver carcinoma itself, very high RNA expression is a good indication for therapeutic evaluation of TD02 inhibitors (Pilotte L et al., Proc Natl Acad Sci U S A, 2012, 109(7), 2497-502). The above thus provides a clear rationale for TD02 activity modulation in the control of liver tumor development.
In addition to expression in liver, TD02 is expressed in neurons, microglia and astrocytes and the potential benefit of TD02 inhibition in the context of glioma was shown in another animal model. Platten and collaborators demonstrated that the

3 tryptophan catabolite kynurenine produced by TDO expressed in the tumor cells suppresses antitumour immune responses and promotes tumor-cell survival and motility through the AHR in an autocrine/paracrine fashion (Opitz CA et al., Nature, 2011, 478(7368), 197-203). The TDO-AHR pathway is active in human brain tumors and is associated with malignant progression and poor survival. Further evidence came from the accumulation of a downstream metabolite, quinolinic acid which accumulates in human gliomas and was associated with a malignant phenotype (Sahm et al., Cancer Res, 2013, 73(11), 3225-34). Here tryptophan catabolism was shown to occur in microglia cells as well. The above data thus provides evidence for TD02 targeting in glioma with brain-penetrant small molecules.
Other tumor types in which TD02 m RNA was found are breast carcinoma, bladder, renal cell, pancreatic, colorectal, head & neck carcinoma and lung carcinoma as well as melanoma thus broadening the scope of TD02 targeting beyond HCC and glioma (Pilotte Let al., Proc Natl Acad Sci U S A, 2012, 109(7), 2497-502).
The enhanced Tryptophan degradation observed in patients with gynecological cancers (ovarian carcinoma, cervical cancer, endometrial cancer) provides additional rationale for TD02 targeting in those cancers (Sperner-Unterweger B et al, Immunology, 2011, 216 (3); 296-301).
The tryptophan catabolism in some cancers might be also increased by the expression of indoleamine 2,3-dioxygenase (ID01) by tumor cells (Uyttenhove, C. et al., Nat. Med., 2003, 9, 1269-1274).
Because tryptophan catabolism is induced by inflammatory mediators, notably IFN-gamma, it is thought to represent an endogenous mechanism that restricts excessive immune responses, thereby preventing immunopathology. However in the context of cancer, there is strong evidence that suppression of antitumor immune responses in precancerous lesions and established cancers by tryptophan catabolism promotes tumor growth, which would make such catabolism an attractive target for therapeutic intervention (Dolu i6 E and Frederick R., Expert Opin Ther Pat., 2013, 23(10), 1367-81).
Hence, a considerable effort is being made to identify selective and efficient inhibitors of tryptophan catabolism to enhance the efficacy of conventional chemotherapy, immune

4 checkpoints (Holmgaard RB et al., J Exp Med., 2013, 210(7), 1389-402) or therapeutic vaccines.
In the context of neurological brain disorders, TD02 expression has been demonstrated in neurons, brain vasculature and additionally in the case of schizophrenia in astroglial cells (Miller C et al., 2004, Neurobiology Dis, 15(3):618-29). The kynurenine pathway is now considered as a therapeutic target in cognitive diseases like bipolar disorder or Tourette syndrome and neurodegenerative disorders like Alzheimer, motor neuron disease like Amyotrophic lateral sclerosis, Multiple sclerosis, Huntington or Parkinson's disease (Stone TW, 2013, Br J of Pharmacol, 169(6): 1211-27; Wu et al, 2013, Plos One, 8(4):e59749; FOvesi et al, 2012, J Neural Transm, 119(2):225-34; Widner et al, 2002, J Neural Transm, 109(2):181-9; Comings et al, 1996, Pharmacogenetics, 6(4):307-18; Forrest 2010, J Neurochem, 112(1):112-22).
Cognitive changes related to Tryptophan catabolism have also been shown in patients infected with human immunodeficiency virus type-1 (HIV), called HIV-associated neurocognitive disorder (HAND) (Davies et al, 2010, Int J of Tryptophan Res, 3:121-40).
In addition, T cell hyporesponsiveness has been recently associated with the Tryptophan catabolic pathway in HIV-infected patients with possibly extension to other chronic infectious diseases like e.g. Hepatitis C.
Some TD02 inhibitors were proposed in W02010/008427 and by Dolusic, E. et al.
(Dolusic et al., J. Med. Chem., 2011, 54, 5320-5334), however either their affinity for the target is limited, or their pharmacokinetic properties are not suitable for development as a drug for human use.
Therefore, there is a need for new TD02 inhibitors with improved efficacy for cancer treatment and/or prevention.
SUMMARY OF THE INVENTION
The present invention provides new TD02 inhibitors which may be administered to a mammalian subject having a condition or disease where it is desirable to modulate, and in particular decrease, activity of TD02, including, without limitation, patients diagnosed with cancer, or any subject being at risk of developing a cancer. Also provided are compositions containing these compounds and uses thereof.
In one aspect, a compound of Formula I is provided or a pharmaceutically acceptable salt, solvent or solvate thereof, where Al, A2, A3, Yl, Y2, Y4, R1, R2, R3, X1 and X3

5 are as defined herein.
In one embodiment, a first one of A1, A2 and A3 is N, a second one of A1, A2 and A3 is C and the third one of A1, A2 and A3 is N or 0. In another embodiment, A2 is N
and one of A1 and A3 is N or S and the other is C. In yet another embodiment, A1 or A3 is S, A1-Y1 or A3-Y3 is SO2. In still a further embodiment, A2 is C and one of A1 and A3 is N and the other is N or 0. In yet a further embodiment, A1 or A3 is 0, and C is substituted with CR6R7R8 as defined herein and one of R6, R7, 1:18 is a 1. wherein Al or A3 is 0, and C is substituted with CR6R7R8 and R6, R7 or 1:18 is heterocyclyl or Cl -heterocycyl, the heterocyclyl is piperidine, pyrrolidine, piperazine, morpholine, or 2,6-diazaspiro[3.3]heptane, any of which may be optionally substituted with one or more of Cl -C3 alkyl, amino, hydroxyl, halogen, COCH3 , COOH, or SO2CH3. In yet a further embodiment, one of A1, A2 or A3 is S or A1-y1, A2-y2, or A3-Y3 is SO2; one of A1, A2 or A3 is N or C and one of A1, A2 and A3 is C. In a further embodiment, X1 and X2 are independently H or F. In still another embodiment, R1, R2 and R3 represent each independently H, halogen or methyl, or may each be H.
In a further aspect, a pharmaceutical composition is provided which comprises a compound according to Formula I is provided, or a pharmaceutically acceptable enantiomer, salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
In yet another aspect, a medicament is provided which comprises a compound according to Formula I, or a pharmaceutically acceptable enantiomer, salt or solvate thereof.
In yet a further aspect, a compound of Formula I, or a pharmaceutically acceptable enantiomer, salt or solvate thereof is provided, for use in the treatment and/or prevention of cancer, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV
and HIV, depression, and obesity, or for use as TD02 inhibitor.

6 In still another aspect, a method of treating and/or preventing of cancer, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity, or inhibiting TD02 is provide. The method comprises administering a compound of Formula I, or a pharmaceutically acceptable salt thereof.
In a further aspect, a process for manufacturing a compound of Formula I or a pharmaceutically acceptable enantiomer, salt or solvate thereof is provide.
The process comprises:
(al) reacting a compound of Formula (i) H

(i) wherein X1 and X2 represent each independently H, halogen, alkyl, haloalkyl;
Z1 represents H or an amino protecting group;
Y represents an halogen, an alkylsulfonyloxy having 1-6 carbon atoms or arylsulfonyloxy having 6-10 carbon atoms;
with a compound of Formula (ii) yl y2 R3 \A1,A2' R2 µY3 0- \õ

(ii) wherein R1, R2, R3, A1, A2, A3, Yl, Y2 and Y3 are as defined herein; and

7 Z2 and Z3 represent H or alkyl groups, with the possibility for Z2 and Z3 to form a ring;
so as to obtain a compound of Formula (iii), yl y2 \A1,A2' R3 ,-=,µ
=;, -1 A3 R2 0. \y3 \ H

H i (iii) 5 wherein Z1, Xl, X2, R1, R2, R3, Al, A2, A3, Yl, Y2 and Y3 are defined herein;
and (b-1) in the case wherein Z1 is not H, deprotecting the indole amine of compound of Formula (iii), to afford compound of Formula I.
10 Still other aspects and advantages of the invention will be apparent from the following detailed description of the invention.
DETAILED DESCRIPTION
Compounds This invention relates to compounds of Formula I

8 yl y2 \A1 A2' R2 Os µY3 401 \ H

or a pharmaceutically acceptable enantiomer, salt or solvate thereof, wherein:

X1 and X2 represent each independently H, halogen, alkyl, or haloalkyl;
R1, R2 and R3 represent each independently H, halogen, C1-C6 alkyl, alkoxy, or haloalkyl, optionally substituted by one or more substituents selected from halogen, hydroxyl, OR4, COOR4, CONR4R5, NR4COR5, NR4R5, S02R4, SO2NR4R5, NR4S02R5, S02R4, aryl, CO-alkyl, or C1-C6 alkyl which is optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R4 and R5 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino;
A1, A2 and A3 represent each independently C, N, S or 0, wherein when A1, A2 or A3 is S, Al-Y1, A2-Y2 or A3-Y3 is optionally SO2;
each of Yl, Y2 and Y3 is either absent or represent independently a) a hydrogen atom;
b) oxo;
c) SH
d) CR6R7R8, NR6R7 and OR6 wherein R6, R7 and 1:18 represent each independently:
i) a hydrogen atom;
ii) halogen;
iii) hydroxyl;

9 iv) OR9 or NR9R1 wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6_alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, CO-alkyl, or S02R11, wherein R11 represents a hydrogen atom or a group, optionally substituted, selected from Cl -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, hydroxyl, or amino;
v) Cl -Cl 0 alkyl, linear or branched; optionally substituted with up to three substituents selected from halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10 , NR9R10, S02R9, S02NR9R10, NR9S02R10, SOR9, aryl, or CO-alkyl, wherein R9 and ri -113 represent each independently a hydrogen atom or a group, optionally substituted, selected from Cl -C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino;
vi) heterocyclyl or Cl -C2 alkyl - heterocyclyl; wherein the heterocyclyl is optionally substituted with up to three substituents halogen, hydroxyl, oxo, OR9, COOR9, CONR9R19, NR9COR19, NR9R19, S02R9, S02NR9R19, NR9S02R19, S02R9, aryl, CO-alkyl, or alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from Cl -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino;
vii) -CO-R11 or -S02R11 wherein R11 represents a group selected from hydroxy, amine, alkyl, heterocyclyl; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, S02R9, S02NR9R10, NR9S02R10, SOR9, aryl, CO-alkyl, or Cl -C6 alkyl which is optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from Cl -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino;
viii) optionally when Yl, Y2 or Y3 is CR6R7R8, R6, R7 and the carbon atom to which they are attached form together a ring selected from:

cycloalkyl, optionally substituted with up to three substituents selected from halogen, hydroxyl, OR9, COOR9, CONR9R19, NR9COR19, NR9R19, S02R9, S02NR9R19, NR9S02R19, S02R9, aryl, CO-alkyl, or C1-C6 alkyl which is optionally substituted by 5 one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R19 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino; or

10 heterocyclyl, optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R19, NR9COR19, NR9R19, S02R9, S02NR9R19, NR9S02R19, S02R9, aryl, CO-alkyl, or a C1-C6 alkyl which is optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R19 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino; or ix) optionally when Y1 , Y2 or Y3 is NR6R7, R6, R7 and the nitrogen atom to which they are attached form together a ring; optionally substituted with up to three substituents selected from halogen, hydroxyl, OR9, COOR9, CONR9R19, NR9COR19, NR9R19, S02R9, S02NR9R19, NR9S02R11, S02R9, aryl, CO-alkyl, or C1-C6 alkyl which is optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R19 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino;
and wherein

-11 ri represents a hydrogen atom or an optionally substituted group selected from aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino; or R11 represents an alkyl group optionally substituted with up to three substituents selected from halogen, hydroxyl, OR12, c00R12, c0NR12R13, NR12c0R13, NR12R13, so2R12, SO2NR12R13, NR12s02R13, so2-1112, or aryl; wherein R12 and R13 represent each independently a hydrogen atom or a group, optionally substituted, selected from Cl-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino;
dotted lines stand for single or double bonds;
provided that A1, A2 and A3 are not all C;
provided that when one of A1 or A3 is N the two others are not both C; and provided that when one of A1, A2 and A3 is S, only one S is present. at least one of the other two is C, and the other is C or N;
provided that compound of Formula I is not 3-(benzofuran-5-yI)-6-chloro-1H-indole or 3-(benzo[d][1 ,3]dioxo1-5-y1)-1 H-indole.
In another embodiment, in Formula I:
X1 and X2 represent each independently H, halogen, alkyl, haloalkyl, preferably H
or F;
R1, R2 and R3 represent each independently H, halogen, C1-C6 alkyl, alkoxy, haloalkyl, optionally substituted by one or more substituents selected from the group comprising halogen, hydroxyl, OR4, COOR4, CONR4R5, NR4COR5, NR4R5, S02R4, SO2NR4R5, NR4S02R5, S02R4, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R4 and R5 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
preferably R1, R2 and R3 represent each independently H, halogen or alkyl, preferably R1, R2 and R3 represent each independently H, halogen or methyl, preferably R1, R2 and R3 represent each H;
A1, A2 and A3 represent each independently C, N or 0;
each of Yl, Y2 and Y3 is either absent or represent independently ¨ a hydrogen atom;
¨ oxo;
¨ CR6R7R8, NR6R7 and OR6 wherein R6, R7 and 1:18 represent each independently:
= a hydrogen atom;

12 = halogen, preferably F, Cl or I, more preferably F;
= hydroxyl;
= OR9 or NR9R1 wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, CO-alkyl, S02R11, wherein R11 represents a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= C1-C10 alkyl, linear or branched, preferably methyl, ethyl or propyl;
optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R1 , NR9COR10, NR9R10, S02R9, S02NR9R10, NR9S02R10, SOR9, aryl, CO-alkyl, wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R10 , NR9COR10, NR9R10, S02R9, S02NR9R10, NR9S02R10, S02R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and ¨113 ri represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= -CO-R11 or ¨S02R11 wherein R11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, S02R9, S02NR9R10 , NR9S02R10, SOR9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6

13 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= in CR6R7R8, R6, R7 and the carbon atom to which they are attached form together a ring, said ring being preferably selected from:
cycloalkyl, optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, S02R9, S02NR9R10 , NR9S02R10, S02R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, S02R9, S02NR9R10 , NR9S02R10, S02R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= in NR6R7, R6, R7 and the nitrogen atom to which they are attached form together a ring, said ring being preferably an heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, S02R9, S02NR9R10, NR9S02R11, S02R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl,

14 heteroarylalkyl, alkylheteroaryl, amino; and wherein R11 represents a hydrogen atom or an optionally substituted group selected from aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino; or ¨11 ri represents an alkyl group optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR12, c00R12, c0NR12R13, NR12C0R13, NR12R13, s02R12, S02NR12R13, NRi2s02R13, so2R12, aryl,; wherein R12 and R13 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
dotted lines stand for single or double bonds;
provided that A1, A2 and A3 are not all C;
provided that when one of A1, A2 and A3 is N, the two others are not both C;
provided that compound of Formula I is not 3-(benzofuran-5-yI)-6-chloro-1H-indole or 3-(benzo[d][1 ,3]dioxo1-5-y1)- 1 H-indole.
According to one embodiment, the fused heterocycle which substitutes the indole ring in Formula I is aromatic. In another embodiment, the fused heterocycle which substituted the indole ring in Formula I is partially aromatic.
In a further embodiment, the heterocycle which substituted the indole ring in Formula I is non-aromatic.
According to a preferred embodiment, in Formula I, X1 and X2 represent each independently H or halogen, preferably H or F. According to a specific embodiment, X1 represents H and X2 represents F. According to a preferred embodiment, in Formula I, R1, R2 and R3 represent each H. According to a specific embodiment, in Formula I, X1 and X2 represent each independently H or halogen and R1, R2 and R3 represent each H;
preferably X1 represents H and X2 represents F and R1, R2 and R3 represent each H
According to one embodiment, in Formula I, a first one of A1, A2 and A3 is N, a second one of A1, A2 and A3 is C and the third one of A1, A2 and A3 is N or 0.
According to one embodiment, in Formula I, A2 is N and one of A1 and A3 is N
or S r and the other is C.

According to one embodiment, in Formula 1, A2 is C and one of Al and A3 is N
and the other is N or 0. In one embodiment, wherein Al or A3 is 0, and C is substituted with CR6R7R8 and R6, R7 or 1:18 is heterocyclyl or C1-heterocycyl, the heterocyclyl is piperidine, pyrrolidine, piperazine, morpholine, or2,6-diazaspiro[3.3]heptane, any of 5 which may be optionally substituted with one or more of C1-C3 alkyl, amino, hydroxyl, halogen, COCH3 , COOH, or SO2CH3.
According to another embodiment, in Formula 1, Al or A3 is S, A1-Y1 or A3-Y3 is SO2.
Optionally, wherein one of Al, A2 or A3 is S or A1 A2-y2, or A3-Y3 is SO2;
one of Al, A2 or A3 is N or C and one of Al, A2 and A3 is C.
10 In one embodiment, preferred compounds of Formula I are those of Formula yl y2 /

=;µ .)A
R2 Os µY3 H
x2 401 N
H k and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein Xl, x2, Ri, R2, R3, Ai, A3, yl Y2 and Y3 are as defined in Formula I.
According to one embodiment, in Formula 11-1, Al and A3 are not both C.
According to

15 antoher embodiment, one of Al and Al is S and the other is C, A1-Y1 or A3-Y3 is optionally SO2, and the C is optionally substituted with oxo.
In one embodiment, preferred compounds of Formula I are those of Formula 11-2 yl y2 Ai-C/
R3 ,-=;,-)A3 R2 µY3 H
X2 lel N
H

16 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein Xl, X2, R1, R2, R3, Al, A3, Yl, Y2 and Y3 are as defined in Formula I.
According to one embodiment, in Formula 11-1, {Al, A3} are not {C, N}, {N, C}
or {C, C}.
In one embodiment, preferred compounds of Formula I are those of Formula 11-1 a yl y2 \Al 1\1/
R3 ,-=, \
s;,-,N
' Y3 0-- µ

\ H

II-la and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein Xl, X2, R1, R2, R3, Al, Yl, Y2 and Y3 are as defined in Formula I.
In one embodiment, preferred compounds of Formula I are those of Formula II-lb yl y2 \N¨N/

s' =A3 \ H
X2 1.1 N

11-1 b and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein Xl, X2, R1, R2, R3, A3, Yl, Y2 and Y3 are as defined in Formula I.
In one embodiment, preferred compounds of Formula I are those of Formula II-2a

17 yl y2 \Al CZ

-'N
µY3 c'-H

H
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3, A1, Yl, Y2 and Y3 are as defined in Formula I.
According to one embodiment, in Formula II-2a, A1 is not C.
In one embodiment, preferred compounds of Formula I are those of Formula II-2b yl y2 \N¨cz -' A3 R2 0 µY3 H

H
II-2b and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein Xl, X2, R1, R2, R3, A3, Yl, Y2 and Y3 are as defined in Formula I.
According to one embodiment, in Formula II-2b, A3 is not C.
In one embodiment, preferred compounds of Formula I are those of Formula II-1a1

18 yi R3 --1\µI
N. y3 H R2 4Ik N
R

\ H
X2 lel N
H k !Hai and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, x2, Ri, R2, R3, r ¨1 and Y3 are as defined in Formula I.
According to a preferred embodiment, in Formula 11-1a1 , Y1 represents H and Y3 is as defined in Formula 1, preferably, Y3 represents:
¨ a hydrogen atom;
¨ CR6R7R8 wherein R6, R7 and 1:18 represent each independently:
= a hydrogen atom;
= Cl -C10 alkyl, linear or branched, preferably methyl, ethyl or propyl;
optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R19, NR9COR19, NR9R19, S02R9, S02NR9R19, NR9S02R19, SOR9, aryl, CO-alkyl, wherein R9 and R19 represent each independently a hydrogen atom or a group, optionally substituted, selected from Cl -C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R19, NR9COR19, NR9R19, S02R9, S02NR9R19, NR9S02R19, S02R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and ,113 ri represent each independently a hydrogen atom or a group, optionally substituted, selected from Cl -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;

19 = -CO-R11 wherein R11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R19, NR9COR19, NR9R19, S02R9, S02NR9R19, NR9S02R19, SOR9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= R6, R7 and the carbon atom to which they are attached form together a ring, said ring being preferably an heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R16, NR9COR16, NR9R16, S02R9, S02NR9R10 , NR9S02R16, S02R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
In one embodiment, preferred compounds of Formula I are those of Formula II-1a2 y 1 Nzy2 R3 / \
est N

H R

\
x2 401 N H

11-1a2 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3, Y1 and Y2 are as defined in Formula I.

According to a preferred embodiment, in Formula II-1a2, Y1 represents H and Y2 is as defined in Formula I, preferably, Y2 represents:
¨ a hydrogen atom;
¨ CR6R7R8 wherein R6, R7 and 1:18 represent each independently:
5 = a hydrogen atom;
= C1-C10 alkyl, linear or branched, preferably methyl, ethyl or propyl;
optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R1 , NR9COR10, NR9R10, S02R9, S02NR9R10, NR9S02R10, SOR9, aryl, 10 CO-alkyl, wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, 15 morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R1 , NR9COR10, NR9R10, S02R9, S02NR9R10, NR9S02R10, S02R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and

20 ri ¨113 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= -CO-R11 or ¨S02R11 wherein R11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, S02R9, S02NR9R10 , NR9S02R10, SOR9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;

21 = R6, R7 andthe carbon atom to which they are attached form together a ring, said ring being preferably an heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R19, NR9COR19, NR9R19, S02R9, S02NR9R19, NR9S02R19, S02R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R19 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
In one embodiment, preferred compounds of Formula I are those of Formula 11-1b1 yi R3 \N¨N
\
gik y 3 H R

\ H
X2 lel N
H k 11-1b1 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3, Y1 and Y3 are as defined in Formula I.
According to a preferred embodiment, in Formula 11-1b1, Y3 represents H and Y1 is as defined in Formula 1, preferably, Y1 represents:
¨ a hydrogen atom;
¨ CR6R7R8 wherein R6, R7 and 1:18 represent each independently:
= a hydrogen atom;
= C1-C10 alkyl, linear or branched, preferably methyl, ethyl or propyl;
optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R19, NR9COR19, NR9R19, S02R9, S02NR9R19, NR9S02R19, SOR9, aryl, CO-alkyl, wherein R9 and R19 represent each independently a hydrogen

22 atom or a group, optionally substituted, selected from Cl -C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R16, NR9COR16, NR9R16, S02R9, S02NR9R10, NR9S02R16, S02R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and ri ¨113 represent each independently a hydrogen atom or a group, optionally substituted, selected from Cl -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= -CO-R11 or ¨S02R11 wherein R11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R16, NR9COR16, NR9R16, S02R9, S02NR9R10 , NR9S02R16, SOR9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from Cl -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= R6, R7 and the carbon atom to which they are attached form together a ring, said ring being preferably an heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R16, NR9COR16, NR9R16, S02R9, S02NR9R10 , NR9S02R16, S02R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from Cl -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.

23 In one embodiment, preferred compounds of Formula I are those of Formula 11-1b2 N-Nr lir y3 H R

\ H

11-1b2 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, x2, Ri, R2, R3, r µ,2 and Y3 are as defined in Formula I.
According to a preferred embodiment, in Formula 11-1b2, Y3 represents H and Y2 is as defined in Formula 1, preferably, Y2 represents:
¨ a hydrogen atom;
¨ CR6R7R8 wherein R6, R7 and 1:18 represent each independently:
= a hydrogen atom;
= C1-C10 alkyl, linear or branched, preferably methyl, ethyl or propyl;
optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R1 , NR9COR10, NR9R10, S02R9, S02NR9R10, NR9S02R10, SOR9, aryl, CO-alkyl, wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R1 , NR9COR10, NR9R10, S02R9, S02NR9R10, NR9S02R10, S02R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and .-.10 ri represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;

24 = -CO-R11 or ¨S02R11 wherein R11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R19, NR9COR19, NR9R19, S02R9, S02NR9R19, NR9S02R19, SOR9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= R6, R7 and the carbon atom to which they are attached form together a ring, said ring being preferably an heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R16, NR9COR16, NR9R16, S02R9, S02NR9R10 , NR9S02R16, S02R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
In one embodiment, preferred compounds of Formula I are those of Formula II-2a1 yl y2 R3 \ NI
R2 .
H R

\ H

11-2a1 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3, Y1 and Y2 are as defined in Formula I.

According to a preferred embodiment, in Formula 11-2a1, Y1 represents H and Y2 is as defined in Formula 1, preferably, Y2 represents:
¨ a hydrogen atom;
¨ CR6R7R8, NR6R7 and OR6 wherein R6, R7and 1:18 represent each 5 independently:
= a hydrogen atom;
= OR9 or NR9R1 wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, 10 amino, CO-alkyl, S02R11, wherein R11 represents a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= C1-C10 alkyl, linear or branched, preferably methyl, ethyl or propyl;
optionally substituted with up to three substituents selected from the 15 group comprising halogen, hydroxyl, OR9, COOR9, CONR9R1 , NR9COR10, NR9R10, S02R9, S02NR9R10, NR9S02R10, SOR9, aryl, CO-alkyl, wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, 20 alkylheteroaryl, amino;
= heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R1 , NR9COR10, NR9R10, S02R9, S02NR9R10, NR9S02R10, S02R9, aryl, CO-

25 alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and ¨113 ri represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= -CO-R11 or ¨S02R11 wherein R11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, S02R9, S02NR9R10 ,

26 NR9S02R10, SOR9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from Cl -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= R6, R7 andthe carbon atom to which they are attached form together a ring, said ring being preferably an heterocyclyl, preferably selected from morpholine, piperazine or piperidine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, S02R9, S02NR9R10 , NR9S02R10, S02R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from Cl -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
In one embodiment, preferred compounds of Formula I are those of Formula II-2a2 R2 gli H R

\ H
X2 . N
H H
II-2a2 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3 and Y2 are as defined in Formula I.
According to a preferred embodiment, in Formula II-2a2, Y2 represents:
¨ a hydrogen atom;
¨ CR6R7R8, NR6R7 and OR6 wherein R6, R7and 1:18 represent each independently:
= a hydrogen atom;

27 = heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R1 , NR9COR10, NR9R10, S02R9, S02NR9R10, NR9S02R10, S02R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and .-.10 ri represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= -CO-R11 or ¨S02R11 wherein R11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, S02R9, S02NR9R10 , NR9S02R10, SOR9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
In one embodiment, preferred compounds of Formula I are those of Formula II-2b1 R3 1\1(_ I
-R2 = N3 H R

\ H
X2 1.1 N

II-2b1 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3, Y2 and Y3 are as defined in Formula I.

28 According to a preferred embodiment, in Formula II-2b1, Y3 represents H and Y2 is as defined in Formula I, preferably, Y2 represents:
¨ a hydrogen atom;
¨ CR6R7R8 wherein R6, R7 and 1:18 represent each independently:
= a hydrogen atom;
= OR9 or NR9R1 wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, CO-alkyl, S02R11, wherein R11 represents a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= C1-C10 alkyl, linear or branched, preferably methyl, ethyl or propyl;
optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R1 , NR9COR10, NR9R10, S02R9, S02NR9R10, NR9S02R10, SOR9, aryl, CO-alkyl, wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= heterocyclyl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R1 , NR9COR10, NR9R10, S02R9, S02NR9R10, NR9S02R10, S02R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and ¨113 ri represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
In one embodiment, preferred compounds of Formula I are those of Formula II-2b2

29 N_' H
=-1( \ H
X2 lel N
H il II-2b2 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3 and Y2 are as defined in Formula I, wherein the dotted line is an absent or a bond.
According to a preferred embodiment, in Formula II-2b2, when the dotted line is absent and there is a single bond between the N and C, Y2 is oxo; and when the dotted line is present and there is a doube bond between the N and C Y2 represents:
¨ a hydrogen atom;
¨ CR6R7R8, NR6R7 and OR6 wherein R6, R7 and 1:18 represent each independently:
= a hydrogen atom;
= heterocyclyl or Cl -heterocycl, preferably selected from piperidine, pyrrolidine, piperazine, morpholine or 2,6-diazaspiro[3.3]heptane;
optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R19, NR9COR19, NR9R19, S02R9, S02NR9R19, NR9S02R19, S02R9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and ¨113 ri represent each independently a hydrogen atom or a group, optionally substituted, selected from Cl -C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino;
= -CO-R11 or ¨S02R11 wherein R11 represents a group selected from amine, alkyl, heterocyclyl (preferably piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide); optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R19, NR9COR19, NR9R19, S02R9, S02NR9R19, NR9S02R10, SOR9, aryl, CO-alkyl, alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R1 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 5 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino.
= In one embodiment, one ore more of the heterocycles is substituted with at least one of H or a group selected from SO2CH3, C1-C3 lower akyl, preferably CH3, or COOH.
10 In one embodiment, preferred compounds of Formula I are those of Formula II-2b3 yl y2 \N¨c/
2d:-17 R

\ H

H I-I
II-2b3 and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein Xl, X2, R1, R2, R3, Y1, and Y2 and Y3 are as defined in Formula I.
In one embodiment of Formula II-2b3, R1, R2 or R3 are each independently H, halogen, 15 or C1-C6 alkyl, preferably, Cl alkyl. In a further embodiment of Formula II-2b3, X1 and X2 are independently H or halogen.
Particularly preferred compounds of Formula I of the invention are those listed in Table 1 hereafter.

Cpd n Structure Chemical name --.....N
\NH
. 6-(6-fluoro-1 H-indo1-3-y1)-1 H-indazole 1.1 \
F H
NI\I 0 41i NH2 2-(6-(6-fluoro-1 H-indo1-3-y1)-1 H-indazol-1 -yl)acetamide FSH
----õN NH
\
Ilk N...........õ......õ,................õ
6-(6-fluoro-1 H-indo1-3-y1)-1 -3 (piperidin-4-ylmethyl)-1 H-indazole 0 \
F H
----,,N NC) \
i 1 -(4-((6-(6-fluoro-1 H-indo1-3-k N....,....õ.............,,....õ,......õ.
yI)-1 H-indazol-1 -yl)methyl)piperidin-1 -yl)ethanone \
F H
- NI
----\I , ......,,,,..y.NH, 3-(6-(6-fluoro-1 H-indo1-3-y1)-1 H-indazol-1 -yl)propanamide li N\
F H
---....N
\
ilk N
6-(6-fluoro-1 H-indo1-3-y1)-1 -6 .õ,....___,NH
(piperidin-4-yI)-1 H-indazole 0 \
F H

Cpd n Structure Chemical name 1 -(4-(6-(6-fluoro-1 H-indo1-3-7 \Nl(y1)-1 H-indazol-1 -yl)piperidin-1 -yl)ethanone = N
HN,N
gli5-(6-fluoro-1 H-indo1-3-y1)-1 H-indazole N

o 41k 2-(5-(6-fluoro-1 H-indo1-3-y1)-1 H-indazol-1 -yl)acetamide N
5-(6-fluoro-1 H-indo1-3-y1)-1 -(piperidin-4-ylmethyl)-1 H-indazole FS

1 -(4-((5-(6-fluoro-1 H-indo1-3-11 --N y1)-1 H-indazol-1 -yl)methyl)piperidin-1 -410 yl)ethanone F \

Cpd n Structure Chemical name NH, IN
3-(5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-yl)propanamide FS
HN
N

4111' 5-(6-fluoro-1H-indo1-3-y1)-1-(piperidin-4-y1)-1H-indazole N
1-(4-(5-(6-fluoro-1H-indo1-3-14y1)-1H-indazol-1-yl)piperidin-1-4, yl)ethanone F H

/
411r 2-(6-(6-fluoro-1H-indo1-3-y1)-2H-indazol-2-ypacetamide \
r, Cpd n Structure Chemical name o/
1-(4-((6-(6-fluoro-1H-indo1-3-y1)-2H-indazol-2-16 / yl)methyl)piperidin-1-iryl)ethanone F 10 \
H
HAI
fLO
/ NI\N 3-(6-(6-fluoro-1H-indo1-3-y1)-17 411r 2H-indazol-2-yhpropanamide F 01 \
H

/ NI\N

4It' 6-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-y1)-2H-indazole F&
\

/ 1-(4-(6-(6-fluoro-1H-indo1-3-19 4it, y1)-2H-indazol-2-yhpiperidin-1-ypethanone F 01111\
N
H

Cpd n Structure Chemical name NH, 2-(5-(6-fluoro-1H-indo1-3-y1)-2H-indazol-2-yl)acetamide FS
o c.)\, 1-(4-((5-(6-fluoro-1H-indo1-3-y1)-2H-indazol-2-yl)methyl)piperidin-1-*--- yl)ethanone FH

3-(5-(6-fluoro-1H-indo1-3-y1)-2H-indazol-2-yl)propanamide F

5-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-y1)-2H-indazole FS

Cpd n Structure Chemical name /Lo N,N,01 / 1-(4-(5-(6-fluoro-1H-indo1-3-4k y1)-2H-indazol-2-yl)piperidin-1-ypethanone \
el N
F H
HN,, Airr& \I
Mr 25 5-(6-fluoro-1H-indo1-3-y1)-1 H-benzo[d]imidazole \
FSH
HN.i, 26 4* 5-(6-fluoro-1H-indo1-3-y1)-2-methy1-1H-benzo[d]imidazole el \
N
F H
HAI
= y (5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-yl)methanamine \
IP N
F H
litY 1-(5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-y1)-N,N-climethylmethanamine FOH

Cpd n Structure Chemical name OH
HNX
y 2-(((5-(6-fluoro-1H-indo1-3-y1)-lit 1H-benzo[d]imidazol-2-yl)methyl)amino)ethanol 110\
N
F H
HN"---"(0 yN-((5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-yl)methypacetamide \
F 401 rl NH, L 2-amino-N-((5-(6-fluoro-1 H-indo1-3-y1)-1 H-31= N
benzo[d]imidazol-2-yl)methyl)acetamide \
F 101 rl 1,0 HN''''....0 yN-((5-(6-fluoro-1H-indo1-3-y1)-= 1H-benzo[d]imidazol-2-yl)methyl)methanesulfonamide \

Cpd n Structure Chemical name \µ, N
y 5-(6-fluoro-1H-indo1-3-y1)-2-((4-methylpiperazin-1-yl)methyl)-1H-= benzo[d]imidazole FOH

\I
N5-(6-fluoro-1H-indo1-3-y1)-2-34 y ((4-(methylsulfonyl)piperazin-1-yl)methyl)-1 H-. benzo[d]imidazole F * \
H
NH, NHIf = N 2-(5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-ypethanamine FOH
.........õ0 \II-1 H
N N-(2-(5-(6-fluoro-1H-indo1-3-36 y1)-1H-benzo[d]imidazol-2-. ljN
yl)ethyl)acetamide F 01 \
H

Cpd n Structure Chemical name 1____0 \IF1 INI N-(2-(5-(6-fluoro-1H-indo1-3-37 = L y1)-1H-benzo[d]imidazol-2-ypethyhmethanesulfonamide \
it N
F H
H 0µ
N..............õõ/\,......../
. L 5-(6-fluoro-1H-indo1-3-y1)-2-(2-(methylsulfonyhethyl)-1H-benzo[d]imidazole el \
F H
NH
H
N
= IN 5-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-y1)-1H-benzo[d]imidazole \

F H
H
N
5-(6-fluoro-1H-indo1-3-y1)-2-(1-40 = LI (methylsulfonyl)piperidin-4-y1)-1H-benzo[d]imidazole \

F H
H NH, N,...._..,õ/
IN
41 41, 5-(6-fluoro-1H-indo1-3-y1)-1 H-benzo[d]imidazol-2-amine FOH

Cpd n Structure Chemical name NH
. ---1( N-(5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-yl)acetam ide F 01 \
H
CtiO
H \IH
N..._.._., N-(5-(6-fluoro-1H-indo1-3-y1)-43 = IN 1H-benzo[d]imidazol-2-yl)methanesulfonamide 10 \
F H
/
[NIN
H
44 = IN
1-(5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-y1)-N-methylmethanamine F il \
H
n) HN N
v.,.........1.-- \,........./
4/ 4-((5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-yl)methyl)morpholine F el \
H

H
N
41 IN--(-)V--N1-12 3-(5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-yl)propanamide F el \
H

Cpd n Structure Chemical name . N
5-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazole 0 \
F H

48 iiii. L, 5-(6-fluoro-1H-indo1-3-y1)-2-methylbenzo[d]oxazole FSH
NH
0,............õ,/\,,,..õ.õ/
49 . LI 5-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-yl)benzo[d]oxazole r I. \ , F

N
0"-....

. N 1-(4-(5-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-yl)piperidin-1-yl)ethanone F el \
r, 0-õ/"
L H_<
51 4, N-(5-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-yl)acetamide FIH

Cpd n Structure Chemical name H
N¨LO
0,..../ N
. IN N-(5-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-yl)methanesulfonamide el \

N.......õ........, = 6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazole F 0 \
H
N
54 . 6-(6-fluoro-1H-indo1-3-y1)-2-methylbenzo[d]oxazole \
li N
F H
_TON \
= 6-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-yl)benzo[d]oxazole \
Ili N
F H
-.-raN/L0 N
1-(4-(6-(6-fluoro-1H-indo1-3-= yl)benzo[d]oxazol-2-yl)piperidin-1-yl)ethanone \

F H

Cpd n Structure Chemical name NH
NõT"
. N-(6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-yl)acetamide F 01 \
H
ILc) \NH
N......
N-(6-(6-fluoro-1H-indo1-3-58 4. 0 yl)benzo[d]oxazol-2-yl)methanesulfonamide \

F H
N...õ...{-N/-"IIH
4. NH
6-(6-fluoro-1H-indo1-3-y1)-2-59 (piperazin-1-ylmethyl)-1H-benzo[d]imidazole \
F el H

N_(--1 ifk IVH lip 2-(6-(6-fluoro-1H-indo1-3-y1)-60 1H-benzo[d]imidazol-2-yl)acetam ide S N\
F
H
0.õ...rN
46 k NH
5-(6-fluoro-1H-indo1-3-y1)-2-61(piperazin-1-F 40 \ ylmethyl)benzo[d]oxazole N
H
0...õ.,N
,Li 5-(6-fluoro-1H-indo1-3-y1)-2-62((4-methylpiperazin-1-F el \ yl)methyl)benzo[d]oxazole H

Cpd n Structure Chemical name õtar N
5-(6-fluoro-1H-indo1-3-y1)-2-63(morpholinomethyhbenzo[d]ox F 40 \ azole H

C?7-11.0 . 6 2-(6-(6-fluoro-1H-indo1-3-y1)-2-oxobenzo[d]oxazol-3(21-1)-ypacetamide Fl \
H
H
N,.0 1 5-(6-fluoro-1H-indo1-3-y1)-1 H-ilo NH
65 benzo[d]imidazol-2(31-1)-one Fl \
H
N.........(N/--I
. 6-(6-fluoro-1H-indo1-3-y1)-2-(morpholinomethyhbenzo[d]ox F 40 \ azole H

0...11 3-(6-(6-fluoro-1H-indo1-3-y1)-2-4. 6 oxobenzo[d]oxazol-3(21-1)-yl)propanamide FIN
H
Nr-Nr-11 \--,./ ' . 6-(6-fluoro-1H-indo1-3-y1)-2-((4-methylpiperazin-1-yl)methyhbenzo[d]oxazole \
N
H

Cpd n Structure Chemical name 0,r 4/ i\i jt 2-(5-(6-fluoro-1H-indo1-3-y1)-2-69 oxobenzo[d]oxazol-3(21-1)-F el \ yl)acetamide H

`b o..,... N. µµ._ N-((5-(6-fluoro-1H-indo1-3-70 yl)benzo[d]oxazol-2-F \
S N yl)methyl)methanesulfonamide H
0, =3-(5-(6-fluoro-1H-indo1-3-y1)-2-71 N oxobenzo[d]oxazol-3(21-1)-101yl\
)propanamide FN
H
S
. I 3-(benzo[b]thiophen-5-y1)-6-72 fluoro-1H-indole \
F lei H

)L--0_1(-11 . kj N-((5-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-yl)methyl)acetamide \
F el N
H

N/-N'H --() 74 41 N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-yl)methyl)methanesulfonamide F \

H

Cpd n Structure Chemical name )1----Nf-t1 75 41 N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-yl)methyl)acetamide F 101 N\
H
N,r NH2 (6-(6-fluoro-1H-indo1-3-. yl)benzo[d]oxazol-2-F 0 N\ yl)methanamine H
NH
) -N
\ I 5-(6-fluoro-1H-indo1-3-y1)-2-.4Ikt (piperidin-4-ylmethyl)-2H-indazole S N\
F
H
L...../ H
41 6-(6-fluoro-1H-indo1-3-y1)-2-(piperazin-1-ylmethyl)benzo[d]oxazole \
H
46 3-(benzo[b]thiophen-6-y1)-6-F 40 N\ fluoro-1H-indole H

Cpd n Structure Chemical name . 5-(6-fluoro-1H-indo1-3-y1)-2-(2-(methylsulfonypethypenzo[d]
oxazole el N`
F
H
0_.{--NH2 (5-(6-fluoro-1H-indo1-3-. 1\1 yl)benzo[d]oxazol-2-F el \ yl)methanamine H

I 3-(benzofuran-5-y1)-6-fluoro-82 1H-indole F I. N\
H

N--zrANH2 = 3-(6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-yl)propanamide F 101 N\
H
Nz-_--1 0 2-(6-(6-fluoro-1H-indo1-3-y1)-84 1H-benzo[d]imidazol-1-yl)acetamide \
F H

Ce-Alm \VW
Arli Ri 2-(5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-1-yl)acetamide Fl \
H

Cpd n Structure Chemical name 49 3-(5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-y1)-1-morpholinopropan-1-one 1001 N\
F
H
o 3-(5-(6-fluoro-1H-indo1-3-y1)-N,,,, / INI)LN 1H-indazol-1-y1)-1-(4-41k N methylpiperazin-1-yl)propan-1-one Fl ' H

/N-N)LN N-(2-(dimethylamino)ethyl)-3-H
88 . N (5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-yl)propanamide F lei N\
H

/N-NN
H
H
fit 3-(5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-y1)-N-(2-hydroxyethyl)propanamide el N\
F
H

/N-N)LN 3-(5-(6-fluoro-1H-indo1-3-y1)-H
0= =0 1H-indazol-1-y1)-N-(2-(methylsulfonyl)ethyl)propana \
F mide N
H

Cpd n Structure Chemical name N-NN
NH 3-(5-(6-fluoro-1H-indo1-3-y1)-91 . 1H-indazol-1-y1)-1-(piperazin-1-yl)propan-1-one \
Fl H

4. NH
6-(6-fluoro-1H-indo1-3-yl)indolin-2-one \

H

411 N .....,..,.
3-(6-(6-fluoro-1H-indo1-3-y1)-93 1H-benzo[d]imidazol-1-\
N yl)propanamide F
H

CI, . RI 3-(5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-1-yl)propanamide \

H

As pl) N 1-(4-(6-(6-fluoro-1H-indo1-3-WI yl)benzo[d]oxazol-2-yl)piperidin-1-yl)ethanone \
ES
H

Cpd n Structure Chemical name k---ip p N, 6-(6-fluoro-1H-indo1-3-y1)-2-(1-. (methylsulfonyl)piperidin-4-yl)benzo[d]oxazole 10 N\
F
H

HN
97 451t 5-(6-fluoro-1H-indo1-3-yl)indolin-2-one FIN

6-(6-fluoro-1H-indo1-3-98 . yl)benzo[d]oxazol-2-amine 0 \
F
H
0 0, -:--0 N N-((6-(6-fluoro-1H-indo1-3-f-H-99 46 yl)benzo[d]oxazol-2-yl)methyl)-2-methoxyethanesulfonamide FS N\
H
0 2-(dimethylamino)-N-((6-(6-7.---/
--Nf- hi- ,0 fluoro-1H-indo1-3-. yl)benzo[d]oxazol-2-yl)methyl)ethanesulfonamide lel FN

Cpd n Structure Chemical name N
AS
6-(6-fluoro-1H-indo1-3-y1)-2-(2-101 W (methylsulfonypethypenzo[d]
oxazole H

Nf-h1)1--NH2 1-((6-(6-fluoro-1H-indo1-3-102 = yl)benzo[d]oxazol-2-yl)methyl)urea N i\LN-7---NH2 lr_ji.....
103 Hllit 1-carbamoy1-1-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-211)methypurea 40 N\
F
H
H
N-N
40, 104 I 5-(1H-indo1-3-y1)-1H-indazole S\N
H
N N
r\N-Me a 105 W 6-(6-fluoro-1H-indo1-3-y1)-2-(2-(4-methylpiperazin-1-yl)ethyl)benzo[d]oxazole F lei N\
H

Cpd n Structure Chemical name o OH
N/-HN' -:--C) N-((6-(6-fluoro-1H-indo1-3-106 46 yl)benzo[d]oxazol-2-yl)methyl)-2-hydroxyethanesulfonamide S N\
F
H

O N-((6-(6-fluoro-1H-indo1-3-N._f V-----j ----0 yl)benzo[d]oxazol-2-yl)methyl)-. 2-morpholinoethanesulfonamide S N\
F
H
--N
. NH
108 6-(1H-indo1-3-y1)-1H-indazole S\N
H
il) 6-(1H-indo1-3-101 yl)benzo[d]oxazole H
(NH
. 6-(6-fluoro-1H-indo1-3-y1)-2-(2-(piperazin-1-ypethyl)benzo[d]oxazole el N\
F
H
0_..a mit 11 Mr 5-(6-chloro-1H-indo1-3-111 yl)benzo[d]oxazole I.
CI H

Cpd n Structure Chemical name N SH
. 1r 6-(6-fluoro-1H-indo1-3-112 yl)benzo[d]oxazole-2-thiol Fl \
H
H
. 6-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-F 40ylmethyl)benzo[d]oxazole H

le Nr-hr0 114 = N-((6-(1H-indo1-3-yl)benzo[d]oxazol-2-yl)methyl)methanesulfonamide 40 \
H

(S)-N-((6-(6-fluoro-1H-indo1-3-NNH)Lc N
yl)benzo[d]oxazol-2-yl)methyl)-115 = 1-methylpyrrolidine-2-carboxamide Fl \
H
N 1:1"---. 6-(6-fluoro-1H-indo1-3-y1)-2-116 methoxybenzo[d]oxazole lel F
H

õ, N--:/ if \ NH2 Amino ([6-(6-fluoroindo1-3-117 O yl)benzoxazol-2-yl]methyl}sulfonamide FO \
H

Cpd n Structure Chemical name oTh sit 1, 11111F 5-(1H-indo1-3-yl)benzo[d]oxazole S\N
H
N2 6-(6-fluoro-1H-indo1-3-y1)-2-119 . 6 ((I -(methylsulfonyl)piperidin-4-yl)methyl)benzo[d]oxazole F I. N\
H

0A.,,..
CN' 6-(6-fluoro-1H-indo1-3-y1)-2-(2-Nf/ (4-(methylsulfonyl)piperazin-1-. ypethyl)benzo[d]oxazole F I. N\
H
0Th gi Ikl 11111 5-(5-chloro-1H-indo1-3-CI yl)benzo[d]oxazole H
/
o _ 0 N-((6-(6-fluoro-1H-indo1-3-N hy õy----, -,--c) yl)benzo[d]oxazol-2-yl)methyl)-It 122 f-2-(4-methylpiperazin-1-yl)ethanesulfonamide 0 N\
F
H

Cpd n Structure Chemical name 0 )\1 N-((6-(6-fluoro-1 H-indol-3-N N'0 yl)benzo[d]oxazol-2-yl)methyl)-2-(piperazin-1-yl)ethanesulfonamide 40 \
0 _ N/H-yl)benzo[d]oxazol-2-yl)methyl)---fik 2-(pyrrolidin-1-yl)ethanesulfonamide FSH
Nr01 fik6-(6-fluoro-1H-indo1-3-y1)-2-((1-methylpiperidin-4-yl)methyl)benzo[d]oxazole Ed_s/2 N-((6-(6-fluoro-1H-indo1-3-o 6 yl)benzo[d]oxazol-2-yl)methyl)-2-(4-(methylsulfonamido)piperidin-1-yl)ethanesulfonamide \

NIzz_CH-8 N-((6-(6-chloro-1H-indo1-3-yl)benzo[d]oxazol-2-yl)methyl)methanesulfonamide Cpd n Structure Chemical name V
N/-N' 128 . N-((6-(5-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-F yl)methyl)methanesulfonamide I. N\
H

Nif---NH
129yl)benzo[d]oxazol-2-4. 5-((6-(6-fluoro-1H-indo1-3-yl)methyl)imidazolidine-2,4-lel dione F
H

o-NH 5-(6-fluoro-1H-indo1-3-130 1* . yl)benzo[d]isothiazol-3(21-I)-one 1,1-dioxide 101 \
F
H

. 6 2-(6-(5-fluoro-1H-indo1-3-y1)-2-oxobenzo[d]oxazol-3(2H)-ypacetamide F
0 \
H

NH
132 . 0 5-(6-fluoro-1H-indo1-3-yl)isoindoline-1,3-dione 0 \
F
H

Cpd n Structure Chemical name NH
gitt 6-fluoro-3-(isoindolin-5-y1)-1 H-indole \
FS N
H
NH
= e 6-(6-fluoro-1H-indo1-3-134 yl)benzo[d]isothiazol-3(21-I)-F
\ one 1,1-dioxide H

A-NH
. 5-(6-fluoro-1H-indo1-3-y1)-2,3-dihydrobenzo[d]isothiazole F
1,1-dioxide \
el H
H
..--(.."
41 6-(6-fluoro-1H-indo1-3-y1)-3-W/ (piperidin-4-yl)benzo[d]oxazol-2(3H)-one \
FS N
H
1\1-__ fik(6-(6-fluoro-1H-indo1-3-y1)-2-137 H=
methylbenzo[d]oxazol-5-yl)methanol \

H

0A_Nr . . 5-(6-fluoro-1H-indo1-3-y1)-2-methylbenzo[d]isothiazol-H
F
3(2)-one 1,1-dioxide \
el H

Cpd n Structure Chemical name Me ?----NH 2-(2-(cis-3,5-Nj'irMe dimethylpiperazin-1-ypethyl)-6-(6-fluoro-1H-indo1-3-41kt yl)benzo[d]oxazole lel F
H
OH

1-(2-(6-(6-fluoro-1H-indo1-3-. yl)benzo[d]oxazol-2-yl)ethyl)piperidin-4-ol el N\
F
H
-..:
Nff NH
2-(2-( trans-2,5-dimethylpiperazin-1-ypethyl)-O 6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazole Fl \
H
NH
J . = , , , (+)-2-(2-((3R,5R)-3,5-Nf/ dimethylpiperazin-1-ypethyl)-. 6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazole Fl \
H

Cpd n Structure Chemical name 2-(2-(2,6-diazaspiro[3.3]heptan-2-git ypethyl)-6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazole F N

NH
(-)-2-(2-((3S,5S)-3,5-N zzr/ dimethylpiperazin-1-ypethyl)-6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazole N\
cNH OH
AIL 4-(2-(6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-yl)ethyl)piperazine-2-carboxylic acid 40 \
No 3-(benzofuran-6-yI)-6-fluoro-146 1H-indole FSN\
or pharmaceutically acceptable enantiomers, salts and solvates thereof.
In Table 1, the term "Cpd" means compound.
The compounds of Table 1 were named using ChemBioDraw Ultra version 12.0 (PerkinElmer).
The compounds of Formula 1 and subformulae thereof may contain an asymmetric center and thus may exist as different stereoisomeric forms. Accordingly, the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers and their non-racemic mixtures as well. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be performed by any suitable method known 5 in the art.
The compounds of the invention may be in the form of "pharmaceutically acceptable salts". Pharmaceutically acceptable salts of the compounds of Formula I
include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, lactobionate, benzenesulfonate, 10 lau rate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mandalate, bitartrate, methylbromide, bromide, 15 methylnitrate, calcium edetate, mucate, napsylate, chloride, clavulanate, N oleate, edetate, estolate, pantothenate, polygalacuronate, salicylate, glutamate, glycollylarsanilate, sulfate, hexylrosorcinate, subacetate, hydrabamine, hydroxynaphthaloate, etolate, triethiodid, valerate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, 20 phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tan nate, tartrate, tosylate, trifluoroacetate and xinofoate salts.
Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, ornithine, N,N-dibenzyethelenediamine, 25 piperazine, tri(hydroxymethyl_aminomethane, tetramethylammonium hydroxide, -methylgucamine, ammonium salt, potassium, sodium, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. Preferred, pharmaceutically acceptable salts include

30 hydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate, nitrate, citrate, and acetate.
When the compounds of the invention contain an acidic group as well as a basic group the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention. When the compounds of the invention contain a hydrogen-donating heteroatom (e.g. NH), the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule.
Pharmaceutically acceptable salts of compounds of Formula I may be prepared by one or more of these methods:
(i) by reacting the compound of Formula 1 with the desired acid;
(ii) by reacting the compound of Formula 1 with the desired base;
(iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula 1 or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid; or (iv) by converting one salt of the compound of Formula Ito another by reaction with an appropriate acid or by means of a suitable ion exchange column.
All these reactions are typically carried out in solution. The salt, may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
The degree of ionization in the salt may vary from completely ionized to almost non-ionized.
The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts, which are as defined above. These salts may be prepared by standard procedures, e.g. by reacting a free acid with a suitable organic or inorganic base. Where a basic group is present, such as amino, an acidic salt, i.e.
hydrochloride, hydrobromide, acetate, palmoate, and the like, can be used as the dosage form.
Also, in the case of an alcohol group being present, pharmaceutically acceptable esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
All references to compounds of Formula !throughout this specification, includes all of ts subformulae, Formula!! (including 11-1, II-1a, 11-1 al , 11-1a2,11-1b, 11-1b1,11-1b2,11-2, II-2a, II-2a1, II-2a2, II-2b, II-2b1, II-2b2, II-2b3) include references to enantiomers, salts, solvates, polymorphs, multi - component complexes and liquid crystals thereof.

The compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically-labeled compounds of Formula I.
In addition, although generally, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are preferred, it should be noted that the invention in its broadest sense also included non-pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention. For example, salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I above.
The invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I.
Process for manufacturing The compounds of Formula I can be prepared by different ways with reactions known to a person skilled in the art.
The invention further relates to a first process for manufacturing of compounds of Formula I
yl y2 \A1 A2' R3.- `, \
=;= ¨' A3 R2 Os '\(3 \ H

H id I
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3, A1, A2, A3, Yl, Y2 and Y3 are as defined in Formula I;
comprising:

(al) reacting a compound of Formula (i) H Y

el \ H

H i (i) wherein X1 and X2 are as defined in Formula I;
Z1 represents H or an amino protecting group such as for example an arylsulphonyl, a tert-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known to those skilled in the art Y represents an halogen (preferably iodine, bromine or chlorine), an alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any leaving group known to those skilled in the art with a compound of Formula (ii) yl y2 \A1,AZ

,4...
si::; A3 R2 0' 'y3 Ri Z2 .

(ii) wherein R1, R2, R3, A1, A2, A3, Yl, Y2 and Y3 are as defined in Formula I;
Z2 and Z3 represent H or alkyl groups, with the possibility for Z2 and Z3 toform a ring;

so as to obtain a compound of Formula (iii), yl y2 "A1A2' s;- -,A3 R2 a µY3 401 \ H

H i (iii) wherein Z1, Xl, X2, R1, R2, R3, A1, A2, A3, Yl, Y2 and Y3are as defined above;
and (bl) in the case wherein Z1 is not H, deprotecting the indole amine of compound of Formula (iii), to afford compound of Formula I.
According to one embodiment, step (al) of the process of the invention may be performed with or without a catalyst such as but not limited to Pd2(dba)3, Pd(PPh3)4, dichlorobis(triphenylphosphine)palladium(II) or 1,1'-bis(diphenylphosphino)ferrocene-dichloro palladium(II), Pd(OAc)2, or Pd/C in the presence or absence of an additional ligand, such as but not limited to X-Phos, S-Phos, P(oTo1)3, PPh3, BINAP, P(tBu)3or any other suitable phosphine ligand known to those skilled in the art.
According to one embodiment, step (al) of the process of the invention may be performed in the presence of bases such as but not limited to K3PO4, K2CO3, Na2CO3.
According to one embodiment, step (al) of the process of the invention may be performed in the presence of a suitable solvent such as but not limited to dioxane, THF, DMF, water or mixtures thereof, preferably in a mixture of dioxane or THF and water.
According to one embodiment, step (al) of the process of the invention may be performed at a temperature ranging from 20 C to about 180 C, with or without microwave irradiation, for a period ranging from 10 minutes to a few hours, e.g. 10 minutes to 24 h.

According to one embodiment, the deprotection (b1) may be performed, depending on the nature of the group Z1, by treatment with bases, such as but not limited to sodium hydroxide, potassium hydroxide, potassium carbonate. According to one embodiment, the deprotection may be performed in the presence or absence of a suitable solvent 5 such as but not limited to methanol, ethanol, isopropanol, tert-butanol, THF, DMF, Dioxane, water or a mixture thereof. According to one embodiment, the deprotection may be performed at a temperature ranging from 20 C to 100 C, preferably at about 85 C, for a few hours, e.g. one hour to 24 h.
According to an alternative embodiment, the deprotection (b1) may be performed, 10 depending on the nature of the group Z1 in the presence of strong acids, such as but not limited to HCI, TFA, HF, HBr. According to one embodiment, the deprotection may be performed in the presence or absence of a suitable solvent such as methanol, ethanol, isopropanol, tert-butanol, THF, DMF, Dioxane, water or a mixture thereof.
According to one embodiment, the deprotection may be performed at a temperature between about 15 20 C to about 100 C, for a period comprised between 10 minutes and a few hours, e.g.
10 minutes to 24 h.
The invention further relates to a second process of manufacturing of compounds of Formula I
yl y2 A1 A2' R2 CY µY3 \ H

I

and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein X1, X2, R1, R2, R3, A1, A2, A3, Yl, Y2 and Y3 are as defined in Formula I;
with the condition that at least one of Yl, Y2 and Y3 is not H or absent;
comprising:
25 (a2) alkylating a compound of Formula (iv) yl' y2' \
A1 A2' R2 Os \y3 \H

(iv) wherein Xl, X2, R1, R2, R3, Al, A2, A3, are as defined in Formula I, Y1', Y2' and Y3' represent respectively Yl, Y2 and Y3 as defined in Formula I
with the condition that at least one of Y1', Y2' and Y3' is H;
Z1 represents H or an amino protecting group such as for example an arylsulphonyl, a tert-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known to those skilled in the art;
so as to obtain a compound of Formula (v) yl y2 \Ai-Az ' 2 'A3 ss: ¨
R 0 µY3 \ H

(V) wherein Xl, X2, R1, R2, R3, Al, A2, A3, Yl, Y2, Y3 and Z1 are defined as above with the condition that at least one of Yl, Y2 and Y3 is not H or absent;
and (b2) in the case wherein Z1 is not H, deprotecting the indole nitrogen of compound of Formula (v), to afford compound of Formula I.
According to one embodiment, alkylation step (a2) is performed in presence of a compound of Formula (vi) Y4- x wherein Y4 represent Yl, Y2 or Y3, as defined in Formula 1, with the condition that Y4 is not H or absent;
X represents an halogen (preferably iodine, bromine or chlorine), alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoro-methylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl-or p-tolylsulfonyloxy), or any other leaving group known to those skilled in the art.
According to one embodiment, step (a2) of the process of the invention may be performed in the presence of bases such as but not limited to potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium diisopropyl amide, buthyl lithium.
According to one embodiment, step (a2) of the process of the invention may be performed in the presence of a suitable solvent such as but not limited to DMF, methanol, ethanol, isopropanol, tert-butanol, THF, dioxane, dichloromethane, water.
According to one embodiment, step (a2) of the process of the invention may be performed in the presence or absence of catalytic amounts of appropriate iodide salts, such as but not limited to tetrabutylammonium iodide.
According to one embodiment, step (a2) of the process of the invention may be performed at a temperature ranging from 20 C to about 180 C, with or without microwave irradiation.
According to one embodiment, step (a2) of the process of the invention may be performed for a period ranging from 10 minutes and a few hours, e.g. 10 minutes to 24 h.
According to one embodiment, the deprotection step (b2) may be performed in conditions described above for deprotection (b1).
The invention further relates to a third process of manufacturing of compounds of Formula 11-2a1 wherein Y1 is H:

R3 HN--( R2 41k H R

\ H
)(2 1101 N

II-2a1, Y1 is H
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein Xl, X2, R1, R2, R3, and Y2 are as defined in Formula I;
comprising:
(a3) reacting a compound of Formula (vii) \ H

(vii) wherein X1, X2, R1, R2, R3 are as defined above; and Z1 represents H or an amino protecting group such as for example an arylsulphonyl, a tert-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known to those skilled in the art;
with a compound of Formula (viii) y A y2 (Viii) wherein Y2 is defined as above; and Y represents an hydroxyl, halogen (preferably iodine, bromine or chlorine), alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any other leaving group known to those skilled in the art;
so as to obtain a compound of Formula (ix) R3 HN-_( H R

\ H
X2 . N
H
(ix) wherein X1, X2, R1, R2, R3, Y2 and Z1 are defined as above;
and (b3) in the case wherein Z1 is not H, deprotecting the indole amine of compound of Formula (ix), to afford compound of II-2a1 wherein Y1 is H.
According to one embodiment, when Y represents hydroxyl, step (a3) of the process of the invention may be performed in the presence of a suitable amide coupling reagent, such as but not limited to HATU, DCC, DIC, BOP, PyBOP, in the presence or absence of additional additives such as but not limited to HOBt.
According to one embodiment, step (a3) of the process of the invention may be performed in the presence of bases such as but not limited to triethylamine, diisopropylethylamine, DBU, cesium carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.
According to one embodiment, step (a3) of the process of the invention may be performed in the presence of a suitable solvent such as but not limited to Dichloromethane, DMF, THF, dioxane.
According to one embodiment, step (a3) further comprises adding a suitable acid, such as but not limited to acetic acid, wherever necessary to complete cyclization.

According to one embodiment, step (a3) of the process of the invention may be performed at a temperature ranging from 20 C to about 180 C, with or without microwave irradiation.
According to one embodiment, step (a3) of the process of the invention may be 5 performed for a period ranging from 10 minutes and a few hours, e.g. 10 minutes to 24 h.
According to one embodiment, the deprotection step (b3) may be performed in conditions described above for deprotection (b1).
The invention further relates to a fourth process for manufacturing of compounds of 10 Formula I
yl y2 \Al4t2' =;s ¨' A3 Os \y3 H 1=11 0 \ H

H I-I
I
and pharmaceutically acceptable enantiomers, salts and solvates thereof, wherein Xl, X2, R1, R2, R3, A1, A2, A3, Yl, Y2 and Y3 are as defined in Formula I;
15 comprising:
(a4) reacting a compound of Formula (x) d z3 H "13-C3 \ H
x2 el N

(x) wherein X1 and X2 are as defined in Formula I;
Z1 represents H or an amino protecting group such as for example an arylsulphonyl, a tert-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, a benzyl or any other suitable protecting group known to those skilled in the art Z2 and Z3 represent H or alkyl groups, with the possibility for Z2 and Z3 toform a ring;
with a compound of Formula (xi) yl y2 \A1,A2' R3 ,--õ
=.,--'A3 R2 a µy3 (Xi) wherein R1, R2, R3, A1, A2, A3, Yl, Y2 and Y3 are as defined in Formula I;
Y represents an halogen (preferably iodine, bromine or chlorine), an alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy), or any leaving group known to those skilled in the art so as to obtain a compound of Formula (Xii), yl y2 \A1,A2' R3 ."`o s;..'A3 R2 Os µy3 40 \ H
x2 H1 (xii) wherein Z1, Xl, X2, R1, R2, R3, A1, A2, A3, Yl, Y2 and Y3 are as defined above;
and (b4) in the case wherein Z1 is not H, deprotecting the indole amine of compound of Formula (xii), to afford compound of Formula I.
According to one embodiment, step (a4) of the process of the invention may be performed with or without a catalyst such as but not limited to Pd2(dba)3, Pd(PPh3)4, dichlorobis(triphenylphosphine)palladium(II) or 1,1'-bis(diphenylphosphino)ferrocene-dichloro palladium(II), Pd(OAc)2, or Pd/C in the presence or absence of an additional ligand, such as but not limited to X-Phos, S-Phos, P(oTo1)3, PPh3, BINAP, P(tBu)3 or any other suitable phosphine ligand known to those skilled in the art.
According to one embodiment, step (a4) of the process of the invention may be performed in the presence of bases such as but not limited to K3PO4, K2CO3, Na2CO3.
According to one embodiment, step (a4) of the process of the invention may be performed in the presence of a suitable solvent such as but not limited to dioxane, THF, DMF, water or mixtures thereof, preferably in a mixture of dioxane or THF and water.
According to one embodiment, step (a4) of the process of the invention may be performed at a temperature ranging from 20 C to about 180 C, with or without microwave irradiation, for a period ranging from 10 minutes to a few hours, e.g. 10 minutes to 24 h.
According to one embodiment, the deprotection step (b4) may be performed in conditions described above for deprotection (b1).
In general, the synthesis pathways for any individual compound of Formula (I) will depend on the specific substituents of each molecule and upon the ready availability of intermediates necessary; again such factors being appreciated by those of ordinary skill in the art.
According to a further general process, compounds of Formula I can be converted to alternative compounds of Formula I, employing suitable interconversion techniques well known by a person skilled in the art.

Compounds of the Formula I and related formulae can furthermore be obtained by liberating compounds of the Formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
Preferred starting materials for the solvolysis or hydrogenolysis are those which conform to the Formula I and related formulae, but contain corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino-protecting group instead of an H atom bonded to an N
atom, in particular those which carry an R*-N group, in which R* denotes an amino-protecting group, instead of an HN group, and/or those which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group, for example those which conform to the Formula I, but carry a -COOR** group, in which R** denotes a hydroxyl-protecting group, instead of a -COOH group.
It is also possible for a plurality of - identical or different - protected amino and/or hydroxyl groups to be present in the molecule of the starting material. If the protecting groups present are different from one another, they can in many cases be cleaved off selectively.
The term "amino-protecting group" is known in general terms and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protecting groups are removed after the desired reaction (or reaction sequence), their type and size are furthermore not crucial; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term "acyl group" is to be understood in the broadest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxy-icarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
Examples of such acyl groups are alkanoyl, such as acetyl, propionyl and butyryl;
aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl;
aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxy-icarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl) and 2-iodoethoxycarbonyl;
aralkoxycarbonyl, such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr. Preferred amino-protecting groups are BOC
and Mtr, further-more CBZ, Fmoc, benzyl and acetyl.
The term "hydroxyl-protecting group" is likewise known in general terms and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.
The nature and size of the hydroxyl-protecting groups are not crucial since they are removed again after the desired chemical reaction or reaction sequence;
preference is given to groups having 1-20, in particular 1-10, carbon atoms. Examples of hydroxyl-protecting groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butyl are particularly preferred.
The compounds of the Formula I and related formulae are liberated from their functional derivatives - depending on the protecting group used - for example strong inorganic acids, such as hydrochloric acid, perchloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, TFA or sulfonic acids, such as benzene-or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but is not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as dichloromethane, furthermore also alcohols, such as methanol, ethanol or isopropanol, and water.
Mixtures of the above-mentioned solvents are furthermore suitable. TFA is preferably used in excess without addition of a further solvent, and perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperatures for the cleavage are advantageously between about 0 and about 50 C, preferably between 15 and 30 C (room temperature).
The BOC, OtBu and Mtr groups can, for example, preferably be cleaved off using TFA in dichloromethane or using approximately 3 to 5N HCI in dioxane at 15-30 C, and the FMOC group can be cleaved off using an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 C.

Protecting groups which can be removed hydrogenolytically (for example CBZ, benzyl or the liberation of the amidino group from the oxadiazole derivative thereof) can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble-metal catalyst, such as palladium, advantageously on a support, such 5 as carbon). Suitable solvents here are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at temperatures between about 0 and 100 C and pressures between about 1 and 200 bar, preferably at 20-30 C and 1-10 bar.
Hydrogenolysis of the CBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol or using 10 ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30 C.
Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, trifluoromethylbenzene, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-15 butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone;
amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethykformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl 20 sulfoxide (DMS0); carbon disulfide; carboxylic acids, such as formic acid or acetic acid;
nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents.
Esters can be hydrolysed, for example, using HCI, H2504, or using Li0H, NaOH
or KOH
in water, water/THF, water/THF/ethanol or water/dioxane, at temperatures between 0 25 and 100 C.
Free amino groups can furthermore be acylated in a conventional manner using an acyl chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, advantageously in an inert solvent, such as dichloromethane or THF and/or in the presence of a base, such as triethylamine or pyridine, at temperatures between 30 and +30 C.

For all the protection and deprotection methods, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley Interscience, 3rd Edition 1999.
Reaction schemes as described in the example section are illustrative only and should not be construed as limiting the invention in any way.
Applications The invention is further directed to the use of the compounds of the invention or pharmaceutically acceptable enantiomers, salts and solvates thereof as TD02 inhibitors.
Accordingly, in a particularly preferred embodiment, the invention relates to the use of compounds of Formula I and subformulae in particular those of Table 1 above, or pharmaceutically acceptable enantiomers, salts and solvates thereof, as TD02 inhibitors.
Accordingly, in another aspect, the invention relates to the use of these compounds or enantiomers, salts and solvates thereof for the synthesis of pharmaceutical active ingredients, such as TD02 inhibitors.
In one embodiment, the invention relates to the use of compounds of Formula I
and subformulae in particular those of Table 1 above, or pharmaceutically acceptable enantiomers, salts and solvates thereof, for increasing immune recognition and destruction of the cancer cells.
The compounds of the invention are therefore useful as medicaments, in particular in the prevention and/or treatment of cancer.
In one embodiment, compounds of the invention or pharmaceutically acceptable enantiomers, salts or solvates thereof are for use in the treatment and/or prevention of cancer, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity.

The invention further relates to a method for treatment or prevention of cancer, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity, which comprises administering to a mammalian species in need thereof a therapeutically effective amount of the compound according to the invention or a pharmaceutically acceptable enantiomers, salts or solvates thereof.
Various cancers are known in the art. The cancer may be metastatic or non-metastatic.
The cancer may be may be familial or sporadic. In some embodiments, the cancer is selected from the group consisting of: leukemia and multiple myeloma.
Additional cancers that can be treated using the methods of the invention include, for example, benign and malignant solid tumours and benign and malignant non-solid tumours.
Examples of solid tumours include, but are not limited to: biliary tract cancer, brain cancer (including glioblastomas and medulloblastomas), breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, intraepithelial neoplasms (including Bowen's disease and Paget's disease), liver cancer, lung cancer, neuroblastomas, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, renal cancer (including adenocarcinoma and Wilms tumour), sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, basocellular cancer and squamous cell cancer), testicular cancer including germinal tumours (seminomas, and non-seminomas such as teratomas and choriocarcinomas), stromal tumours, germ cell tumours, and thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma).
Examples of non-solid tumours include but are not limited to hematological neoplasms.
As used herein, a hematologic neoplasm is a term of art which includes lymphoid disorders, myeloid disorders, and AIDS associated leukemias.
Lymphoid disorders include but are not limited to acute lymphocytic leukemia and chronic lymphoproliferative disorders (e.g., lymphomas, myelomas, and chronic lymphoid leukemias). Lymphomas include, for example, Hodgkin's disease, non-Hodgkin's lymphoma lymphomas, and lymphocytic lymphomas). Chronic lymphoid leukemias include, for example, T cell chronic lymphoid leukemias and B cell chronic lymphoid leukemias.
The invention also provides for a method for delaying in patient the onset of cancer comprising the administration of a pharmaceutically effective amount of a compound of Formula I or pharmaceutically acceptable enantiomer, salt and solvate thereof to a patient in need thereof.
Preferably, the patient is a warm-blooded animal, more preferably a human.
The compounds of the invention are especially useful in the treatment and/or prevention of cancer.
In a specific embodiment, the compounds of the invention are especially useful in the treatment and/or prevention of cancer.
The invention further provides the use of a compound of Formula I or a pharmaceutically acceptable enantiomer, salt and solvate thereof for the manufacture of a medicament for treating and/or preventing cancer.
According to a further feature of the present invention there is provided a method for modulating TD02 activity, in a patient, preferably a warm blooded animal, and even more preferably a human, in need of such treatment, which comprises administering to said patient an effective amount of compound of the present invention, or a pharmaceutically acceptable enantiomer, salt and solvate thereof.
Formulations The invention also provides pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable enantiomer, salt and solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. As indicated above, the invention also covers pharmaceutical compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable enantiomer, salt and solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients.

Another object of this invention is a medicament comprising at least one compound of the invention, or a pharmaceutically acceptable enantiomer, salt and solvate thereof, as active ingredient.
According to a further feature of the present invention there is provided the use of a compound of Formula I or a pharmaceutically acceptable enantiomer, salt and solvate thereof for the manufacture of a medicament for modulating TD02 activity in a patient, in need of such treatment, which comprises administering to said patient an effective amount of compound of the present invention, or a pharmaceutically acceptable enantiomer, salt and solvate thereof.
Generally, for pharmaceutical use, the compounds of the invention may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
By means of non-limiting examples, such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms ¨ which may be solid, semi-solid or liquid, depending on the manner of administration ¨ as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person;
reference is made to the latest edition of Remington's Pharmaceutical Sciences.
Some preferred, but non-limiting examples of such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulations can optionally contain other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, 5 fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc.. The compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein.
The pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, 10 ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use.
Depending on the condition to be prevented or treated and the route of administration, the active compound of the invention may be administered as a single daily dose, 15 divided over one or more daily doses, or essentially continuously, e.g.
using a drip infusion.
DEFINITIONS
In the present invention, the following terms have the following meanings:
Where groups may be substituted, such groups may be substituted with one or more 20 substituents, and preferably with one, two or three substituents.
Substituents may be selected from but not limited to, for example, the group comprising halogen, hydroxyl, oxo, nitro, amido, carboxy, amino, cyano haloalkoxy, and haloalkyl.
The term "halogen" means fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
The following definitions are used in connection with the compounds described herein.
25 In general, the number of carbon atoms present in a given group is designated "Cx to Cy", where x and y are the lower and upper limits, respectively. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.
Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are determined by naming from left to right the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. As used herein, "optionally substituted" means that at least 1 hydrogen atom of the optionally substituted group has been replaced.
The term "alkyl" by itself or as part of another substituent refers to a hydrocarbyl radical of Formula C,1-12n 1 wherein n is a number greater than or equal to 1. Alkyl groups may contain 1 to 10 carbons (inclusive), i.e., Cl, C2, C3, C4, C5, C6, C7, C8, C9 or C10, i.e., C1-C10 alkyl. In certain embodiments, alkyl groups of this invention comprise from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, more preferably from 1 to carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g. n-pentyl, iso-pentyl), and hexyl and its isomers (e.g. n-hexyl, iso-hexyl).
The term "haloalkyl" alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above. Non-limiting examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoro methyl and the like. In one example, the haloalkyl is a Cl to C6 alkyl group substituted with at least one halogen. In another example, the haloalkyl is a Cl to C4 alkyl group substituted with at least one halogen. Each halogen substitution may be independently selected.
The term "cycloalkyl" as used herein is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures.
Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 10, more preferably from 3 to 8 carbon atoms still more preferably from 3 to 6 carbon atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, with cyclopropyl being particularly preferred.
The term "heteroatom" referns to a sulfur, nitrogen or oxygen atom.
Where at least one carbon atom in a cycloalkyl group is replaced with a heteroatom, the resultant ring is referred to herein as "heterocyclyl".

The terms "heterocyclyl" or "heterocycle" as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocycle may contain 3 to 7 carbon atoms (inclusive), or an integer therebetween. Any of the carbon atoms of the heterocyclic group may be substituted by oxo (for example piperidone, pyrrolidinone).The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms. Non limiting exemplary heterocyclic groups include piperidinyl, azetidinyl, tetrahydropyranyl, piperazinyl, imidazolinyl, morpholinyl, oxetanyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, indolyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, thiomorpholinyl, thiomorpholinylsulfoxide, thiomorpholinylsulfone, pyrrolizinyl.
The term "aryl" as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl) or linked covalently, typically containing 5 to 12 atoms; preferably 6 to 10, wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic (carbon-containing ring) systems enumerated herein. Non- limiting examples of aryl comprise phenyl, biphenylyl, biphenylenylnaphthalenyl, indenyl.
The term "heteroaryl" as used herein by itself or as part of another group refers but is not limited to 5 to 12 carbon-atom aromatic rings or ring systems containing 1 to 2 rings which are fused together or linked covalently, typically containing 5 to 6 atoms; at least one of which is aromatic, in which one or more carbon atoms in one or more of these rings is replaced by oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring. Non-limiting examples of such heteroaryl, include: pyridazinyl, pyridinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyrimidyl, pyrazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl.
The term "arylalkyl" refers to any group -alkyl-aryl. The term "alkylaryl"
refers to any group -aryl-alkyl.
The term "heteroarylalkyl" refers to any group -alkyl-heteroaryl. The term "alkylheteroaryl" refers to any group -heteroaryl-alkyl.
The term "alkoxy" refers to any group 0-alkyl. The term"haloalkoxy" refers to any group 0-haloalkyl.
The term "oxo" refers to a =0 moiety.
The term "amino" refers to a -NH2 group or any group derived thereof by substitution of one nor two hydrogen atom by an organic aliphatic or aromatic group.
Preferably, groups derived from -NH2 are "alkylamino" groups, i.e. N-alkyl groups, comprising monoalkylamino and dialkylamino. Non-limited examples of , the term "amino"
include NH2, NHMe or NMe2.
The term "amino-protecting group" refers to a protecting group for an amine function.
According to a preferred embodiment, the amino-protecting group is selected in the groups comprising: arylsulphonyl, tert-butoxy carbonyl, methoxymethyl, para-methoxy benzyl or benzyl.
The term "leaving group" refers to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. According to a preferred embodiment, the leaving group is selected in the groups comprising: halogen, preferably iodine, bromine or chlorine; alkylsulfonyloxy having 1-6 carbon atoms, preferably methylsulfonyloxy or trifluoromethylsulfonyloxy; or arylsulfonyloxy having 6-10 carbon atoms, preferably phenyl- or p-tolylsulfonyloxy.

The term "solvate" is used herein to describe a compound in this invention that contains stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptable solvent molecule, e.g., ethanol. Typically, a solvate does not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents to non-solvate compounds of Formula I and its subformula as defined herein. The term "solvate" as used herein is a combination, physical association and/or solvation of a compound of the present invention with a solvent molecule. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase and isolatable solvates. "Solvate" may encompass solvates of salts of the compounds of Formula I.
The term "hydrate" refers to when the solvent molecule is water and may be an inorganic salt containing nH20, wherein n is the number of water molecules per formula unit of the salt. N may be 1/2, 11/2 , or an integer from 1 to 10. A hydrate which has lost water The compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and prodrugs thereof and isotopically- labeled compounds of Formula I.
The invention also generally covers all pharmaceutically acceptable predrugs and prodrugs of the compounds of Formula I.
The term "prodrug" as used herein means the pharmacologically acceptable derivatives of compounds of Formula I, such as for example esters, whose in vivo biotransformation product generates the biologically active drug. Prodrugs are generally characterized by increased bio-availability and are readily metabolized into biologically active compounds in vivo.
The term "predrug", as used herein, means any compound that will be modified to form a drug species, wherein the modification may take place either inside or outside of the body, and either before or after the predrug reaches the area of the body where administration of the drug is indicated.

The term "patient" refers to a warm-blooded animal, more preferably a human, who/which is awaiting the receipt of, or is receiving medical care or is/will be the object of a medical procedure.
The term "human" refers to a subject of both genders and at any stage of development 5 (i.e. neonate, infant, juvenile, adolescent, adult).
The terms "treat", "treating" and "treatment", as used herein, are meant to include alleviating, attenuating or abrogating a condition or disease and/or its attendant symptoms.
The terms "prevent", "preventing" and "prevention", as used herein, refer to a method of 10 delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient's risk of acquiring a condition or disease.
The term "therapeutically effective amount" (or more simply an "effective amount") as used herein means the amount of active agent or active ingredient that is sufficient to 15 achieve the desired therapeutic or prophylactic effect in the patient to which/whom it is administered.
The term "administration", or a variant thereof (e.g. "administering"), means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be 20 treated or prevented.
By "pharmaceutically acceptable" is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.
The term "pharmaceutical vehicle" as used herein means a carrier or inert medium used as solvent or diluent in which the pharmaceutically active agent is formulated and/or 25 administered. Non-limiting examples of pharmaceutical vehicles include creams, gels, lotions, solutions, and liposomes.

The words "comprise", "comprises", and "comprising" are to be interpreted inclusively rather than exclusively. The works "consist", "consisting", and its variants, are to be interpreted exclusively, rather than inclusively.
As used herein, the term "about" means a variability of 10 % from the reference given, unless otherwise specified.
EXAMPLES
The present invention will be better understood with reference to the following examples. These examples are intended to representative of specific embodiments of the invention, and are not intended as limiting the scope of the invention.
I. CHEMISTRY EXAMPLES
The mass spectrometry (MS) data provided in the examples described below were obtained as followed: Mass spectrum: LC/MS Agilent 6110 (Electron Spray Ionization, ESI) or a Waters Acquity SOD (ES I) The NMR data provided in the examples described below were obtained as followed:
Bruker Ultrashield TM 400 PLUS and Bruker Fourier 300 MHz and TMS was used as an internal standard.
The microwave chemistry was performed on a single mode microwave reactor Initiator Microwave System EU from Biotage.
Preparative High Performance Liquid Chromatography (HPLC) purifications were performed with a mass directed autopurification Fractionlynx from Waters equipped with a XbridgeTM Prep C18 OBD column 19x150 mm 5 m, unless otherwise reported. All HPLC purifications were performed with a gradient of CH3CN /H20/NH4HCO3 (5 mM), CH3CN /H20/TFA (0.1%), or CH3CN /H20/NH3 H20 (0.1%).
The following abbreviations are used herein and have the indicated definitions:
ACN is acetonitrile; DMSO is dimethylsulfoxide; DCM is dichloromethane; DIPEA
is diisopropylethylamine; DMF is N,N-dimethylformamide; dppf is 1,1'-bis(diphenylphosphino)ferrocene; Et0H is ethanol; HATU is 2-(1H-7-azabenzotriazol-1-y1)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium; Hz is hertz;
KOAc is potassium acetate; Me0H is methanol; MHz is megahertz; mM is millimolar;
mL is milliliter; min is minutes; mol is moles; M is molecular ion; [M+H] is protonated molecular ion; N is normality; NMR is nuclear magnetic resonance; PPh3is triphenylphosphine; psi is pound per square inch; PPM is parts per million; qd po means daily by mouth; rt is room temperature; RT is retention time; TLC is thin layer chromatography; TFA is trifluoroacetic acid; TEA is triethylamine.
1.1. SYNTHESIS OF INTERMEDIATES
Intermediate 1: 6-fluoro-3-iodo-1-(phenylsulfonyI)-1H-indole FIN
bo2ph The title compound was prepared using the same procedure as reported (W02010/136491A1 ).
Intermediate 2:
tert-butyl 6-fluoro-3-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-indole-l-carboxylate C'?i----B-101 \
F
boc The title compound was prepared using the same procedure as reported (US2014/256706 Al).
Intermediate 3: 6-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-indazole A mixture of 6-bromo-1H-indazole (700 mg; 3.55 mmol), 4,4,4',4',5,5,5',5'-octamethy1-2,2'-bi(1,3,2-dioxaborolane) (1.50 g; 5.91 mmol), Pd(dppf)C12=DCM (290 mg;
0.36 mmol) and KOAc (1.04 g; 10.6 mmol) in DMF (20 mL) was stirred at 100 C for 15 hours under nitrogen. The mixture was concentrated in vacuo, suspended in Et0Ac (30 mL), filtered through Celite, and concentrated to afford 866 mg (100%) of the title compound as a brown semi-solid, which was used directly without further purification. LC-MS
for C13H17BN202+H [M+H]: calcd. 245.1; found: 245Ø
Intermediate 4: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazole N
HN' ' F
10 02Ph To a mixture of 6-fluoro-3-iodo-1-(phenylsulfony1)-1H-indole (Intermediate 1;
400 mg;
1.00 mmol), 6-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-indazole (Intermediate 3;
366 mg; 1.50 mmol) and C52CO3 (978 mg; 3.00 mmol) in DME (9 mL) and water (3 mL) was added Pd(dppf)C12=DCM (82 mg; 0.1 mmol) under nitrogen. The mixture was 15 heated at 150 C for 1 hour in a microwave reactor. The mixture was filtered through Celite and diluted with Et0Ac (100 mL) and water (100 mL). The aqueous layer was extracted with Et0Ac (50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by a silica gel chromatography (petroleum ether/Et0Ac = 5/1 ¨ 2/1) to afford 390 mg (100%) of the title 20 compound as a yellow solid. LC-MS for C21 Hi 4FN302S+H [M+H]: calcd.
392.1; found:
391.8. 1H NMR (300 MHz, DMSO-d6) 6 [ppm]: 13.13 (s, 1H), 8.20 ¨ 8.11 (m, 4H), 7.93 ¨7.78 (m, 4H), 7.77 ¨ 7.70 (m, 1H), 7.65 ¨7.60 (m, 2H), 7.44 (dd, J= 9.3, 2.1 Hz, 1H), 7.26 (ddd, J= 9.3, 9.0, 2.1 Hz, 1H).

Intermediate 5: tert-butyl 4-((6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate and tert-butyl 4-((6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2H-indazol-2-Amethyl)piperidine-1-carboxylate Boc Boo -Nall \-----C---1\IN''1\l'\ i . =
F' \ F 40 \
bo2ph o2ph A mixture of 6-fluoro-3-iodo-1-(phenylsulfony1)-1H-indole (Intermediate 1;
1.00 g; 2.55 mmol), tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (1.10 g; 3.75 mmol) and Cs2CO3 (1.66 g; 5.09 mmol) in DMF (40mL) was stirred at 60 C
overnight under nitrogen. The mixture was cooled to room temperature, diluted with Et0Ac (100 mL), filtered, concentrated, and purified by a silica gel chromatography (petroleum ether/Et0Ac = 6/1 ¨ 2/1) to afford 1.11 g (74%) of a mixture of the title compounds as a yellow solid. LC-MS for C32H33FN404S+11+ [M+H]: calcd. 589.2; found: 588.9.
Intermediate 6: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1-(piperidin-4-ylmethyl)-1 H-indazole hydrochloride and 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(piperidin-4-ylmethyl)-2H-indazole hydrochloride HCI Hilz HCI HNall N
N' N"\ 1 e =
FIN \

02Ph 02Ph To a solution of tert-butyl 4-((6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate and tert-butyl 4-((6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2H-indazol-2-yOmethyl)pipendine-1-carboxylate (Intermediate 5;
1.06 g; 1.80 mmol) in Me0H (40 mL) was added concentrated aqueous HCI (16 mL; 37%). The reaction mixture was stirred for 1 hour and concentrated in vacuo to afford 1.55 g (quant.) of the title compound as a yellow solid, which was used directly without further purification. LC-MS for C27H25FN402S+H [M+H]: calcd. 489.2; found: 488.9.
5 Intermediate 7: 1-(4-((6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazol-1-yl)methyl)piperidin-1-ypethanone --(--NIN-41kt Fl \
02Ph To a solution of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1-(piperidin-4-ylmethyl)-1 H-indazole hydrochloride and 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(piperidin-4-10 ylmethyl)-2H-indazole hydrochloride (Intermediate 6; 650 mg; 1.24 mmol) and Et3N (372 mg; 3.68 mmol) in DCM (30 mL) was added Acetyl chloride (116.6 mg; 1.48 mmol) under nitrogen. The reaction mixture was stirred for 1 hour and quenched with saturated aqueous NaHCO3 (30 mL). The aqueous layer was extracted with DCM (70 mLx2).
The combined organic layers were washed with brine (20 mL), dried over anhydrous 15 Na2SO4, filtered, concentrated, and purified by preparative TLC (Et0Ac) to afford 267 mg (40%) of the title compound as a yellow solid. LC-MS for C29H27FN403S+H
[M+H]:
calcd. 531.2; found: 530.9.
Intermediate 8: 3-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazol-1-yl)propanamide Ce--N'N

F
02Ph A mixture of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazole (Intermediate 4;
200 mg; 0.51 mmol), 3-bromopropanamide (389 mg; 2.56 mmol), K2CO3 (211 mg;
1.53 mmol) and KI (85 mg; 0.51 mmol) in DMF (6 mL) was heated at 130 C for 2 hours in a microwave reactor. The mixture was poured into H20 (20 mL) and the aqueous layer was extracted with Et0Ac (50 mLx2). The combined organic layers were washed with brine (100 mLx3), dried over anhydrous Na2SO4, filtered, concentrated, and purified by a silica gel chromatography (petroleum ether/Et0Ac = 2/1 ¨ 0/1) to afford 95 mg (40%) of the title compound as a yellow solid. LC-MS for C24H19FN403S+H [M+H]:
calcd.
463.1; found: 462.8.
Intermediate 9: tert-butyl 4-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazol-1-yl)piperidine-1-carboxylate and tert-butyl 4-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2H-indazol-2-yl)piperidine-1-carboxylate Boc (1\1 Boc,NaN,N N
N"\ i . =
\ \
F el N F 1401 N
02Ph 02Ph A mixture of 6-fluoro-3-iodo-1-(phenylsulfonyI)-1H-indole (Intermediate 1; 560 mg; 1.43 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (0.60 g;
2.15 mmol) and C52CO3 (1.00 g; 3.07 mmol) in DMF (22 mL) was stirred at 60 C overnight under nitrogen. The mixture was cooled to room temperature, diluted with Et0Ac (100 mL), filtered, and concentrated to afford 820 mg (quant.) of a mixture of the title compounds as a yellow solid, which was used directly without further purification. LC-MS
for C31 H31 FN 404S+H [M+H]: calcd. 575.2; found: 574.8.
Intermediate 10: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1-(piperidin-4-y1)-1 H-indazole hydrochloride and 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(piperidin-4-yI)-2H-indazole hydrochloride NH HCI
c N
HCI HNaN,N, NI' i \ i . =
F 0 \ \
F el N
02Ph 02Ph Following the general method as outlined in Intermediate 6, starting from tert-butyl 4-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazol-1-yl)piperidine-1-carboxylate and tert-butyl 4-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2H-indazol-2-yl)piperidine-1-carboxylate (Intermediate 9; 820 mg; 1.43 mmol), 730 mg (100%) of a mixture of the title compounds was obtained as a yellow solid, which was used directly without further purification. LC-MS for C26H23FN402S+H [M+H]: calcd. 475.2; found: 474.8.
Intermediate 11: 5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-indazole >-1 \ N
VI N' H
A mixture of 5-bromo-1H-indazole (500 mg; 2.54 mmol), 4,4,4',4',5,5,5',5'-octamethy1-2,2'-bi(1,3,2-dioxaborolane) (1.29 g; 5.08 mmol), Pd(dppf)C12=DCM (200 mg;
0.24 mmol) and KOAc (1.24 g; 12.6 mmol) in DMF (10 mL) was stirred at 90 C for 15 hours under nitrogen. The mixture was concentrated in vacuo, diluted with Et0Ac (100 mL), washed with H20 (50 mLx2), brine (50 mL), dried over anhydrous Na2SO4, filtered through Celite, and concentrated to afford 1.18 g (quant.) of the title compound as a yellow oil, which was used directly without further purification. LC-MS for C13F117BN202+H
[M+H]: calcd.
245.1; found: 245.2.
Intermediate 12: 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazole N-NH
i git Fl \
02Ph To a mixture of 6-fluoro-3-iodo-1-(phenylsulfony1)-1H-indole (Intermediate 1;
200 mg;
0.50 mmol), 5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-indazole (Intermediate 11; 345 mg crude; 0.74 mmol) and Cs2CO3 (488 mg; 1.50 mmol) in DME (6 mL) and water (2 mL) was added Pd(dppf)C12=DCM (40 mg; 0.05 mmol) under nitrogen. The mixture was heated at 150 C for 30 minutes in a microwave reactor. The mixture was filtered through Celite and diluted with Et0Ac (100 mL) and water (100 mL).
The aqueous layer was extracted with Et0Ac (50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 300 mg (quant.) of the title compound as a yellow oil, which was used directly without further purification. LC-MS for C21 F114FN302S H [M+H]: calcd. 392.1; found:
392Ø
Intermediate 13: 2-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazol-1-yl)acetamide and 2-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2H-indazol-2-ypacetamide oNH2 (ON- N
-N
/
\ /
= =
Fl \ FIN
bo2ph o2ph A mixture of 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazole (Intermediate 12;
500 mg; 1.28 mmol), 2-bromoacetamide (900 mg; 6.52 mmol), K2CO3 (540 mg; 3.91 mmol) and K1(220 mg; 1.33 mmol) in DMF (12 mL) was heated at 130 C for 4 hours in a microwave reactor. The mixture was poured into H20 (10 mL) and extracted with Et0Ac (20 mLx4). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 353 mg (62%) of a mixture of the title compounds as a brown solid, which was used directly without further purification. LC-MS for C23H17FN403S+H [M+H]: calcd. 449.1; found: 448.8.
Intermediate 14: tert-butyl 4-((5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate and tert-butyl 4-((5-(6-fluoro-1-(phenylsulfony1)-1 H-indo1-3 -y1) -2 H-indazol-2-yl)methyl)pip eridin e-1 -car boxylate Boc ,o, ,,N,...-..õõõ..-...õõ,%1 'N
\ I
e N-Boc =
F 40 \ F
bo2ph o2Ph Following the general method as outlined in Intermediate 5, starting from 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazole (Intermediate 12; 1.50 g; 3.83 mmol) and tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (1.34 g;
4.57 mmol), 1.97 g (88%) of a mixture of the title compounds was obtained as a brown oil, which was used directly without further purification. LC-MS for C32H33FN404S+11+ [M+H]:
calcd.
589.2; found: 588.8.
Intermediate 15: tert-butyl 4-((5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate "
N'Boc 40 \
To a solution of tert-butyl 4-((5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate and tert-butyl 4-((5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2H-indazol-2-Amethyl)piperidine-1-carboxylate (Intermediate 14;
2.00 g;
5 3.40 mmol) in Me0H (40 mL) was added a solution of NaOH (679 mg; 17.0 mmol) in water (2 mL). The reaction mixture was stirred at 85 C for 30 minutes, concentrated, and purified by a silica gel chromatography (petroleum ether/Et0Ac = 3/1) to afford 1.18 g (77%) of the title compound as a yellow solid. LC-MS for C26H29FN402+H
[M+H]:
calcd. 449.2; found: 448.9 10 Intermediate 16: 3-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazol-1-yl)propanamide and 3-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2H-indazol-yl)propanamide NH

'N
\
=
\ \
02Ph 02 P h Following the general method as outlined in Intermediate 8, starting from 5-(6-fluoro-1-15 (phenylsulfony1)-1H-indol-3-y1)-1H-indazole (Intermediate 12; 490 mg;
1.25 mmol), 492 mg (85%) of a mixture of the title compounds was obtained as a brown solid, which was used directly without further purification. LC-MS for C24H19FN403S+H [M+H]:
calcd.
463.2; found: 462.8.
Intermediate 17: tert-butyl 4-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazol-1-20 yl)piperidine-1-carboxylate N,Boc /N ,N.,) =
Fl \
02Fh To a mixture of 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazole (Intermediate 12; 1.80 g; 4.60 mmol) and Cs2CO3 (3.75 g; 11.5 mmol) in DMF (35 mL) was added tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (1.93 g; 6.91 mmol) under nitrogen.
The reaction mixture was stirred at 70 C overnight. The mixture was poured into ice-water (180 mL) and extracted with Et0Ac (80 mLx3). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by a silica gel chromatography (petroleum ether/Et0Ac = 5/1 ¨ 2/1) to afford 1.75 g (66%) of the title compound as a yellow solid. LC-MS
for C31 H31 FN 404S+H [M+H]: calcd. 575.2; found: 574.9.
Intermediate 18: tert-butyl 4-(5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-yl)piperidine-1-carboxylate B
Noc -N,N) /
40 N\
F
H
To a solution of tert-butyl 4-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazol-1-yl)piperidine-1-carboxylate (Intermediate 17; 1.75 g; 3.05 mmol) in Me0H (60 mL) was added a solution of NaOH (800 mg; 20.0 mmol) in water (6 mL). The reaction mixture was stirred at 85 C for 6 hours and concentrated in vacuo. The residual was dissolved in Et0Ac (80 mL), washed with water (40 mL), brine (40 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by a silica gel chromatography (petroleum ether/Et0Ac = 5/1 ¨ 2/1) to afford 600 mg (45%) of the title compound as a yellow oil.

LC-MS for C25H27FN402+H -(CH3)2C=CH2 [M+H-(CH3)2C=CH2]: calcd. 379.2; found:
378.9.
Intermediate 19: 1 -(4-((6-(6-fluoro-1 -(phenylsulfony1)-1 H-indo1-3-y1)-2H-indazol-2-yl)methyl)piperidin-1-ypethanone 1\l' I
\ 1 41Ikt F
02Ph 358 mg (54%) of the title compound was obtained as a yellow solid after purification by preparative TLC (Et0Ac) as a regio-isomer with intermediate 7. LC-MS for C29H27FN403S+1-1 [M+H]: calcd. 531.2; found: 530.9.
Intermediate 20: 3-(6-(6-fluoro-1-(phenylsulfony1)-1 H-indo1-3-y1)-2H-indazol-yl)propanamide NH
0, 2 N
N' = i \ i bo2ph The title compound (70 mg, 29%) was obtained as a yellow solid after purification by silica gel chromatography (petroleum ether/Et0Ac = 2/1 ¨ 0/1) during the preparation of Intermediate 8.
Intermediate 21: tert-butyl 4-((5-(6-fluoro-1H-indo1-3-y1)-2H-indazol-2-yl)methyl)piperidine-1-carboxylate Boc p, N'N
\ i FSH
The title compound (377 mg, 25%) was obtained as a yellow solid after purification by silica gel chromatography (petroleum ether/Et0Ac = 3/1) during the preparation of Intermediate 15. LC-MS for C26H29FN402+H [M+H]: calcd. 449.2; found: 448.9 Intermediate 22: 5-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-ylmethyl)-2H-indazole plid -N
\ I
=
FSH
A solution of tert-butyl 4-((5-(6-fluoro-1H-indo1-3-y1)-2H-indazol-2-yl)methyl)piperidine-1-carboxylate (Intermediate 21; 189 mg; 0.42 mmol) in saturated HCI in 1,4-dioxane (10 mL) was stirred at room tempreture for 1 hour. The reaction mixture was concentrated in vacuo, diluted with water (20 mL), and extracted with Et0Ac (50 mLx3). The aqueous layer was basified with aqueous NaOH to pH = 13 and extracted with Et0Ac (80 mLx3).
The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative TLC (DCM/Me0H = 10/1) to afford 136 mg (93%) of the title compound as a yellow solid. LC-MS for C21 F121FN4+H [M+H]: calcd. 349.2;
found:
348.9.
Intermediate 23: tert-butyl 4-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2H-indazol-2-yl)piperidine-1-carboxylate BOC
-N
\
=
1.1 \
02Ph The title compound (380 mg, 14%) was obtained as a yellow solid after purification by silica gel chromatography (petroleum ether/Et0Ac = 5/1 ¨ 2/1) during the preparation of Intermediate 17. LC-MS for C31 H31 FN 404S+H [M+H]: calcd. 575.2; found:
574.9.
Intermediate 24: tert-butyl 4-(5-(6-fluoro-1H-indo1-3-y1)-2H-indazol-211)piperidine-1-carboxylate BOC
-N
\
=
40 N\
Following the general method as outlined in Intermediate 15, starting from tert-butyl 4-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2H-indazol-2-Apiperidine-1-carboxylate (Intermediate 23; 1.75 g; 3.04 mmol), 0.6 g (45%, not very pure) of the title compound was obtained as a yellow oil purification by silica gel chromatography (petroleum ether/Et0Ac = 5/1 ¨ 2/1). LC-MS for C25H27FN402+11+ [M+H]: calcd. 435.5;
found: 434.9.
Intermediate 25: tert-butyl 5-bromo-1H-benzo[climidazole-1-carboxylate and tert-butyl 6-bromo-1H-benzo[climidazole-1-carboxylate Br N

N Br SI
boc boc To a mixture of 5-bromo-1H-benzo[climidazole (1.00 g; 5.08 mmol) in THF (50 mL) was added Boc20 (1.33 g; 6.09 mmol), Et3N (770 mg; 7.61 mmol) and DMAP (62 mg;
0.51 mmol). The mixture was stirred at room temperature overnight under nitrogen and concentrated in vacuo. The residue was dissolved in Et0Ac (150 mL), washed with H20 (80 mLx2), brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.30 g (86%) of a mixture of the title compounds as a yellow oil, which was used directly without further purification. LC-MS for C12H13BrN202+H -(CH3)2C=CH2[M+H-(CH3)2C=CH2] : calcd. 241.0; found: 240.9. 1H NMR (300 MHz, CDC13) 6 [ppm]:
8.42 (s, 0.5H), 8.40 (s, 0.5H), 8.20 (s, 0.5H), 7.95 (s, 0.5H), 7.88 (d, J= 8.7 Hz, 0.5H), 7.66 (d, J
= 8.7 Hz, 0.5H), 7.55 ¨ 7.44 (m, 1H), 1.71 (s, 9H) as a mixture of tautomers.
Intermediate 26: tert-butyl 5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-benzo[climidazole-1-carboxylate and tert-butyl 6-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-benzo[climidazole-1-carboxylate >---,06 )_=: B SO NN
40 NN 6 boc boc Following the general method as outlined in Intermediate 3, starting from tert-butyl 5-bromo-1H-benzo[climidazole-1-carboxylate and tert-butyl 6-bromo-1H-benzo[climidazole-1-carboxylate (Intermediate 25; 500 mg; 1.68 mmol), 1.09 g (quant.) of a mixture of the title compounds was obtained as a yellow oil, which was used directly without further purification. LC-MS for C18H25BN204+H [M+H]: calcd. 345.2;
found:
345Ø
Intermediate 27: 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazole NNH
=
Fl \
02Ph Following the general method as outlined in Intermediate 4, starting from tert-butyl 5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-benzo[climidazole-1-carboxylate and tert-butyl 6-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-benzo[climidazole-1-carboxylate (Intermediate 26; 730 mg crude; 0.46 mmol) and 6-fluoro-3-iodo-1-(phenylsulfony1)-1H-indole (Intermediate 1; 300 mg; 0.75 mmol), 550 mg (quant.) of the title compound was obtained as a black oil, which was used directly without further purification. LC-MS for C21 Hi 4FN302S+H [M+H]: calcd. 392.1; found: 391.9.
Intermediate 28: tert-butyl 5-bromo-2-methyl-1H-benzo[climidazole-1-carboxylate Br ,N

boc Following the general method as outlined in Intermediate 25, starting from 5-bromo-2-methy1-1H-benzo[climidazole (3.0 g; 13.51 mmol), 1.14 g (27%) of the title compound was obtained as a white solid after purification by a silica gel chromatography (petroleum ether/Et0Ac = 8/1 ¨ 5/1). LC-MS for Ci3H15BrN202+H -(CH3)2C=CH2 [M+H-(CH3)2C=CH2]: calcd. 256.0; found: 256.8. 1H NMR (300 MHz, CDCI3) 6 [ppm]:
7.79 (d, J=
8.7 Hz, 1H), 7.79 (d, J= 2.0 Hz, 1H), 7.76 (m, 2H), 7.41 (dd, J= 8.7, 2.0 Hz, 1H), 2.82 (s, 3H), 1.72 (s, 9H).
Intermediate 29: tert-butyl 2-methyl-5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1 H-benzo[climidazole-l-carboxylate N
el N-boc Following the general method as outlined in Intermediate 3, starting from tert-butyl 5-bromo-2-methy1-1H-benzo[c]imidazole-1-carboxylate (Intermediate 28; 1.14 g;
3.67 mmol), 1.51 g (quant.) of the title compound was obtained as a white solid after purification by a silica gel chromatography (petroleum ether/Et0Ac = 5/1). LC-MS for C19H27BN204+H [M+H]: calcd. 359.2; found: 359Ø 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 7.91 (d, J= 8.2 Hz, 1H), 7.84 (s, 1H), 7.64 (d, J= 8.2 Hz, 1H), 2.72 (s, 3H), 1.66 (s, 9H), 1.32 (s, 12H).
Intermediate 30: 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-methyl-1H-benzo[climidazole NI), NH
.

02ph Following the general method as outlined in Intermediate 4, starting from tert-butyl 2-methy1-5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-benzo[c]imidazole-1-carboxylate (Intermediate 29; 1.08 g; 3.01 mmol) and 6-fluoro-3-iodo-1-(phenylsulfony1)-1H-indole (Intermediate 1; 802 mg; 1.99 mmol), 870 mg (quant.) of the title compound was obtained as a black solid after purification by a silica gel chromatography (DCM/Me0H = 40/1 ¨ 20/1). LC-MS for C22H16FN302S+H [M+H]: calcd. 406.1;
found:
405.8.
Intermediate 31: 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-211)benzene-1,2-diamine CV .
/ N
To a mixture of 4-bromobenzene-1,2-diamine (10.8 g; 57.7 mmol), KOAc (17.0 g;

mmol) and 44,4,4',4',5,5,5',5'-octamethy1-2,2'-bi(1,3,2-dioxaborolane) (16.1 g; 63.4 mmol) in dioxane (200 mL) was added Pd(dppf)C12=DCM (2.36 g; 2.89 mmol) under nitrogen.
The reaction mixture was stirred at 100 C for 16 hours, cooled to room temperature, filtered, concentrated, and purified by a silica gel chromatography (petroleum ether/Et0Ac =5/1 - 2/1) to afford 11.6 g (86%) of the title compound as a brown oil. LC-MS for C12H19BN202+H [M+H]: calcd. 235.2; found: 235Ø 1H NMR (400 MHz, CDC13) 6 [ppm]: 7.22 (d, J= 7.7 Hz, 1H), 7.16 (s, 1H), d, J= 7.7 Hz, 1H, 1.32 (s, 12H).
Intermediate 32: 4-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzene-1,2-diamine N

F lei bo2ph A mixture of 6-fluoro-3-iodo-1-(phenylsulfony1)-1H-indole (Intermediate 1;
19.9 g; 49.6 mmol), 4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-211)benzene-1,2-diamine (Intermediate 31; 11.6 g; 49.6 mmol), Pd(dppf)C12=DCM (2.0 g; 2.45 mmol), K2CO3 (20.5 g; 148 mmol) in dioxane (300 mL) and water (60 mL) was stirred at 100 C for 2 hours under nitrogen. The reaction mixture was cooled to room temperature, filtered, concentrated, and purified by a silica gel chromatography (DCM/Me0H = 200/1 -20/1) to afford 7.0 g (37%) of the title compound as a brown oil. LC-MS for C20H16FN302S+H
[M+H]: calcd. 382.1; found: 381.8. 1H NMR (400 MHz, CDC13) 6 [ppm]: 7.90 (d, J= 7.6 Hz, 1H), 7.77 (dd, J = 9.7, 2.0 Hz, 1H), 7.68 (dd, J = 8.7, 5.3 Hz, 1H), 7.58 -7.53 (m, 2H), 7.49 - 7.43 (m, 2H), 7.01 (ddd, J = 9.3, 8.7, 2.3 Hz, 1H), 6.94 - 6.89 (m, 2H), 6.78 (d, J = 7.6 Hz, 1H).
Intermediate 33: 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(2-(methylthio)ethyl)-1 H-b enzo[climidazole sz NNH
=
FINF
bo2Ph To a mixture of 4-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzene-1,2-diamine (Intermediate 32; 500 mg; 1.31 mmol) and 3-(methylthio)propanoic acid (157 mg;
1.31 mmol) in DCM (10 mL) at 0 C was added HATU (748 mg; 1.97 mmol) and Et3N (265 mg; 2.62 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 30 minutes, diluted with DCM (60 mL), washed with water (30 mL), brine (20 mLx2), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was diluted with toluene (10 mL) and heated to ref lux for 16 hours. The reaction mixture was concentrated in vacuo and purified by a silica gel chromatography (petroleum ether/Et0Ac = 100/1 ¨ 6/1) to afford 460 mg (75%) of the title compound as a brown oil, which was used directly without further purification. LC-MS for C24H20FN302S2+H
[M+H]: calcd. 466.1; found: 465.8.
Intermediate 34: 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(2-(methylsulfonypethyl)-1H-benzo[climidazole ,s"
0) NINH
.
F SI
bo2ph To a solution of 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(2-(methylthio)ethyl)-1H-benzo[climidazole (Intermediate 33; 460 mg; 0.99 mmol) in DCM (15 mL) at 0 C
was added mCPBA (500 mg; 2.46 mmol; 85%) in portions. The reaction mixture was slowly warmed to room temperature and stirred for 30 minutes. The mixture was washed with satu red aqueous NaHS03 (20 mL) and the aqueous layer was extracted with DCM
(30 mLx2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 170 mg (34%) of the title compound as a brown solid, which was used directly without further purification. LC-MS
for C24H20FN304S2-H- [M-Hy: calcd. 496.1; found: 495.9. 1H NMR (300 MHz, CDCI3) 6 [ppm]: 7.97 ¨ 7.89 (m, 2H), 7.83 ¨ 7.75 (m, 1H), 7.75 ¨ 7.66 (m, 3H), 7.65 ¨
7.52 (m, 2H), 7.51 ¨ 7.41 (m, 3H), 7.09 ¨ 6.98 (m, 1H), 3.70 ¨ 3.61 (m, 2H), 3.59 ¨
3.48 (m, 2H), 2.97 (s, 3H).
Intermediate 35:
tert-butyl 2-(2-amino-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)phenylamino)-2-oxoethyl(methyl)carbamate and tert-butyl 2-(2-amino-4-(6-fluoro-1-(phenylsulfonyI)-1H-indo1-3-yl)phenylamino)-2-oxoethyl(methyl)carbamate \N_Boc Boc,d H. H2N NH
. 411t F 40N F lel 02Ph 02Ph To a solution of 2-(tert-butoxycarbonyl(methyl)amino)acetic acid (165 mg, 0.87 mmol) and HATU (364 mg, 0.96 mmol) in THF (10 mL) and DMF (1 mL) was added DIPEA
(187 mg, 1.45 mmol). The reaction mixture was stirred for 10 minutes before 4-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1) benzene-1, 2-diamine (Intermediate 32, 500 mg, 1.31 mmol) was added. The mixture was stirred at room temperature for 60 minutes.
The mixture was concentrated in vacuo, diluted with Et0Ac (30 mL), washed with water (30 mLx3), dried over anhydrous Na2SO4, filtered, and concentrated to afford 670 mg (>100%) of the title compound as a black solid, which was used directly without further purification. LC-MS for C22H17CIFN303S+H -(CH3)2C=CH2 [M+H-(CH3)2C=CH2] :
calcd.
497.1; found: 496.8.

Intermediate 36: tert-butyl (5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1 H-b enzo[climidazol- 2-yl)m ethy 1(m ethyl) c arb am ate Boc N)---/ NH

bo2ph A mixture of tert-butyl 2-(2-amino-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)phenylamino)-2-oxoethyl(methyl)carbamate and tert-butyl 2-(2-amino-4-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)phenylamino)-2-oxoethyl(methyl)carbamate (Intermediate 35, 670 mg crude, 0.87 mmol) in AcOH (10 mL) was stirred at 50 C for 6 hours.
The mixture was cooled to room temperature, neutralized with saturated aqueous Na2CO3 to pH = 8, and extracted with Et0Ac (50 mLx3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford 640 mg (100%) of the title compound as a black solid, which was used directly without further purification. LC-MS
for C28H27FN404S+H [M+H]: calcd. 535.2; found: 534.8.
Intermediate 37: tert-butyl (5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[climidazol-2-yl)methyl(methyl)carbamate (1-Boc N" NH
FIN
Following the general method as outlined in Intermediate 15, starting from tert-butyl (5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazol-2-yl)methyl(methyl)carbamate (Intermediate 36, 640 mg crude, 0.87 mmol), 470 mg (100%) of the title compound was obtained as a black solid, which was used directly without further purification. LC-MS for C22H23FN402+H [M+H]: calcd. 395.2;
found:
394.9.
Intermediate 38: N-(2-amino-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)pheny1)-2-chloroacetamide and N-(2-amino-4-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)pheny1)-2-chloroacetamide ci CI
H0 C) . =
\
F lelN F 01 N
02Ph 02Ph To a stirred solution of 4-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzene-1,2-diamine (Intermediate 32, 3.81 g, 10.0 mmol), chloroacetic acid (945 mg, 10.0 mmol) and Et3N
(2.02 g, 20.0 mmol) in DCM (40 mL) at 0 C was added HATU (3.80 g, 10.0 mmol).
The reaction mixture was stirred at room temperature for 1 hour, diluted with water (50 mL), and concentrated in vacuo to remove most DCM. The aqueous mixture was extracted with Et0Ac (40 mLx3). The combined organic layer was washed with brine (30 mLx2), dried over anhydrous Na2SO4, filtered, and concentrated to afford 3.96 g (87%) of the title compound as a brown oil, which was used directly without further purification.
LC-MS for C22H17CIFN303S+H [M+H]: calcd. 458.1; found: 457.7.
Intermediate 39: 2-(chloromethyl)-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1 H-benzo[climidazole cl NNid 4Ik FIN
b 02 Ph A mixture of N-(2-amino-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)pheny1)-2-chloroacetamide and N-(2-amino-4-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)pheny1)-2-chloroacetamide (Intermediate 38, 3.96 g, 8.65 mmol) in AcOH (20 mL) was stirred at 50 C for 16 hours. The mixture was concentrated in vacuo to remove most AcOH.
The residue was diluted with Et0Ac (100 mL), washed with saturated aqueous NaHCO3 (30 mLx2), brine (30 mLx2), dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel chromatography (DCM/ Me0H = 200/1 ¨ 50/1) to afford 3.20 g (84%) of the title compound as a brown solid. LC-MS for C22H15CIFN302S+H
[M+H]:
calcd. 440.1; found: 439.8.
Intermediate 40: 3-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazol-2-yl)propanoic acid N" NH
Fl ' 02Ph A solution of 4-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzene-1,2-diamine (Intermediate 32, 500 mg, 1.31 mmol) and succinic anhydride (160 mg, 1.60 mmol) in 1,4-dioxane (8 mL) was heated at 80 C for 48 hours. The mixture was concentrated and purified by silica gel chromatography (DCM/Me0H = 18/1) to afford 0.60 g (99%) of the title compound as a white solid. LC-MS for C24H18FN304S+H [M+H]: calcd.
464.1;

found: 464Ø 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 12.30 (s, 1H), 8.15 (d, J=
7.7 Hz, 2H), 8.06 (s, 1H), 7.87 - 7.80 (m, 2H), 7.77 - 7.70 (m, 2H), 7.66 - 7.60 (m, 2H), 7.57 (d, J= 8.3 Hz, 1H), 7.44 (d, J= 8.3 Hz, 1H), 7.24 (ddd, J= 9.3, 8.7, 2.2 Hz, 1H), 3.57 (s, 1H), 3.07 (t, J= 7.1 Hz, 2H), 2.82 (t, J= 7.1 Hz, 2H).
Intermediate 41: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2,3-dihydro-1 H-benzo[cipyrrolo[1,2-a]imidazol-1-one i--i\I 0 N
4#
ES \
02Ph To a solution of 3-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazol-2-yl)propanoic acid (Intermediate 40, 521 mg, 1.12 mmol), HATU (855 mg, 2.25 mmol) and Et3N (454 mg, 4.49 mmol) in THF (15 mL) was added NH4C1 (120 mg, 2.24 mmol) under nitrogen. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (30 mL) and extracted with DCM (50 mLx2) and Et0Ac (50 mLx2). The combined organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 556 mg (>100%) of the title compound as a yellow solid, which was used directly without further purification. LC-MS
for C24H16FN303S+H [M+H]: calcd. 446.1; found: 446Ø
Intermediate 42: 5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-Abenzo[cloxazole N() 4.

Following the general method as outlined in Intermediate 3, starting from 5-bromobenzo[cloxazole (500 mg, 2.52 mmol), 576 mg (93%) of the title compound was obtained as a white solid after purification by silica gel chromatography (petroleum ether /Et0Ac = 100/1 ¨ 30/1). LC-MS for C13H16BN03+H [M+H]: calcd. 246.1; found:
246Ø
1H NMR (400 MHz, CDCI3) 6 [ppm]: 8.26 (s, 1H), 8.10 (s, 1H), 7.86 (d, J= 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 1.37 (s, 12H).
Intermediate 43: 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[c]oxazole NO
4lik Si F
02Ph Following the general method as outlined in Intermediate 4, starting from 5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-211)benzo[cloxazole (Intermediate 42, 330 mg, 1.35 mmol) and 6-fluoro-3-iodo-1-(phenylsulfonyI)-1H-indole (Intermediate 1, 540 mg, 1.35 mmol), 423 mg (80%) of the title compound was obtained as a white solid after purification by recrystallization with Me0H. LC-MS for C21 Hi3FN203S+HIM Fir:
calcd.
393.1; found: 392.8. 1H NMR (400 MHz, CDCI3) 6 [ppm]: 8.16 (s, 1H), 7.99 -7.93 (m, 3H), 7.81 (dd, J= 9.5, 2.1 Hz, 1H), 7.73 -7.65 (m, 3H), 7.62 - 7.57 (m, 2H), 7.53 - 7.47 (m, 2H), 7.07 (ddd, J = 9.2, 8.7, 2.2 Hz, 1H).
Intermediate 44: 2-methy1-5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)benzo[cloxazole N
) / _(-) 411, ),R) Following the general method as outlined in Intermediate 3, starting from 5-bromo-2-methylbenzo[cloxazole (564 mg, 2.66 mmol), 688 mg (100%) of the title compound was obtained as a brown semi-solid, which was used directly without further purification. LC-MS for C14H1813NO3+H [M+H]: calcd. 260.1; found: 260Ø
Intermediate 45: 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-methylbenzo[cloxazole N
) / -r, e \

02Ph Following the general method as outlined in Intermediate 4, starting from 2-methy1-5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-211)benzo[cloxazole (Intermediate 44, 688 mg, 2.66 mmol) and 6-fluoro-3-iodo-1-(phenylsulfonyI)-1H-indole (Intermediate 1, 711 mg, 1.77 mmol), 718 mg (100%) of the title compound was obtained as a yellow solid after purification by silica gel chromatography (petroleum ether/Et0Ac = 5/1 ¨ 2/1).
LC-MS
for C22H15FN203S+H [M+H]: calcd. 407.1; found: 406.8. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 8.20 - 8.14 (m, 3H), 7.97 (d, J= 0.8 Hz, 1H), 7.88 - 7.81 (m, 2H), 7.79 - 7.70 (m, 2H) , 7.69 - 7.60 (m, 3H), 7.23 (ddd, J = 9.2, 8.8, 2.4 Hz, 1H), 2.65 (s, 3H) .
Intermediate 46: tert-butyl (2-((2-amino-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)phenyl)amino)-2-oxoethyl)carbamate NH, . TINrEIN-Boc F
02Ph To a stirred solution of tert-butoxycarbonylamino-acetic acid (153 mg, 0.87 mmol) and DIEA (188.14 mg, 1.46 mmol) in anhydrous THF /DMF (10 mL /1 mL) was added HATU
(363.66 mg, 0.96 mmol) at 0 C. The mixture was stirred for 10 mins and 4-(1-Benzenesulfony1-6-fluoro-1H-indo1-3-y1)-benzene-1,2-diamine (Intermediate 32, 500 mg, 1.31 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour.

The mixture was quenched with water (20 mL) and extracted with Et0Ac (30 mLx3).
The combined organic layer was washed with brine (20 mLx3), dried over anhydrous Na2Sa4and filtered. The filtrate was concentrated to afford 678 mg (96%) of the title compound as a black semi-solid, which was used directly without further purification.
LC-MS for C2+127FN405S+H : [M+H]: calcd. 539.2; found: 538.8 Intermediate 47: tert-butyl ((6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1 H-benzo[d]imidazol-2-yl)methyl)carbamate BOC
N,...{11' = NH
F [101 02ph A mixture of tert-butyl (2-((2-amino-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)phenyl)amino)-2-oxoethyl)carbamate (Intermediate 46, 678 mg, 1.31 mmol) in AcOH
(10 mL) was stirred at 51 C for 6 hours under nitrogen. The mixture was neutralized with aqueous of Na2CO3 to pH= 8 and extracted with Et0Ac (50 mLx3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 637 mg (93 /0) of the title compound as a black semi-solid, which was used directly without further purification. LC-MS
for C2+125FN404S+H [M+H]: calcd. 521.2; found: 520.8. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]:12.29 (d, J= 20.0 Hz, 1H), 8.16 (d, J= 7.8 Hz, 2H), 8.08 (d, J= 11.5 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.74 (ddd, J = 11.4, 3.6, 1.2 Hz, 1H), 7.69 - 7.60 (m, 2H), 7.57 - 7.44 (m, 3H), 7.29 - 7.21 (m, 1H), 4.38 (d, J = 5.7 Hz, 2H), 2.70 (d, J = 8.2 Hz, 1H), 1.42 (s, 9H).
Intermediate 48: tert-butyl ((6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-yl)methyl)carbamate Boc N,........r[Ni O NH
1.1 N\
F
H
To a solution of ((6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[d]imidazol-2-yl)methyl)carbamate (Intermediate 47, 587 mg, 1.13 mmol) in Me0H (30 mL) was added NaOH (451 mg, 11.28 mmol). The mixture was stirred at 85 C for 2 hours.
The reaction mixture was cooled to room temperature and concentrated to afford 429 mg (100%) of the title compound as a black semi-solid, which was used directly without further purification. LC-MS for C21 F121 FN 402+1-1 [M+H]: calcd. 381.2;
found: 380.9.
Intermediate 49: N-(2-amino-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)pheny1)-2-(dimethylamino)acetamide NH, = 'rr F .
02Ph To a stirred solution of dimethylamino-acetic acid (110 mg, 0.79 mmol) and DIEA (201 mg, 1.56 mmol) in anhydrous THF (10 mL) was added HATU (385 mg, 1.01 mmol) at C. The mixture was stirred for 10 mins and 4-(1-benzenesulfony1-6-fluoro-1H-indo1-3-yI)-benzene-1,2-diamine (Intermediate 32, 300 mg, 0.78 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched with water (20 mL) and extracted with Et0Ac (30 mLx3). The combined organic layer was washed with brine (20 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 363 mg (100%) of the title compound as a black semi-solid, which was used directly without further purification. LC-MS for C24H23FN403S+H
[M+H]:
calcd. 467.2 found: 466.8.
Intermediate 50: 1-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[d]imidazol-2-yI)-N,N-dimethylmethanamine N,....{"-N\/
fk NH
lel \
F N
02 Ph A mixture of Ni2-amino-5-(1-benzenesulfony1-6-fluoro-1H-indol-3-y1)-pheny1]-2-dimethylamino-acetamide (Intermediate 49, 363 mg, 0.78 mmol) in AcOH (15 mL) was stirred at 51 C for 5 hours under nitrogen. The mixture was neutralized with aqueous of Na2CO3 to pH=8 and extracted with Et0Ac (50 mLx3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 441 mg (93%) of the title compound as a black semi-solid, which was used directly without further purification. LC-MS for C24H21FN402S+H
[M+H]:
calcd. 449.1; found: 449Ø
Intermediate 51: tert-butyl (2-(((6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-yl)methyl)amino)-2-oxoethyl)carbamate x..../N-BOC
Nz......{-HN
= NH
10 \
F N
H
To a stirred solution of tert-butoxycarbonylamino-acetic acid (250 mg, 1.43 mmol) and DIEA (308 mg, 2.39 mmol) in anhydrous THF/DMF (20/2 mL) was added HATU (651 mg, 1.71 mmol) at 0 C. The mixture was stirred for 10 min and (6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-yl)methanamine (Compound 27, 400 mg, 1.43 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (20 mL) and extracted with Et0Ac (30 mLx3).
The combined organic layer was washed with brine (20 mLx3) and dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 624 mg (100%) of the title compound as a black semi-oil, which was used directly without further purification. LC-MS for C23H24FN503+H [M+H]: calcd. 438.2; found: 437.9 Intermediate 52: 2-acetamido-N-(2-amino-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)phenyl)acetamide H

' n,J<

F
02Ph To a solution of N-acetylglycine (102 mg, 0.87 mmol) and DIPEA (226 mg, 1.75 mmol) in THF (10 mL) and DMF (1mL) was added HATU (365 mg, 0.96 mmol). The reaction mixture was stirred at 0 C for 20 minutes before 4-(6-fluoro-1-(phenylsulfonyI)-1H-indol-3-yl)benzene-1,2-diamine (Intermediate 32, 500 mg, 1.31 mmol) was added. The mixture was stirred at room temperature for 2 hours, concentrated and diluted with Et0Ac (50mL) and water (40mL). The organic layer was dried over anhydrous Na2504, filtered and concentrated to afford 458 mg (>100%) of the crude title compound as a brown solid, which was used directly without further purification. LC-MS for C24H21 FN404S H [M+H]: calcd. 481.1; found: 480.8.
Intermediate 53: N-((6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[d]imidazol-2-yl)methypacetamide o A\-----N ........õ(-H
4. NH

F
02Ph A mixture of 2-acetamido-N-(2-amino-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)phenyl)acetamide (Intermediate 52, 458 mg crude, 0.87 mmol) in HOAc (15 mL) was stirred at 50 C for 2.5 hours under nitrogen. The reaction mixture was cooled to room temperature, adjusted to pH = 7 with saturate aqueous NaHCO3 and extracted with Et0Ac (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to afford 470 mg (100%) of the crude title compound as a black solid, which was used directly without further purification. LC-MS for C24H19FN403S+H

[M+H]: calcd. 463.1; found: 462.8.
Intermediate 54: tert-butyl 4-((2-amino-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)phenyl)carbamoyl)piperidine-1-carboxylate H
ilk Nr0.....B0C
Fl \
02Ph A mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (430 mg, 1.88 mmol), DIPEA (520 mg, 4.02 mmol) and HATU (1.0 g, 2.63 mmol) in THF (10 mL) and DMF
(1 mL) was stirred at room temperature for 15 minutes before 4-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzene-1,2-diamine (Intermediate 32, 1.0 g, 2.62 mmol) was added. The mixture was stirred at room temperature for 12 hours before it was concentrated. The mixture was quenched with water and extracted with Et0Ac.
The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to afford 1.6 g (>100%) of the crude title compound as a black oil, which was used directly without further purification. LC-MS for C31H33FN405S+H [M+H]: calcd. 593.2;
found:
592.9.
Intermediate 55: tert-butyl 4-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1 H-benzo[d]imidazol-2-yl)piperidine-1 -carboxylate Boc N, 411, N H
FIN
bo2ph A mixture of tert-butyl 4-((2-amino-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)phenyl)carbamoyl)piperidine-1-carboxylate (Intermediate 54, 1.60 g crude, 1.88 mmol) in HOAc (20 mL) was stirred at 50 C for 4 hours under nitrogen. The reaction mixture was cooled to room temperature, concentrated, adjusted to pH = 11 with aqueous K2CO3 and extracted with Et0Ac. The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to afford 660 mg (60%) of the crude title compound as a yellow solid, which was used directly without further purification. LC-MS
for C31 H31 FN 404S+H [M+H]: calcd. 575.2; found: 574.9.
Intermediate 56: tert-butyl 4-(6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-yl)piperidine-1-carboxylate Boc N
. NH
\
FIN
Following the general method as outlined in Compound 1, starting from tert-butyl 4-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazol-2-yl)piperidine-1-carboxylate (Intermediate 55, 660 mg, 1.15 mmol), 600 mg (>100%) of the crude title compound was obtained as a black oil, which was used directly without further purification. LC-MS for C25H27FN402+11+ [M+H]: calcd. 435.2; found: 434.9.
Intermediate 57: 2-amino-5-(6-fluoro-1H-indo1-3-yl)phenol OOH
FON\
To a solution of 6-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-benzooxazole (702 mg, 1.81 mmol) in Me0H (100 mL) was added NaOH (212 mg, 5.31 mmol). The mixture was stirred at 65 C for 3 hours. The mixture was concentrated to dryness in vacuo to give 500 mg of the title compound as a brown solid, which was used directly without further purification. LC-MS for C14H11FN2O+H [M+H]: calcd. 243.1; found: 243.2.
Intermediate 58: Ni2-amino-5-(1-benzenesulfony1-6-fluoro-1H-indol-3-y1)-pheny1]-2-chloro-acetamide & Ni2-amino-4-(1-benzenesulfony1-6-fluoro-1H-indol-3-y1)-pheny1]-2-chloro-acetamide HN
CI
= N
& NH2 CI

SO2Ph SO2Ph To a stirred solution of 4-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-benzene-1,2-diamine (3.81 g, 10.0 mmol), chloro-acetic acid (945 mg, 10.0 mmol) and TEA
(2.0 g, 20.0 mmol) in DCM (40 mL) was added HATU (3.8 g, 10.0 mmol) at 0 C. The reaction mixture was stirred at room temperature for 1 hour, quenched with water (50 mL) and concentrated to remove most of the DCM. The aqueous mixture was extracted with Et0Ac (40 mLx3). The combined organic layer was washed with brine (30 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 3.96 g (87%) of the title compound as a brown oil, which was used to next step without further purification. LC-MS for C22H17CIFN303S+H [M+H]: calcd. 458.1; found: 457.7.
Intermediate 59: 6-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-2-chloromethyl-1 H-benzoimidazole iik NH
Fl \
SO2Ph A mixture of Ni2-amino-5-(1-benzenesulfony1-6-fluoro-1H-indol-3-y1)-pheny1]-2-chloro-acetamide & Ni2-amino-4-(1-benzenesulfony1-6-fluoro-1H-indol-3-y1)-pheny1]-2-chloro-acetamide (3.96 g, 8.66 mmol) in AcOH (20 mL) was stirred at 50 C for 16 hours and concentrated to remove most AcOH. The residue was diluted with Et0Ac (100 mL), washed with aqueous NaHCO3 (30 mLx2), brine (30 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to residue, which was purified by silica gel chromatography (DCM/ Me0H =200/1 ¨ 50/1) to afford 3.20 g (84%) of the title compound as a brown solid. LC-MS for C22H15CIFN302S+H [M+H]: calcd. 440.1;
found: 439.8.
Intermediate 60: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole Nz.....{-N/"Ii = NH

SO2Ph A mixture of 6-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-2-chloromethyl-1 H-benzoimidazole (Intermediate 59, 200 mg, 0.456 mmol), 1-methyl-piperazine (73 mg, 0.729 mmol) and TEA (92 mg, 0.91 mmol) in DMF (3 mL) was stirred at 50 C for 1 hour.
The mixture was diluted with water (20 mL), extracted with DCM (30 mLx3), washed with brine (30 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness to afford 290 mg (>100%) of the crude title compound as a brown oil. LC-MS for C27H26FN502S+H [M+H]: calcd. 504.2; found: 503.8.

Intermediate 61: 2-(((6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[d]imidazol-2-yl)methyl)amino)ethanol N___,ClinjH
= NH

F
SO2Ph A mixture of 6-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-2-chloromethyl-1 H-benzoimidazole (Intermediate 59, 200 mg, 0.456 mmol), 2-amino-ethanol (55 mg, 0.911 mmol) and TEA (92 mg, 0.911 mmol) in DMF (3 mL) was stirred at 50 C for 2 hours.
Then it was diluted with Et0Ac (50 mL), washed with brine (30 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness to afford 116 mg (55%) of the crude title compound as a brown solid. LC-MS for C24H21 FN403S+H
[M+H]: calcd. 465.1; found: 464.9.
Intermediate 62: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(piperazin-1-ylmethyl)-1H-benzo[d]imidazole Nz{--V-11 \ H
= NH .-z F lel SO2Ph A mixture of 6-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-2-chloromethyl-1 H-benzoimidazole (Intermediate 59, 439 mg, 1.0 mmol) and piperazine (258 mg, 3.0 mmol) in DMF (5 mL) was stirred at 60 C for 0.5 hour. Then the mixture was diluted with water (50 mL), extracted with Et0Ac (50 mLx2).The organic layer was washed with brine (30 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by a silica gel column chromatography (DCM/Me0H = 20/1 to 5/1) to afford 176 mg (36%) of the title compound as a yellow solid.
LC-MS for C26H24FN502S+11+ [M+H]: calcd. 490.2; found: 490.5.

Intermediate 63: tert-butyl (2-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-benzo[d]imidazol-2-yl)ethyl)carbamate NHBoc 4k NH
F 1 N\
02Ph The solution of 3-tert-Butoxycarbonylamino-propionic acid (2.0 g, 10.5 mmol), HATU
(4.5 g, 11.5 mmol) and DIPEA (17.8 g, 17.8 mmol) in THF (100 mL) was stirred at room temperature for 10 min before (4-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzene-1,2-diamine (Intermediate 32, 6.0 g, 15.8 mmol) was added. The mixture was stirred at r. t for 2 h. Then it was diluted with Et0Ac (100 mL), washed with water (100 mLx3), dried over Na2SO4 and concentrated to give the crude product which is used for next step without further purification.
The crude product was dissolved in AcOH (10 mL) and stirred at 50 C for 6 hrs before it was quenched with aq NaHCO3.The pH was adjusted to 7. The mixture was extracted with Et0Ac (100 mLx3), dried over anhydrous Na2SO4 and concentrated to give the crude product (4.17 g) which is used for next step without further purification.
Intermediate 64: 2-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[d]imidazol-2-ypethanamine N...._ et NH
\
FIN
02Ph (2-[6-(1-Benzenesulfony1-6-fluoro-1H-indol-3-y1)-1H-benzoimidazol-2-y1]-ethy1}-carbamic acid tert-butyl ester (Intermediate 63, 4.17 g, 7.80 mmol) was dissolved in (40 mL) and stirred at r. t for 1 h. The mixture was diluted with Et0Ac (100 mL), washed with brine (50 mLx3), dried over Na2SO4 and concentrated to give the crude product which is purified by prep ¨ HPLC to afford the title compound (1.80 g, 53%) as a yellow solid. 1H NMR (400 MHz, CDCI3) 6 [ppm]: 7.93 (d, J= 8.8 Hz, 2H), 7.80 (dd, J=
9.6, 2.0 Hz, 1H), 7.74 - 7.67 (m, 1H), 7.65 (s, 1H), 7.59 - 7.55 (m, 2H), 7.49 - 7.39 (m, 4H), 7.04 (td, J = 8.8, 1.6 Hz, 1H), 3.24 (t, J = 5.6 Hz, 2H), 3.06 (t, J = 5.2 Hz, 2H).
Intermediate 65: N-{2-[6-(1-Benzenesulfony1-6-fluoro-1H-indol-3-y1)-1H-benzoimidazol-2-y1]-ethyl}-methanesulfonamide oo NH
41, NH
F
IN
02Ph To a solution of 246-(1 -Benzenesulfony1-6-fluoro-1H-indo1-3-y1)-1H-benzoimidazol-2-y1]-ethylamine (Intermediate 64, 700 mg, 1.61 mmol) in DCM (20 mL) was added TEA
(488 mg, 4.83 mmol) and the mixture was stirred at r.t for 10 min. Then MsCI (147 mg, 1.29 mmol) was added to the reaction mixture. The reaction was stirred at room temperature overnight and then diluted with DCM (50 mL). The mixture was washed with water (50 mLx3), dried over anhydrous Na2SO4 and concentrated to give the product (430 mg, 52%).
Intermediate 66: N-(2-(6-(6-fluoro-1-(phenylsulfonyI)-1 H-indo1-3-y1)-1 H-benzo[d]imidazol-2-y1) ethyDacetamide t\JH
NH
40 N\
02 Ph To a solution of 246-(1 -Benzenesulfony1-6-fluoro-1H-indo1-3-y1)-1H-benzoimidazol-2-y1]-ethylamine (Intermediate 64, 700 mg, 1.61 mmol) in DCM (20 mL) was added TEA
(488 mg, 4.83 mmol) and the mixture was stirred at r.t for 10 min before AcCI (101 mg, 1.29 mmol) was added to the reaction mixture. The reaction was stirred at room temperature overnight and then diluted with DCM (50 mL). The mixture was washed with water (50 mLx3), dried over anhydrous Na2SO4, filtered and concentrated to give the product (429 mg, 57%).
Intermediate 67: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole ms NH
1.1 SO2Ph To a stirred solution of 6-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-2-piperazin-1-ylmethyl-1H-benzoimidazole (Intermediate 62,96 mg, 0.196 mmol) and TEA (59 mg, 0.588 mmol) in DCM (10 mL) was added MsCI (27 mg, 0.236 mmol) at 0 C. The mixture was stirred at room temperature for 0.5 hour, diluted with Et0Ac (50 mL), washed with water (30 mL) and brine (30 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by a silica gel column chromatography (DCM/Me0H = 100/1 to 20/1) to afford 80 mg (72%) of the title compound as a brown solid.

Intermediate 68: 2-(5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-yl)acetonitrile HNICON
I.
To a stirred solution of 4-(6-fluoro-1H-indo1-3-y1)-benzene-1,2-diamine (Intermediate 32, 296 mg, 1.23 mmol), cyano-acetic acid (104 mg, 1.23 mmol) and TEA (248 mg, 2.46 mmol) in DCM (10 mL) was added HATU (467 mg, 1.23 mmol) at 0 C. The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was diluted with Et0Ac (50 mL), washed with brine (30 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and AcOH (10 mL) was added. The mixture was stirred at 65 C for 3 hours. The mixture was cooled and AcOH was removed. The mixture was basified with aqueous Na2CO3 (20 mL, 1M) and extracted with Et0Ac (30 mLx2). The combined organic layer was washed with brine (30 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM/Me0H = 100/1 to 20/1) to afford 186 mg (52%) of the title compound as a brown solid. LC-MS for C17H11FN4+H [M+H]: calcd. 291.1;
found:
291.3.
Intermediate 69: 2-amino-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)phenol = OH
\
bo2ph Following the general method as outlined in Intermediate 32, starting from 6-fluoro-3-iodo-1-(phenylsulfony1)-1H-indole (Intermediate 1, 6.0 g, 25.53 mmol) and 2-amino-5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenol (6.83 g, 17.02 mmol), 4.3 g (66%) of the title compound was obtained as a white solid. LC-MS for C20H15FN203S-H- [M-Hy:
calcd. 381.1; found: 381.3. 1H NMR (300 MHz, DMSO-d6) 6 [PPrn]: 9.20 (s, 1H), 8.10 (d, J= 7.5 Hz, 2H), 7.89 - 7.66 (m, 4H), 7.61 (t, J= 7.5 Hz, 2H), 7.22 (t, J= 8.1 Hz, 1H), 6.95 (s, 1H), 6.89 (d, J= 7.9 Hz, 1H), 6.67 (d, J= 8.1 Hz, 1H), 4.77(s, 2H).
Intermediate 70: 2-amino-4-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)phenol OH
fi NH2 F lel SO2Ph Following the general method as outlined in Intermediate 32, starting from 2-amino-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-phenol (11.0 g, 46.7 mmol) and 6-fluoro-3-iodo-1-(phenylsulfony1)-1H-indole (Intermediate 1, 12.5 g, 31.2 mmol), 7.2 g (60%) of the title compound was obtained as a brown solid. 1H NMR (400 MHz, CDC13) 6 [ppm]:
7.91 (s, 1H), 7.89 (s, 1H), 7.77 (dd, J = 10.0, 2.0 Hz, 1H), 7.66 (dd, J =
8.8, 4.8 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.51 - 7.44 (m, 2H), 7.02 (td, J = 8.8, 2.0 Hz, 1H), 6.94 (s, 1H), 6.89 - 6.85 (m, 1H), 6.83 - 6.79 (m, 1H), 4.99 (brs, 1H), 3.80 - 3.69 (m, 2H).
Intermediate 71: 2-(chloromethyl)-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazole 4li FO \
SO2Ph To a stirred mixture of 2-amino-4-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-phenol (Intermediate 70, 2.5 g, 6.54 mmol) in DCM (25 mL) at 0 C was added chloro-acetyl chloride (887 mg, 7.85 mmol) and then TEA (990 mg, 9.81 mmol) slowly. The mixture was stirred at room temperature for 30 minutes before it was concentrated to afford brown oil. The above residue was diluted with AcOH (20 mL) and refluxed under nitrogen for 16 hours. Then it was cooled to room temperature and concentrated. The residue was suspended with sat.NaHCO3 (50 mL) and extracted with Et0Ac (50 mLx2).

The combined organic layer was washed with brine (30 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by a silica gel column chromatography (petroleum ether/Et0Ac = 10/1 - 5/1) to afford 1.1 g (38%) of the title compound as a brown solid. LC-MS for C22H14CIFN203S+11+ [M+H]: calcd. 441.0;
found:
441.4.
Intermediate 72: 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(piperazin-1-ylmethyl)benzo[d]oxazole ilk 1101 1\
F
SO2Ph To a stirred solution of piperazine (Intermediate 71, 195 mg, 2.27 mmol) in DMF (5 mL) at 60 C was added 2-(chloromethyl)-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)benzo[d]oxazole (Intermediate 71, 100 mg, 0.23 mmol). The mixture was stirred for 30 minutes. Then it was cooled to room temperature and diluted with Et0Ac (50 mL), washed with brine (30 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness to afford 80 mg (72%) of the title compound as a brown oil.
LC-MS for C26H23FN403S+11+ [M+H]: calcd. 491.2; found: 491.6.
Intermediate 73: 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-((4-methylpiperazin-1-yl)methyl)benzo[d]oxazole \\I
F lel SO2Ph 2-(chloromethyl)-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)benzo[d]oxazole (Intermediate 71, 200 mg, 0.45 mmol) was added to a stirred solution of 1-methyl-piperazine (450 mg, 4.5 mmol) in DMF (3 mL) at 60 C. The mixture was stirred for 30 minutes, cooled and diluted with Et0Ac (50 mL). The organic layer was washed with brine (30 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness to afford 160 mg (70%) of the title compound as a brown solid.
LC-MS for C27H22FN403S+H [M+H]: calcd. 505.2; found: 505.5.
Intermediate 74: 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(morpholinomethyl)benzo[d]oxazole 0_,CNC) fi F'S \
S02Ph To a stirred solution of morpholine (391 mg, 4.5 mmol) in DMF (5 mL) was added (chloromethyl)-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)benzo[d]oxazole (Intermediate 71, 200 mg, 0.45 mmol) at 60 C. The mixture was stirred for 30 minutes, cooled and diluted with Et0Ac (50 mL). The organic layer was washed with brine (30 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness to afford 100 mg (45%) of the title compound as a brown solid. LC-MS
for C26H22FN304S+H [M+H]: calcd. 492.1; found: 492.5.
Intermediate 75: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazol-2(3H)-one HNIO
O

,o2Ph To a stirred solution of 2-amino-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)phenol (Intermediate 69, 500 mg, 1.3 mmol) and CD! (233 mg, 1.43 mmol) in anhydrous THF
(20 mL) was added TEA (1.08 mL) under nitrogen. The mixture was stirred at room temperature for 8 hours under nitrogen. The reaction mixture was diluted with water (30 mL) and extracted with Et0Ac (60 mLx3). The combined organic layer was washed with water (60 mLx3), dried over anhydrous Na2Sa4and filtered. The filtrate was concentrated to afford 531 mg (100%) of the title compound as a red solid. LC-MS for C21 Hi3FN204S-1-1- [M-Hy : calcd. 407.1; found: 406.8. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]:11.94 (s, 1H), 8.14 (d, J= 8.5 Hz, 1H), 7.87- 7.78 (m, 1H), 7.76- 7.70 (m, OH), 7.68 - 7.60 (m, 2H), 7.49 (d, J= 7.9 Hz, OH), 7.23 (td, J= 9.1, 2.2 Hz, OH), 7.18 (d, J=
7.8 Hz, 1H), 7.02 (s, 2H).
Intermediate 76: 2-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-oxobenzo[d]oxazol-3(2H)-yl)acetamide cl>--Al 0 ALI
w F
02Ph To a stirred solution of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazol-2(31-1)-one (Intermediate 75, 200 mg, 0.48 mmol) and K2CO3 (246 mg, 1.78 mmol) in NMP (6 mL) was added 2-bromoacetamide (61 mg, 0.45 mmol). The mixture was stirred at 60 C for 6 hours. The reaction mixture was filtered. The filtrate was diluted with water (60 mL) and extracted with Et0Ac (60 mLx3). The combined organic layer was washed with water (60 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 183 mg (80%) of the title compound as a yellow solid.
LC-MS for C23H16FN305S+H [M+H] : calcd. 466.1; found: 465.8.
Intermediate 77: 5-(1-Benzenesulfony1-6-fluoro-1H-indo1-3-y1)-1,3-dihydro-benzoimidazol-2-one H
NO
r = NH
ift \
F
N
SO2Ph To a solution of 4-(1-Benzenesulfony1-6-fluoro-1H-indo1-3-y1)-benzene-1,2-diamine (Intermediate 32, 200 mg, 0.50 mmol) in THF was added CD! (170 mg, 1.05 mmol).
The mixture was stirred overnight at room temperature. The solvent was removed to afford 185 mg (88%) of the title compound as a brown oil. LC-MS for C21 Hi4FN303S+H
[M+H]: calcd. 408.1; found: 408.4.
Intermediate 78: 2-chloro-N-(4-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-hydroxyphenyl)acetamide CI
HN-C

F lel SO2Ph To a stirred solution of 2-amino-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)phenol (Intermediate 69, 2.0 g, 5.2 mmol) in THF (200 mL) at 0 C was added TEA (787 mg, 7.8 mmol) followed by chloro-acetyl chloride (712 mg, 6.3 mmol). The mixture was stirred at room temperature for 2 hours before it was concentrated. The residue was extracted with Et0Ac, washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated to dryness to afford 1.4 g (61%) of the title compound as a brown solid.
Intermediate 79: 2-(chloromethyl)-6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)benzo[d]oxazole NcCI
O

F
O2Ph To a stirred solution of 2-chloro-N-(4-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-hydroxyphenyl)acetamide (Intermediate 78, 1.22 g, 2.7 mmol) in xylem (5 mL) was added PPTS (0.67 g, 2.7 mmol). The mixture was stirred at 150 C for 4 hours.
The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (100 mL) and extracted with Et0Ac (50 mLx3). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (Petrol Ether/Ethyl Acetate=2/1) to afford 746 mg (64%) of the title compound as a brown solid. LC-MS for C22H14CIFN203S+11+ [M+H]:
calcd.
441.0; found: 441Ø
Intermediate 80: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(morpholinomethyl)benzo[d]oxazole NNO) 14, F
02Ph To a stirred solution of 2-(chloromethyl)-6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)benzo[d]oxazole (Intermediate 79, 150 mg, 0.34 mmol) in DMF (20mL) at 60 C
was added dropwise morpholine (59 mg, 0.68 mmol) in DMF. The mixture was stirred at 60 C for 1 hour, cooled to room temperature and concentrated. The residue was diluted with Et0Ac (50 mL) and washed with water (40 mLx4). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 130 mg (80%) of the title compound as a brown solid. LC-MS for C26H22FN304S+11+
[M+H]:
calcd. 492.1; found: 492.1.

Intermediate 81: 3-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-oxobenzo[d]oxazol-3(21-1)-yl)propanamide H2N-t\I
_..0 iikbp w F
O2Ph To a stirred solution of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazol-2(3/4)-one (Intermediate 75, 300 mg, 0.73 mmol) and K2CO3 (406 mg, 2.94 mmol) in NMP (6 mL) was added 3-bromopropanamide (101 mg, 0.67 mmol). The mixture was stirred at 63 C for 6 hours. The reaction was filtered. The filtrate was diluted with water (60 mL) and extracted with Et0Ac (60 mLx3). The combined organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 280 mg (80%) of the title compound as a yellow solid. LC-MS for C24F118FN305S-F1- [M-Fly:
calcd. 478.1; found: 477.7.
Intermediate 82: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-((4-methylpiperazin-1-yl)methyl)benzo[d]oxazole \--õ, ----O

02Ph To a stirred solution of 2-(chloromethyl)-6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)benzo[d]oxazole (Intermediate 79, 300 mg, 0.68 mmol) in DMF (20 mL) at 60 C
was added dropwise 1-methyl-piperazine (136 mg, 1.36 mmol) in DMF. The mixture was stirred at 60 C for lhours, cooled to room temperature and concentrated. The residue was diluted with Et0Ac (50 mL) and washed with water (40 mLx4). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 285 mg (84%) of the title compound as a brown solid. LC-MS for C2+125FN403S+H

[M+H]: calcd. 505.2; found: 504.9.
Intermediate 83: 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazol-2(3H)-one 46, NH
FIN
02Ph A solution of 2-amino-4-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1) phenol (Intermediate 70, 1.00 g, 2.61 mmol) and CD! (0.63 g, 3.89 mmol) in THF (50 mL) was stirred at room temperature for 3 hours. The mixture was concentrated to afford 1.60 g (>100%) of the crude title compound as a black oil, which was used directly without further purification.
LC-MS for C21 F113FN204S H [M+H]: calcd. 409.1; found: 408.8.
Intermediate 84: 2-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-oxobenzo[d]oxazol-3(2H)-yl)acetamide 0,r0 0 .N, ji `---- N1H2 to2ph A mixture of 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1) benzo[cloxazol-2(3H)-one (Intermediate 83, 800 mg crude, 1.3 mmol), 2-bromoacetamide (215 mg, 1.56 mmol) and K2CO3 (550 mg, 3.98 mmol) in DMF (10 mL) was stirred at room temperature for 12 hours. The mixture was added into water and extracted with Et0Ac. The combined organic layer was concentrated to afford 600 mg (99%) of the crude title compound as yellow oil, which was used directly without further purification. LC-MS for C23H16FN305S+H [M+H]: calcd. 466.1; found: 465.8.
Intermediate 85: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[d]imidazol-2-amine N...õ..õrNH2 -I
= NH

02Ph Following the general method as outlined in Intermediate 32, starting from 6-fluoro-3-iodo-1-(phenylsulfony1)-1H-indole (Intermediate 1, 1.55 g, 3.86 mmol) and 6-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-benzo[climidazol-2-amine (1.30 g, 5.02 mmol;
prepared as described in US20070117818), 260 mg (17%) of the title compound was obtained as a brown solid. LC-MS for C21 Hi5FN402S+H [M+H]: calcd. 407.1;
found:
407.4.
Intermediate 86: tert-butyl ((5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazol-211)methyl)(methylsulfonyl)carbamate O/
afklo-ct, 44Ik F
SO2Ph A mixture of (tert-butoxy)-N-(methylsulfonyl) carboxamide (53 mg, 0.273 mmol), (chloromethyl)-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)benzo[d]oxazole (Intermediate 71, 100 mg, 0.227 mmol) and K2CO3 (78 mg, 0.568 mmol) in DMF (3 mL) was stirred at 50 C for 2 hours. Then it was cooled to room temperature and quenched with water (10 mL). The mixture was extracted with Et0Ac (10 mLx3), washed with brine (10 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by a preparative TLC (petroleum ether/Et0Ac = 4/1) to afford 50 mg (37%) of the title compound as a yellow solid. LC-MS for C28H26FN307S2+H

[M+H]: calcd. 600.1; found: 600.5.
Intermediate 87: N-((5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)methanesulfonamide :
.s/
O

F
SO2Ph To a solution of Ni5-(1-benzenesulfony1-6-fluoro-1H-indol-3-y1)-benzooxazol-2-ylmethyl]-methanesulfonamide (Intermediate 86, 100 mg, 0.17 mmol) in Et0Ac (2 mL) was added HCl/Et0Ac (2 mL, 4M). The reaction was stirred at room temperature for 16 hours then the mixture was concentrated to dryness to afford 83 mg (100%) of the title compound as a yellow solid. LC-MS for C23H18FN305S2+H [M+H]: calcd. 500.1;
found:
499.9.
Intermediate 88: 3-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-oxobenzo[d]oxazol-3(2H)-yl)propanamide NH
iii Nn.... 2 Fl \
02Ph The mixture of 5-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-3H-benzooxazol-2-one(Intermediate 83, 370 mg, 0.91 mmol), 3-bromo-propionamide(127 mg, 0.91 mmol) and K2CO3(458 mg, 3.31 mmol) in NMP (8 mL) was stirred at 65 C overnight. The reaction mixture was diluted with EA and washed with water (50 mLx4) and brine. The solvent was removed to give 270 mg (62%) as an orange solid. LC-MS for C24H18FN305S-H- [M-Hy: calcd. 408.1; found: 477.8.

Intermediate 89: 2-Benzo[b]thiophen-5-y1-4,4,5,5-tetramethy141,3,2]dioxaborolane k%
Following the general method as outlined in Intermediate 3, starting from 5-bromo-benzo[b]thiophene (500 mg, 2.35 mmol) and 4,4,5,5,4',4',5',5'-Octamethyl -[2,2']bi[[1,3,2]dioxaborolanyl] (776 mg, 3.06 mmol), the tile compound (720 mg, >100%, crude ) was obtained as a yellow oil.
1H NMR (400 MHz, CDCI3) 6 8.31 (s, 1H), 7.89 (d, J= 8.0 Hz, 1H), 7.75 (d, J=
8.0 Hz, 1H), 7.41 (d, J = 5.4 Hz, 1H), 7.35 (d, J = 5.2 Hz, 1H), 1.37 (s, 12H).
Intermediate 90: 3-(benzo[b]thiophen-5-y1)-6-fluoro-1-(phenylsulfony1)-1H-indole "S

F = \
N
02Ph The mixture of 6-fluoro-3-iodo-1-(phenylsulfonyI)-1H-indole (Intermediate 1, 401 mg, 1.0 mmol) , 2-benzo[b]thiophen-5-y1-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (423 mg, 1.30 mmol, crude), and K3PO4 (636 mg, 3.0 mmol) in dioxane (12 mL) and water (3 mL) was bubbled with nitrogen for 5 mins. Pd(dppf)Cl2 (73 mg, 0.1 mmol) was added and the mixture was bubbled with nitrogen for another 5 mins. The mixture was placed into microwave reactor and stirred at 90 C under nitrogen for 1.5 h. The solvent was removed. The residue was dissolved in PE/EA (100 mL, PE/EA=3/1) and filtered through a short plug of silica. The solvent was removed to get 500 mg of the title compound as a yellow oil.
Intermediate 91: tert-butyl ((6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazol-211)methyl)(methylsulfonyl)carbamate o t /
N._._./N' AD
boc w_ F
02Ph To a stirred solution of tert-butyl methylsulfonylcarbamate (155 mg, 0.82 mmol), K2CO3 (235 mg, 1.70 mmol) in DMF (15 mL) was added 2-(chloromethyl)-6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)benzo[d]oxazole (Intermediate 79, 300 mg, 0.68 mmol).
The mixture was stirred at 50 C for 5 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with water (60 mL) and extracted with Et0Ac (60 mLx3). The combined organic layer was washed with water (20 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 198 mg (49%) of the title compound as a yellow solid. LC-MS for C28H26FN307S2+H
[M+H] :
calcd. 600.1; found: 599.8.
Intermediate 92: tert-butyl ((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methyl)(methylsulfonyl)carbamate o \\s/
Nz...rN' t boc O
FS N\
H
To a stirred solution of tert-butyl ((6-(6-fluoro-1-(phenylsulfony1)-1H-indol-yl)benzo[d]oxazol-2-yl)methyl)(methylsulfonyl)carbamate (Intermediate 91, 148 mg, 0.25 mmol) in Me0H (15 mL) was added NaOH (99 mg, 2.5 mmol). The mixture was stirred at 85 C for 1 hour. The reaction mixture was cooled to room temperature and neutralized with HCI (12 M). The mixture was diluted with water (60 mL) and extracted with Et0Ac (60 mLx3). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 114 mg (100%) of the title compound as a black solid. LC-MS for C22H22FN305S+H [M-Boc+Hr: calcd. 360.1; found: 360Ø
Intermediate 93: tert-butyl N-({6-[1 -(benzenesulfony1)-6-fluoro-1H-indo1-3-y1]-1,3-benzoxazol-2-yl}methyl)-N-[(tert-butoxy)carbonyl]carbamate Boc Nz.z.CN:
1Boc fk 40 N\
F
bo2ph To a stirred solution of di-tert-butyl iminodicarboxylate (640 mg, 2.95 mmol), K2CO3 (900 mg, 6.5 mmol) and KI(34 mg, 0.2 mmol) in DMF (30 mL) was added 2-(chloromethyl)-6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)benzo[d]oxazole (Intermediate 79, 1 g, 2.27 mmol) at 60 C. The mixture was stirred at 60 C for 5 hours.The reaction was neutralized with HCI (12 M) and filtered. The filtrate was diluted with water (60 mL) and extracted with Et0Ac (60 mLx3). The combined organic layer was washed with water (60 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 1.4 g (100%) of the title compound as a black oil. LC-MS for C32H32FN307S2+H
[M-Boc+H] : calcd. 522.2 ; found: 522.9.
Intermediate 94: tert-butyl N-[(tert-butoxy)carbony1]-N-([6-(6-fluoro-1H-indol-3-y1)-1,3-benzoxazol-2-yl]methylIcarbamate BOC
Nzf N6'oc lik FSH
To a stirred solution of tert-butyl N-({6-[1 -(benzenesulfony1)-6-fluoro-1H-indo1-3-y1]-1,3-benzoxazol-2-yl}methyl)-N-[(tert-butoxy)carbonyl]carbamate (Intermediate 93;
1.36 g, 2.20 mmol) in Me0H (50 mL) was added NaOH (878 mg, 21.96 mmol). The mixture was stirred at 85 C for 1 hour. The reaction mixture was cooled to room temperature and neutralized with HCI (12 M) and filtered. The filtrate was diluted with water (60 mL) and extracted with Et0Ac (70 mLx3). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel chromatography (petroleum ether/ Et0Ac =6/1 - 2/1) to afford 406 mg (39%) of the title compound as a yellow solid. LC-MS for C26H28FN305+H [M-Boc+H] : calcd. 382.2; found: 381.9.
Intermediate 95: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(piperazin-1-ylmethyl)benzo[d]oxazole N___/---N1H
VI.
ES ' bo2Ph To a stirred solution of 2-(chloromethyl)-6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)benzo[d]oxazole (Intermediate 79, 500 mg, 1.13 mmol) in DMF (20 mL) at 60 C, was added dropwise piperazine (195 mg, 2.26 mmol) in DMF. The reaction was stirred at 60 C for lhour before it was cooled to room temperature and concentrated. The residue was diluted with water (20 mL) and extracted with Et0Ac (20 mLx4).The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 277 mg (50%) of the title compound as a brown solid. LC-MS for C26H23FN403S+H

[M+H]: calcd. 491.2; found: 490.8.
Intermediate 96: 2-(benzo[b]thiophen-6-y1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane Oi 40 \
\_..._0 Following the general method as outlined in Intermediate 3, starting from 6-bromo-benzo[b]thiophene (1.0 g, 4.7 mmol) and 4,4,4',4',5,5,5',5'-octamethy1-2,2'-bi(1,3,2-dioxaborolane (1.78 g, 7.0 mmol), 2.0 g (crude) of the title compound was obtained as a black solid, which was used directly without further purification.
Intermediate 97: 3-(benzo[b]thiophen-6-y1)-6-fluoro-1-(phenylsulfony1)-1H-indole , =
Fl \
bo2ph Following the general method as outlined in Intermediate 90, starting from 6-fluoro-3-iodo-1-(phenylsulfony1)-1H-indole (Intermediate 1, 500 mg, 1.2 mmol) and 2-(benzo[b]thiophen-6-y1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane (Intermediate 96, 420 mg, 1.6 mmol), 338 mg (70%) of the title compound was obtained as a white solid.
Intermediate 98: 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(2-(methylthio)ethypenzo[d]oxazole s, 44ko.._C

so2Ph To a stirred solution of 3-methylsulfanyl-propionic acid (198 mg, 1.65 mmol) in DCM (15 mL) at -10 C was added TEA (317 mg, 3.14 mmol), followed by isobutyl chloroformate (321 mg, 2.36 mmol). The white suspension was stirred at 0 C for 20 minutes before 2-amino-4-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-phenol (Intermediate 70, 600 mg, 1.57 mmol) was added. The mixture was stirred at room temperature for 30 minutes before it was concentrated to dryness. The residue was diluted with AcOH (10 mL), ref luxed for 16 hours, cooled to room temperature and concentrated. The residue was suspended with aqueous NaHCO3 (30 mL), extracted with Et0Ac (40 mLx2). The combined organic layer was washed with brine (30 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated and purified by silica gel column chromatography (petroleum ether/Et0Ac = 20/1 to 5/1) to afford 320 mg (44%) of the title compound as a brown solid. LC-MS for C24H19FN203S2+H [M+H]: calcd.
467.1;
found: 467.5. 1H NMR (400 MHz, CDCI3) 6 [ppm]: 7.97 - 7.92 (m, 2H), 8.85 (d, J= 1.6 Hz, 1H), 7.80 (dd, J = 9.6, 2.4 Hz, 1H), 7.71 - 7.66 (m, 2H), 7.62 - 7.55 (m, 2H), 7.53 -7.46 (m, 3H), 7.06 (td, J = 8.8, 2.4 Hz, 1H), 3.28 (t, J = 7.2 Hz, 2H), 3.06 (t, J = 7.2 Hz, 2H), 2.19 (s, 3H).
Intermediate 99: 5-(6-fluoro-1H-indo1-3-y1)-2-(2-(methylthio)ethyl)benzo[d]oxazole S, 40,0..0 FS N\
H
A mixture of 5-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-2-(2-methylsulfanyl-ethyl)-benzooxazole (320 mg, 0.687 mmol) and NaOH (137 mg, 3.43 mmol) in Me0H (10 mL) was stirred at 65 C for 1 hour before it was cooled to room temperature. The mixture was diluted with water (30 mL) and extracted with Et0Ac (30 mLx2). The combined organic layer was washed with brine (20 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated and purified by silica gel column chromatography (petroleum ether/Et0Ac = 20/1 to 5/1) to afford 70 mg (31%) of the title compound as a yellow solid. LC-MS for C18H16FN20S+H [M+H]: calcd. 327.1; found: 327.4. 1H
NMR
(400 MHz, DMSO-d6) 6 [ppm]: 8.28 (brs, 1H), 7.91 (s, 1H), 7.82 (dd, J= 8.8, 5.2 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.34 (d, J= 2.4 Hz, 1H), 7.13 (dd, J= 9.6, 2.4 Hz, 1H), 6.96 (td, J = 9.2, 2.0 Hz, 1H), 3.93 (t, J = 6.4 Hz, 2H), 3.42 (s, 3H), 3.25 (t, J
= 6.4 Hz, 2H).
Intermediate 100: tert-butyl 6-fluoro-3-(2-(2-(methylthio)ethyl)benzo[d]oxazol-5-y1)-1 H-indole-1-carboxylate S, 44;f/
SI 1\
F Boc To a solution of 5-(6-fluoro-1H-indo1-3-y1)-2-(2-methylsulfanyl-ethyl)-benzooxazole (70 mg, 0.215 mmol) in DCM (10 mL) was added Boc20 (93 mg, 0.429 mmol) at 0 C, followed by DMAP (8 mg, 0.0064 mmol). The mixture was stirred for 30 minutes before it was quenched with ice water (20 mL) and extracted with DCM (30 mLx2). The combined organic layer was washed with brine (20 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness to afford 56 mg (61%) of the title compound as a white solid. LC-MS for C23H23FN203S+H [M+H]: calcd.
427.1;
found: 427.6.
Intermediate 101: tert-butyl 6-fluoro-3-(2-(2-(methylsulfonypethyl)benzo[d]oxazol-5-y1)-1H-indole-1-carboxylate 0'\s"
of /O
I.

F Boc To a stirred solution of 6-fluoro-3-[2-(2-methylsulfanyl-ethyl)-benzooxazol-5-y1]-indole-1-carboxylic acid tert-butyl ester (56 mg, 0.13 mmol) in DCM (5 mL) was added m-CPBA
(80 mg, 0.39 mmol, 85%) at 0 C. The reaction was stirred at r.t. for 20 minutes. The mixture was diluted with aqueous NaHCO3 (20 mL) and extracted with Et0Ac (20 mLx2).
The combined organic layer was washed with brine (20 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative TLC
(petroleum ether/Et0Ac = 3/1) to afford 45 mg (75%) of the title compound as a white solid. LC-MS for C23H23FN205S+H [M+H]: calcd. 459.1; found: 459.6. 1H NMR
(400 MHz, CDC13) 6 [ppm]: 8.18-8.00 (m, 1H), 7.99 - 7.90 (m, 1H), 7.88 (s, 1H), 7.72 - 7.66 (m, 1H), 7.58 - 7.50 (m, 1H), 7.40 - 7.30 (m, 1H), 7.04 (td, J = 8.8, 2.0 Hz, 1H), 3.69 (t, J
= 7.2 Hz, 2H), 3.54 (t, J = 7.2 Hz, 2H), 3.03 (s, 3H), 1.68 (s, 9H).
Intermediate 102: tert-butyl N-({5-[1-(benzenesulfony1)-6-fluoro-1H-indo1-3-y1]-1,3-benzoxazol-2-yl}methyl)-N-[(tert-butoxy)carbonyl]carbamate BOC
0-7--1\1' \I boc 4i lel F
SO2Ph A mixture of 5-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-2-chloromethyl-benzooxazole (Intermediate 71, 100 mg, 0.227 mmol), tert-butyl [(tert-butoxy)carbonylamino]formate (148 mg, 0.682 mmol), KI (38 mg, 0.227 mmol) and K2CO3 (94 mg, 0.682 mmol) in DMF
(5 mL) was stirred at 60 C for 5 hours. Then it was cooled to room temperature, diluted with Et0Ac (30 mL), washed with brine (20 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by a silica gel column chromatography (petroleum ether/Et0Ac = 50/1 to 15/1) to afford 114 mg (81%) of the title compound as a yellow solid. LC-MS for C32H32FN307S+H [M+H]: calcd.
622.2;
found: 622.7.
Intermediate 103: tert-butyl ((5-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-yl)methyl)carbamate 0.__CNHBoc ift F lel \
H
To a solution of tert-butyl N-({5-[1 -(benzenesulfony1)-6-fluoro-1H-indo1-3-y1]-1,3-benzoxazol-2-yl}methyl)-N-[(tert-butoxy)carbonyl]carbamate (Intermediate 102, 114 mg, 0.183 mmol) in Me0H (8 mL) was added NaOH (73 mg, 1.83 mmol). The mixture was ref luxed for 4 hours before it was cooled to room temperature. The solvent was removed.
The residue was diluted with water (20 mL) and extracted with Et0Ac (20 mLx2).
The combined organic layer was washed with brine (20 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by a silica gel column chromatography (petroleum ether/Et0Ac = 10/1 to 3/1) to afford 63 mg (90%) of the title compound as a brown oil. 1H NMR (300 MHz, CDCI3) 6 [ppm]: 8.31 (brs, 1H), 7.92 (s, 1H), 7.82 (dd, J= 9.3, 5.4 Hz, 1H), 7.63 - 7.54 (m, 2H), 7.35 (d, J= 2.4 Hz, 1H), 7.13 (dd, J = 9.3, 2.4 Hz, 1H), 6.97 (td, J = 9.3, 2.4 Hz, 1H), 4.66 (d, J = 5.7 Hz, 2H), 1.49 (s, 9H).
Intermediate 104: 3-(benzofuran-5-y1)-6-fluoro-1-(phenylsulfony1)-1H-indole = I
Fl \
02Ph Following the general method as outlined in Intermediate 90, starting from 6-fluoro-3-iodo-1-(phenylsulfony1)-1H-indole (Intermediate 1, 412 mg, 1.03 mmol) and benzofuran-5-ylboronic acid (250 mg, 1.54 mmol), 340 mg (85%) of the title compound was obtained as a white solid. LC-MS for C22H14FNO3S+H [M+H]: calcd. 392.1; found: 391.8.

NMR (400 MHz, DMSO-d6) 6 [ppm]: 8.17- 8.13 (m, 2H), 8.12 (s, 1H), 8.06 (d, J =
2.2 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.87 (dd, J = 8.8, 5.3 Hz, 1H), 7.82 (dd, J
= 9.9, 2.4 Hz, 1H), 7.76 - 7.69 (m, 2H), 7.67 - 7.60 (m, 3H), 7.24 (ddd, J = 9.5, 8.8, 2.4 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H).
Intermediate 105: tert-butyl 4-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazol-2-yl)piperidine-1-carboxylate Boc .....pr N.....
gli Fl \
O2Ph To a solution of 4-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (394 mg, 1.73 mmol) in dry DCM (10 mL) was added trimethyloxonium tetrafluoroborate (256 mg, 1.73 mmol) in portions at room temperature under nitrogen. The mixture was stirred at room temperature for 24 hours. Then 2-amino-5-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-phenol (Intermediate 69, 726 mg, 1.90 mmol) was added in one portion. The mixture was stirred at room temperature for 4 hours before it was diluted with aqueous NaHCO3 (20 mL) and extracted with DCM (30 mLx3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2Sa4and filtered. The filtrate was concentrated and purified by silica gel chromatography (PE/Et0Ac = 2/1) to afford 540 mg (54%) of the title compound as a brown solid. LC-MS for C31F130FN305S+H
[M+H]:
calcd. 576.2; found: 576.7. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 8.21 (s, 1H), 8.15 (d, J=
7.6 Hz, 2H), 8.04 (s, 1H), 7.89 (dd, J= 4.8, 8.8 Hz, 1H), 7.84 - 7.78 (m, 2H), 7.75 - 7.68 (m, 2H), 7.63 (t, J= 7.6 Hz, 2H), 7.24 (td, J= 1.6, 8.8 Hz, 1H), 3.97 (d, J= 12.8 Hz, 2H), 3.32 - 3.25 (m, 1H), 3.01 (brs, 2H), 2.11 (d, J= 10.8 Hz, 2H), 1.75- 1.65(m, 2H), 1.42 (s, 9H).
Intermediate 106: tert-butyl 4-(6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)piperidine-1-carboxylate BOC
'P
FS N\
H
To a solution of tert-butyl 4-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazol-2-yl)piperidine-1-carboxylate (Intermediate 105, 1.62 g, 2.82 mmol) in methanol (100 mL) was added NaOH (1.13 g, 28.2 mmol) at room temperature. The mixture was stirred at 60 C for 2 hours. The mixture was cooled to room temperature and concentrated. The residue was diluted with water (100 mL) and extracted with Et0Ac (100 mLx3).
The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 1.23 g (99%) of the title compound as a gray solid. LC-MS for C25H26FN303+H [M+H]: calcd. 436.2; found: 436.6.
Intermediate 107: methyl 3-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazol-2-yl)propanoate o Neo-=
F 401 N\
SO2Ph To a stirred solution of succinamic acid methyl ester (500 mg, 3.82 mmol) in 1, 2-dichloro-ethane (10 mL) was added Meerwein's reagent (621 mg, 4.20 mmol) dropwise at room temperature. The mixture was stirred for 16 hours before a solution of 2-amino-5-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-phenol (Intermediate 69, 1.46 g, 3.82 mmol) in anhydrous Me0H (15 mL) was added. The mixture was stirred for a further 3 hours before it was quenched with aqueous NaHCO3 (50 mL) and extracted with Et0Ac (30 mLx3). The combined organic layer was washed with brine (20 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by a silica gel column chromatography (petroleum ether/Et0Ac = 10/1 to 5/1) to afford 110 mg (6%) of the title compound as a brown solid. LC-MS for C26H19FN206S+H [M+H]: calcd.
479.1;
found: 479.6. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 8.21 (s, 1H), 8.16 (d, J= 8.1 Hz, 2H), 8.04 (s, 1H), 7.93-7.59 (m, 7H), 7.23 (td, J = 9.0, 1.8 Hz, 1H), 3.62 (s, 3H), 3.24 (t, J= 9.2 Hz, 2H), 2.94 (t, J= 9.2 Hz, 2H).
Intermediate 108: 3-(6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-Apropanoic acid NeOH
4Ik F lel \
H
A mixture of 346-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-benzooxazol-2-y1]-propionic acid methyl ester (Intermediate 107, 60 mg, 0.126 mmol) and NaOH (50 mg, 1.26 mmol) in Et0H (8 mL) was stirred at 76 C for 1 hour. Then it was cooled to room temperature and concentrated. The mixture was diluted with water (10 mL) and suspended with petroleum ether/Et0Ac = 1/1 (10 mL, v/v). The aqueous layer was acified with 1M HCI to pH = 4 and extracted with Et0Ac (20 mLx3). The combined organic layer was washed with brine (20 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated to dryness to afford 52 mg (70%) of the title compound as a brown oil. LC-MS for C18H13FN203+H [M+H]: calcd. 325.1; found: 325.3.
Intermediate 109: 2-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[d]imidazol-1-yl)acetamide & 2-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[d]imidazol-1-ypacetamide tO
N---_-_ \ 0 O. NH2 AIL I
FINFIN
02Ph 02Ph A mixture of 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazole (Intermediate 27, 1.00 g, 2.55 mmol), 2-bromoacetamide (450 mg, 3.26 mmol) and K2CO3 (700 mg, 5.06 mmol) in NMP (30 mL) was stirred at room temperature for hours. The mixture was added into water dropwise. The yellow precipitate was collected by vacuum filtration. The solid was dissolved in Et0Ac, washed with brine, dried over anhydrous Na2504 and filtered. The filtrate was concentrated and purified by silica gel chromatography (DCM ¨ DCM/Me0H = 9/1, v/v) to afford 400 mg (35%) of a mixture of the title compound and its region-isomer as a yellow solid. It was further purified by chiral preparative HPLC (SFC) to afford 100 mg (9%) the title compound as a white solid and 60 mg (5%) of the other regio-isomer 2-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazol-1-yl)acetamide as a white solid. LC-MS for C23H17FN403S+H
[M+H]: calcd. 449.1; found: 448.8.
Intermediate 110: ethyl 3-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazol-1-yl)propanoate IN
N,õ , z ).L0 Fl ' 02Ph A mixture of 5-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-1H-indazole (Intermediate 12, 6.5 g, 1.66 mmol), acrylic acid ethyl ester (3.32 g, 33.2 mmol) and Cs2CO3 (16.2 g, 49.8 mmol) in DMF (60 mL) was stirred at room temperature for 3 hrs. Then the reaction mixture was poured into water and extracted with Et0Ac (50 mLx3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/Et0Ac = 5/1 - 1/1) to afford 3.5 g (43%) of the title compound as a white solid. LC-MS for C26H22FN304S+H [M+H]: calcd. 492.1; found: 491.8. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 8.16-8.13 (m, 4H), 8.08 (s, 1H), 7.91 -7.87 (m, 1H), 7.85 -7.79 (m, 2H), 7.75 - 7.70 (m, 2H), 7.66 - 7.61 (m, 2H), 7.25 (td, J= 9.2, 2.4 Hz, 1H), 4.68 (t, J=
6.4 Hz, 2H), 4.00 (q, J= 7.2 Hz, 2H), 2.95 (t, J= 6.4 Hz, 2H), 1.10 (t, J= 7.2 Hz, 3H).
Intermediate 111: 3-(5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-yl)propanoic acid N, / 1 NJ )(OH
441k 101 N\
F H
A mixture of NaOH (855 mg, 21.4 mmol) and 3-[5-(1-Benzenesulfony1-6-fluoro-1H-indo1-3-y1)-indazol-1-y1]-propionic acid ethyl ester (Intermediate 110, 3.5 g, 7.13 mmol) in 50 mL of methanol was stirred at 75 C for 30 mins. The mixture was concentrated.
The residue was neutralized with 1 N HCI. The mixture was concentrated to give 4.2 g of the title compound as a yellow solid which was used for the next step without further purification. LC-MS for C18H14FN302+H [M+H]: calcd. 324.1; found: 323.9.

Intermediate 112: tert-butyl 4-(3-(5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-yl)propanoyl)piperazine-1-carboxylate N,N)-LN
/
41k N'Boc FSH
A mixture of 3-[5-(6-fluoro-1H-indo1-3-y1)-indazol-1-y1]-propionic acid (Intermediate 111, 300 mg, crude, 0.93 mmol), Piperazine-1-carboxylic acid tert-butyl ester (173 mg, 0.93 mmol), HATU (530 mg, 1.4 mmol) and DIEA (360 mg, 2.8 mmol) in DMF (5 mL) was stirred at room temperature for 2 hrs. Then the mixture was poured into water, extracted with Et0Ac (50 mLx3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (CH3CN/H20 = 30% - 75%, NH4HCO3) to afford 98 mg (21%) of the title compound as a yellow solid. LC-MS for C27H30FN503+H [M+H]: calcd. 492.2;
found:
491.9.
Intermediate 113: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)indolin-2-one = NH
Fl \
SO2Ph To a mixture of 6-fluoro-3-iodo-1-(phenylsulfonyI)-1H-indole (Intermediate 1, 600 mg, 1.50 mmol), 6-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-ypindolin-2-one (259 mg, 1.00 mmol, prepared as described in W02014140075) and K2CO3 (276 mg, 2.00 mmol) in dioxane (10 mL) and water (1 mL) was added Pd(PPh3)4 (116 mg, 0.10 mmol). The mixture was stirred at 120 C for 2 hrs before it was concentrated. The residue was purified by silica gel chromatography (petroleum ether/Et0Ac = 5/1, v/v) to afford 400 mg (98%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCI3) 6 [ppm]:
7.96 - 7.90 (m, 2H), 7.81 (dd, J = 9.6, 2.4 Hz, 1H), 7.70 - 7.63 (m, 3H), 7.61 - 7.56 (m, 1H), 7.54 - 7.45 (m, 2H), 7.31 (d, J= 7.7 Hz, 1H), 7.22 (dd, J= 7.7, 1.5 Hz, 1H), 7.10 -7.01 (m, 2H), 3.59 (s, 2H).
Intermediate 114: 3-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[d]imidazol-1-yl)propanamide & 3-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[d]imidazol-111)propanamide 1N, -11,1 41 "niNH2 FIN
02Ph SO2Ph A mixture of 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazole (Intermediate 27, 1.66 g, 4.24 mmol), 3-bromopropionamide (970 mg, 6.38 mmol), (100 mg, 0.60 mmol) and K2CO3 (876 mg, 6.34 mmol) in NMP (10 mL) was stirred at 60 C for 12 hrs. Another batch of 3-bromopropionamide (2 mg, 12.7 mmol) and K2CO3 (2 mg, 12.7 mmol) were added and the mixture was stirred at 60 C for another 24 hours.
The mixture was poured into water (150 mL) and extracted with Et0Ac (50 mLx3).
The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel chromatography (DCM ¨ DCM/Me0H =
10/1) to afford 700 mg (37%) of a mixture of the title compound and its region-isomer as colorless oil, which was further purified by chiral preparative HPLC (SFC) to afford 140 mg (7%) the title compound as a white solid and 180 mg (9%) of the other regio-isomer 3-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazol-111)propanamide as a white solid. LC-MS for C24H19FN403S+H [M+H]: calcd. 463.1; found: 462.8.
Intermediate 115: 5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-Aindolin-2-one N

Following the general method as outlined in Intermediate 3, starting from 5-Bromo-1,3-dihydro-indo1-2-one(1.00 g, 4.72 mmol) and 4,4,5,5,4',4',5',5'-Octamethyl-[2,21bi[[1,3,2]dioxaborolanyl] (1.56 g, 6.14 mmol) , the title compound(1.20 g, crude) was obtained as a yellow solid. LC-MS for C14H18BN03+H [M+H]: calcd. 2620.1;
found:
260.4.
Intermediate 116: 1-Benzenesulfony1-6-fluoro-1',3'-dihydro-1H-[3,51biindoly1-2'-one HN
gli F lel 02Ph Following the general method as outlined in Intermediate 32, starting from 6-fluoro-3-iodo-1-(phenylsulfony1)-1H-indole (Intermediate 1, 0.96 g, 2.4 mmol) and 5-(4,4,5,5-Tetramethy141,3,2]dioxaborolan-2-y1)-1,3-dihydro-indol-2-one (0.84 g, 2.0 mmol) , the title compound (440 mg, 45%) was obtained as a yellow solid. LC-MS for C22H15FN203S-H-[M-Hy: calcd. 405.1; found: 405.4. 1H NMR (400 MHz, DMSO) 6 10.49 (s, 1H), 8.12 (d, J= 7.6 Hz, 2H), 8.01 (s, 1H), 7.86 - 7.76 (m, 2H), 7.72 (t, J= 7.5 Hz, 1H), 7.62 (t, J= 7.7 Hz, 2H), 7.55 (s, 1H), 7.51 (d, J= 7.9 Hz, 1H), 7.22 (td, J= 9.1, 2.3 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 3.54 (s, 2H).
Intermediate 117: 6-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-Abenzo[d]oxazol-amine N
0 B 401 c,,,\-NH2 Following the general method as outlined in Intermediate 3, starting from 6-Bromo-benzooxazol-2-ylamine (2.40 g, 11.3 mmol) and 4,4,5,5,4',4',5',5'-Octamethyl-[2,21bi[[1,3,2]dioxaborolanyl](3.73g, 14.7 mmol) , the title compound (2.66 g, 90%) was obtained as a yellow solid. LC-MS for C13H17BN203+H [M+H]: calcd. 261.1;
found:

261.4. 1H NMR (300 MHz, DMSO-d6) 6 [ppm]: 7.58 (s, 2H), 7.48 (s, 1H), 7.46 -7.43 (m, 1H), 7.18 (d, J= 7.8 Hz, 1H), 1.29 (s, 12H).
Intermediate 118: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazol-2-amine NH

O
F lel 02Ph Following the general method as outlined in Intermediate 90, starting from 6-fluoro-3-iodo-1-(phenylsulfony1)-1H-indole (Intermediate 1, 2.77 g, 6.90 mmol) and 6-(4,4,5,5-Tetramethy141,3,2]dioxaborolan-2-y1)-benzooxazol-2-ylamine (1.50 g, 5.77 mmol), the title compound (1.50 g, 64%) was obtained as a yellow solid. LC-MS for C21H14FN303S+H [M+H]: calcd. 408.1; found: 408.5.
Intermediate 119: N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methypethenesulfonamide \Ns"' NI___/---H- \-----4.0 FSH
To a stirred solution of (6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methanamine hydrochloride (Compound 76, 400 mg, 1.26 mmol), TEA (0.5 mL, 3.78 mmol) in DCM

(30 mL) was added 2-chloroethanesulfonyl chloride (0.17 mL, 1.30 mmol) at 0 C
under nitrogen. The mixture was stirred at room temperature for 3 hours under nitrogen. The reaction mixture was diluted with Et0Ac (60 mL) and filtered. The filtrate was concentrated and purified by silica gel column (petroleum ether/ Et0Ac = 2/1) to afford 147 mg (32%) of the title compound as yellow oil. LC-MS for C18H14FN303S+H
[M+H] :
calcd. 372.1; found: 372.5.

Intermediate 120: 6-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-2-yinylbenzo[d]oxazole 4Ik Following the general method as outlined in Intermediate 3, starting from 6-bromo-2-(2-chloro-ethyl)-benzooxazole (950 mg, 3.67 mmol) and B2Pin2 (1.12 g, 4.4 mmol), 700 mg (70%) of the title compound was obtained as a colorless oil.
1H NMR (400 MHz, CDCI3) 6 [ppm]: 7.95 (s, 1H), 7.78 (d, J= 8.0 Hz, 1H), 7.69 (d, J=
8.0 Hz, 1H), 6.76 (dd, J= 17.6, 11.2 Hz, 1H), 6.50 (dd, J= 17.6, 0.8 Hz, 1H), 5.88 (dd, J
= 11.6, 0.8 Hz, 1H), 1.37 (s, 12 H).
Intermediate 121: tert-butyl 6-fluoro-3-(2-yinylbenzo[d]oxazol-6-y1)-1H-indole-carboxylate fit Fl\
Boc Following the general method as outlined in Intermediate 32, starting from 6-(4, 4, 5, 5-tetramethyl-[1, 3, 2]dioxaborolan-2-yI)-2-vinyl-benzooxazole (700 mg, 2.58 mmol) and 3-bromo-6-fluoro-indole-1-carboxylic acid tert-butyl ester (970 mg, 3.10 mmol), 520 mg (53%) of the title compound was obtained as a white solid. 1H NMR (400 MHz, CDCI3) 6 [ppm]: 7.96 (d, J= 8.8 Hz, 1H), 7.78 (dd, J= 8.4, 0.4 Hz, 1H), 7.76 -7.70 (m, 3H), 7.59 (dd, J = 8.0, 1.6 Hz, 1H), 7.07 (td, J = 8.8, 2.4 Hz, 1H), 6.79 (dd, J = 17.6, 11.2 Hz, 1H), 6.50 (dd, J= 17.6, 0.8 Hz, 1H), 5.89 (dd, J= 11.2, 0.8 Hz, 1H), 1.70 (s, 9H).
Intermediate 122: tert-butyl 6-fluoro-3-(2-(2-(methylthio)ethypenzo[d]oxazol-6-y1)-1 H-indole-1-carboxylate s Nf---/
O
1.1 F Boc To a solution of 6-fluoro-3-(2-vinyl-benzooxazol-6-y1)-indole-1-carboxylic acid tert-butyl ester (Intermediate 121, 520 mg, 1.37 mmol) in anhydrous THF (6 mL) was added NaSMe (144 mg, 2.06 mmol) at 0 C. The mixture was slowly warmed to r.t. and heated at 60 C for 30 minutes. The mixture was cooled, diluted with Et0Ac (50 mL), washed with water (20 mL), brine (20 mLx2), dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether/Et0Ac = 20/1 to 10/1) to afford 480 mg (82%) of the title compound as a white solid. 1H NMR (400 MHz, CDCI3) 6 [ppm]: 7.96 (d, J= 9.2 Hz, 1H), 7.78 - 7.69 (m, 4H), 7.57 (dd, J= 8.0, 1.2 Hz, 1H), 7.06 (td, J= 8.8, 2.4 Hz, 1H), 3.29 (t, J= 7.6 Hz, 2H), 3.06 (t, J = 7.6 Hz, 2H), 2.20 (s, 3H), 1.70 (s, 9H).
Intermediate 123: tert-butyl 6-fluoro-3-(2-(2-(methylsulfonypethyl)benzo[d]oxazol-6-y1)-1H-indole-1-carboxylate O\\SfO
/

IF
Boc To a solution of 6-fluoro-342-(2-methylsulfanyl-ethyl)-benzooxazol-6-y1]-indole-1-carboxylic acid tert-butyl ester (480 mg, 1.13 mmol) in DCM (10 mL) was added m-CPBA (391 mg, 2.26 mmol) at 0 C. The mixture was stirred at r.t. for 20 minutes, poured into ice water (30 mL), extracted with Et0Ac (30 mLx2). The combined organic layer was washed with brine (20 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated and purified by silica gel column chromatography (petroleum ether/Et0Ac = 10/1 to 3/1) to afford 390 mg (75%) of the title compound as a yellow solid. LC-MS for C23H23FN205S+H [M+H]: calcd. 459.1; found: 459.6. 1H NMR
(300 MHz, CDCI3) 6 [ppm]: 7.96 (d, J= 8.7 Hz, 1H), 7.78-7.68 (m, 4H), 7.59 (dd, J=
8.4, 1.5 Hz, 1H), 7.07 (td, J = 9.0, 2.4 Hz, 1H), 3.70 (t, J = 7.8 Hz, 2H), 3.54 (t, J
= 7.8 Hz, 2H), 3.03 (s, 3H), 1.70 (s, 9H).
Intermediate 124: N-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazol-2-yl)methanesulfonamide N NH4, =à8 F
,(312ph To a solution of 6-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-benzooxazol-2-ylamine (Intermediate 118, 400 mg, 0.98 mmol) in pyridine (8 mL) was added Methanesulfonyl chloride (224 mg, 1.96 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed and the residue was redissolved in dichloromethane and washed with saturated NH4CI aqueous (20 mLx2) and brine (20 mL). The organic layer was dried and concentrated to afford 350 mg of the title compound (74%) as a black solid. LC-MS for C22H16FN305S2-H- [M-Hy: calcd.
484.1;
found: 484.4.
Intermediate 125: 2-(2-chloroethyl)-6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)benzo[d]oxazole C
Nf/I
F
IN

A solution of 2-amino-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1) phenol (Intermediate 69, 1.6 g, 4.19 mmol) and 3-chloro-propionimidic acid methyl ester ( 3.6 g, 20.94 mmol) in DCM (10 mL) was stirred at room temperature overnight under nitrogen. The reaction mixture was concentrated and diluted with water (50 mL), extracted with Et0Ac (100 mLx3) and the organic layer was concentrated and purified by flash chromatography on silica gel (Petroleum Ether/Et0Ac=5/1) to afford 280 mg (15%) of the title compound as a yellow solid. LC-MS for C23H16CIFN203S+H [M +H]: calcd. 454.1; found:
455.5. 1H
NMR (400 MHz, CDCI3) 6 [ppm]: 7.95 (d, J = 7.9 Hz, 2H), 7.81 (dd, J = 9.2, 1.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.73 -7.66 (m, 3H), 7.59 (t, J = 7.3 Hz, 1H), 7.54-7.48 (m, 3H), 7.07 (td, J= 9.2, 2.4 Hz, 1H), 4.04 (t, J= 6.8Hz, 2H), 3.45 (t, J= 6.8 Hz, 2H).
Intermediate 126: 6-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-Abenzo[d]oxazole 0, Following the general method as outlined in Intermediate 3, starting from 6-bromo-benzooxazole (510 mg, 2.58 mmol) and 4,4,5,5,4',4',5',5'-Octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (856 mg, 3.37 mmol), the title compound (740 mg, >100%) was obtained as a yellow solid. LC-MS for C13H16BN03+H [M+H]: calcd. 246.1;
found:
246.4. 1H NMR (300 MHz, CDCI3) 6 8.15 (s, 1H), 8.05 (s, 1H), 7.84 (dd, J= 8.0, 0.8 Hz, 1H), 7.80 (dd, J = 8.0, 0.5 Hz, 1H), 1.39 (s, 12H).
Intermediate 127: 6-(1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazole N\
02Ph Following the general method as outlined in Intermediate 90, starting from 1-Benzenesulfony1-3-iodo-1H-indole (500 mg, 1.30 mmol) and 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yI)-benzooxazole (442 mg, 1.43 mmol), the title compound (340 mg, 70%) was obtained as a black solid. LC-MS for C21 Hi 4N203S H [M+H]:
calcd.
375.1; found: 375.5.
Intermediate 128: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-vinylbenzo[d]oxazole 44, 1.1 SO2Ph Following the general method as outlined in Intermediate 32, starting from 6-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-2-vinylbenzo[d]oxazole (3.0 g, 11.07 mmol) and 6-fluoro-3-iodo-1-(phenylsulfony1)-1H-indole (Intermediate 1,4.8 g, 12.18 mmol), 2.3 g (50%) of the title compound was obtained as a white solid. LC-Ms for C23H16FN203S+H
[M+H]: calcd. 419.1; found: 419.6. 1H NMR (400 MHz, CDC13) 6 [ppm]: 7.95 (d, J= 7.4 Hz, 2H), 7.85 -7.74 (m, 2H), 7.72 (q, J= 5.1 Hz, 3H), 7.60 (t, J= 7.5 Hz, 1H), 7.57 -7.45 (m, 3H), 7.08 (td, J= 8.9, 2.4 Hz, 1H), 6.78 (dd, J= 17.6, 11.1 Hz, 1H), 6.51 (d, J=
17.6 Hz, 1H), 5.90 (d, J= 11.2 Hz, 1H).
Intermediate 129: 5-(6-chloro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazole o-I.

ol SO2Ph Following the general method as outlined in Intermediate 32, starting from 1-benzenesulfony1-6-chloro-3-iodo-1H-indole (568 mg, 1.36 mmol) and 5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-211)benzo[d]oxazole (Intermediate 42, 500 mg, 2.04 mmol), 340 mg (61%) of the title compound was obtained as a white solid.
LC-MS for C21H13CIN203S+H [M+H]: calcd. 409.0; found: 409.5. 1H NMR (300 MHz, DMSO-d6) 6 [ppm]: 8.82 (s, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 8.13 (d, J= 1.5 Hz, 2H), 8.03 (d, J= 1.8 Hz, 1H), 7.88 (m, 2H), 7.85 (dd, J= 8.4, 1.7 Hz, 1H), 7.73 (d, J=
7.5 Hz, 1H), 7.64 (t, J = 7.6 Hz, 2H), 7.41 (dd, J = 8.6, 1.9 Hz, 1H).

Intermediate 130: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazole-2-thiol H
=N.....z.gS

02Ph The mixture of 2-amino-5-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-phenol(Intermediate 69, 300 mg, 0.78 mmol) and KOH (63 mg, 0.95 mmol, 85%) in ethanol (20 mL) was added CS2(2 mL, 33.16 mmol). The mixture was stirred at 60 C
overnight. The solvent was removed to obtain 450 mg (crude) of the title compound as a yellow solid. LC-MS for C21 Hi3FN203S2-F1- [M-Hy: calcd. 423.1; found: 423.3.
Intermediate 131: tert-butyl 4-((6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)piperidine-1-carboxylate Boc N
NV
410.

SO2Ph To a solution of tert-butyl 4-(2-amino-2-oxoethyl)piperidine-1-carboxylate (500 mg, 2.07 mmol) in DCM (25 mL) was added Me3OBF4 (306 mg, 2.07 mmol. The mixture was stirred at room temperature under N2 overnight. Before 2-amino-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)phenol (Intermediate 69, 872 mg, 2.28 mmol) was added.
The mixture was stirred at 40 C for 2 hrs and then at room temperature overnight. The mixture was concentrated and the residue was purified by silica gel column with PE-EA
(5/1-1/1) to afford 350 mg of the title compound (28%) as a yellow solid. LC-MS for C32H32FN305S+H [M+H]: calcd. 590.2; found: 590.2.

Intermediate 132: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(piperidin-4-ylmethyl)benzo[d]oxazole H
N
NV
O
F SO2Ph 5 To a solution of tert-butyl 4-((6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)piperidine-1-carboxylate (300 mg, 0.51 mmol) in EA(2mL) was added EA-HCI (2 mL, 3N). The mixture was stirred at room temperature for lhr. The mixture was concentrated to afford the title product (249 mg, 100%) as a yellow solid. LC-MS for C27H24FN303S+H [M+H]: calcd. 490.2; found: 490.2.
Intermediate 133: tert-butyl methylsulfonyl((6-(1-(phenylsulfony1)-1H-indol-3-y1)benzo[d]oxazol-2-y1)methyl)carbamate t/
N/ N' t boc fi 01 N\
02Ph To a solution of tert-butyl methylsulfonylcarbamate (900 mg, 4.62 mmol), K2CO3 (1.3 g, 9.63 mmol) in DMF (60 mL) was added 2-(chloromethyl)-6-(1-(phenylsulfony1)-1H-indol-3-y1)benzo[d]oxazole (Intermediate 79, 1.49 g, 3.52 mmol). The mixture was stirred at 50 C for 9 hrs. The reaction mixture was filtered. The filtrate was diluted with water (60 mL) and extracted with Et0Ac (60 mLx3). The combined organic layer was washed with water (60 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel chromatography (petroleum ether/ Et0Ac =6/1 -3/1) to afford 1.25 g (61%) of the title compound as a yellow solid. LC-MS for C28H27N307S2+H [M+H] : calcd. 582.1; found: 582.7. 1H NMR (400 MHz, DMSO-d6) [ppm]:8.22 (s, 1H), 8.13 (d, J= 1.1 Hz, 1H), 8.11 (s, 1H), 8.09 (d, J= 1.3 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.76 (dd, J = 8.3, 1.5 Hz, 1H), 7.73 - 7.68 (m, 1H), 7.61 (t, J = 7.7 Hz, 2H), 7.47 - 7.42 (m, 1H), 7.39 - 7.34 (m, 1H), 5.17 (s, 2H), 3.57 (s, 3H), 1.43 (s, 9H).
Intermediate 134: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-methoxybenzo[d]oxazole N.s...%0, 441k F lei \
SO2Ph A mixture of 2-amino-5-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-phenol (Intermediate 69, 200 mg, 0.52 mmol), tetramethoxy-methane (1.40 g, 10.5 mmol) and toluene-4-sulfonic acid (20 mg, cat.) was stirred at 100 C for 4 hours. The mixture was cooled, concentrated and purified by a silica gel column chromatography (petroleum ether/Et0Ac = 20/1 to 5/1) to afford 120 mg (54%) of the title compound as a white solid.
LC-MS for C22H15FN204S+H [M+H]: calcd. 423.1; found: 423.6. 1H NMR (400 MHz, CDCI3) 6 [ppm]: 7.95 (s, 1H), 7.92 (d, J = 1.6 Hz, 1H), 7.80 (dd, J = 9.6, 2.4 Hz, 1H), 7.72 - 7.67 (m, 1H), 7.66 (s, 1H), 7.60 - 7.54 (m, 3H), 7.52 - 7.48 (m,2H), 7.45 (dd, J =
8.0, 1.6 Hz, 1H), 7.06(td, J = 9.2, 2.4 Hz, 1H), 4.26 (s, 3H).
Intermediate 135: tert-Butoxycarbonylamino([6-(6-fluoroindo1-3-yhbenzoxazol-2-yl]methyl} Sulfonamide N.....zremil,Boc 41k F (101 N\
H
The solution of chloride sulfonyl isocyanate (0.95 mL, 1.1 mmol) in dichloromethane (0.87 mL) was cooled in ice bath. Tert-butanol(0.11 mL, 1.2 mmol) was added and then it was stirred at room temperature for 1 hr. A flask was charged with C-[6-(6-Fluoro-1 H-indo1-3-y1) -benzooxazol-2-y1]-methylamine hydrochloride (Compound 76, 317 mg, 1.0 mmol) and dichloromethane (5 mL). After being cooled to -15 C with ice salt bath, the solution of tertbuyl[chlorosulfonyl]carbamate(prepared as above) was added.
After stirring for 10 mins, triethylamine (606 mg, 6.6 mmol) was added. The cold bath was removed, and the reaction was allowed to warm to 10 C. The reaction was monitored by TLC. When it's done, the mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (DCM/Methano1=40/1-20/1) to afford 240 mg (52%) as a yellow solid. LC-MS for C21F121FN405S+H [M+H]: calcd. 461.1;
found:
461.6. 1H NMR (400 MHz, DMSO) 6 11.48 (s, 1H), 11.02 (s, 1H), 8.55 (t, J= 6.0 Hz, 1H), 7.92 (d, J = 1.0 Hz, 1H), 7.87 (dd, J = 8.8, 5.4 Hz, 1H), 7.80 - 7.70 (m, 2H), 7.69 (dd, J = 8.3, 1.5 Hz, 1H), 7.24 (dd, J= 9.9, 2.4 Hz, 1H), 6.97 (td, J= 9.6, 2.4 Hz, 1H), 4.49 (d, J=
6.0 Hz, 2H), 1.34 (s, 9H).
Intermediate 136: 5-(1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazole 0_11 iiiL lki TIF-01 N\
SO2Ph Following the general method as outlined in Intermediate 32, starting from 3-iodo-1-(phenylsulfony1)-1H-indole (625 mg, 1.63 mmol) and 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yI)-benzooxazole (400 mg, 1.63 mmol), 525 mg (86%) of the title compound was obtained as a yellow solid.
LC-MS for C21 Hi4N203S H [M+H]: calcd. 375.1; found: 375.4 1H NMR (300 MHz, DMSO-d6) 6 [ppm]: 8.81 (s, 1H), 8.17 (s, 1H), 8.15 - 8.07 (m, 3H), 8.04 (d, J= 8.2 Hz, 1H), 7.90 - 7.81 (m, 2H), 7.79 (dd, J= 8.4, 1.8 Hz, 1H), 7.70 - 7.58 (m, 3H), 7.43 - 7.38 (m, 1H), 7.37-7.35 (m, 1H).
Intermediate 137: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-((1-(methylsulfonyl)piperidin-4-yl)methyl)benzo[d]oxazole oo FIN
SO2Ph To a solution of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(piperidin-4-ylmethyl)benzo[d]oxazole (Intermediate 132, 300 mg, 0.613 mmol) in DCM (6 mL), TEA
(186 mg,1.84 mmol) was added at room temperature. Then methanesulfonyl chloride (84 mg, 0.74 mmol) was added into the mixture at 0 C.The mixture was stirred at 0 C
for 2 hrs. H20 (10 mL) was added. The mixture was extracted with DCM (10mLx3).
The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column with PE-EA (4/1-1/1) to afford 275 mg (68%) of the title compound as a white solid. LC-MS for C28H26FN305S2+H [M+H]: calcd. 568.1;
found:
568.1.
Intermediate 138: 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-((1-methylpiperidin-4-yl)methyl)benzo[d]oxazole NV
O
lel F
SO2Ph To a solution of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(piperidin-4-ylmethyl)benzo[d]oxazole (Intermediate 132, 330 mg, 0.67 mmol) in DCM/Me0H
(6/3mL) was added AcOH (122 mg, 2.02 mmol), CH20/H20 (37%, 271 mg, 3.35 mmol) and NaBH(OAc)3 (428 mg, 2.02 mmol). The mixture was stirred at room temperature for 3 hrs before it was quenched with H20 (10 mL). The mixture was extracted with DCM
(15mLx3). The organic layer was dried over Na2SO4, filtered and concentrated.
The residue was purified by silica gel column with DCM-Me0H (100/2) to afford 250 mg (74%) of the title compound as a yellow solid. LC-MS for C28H26FN303S+H
[M+H]:
calcd.504.2; found: 504.2.
Intermediate 139: N-(2,4-dibromophenyI)-2-(2,5-dioxoimidazolidin-4-yl)acetamide NH

H
fi Br B
A mixture of hydantoin-5-acetic acid (1.00 g, 6.32 mmol), HATU (2.86 g, 7.52 mmol) and 2,4,6-collidine (1.42 g, 11.7 mmol) in DMF (50 mL) was stirred at room temperature for 0.5 hour before 2,4-dibromoaniline (1.45 g, 5.78 mmol) was added. The mixture was stirred at room temperature for 12 hours before it was poured into water and Et0Ac. The precipitate was collected by vacuum filtration to afford 450 mg (20%) of the crude title compound as a white solid, which was used directly without further purification. LC-MS
for C11H9Br2N303+H [M+H]: calcd. 389.9; found: 389.6. 1H NMR (300 MHz, DMSO-d6) 6 [ppm]: 10.62 (br s, 1H), 9.64 (br s, 1H), 7.90 ( s, 2H), 7.64 - 7.56 (m, 2 H), 4.31 (td, J=
6.6, 4.2 Hz, 1H), 2.89 - 2.83 (m, 1H), 2.75 -2.50 (m, 1H).
Intermediate 140: 5-((6-bromobenzo[d]oxazol-2-yl)methypimidazolidine-2,4-dione NzrekNH
B
A mixture of N-(2,4-dibromophenyI)-2-(2,5-dioxoimidazolidin-4-yl)acetamide (Intermediate 141, 200 mg, 0.51 mmol), K2CO3 (106 mg, 0.77 mmol), CuBr (150 mg, 1.05 mmol) and pyridine (0.5 mL) in DMF (5 mL) was stirred at 140 C for 2 hours in a microwave reactor. The mixture was partitioned between Et0Ac and saturated aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel chromatography (petroleum ether/Et0Ac = 1/1 ¨
Et0Ac) to afford 75 mg (47%) of the title compound as a yellow semisolid. LC-MS for C11H8BrN303-H- [M-Hy: calcd. 308.0; found: 307.8.
Intermediate 141: tert-butyl 3-(2-((2,5-dioxoimidazolidin-4-Amethyl)benzo[d]oxazol-6-y1)-6-fluoro-1H-indole-1-carboxylate NIzekNH
el F
bac Following the general method as outlined in Intermediate 32, starting from 5-((6-bromobenzo[cloxazol-2-yl)methypimidazolidine-2,4-dione (Intermediate 142, 310 mg, 1.00 mmol) and tert-butyl 6-fluoro-3-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1 H-indole-1-carboxylate (Intermediate 2, 543 mg, 1.50 mmol), 50 mg (11%) of the title compound was obtained as a yellow solid.

LC-MS for C24H21 FN405+11+ [M+H]: calcd. 465.2; found: 464.8. 1H NMR (400 MHz, Me0H-d4) 6 [ppm]: 7.94 (dd, J= 10.1, 2.3 Hz, 1H), 7.86 (d, J= 1.6 Hz, 1H), 7.81 (s, 1H).
7.80 (dd, J= 8.7, 5.4 Hz, 1H), 7.76 (d, J= 8.4 Hz, 1H), 7.66 (dd, J= 8.4, 1.6 Hz, 1H), 7.11 (ddd, J= 9.6, 8.7, 2.3 Hz, 1H), 4.70 (dd, J= 7.2, 4.6 Hz, 1H), 3.54 (dd, J= 16.3, 4.6 Hz, 1H), 3.40 (dd, J= 16.3, 7.2 Hz, 1H), 1.71 (s, 9H).
Intermediate 142: 6-(5-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazol-2(3H)-one HNIO
fb F, N\
02Ph To a stirred solution of 2-amino-5-(1-benzenesulfony1-5-fluoro-1H-indo1-3-y1)-phenol (770 mg, 2.01 mmol) and CD! (359 mg, 2.21 mmol) in anhydrous THF (30 mL) was added TEA (1.68 mL) under nitrogen. The mixture was stirred at room temperature for 12 hours under nitrogen. The reaction was diluted with water (60 mL) and extracted with Et0Ac (60 mLx3). The combined organic layer was washed with water (60 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 820 mg (100%) of the title compound as a yellow solid. LC-MS for C21 Hi 3FN204S-1-1- [M-Hy :
calcd.
407.1; found: 407.5. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.79 (s, 1H), 8.19 (s, 1H), 8.08 (d, J= 7.6 Hz, 2H), 8.03 (dd, J= 9.1, 4.5 Hz, 1H), 7.75 - 7.67 (m, 2H), 7.65 - 7.57 (m, 3H), 7.50 (dd, J= 8.0, 1.2 Hz, 1H), 7.28 (td, J= 9.1, 2.5 Hz, 1H), 7.18 (d, J= 8.1 Hz, 1H).
Intermediate 143: 2-(6-(5-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-oxobenzo[d]oxazol-3(2H)-yl)acetamide iik b F, N\
02Ph To a solution of 6-(5-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazol-2(3/4)-one (400 mg, 0.98 mmol) and K2CO3 (542 mg, 3.92 mmol) in NMP (20 mL) was added 2-bromoacetamide (135 mg, 0.98mmol). The mixture was stirred at 60 C for 6 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with water (60 mL) and extracted with Et0Ac (60 mLx3). The combined organic layer was washed with water (60 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford 183 mg (81%) of the title compound as a yellow solid.
LC-MS for C23F116FN305S-H- [M-Hy: calcd. 464.1; found:464.4. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 8.22 (s, 1H), 8.13 - 8.07 (m, 2H), 8.04 (dd, J= 9.2, 4.4 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.72 (t, J = 7.2 Hz, 1H), 7.66 - 7.55 (m, 4H), 7.40 (s, 1H), 7.33 - 7.26 (m, 2H), 4.50 (s, 2H).
Intermediate 144: dimethyl 4-(1-(tertbutoxycarbony1)-6-fluoro-1H-indol-3-y1)phthalate 0 d . =
FIN
hoc Following the general method as outlined in Intermediate 32, starting from 4-bromo-phthalic acid dimethyl ester(362 mg, 1.33 mmol) and 6-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-indole-1-carboxylic acid tert-butyl ester (Intermediate 2, 400 mg, 1.10 mmol), the title compound (400 mg, 72%) was obtained as a red solid.
LC-MS
for C23H22FN06+H [M+H]: calcd. 428.1; found: 428.6. 1H NMR (400 MHz, CDC13) 6 [ppm]
:7.97 (d, J= 10.0 Hz, 1H), 7.91 (d, J= 2.0 Hz, 1H), 7.88 (d, J= 8.4 Hz, 1H), 7.78 (dd, J= 8.0, 2.0 Hz, 1H),7.77(s, 1H), 7.70 (dd, J= 8.8, 5.2 Hz, 1H), 7.07 (td, J= 8.8, 2.4 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 1.70 (s, 9H).
Intermediate 145: 4-(6-fluoro-1H-indo1-3-yl)phthalic acid OH
OH
gitt .
F 01 \
H
To the solution of 6-fluoro-3-(4,4,5,5-tetramethy141,3,2]dioxaborolan-2-y1) -indole-1-carboxylic acid tert-butyl ester (Intermediate 146, 360 mg, 0.84 mmol) in methanol (10 mL) was added NaOH (135 mg, 3.37 mmol) and the mixture was stirred at room temperature. After 2 hrs NaOH (135 mg, 3.37 mmol) was added and the mixture was stirred for another 4 hrs. The solvent was removed. The residue was diluted with water (10 mL) and the pH was adjusted to 1-2. The mixture was extracted with EA (20 mLx3).The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The solvent was removed to afford 180 mg (72%) of the title compound as a yellow solid. LC-MS for C16H10FN04-H- [M-Hf: calcd. 298.1; found: 298.4. 1H
NMR (400 MHz, DMSO-d6) 6 [ppm]: 12.99 (brs, 2H), 11.64 (s, 1H), 7.92 (d, J= 2.4 Hz, 1H), 7.88 (dt, J=
6.6, 3.0 Hz, 3H), 7.79 (d, J= 8.0 Hz, 1H), 7.25 (dd, J= 10.0, 2.4 Hz, 1H), 7.01 (td, J= 9.4, 2.4 Hz, 1H).
Intermediate 146: tert-butyl 3-(2-(tert-butoxycarbonyl)isoindolin-5-y1)-6-fluoro-1H-indole-1-carboxylate Boc N' O
Fl \
hoc Following the general method as outlined in Intermediate 32, starting from tert-butyl 6-fluoro-3-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1 H-indole-1-carboxylate (Intermediate 2, 260 mg, 0.72 mmol) and 5-bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (278 mg, 0.93 mmol), 178 mg (55%) of the title compound was obtained as a white solid. LC-MS for C26H29FN204+H -56 [M+H-56] : calcd.
397.2;
found: 397.6. 1H NMR (400 MHz, CDCI3) 6 [ppm]: 7.97 - 7.93 (m, 1H), 7.74 -7.59 (m, 2H), 7.53-7.45(m, 2H), 7.37-7.28 (m, 1H), 7.07 - 7.02 (m, 1H), 4.76 - 4.71 (m, 4H), 1.69 (s, 9H), 1.54 (s, 9H).
Intermediate 147: tert-butyl 3-(1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-6-y1)-6-fluoro-1H-indole-1-carboxylate NH
40, boc Following the general method as outlined in Intermediate 32, starting from 6-bromo-2,3-dihydro-benzo[d]isothiazole 1,1-dioxide (70 mg, 0.28 mmol) and 6-Fluoro-3-(4,4,5,5-tetramethyli1,3,2]dioxaborolan-2-y1)-indole-1-carboxylic acid tert-butyl ester (Intermediate 2, 139 mg, 0.42 mmol), 50 mg (29%) of the title compound was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 8.13 (d, J= 8.7 Hz, 2H), 8.03 (dd, J= 8.4, 1.2 Hz, 1H), 7.92 - 7.83 (m, 3H), 7.67 (d, J= 8.1 Hz, 1H), 7.24 (td, J= 9.0, 1.5 Hz, 1H), 4.46 (s, 2H), 1.66 (s, 9H).
Intermediate 148: 4-(1-(tert-butoxycarbony1)-6-fluoro-1H-indo1-3-y1)-2-(N-methylsulfamoyl)benzoic acid OH

,_NH
Fl i3 o c Following the general method as outlined in Intermediate 32, starting from 6-bromo-2-methylbenzo[d]isothiazol-3(2H)-one1,1-dioxide (400 mg, 1.4 mmol) and 6-fluoro-(4,4,5,5-tetramethyli1,3,2]dioxaborolan-2-y1)-indole-1-carboxylic acid tert-butyl ester (Intermediate 2, 790 mg, 2.2 mmol), 150 mg (25%) of the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 9.65 (s, 1H), 7.98 - 7.75 (m, 6H), 7.27 (td, J = 9.2, 2.8 Hz, 1H), 2.39 (s, 3H), 1.66 (s, 9H).
Intermediate 149: tert-butyl 6-fluoro-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-y1)-1H-indole-1-carboxylate HNIO
O

Boc Following the general method as outlined in Intermediate 32, starting from 6-bromo-3H-benzooxazol-2-one (600 mg, 2.80 mmol) and 6-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-y1)-indole-1-carboxylic acid tert-butyl ester (Intermediate 2, 1.21 g, 3.36 mmol), 450 mg (45%) of the title compound was obtained as a white solid.

NMR (400 MHz, CDCI3) 6 [ppm]: 8.56 (s, 1H), 7.95 (d, J = 9.6 Hz, 1H), 7.69-7.64 (m, 1H), 7.46 (s, 1H), 7.42 (dd, J = 8.0, 1.6 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.06 (td, J=
8.8, 2.4 Hz, 1H), 3.71 (s, 1H), 1.70 (s, 9H).
Intermediate 150: tert-butyl 3-(3-(1-(tert-butoxycarbonyl)piperidin-4-yI)-2-oxo-2,3-di hydrobenzo[d]oxazol-6-y1)-6-fluoro-1H-indole-1-carboxylate Boccii_ gat- 1 lir F lel Boc To a stirred solution of 6-fluoro-3-(2-oxo-2,3-dihydro-benzooxazol-6-y1)-indole-1-carboxylic acid tert-butyl ester (Intermediate 151, 450 mg, 1.22 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (369 mg, 1.83 mmol) and PPh3 (480 mg, 1.83 mmol) in anhydrous THF (10 mL) was added DIAD (370 mg, 1.83 mmol) at 0 C.
The mixture was stirred at room temperature for 16 hours under N2 before it was diluted with Et0Ac (50 mL), washed with water (20 mL) and brine (20 mLx2). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by a silica gel column chromatography (petroleum ether/Et0Ac = 30/1 to 10/1) and preparative TLC (petroleum ether/Et0Ac = 10/1) to afford 125 mg (17%) of the title compound as a white solid. LC-MS for C301-134FN306+H [M+H]: calcd. 552.2;
found:
552.8. 1H NMR (400 MHz, CDCI3) 6 [ppm]: 7.94 (d, J= 10.0 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.46 (s, 1H), 7.40 (dd, J = 8.0, 2.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.06 (td, J = 8.8, 2.4 Hz, 1H), 4.43 - 4.30 (m, 3H), 2.95 - 2.83 (m, 2H), 2.36 - 2.24 (m, 2H), 1.95 -1.88 (m, 2H), 1.70 (s, 9H), 1.51 (s, 9H).
Intermediate 151: tert-butyl 6-fluoro-3-(2-methy1-1,1-dioxido-3-oxo-2,3-dihydrobenzo[clisothiazol-5-y1)-1H-indole-1-carboxylate -Nr . 6 F I.
boc To a solution of tert-butyl 3-(1,1-dioxido-3-oxo-2,3-dihydrobenzo[c]isothiazol-5-y1)-6-fluoro-1H-indole-1-carboxylate (Compound 130 Step 1, 246 mg, 0.59 mmol) and (245 mg, 1.77 mmol) in acetone (10 mL) was added Mel (126 mg, 0.89 mmol). The reaction mixture was stirred at 40 C overnight. The reaction was filtered, concentrated and triturated in Me0H to afford 60 mg (24%) of the title compound as a yellow solid. 1H
NMR (400 MHz, DMSO-d6) 6 [PPrn]: 8.43 - 8.38 (m, 2H), 8.35 (s, 1H), 8.33 (s, 1H), 7.97 - 7.91 (m, 2H), 7.28 (td, J = 9.2, 2.4 Hz, 1H), 3.21 (s, 3H), 1.67 (s, 9H).
Intermediate 152: tert-butyl 6-(2-(6-(6-fluoro-1H-indo1-3-yhbenzo[d]oxazol-2-yhethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate N_Boc NISJ
N...:...r/
=
\

H
To a stirred solution of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-vinylbenzo[d]oxazole (Intermediate 128, 100 mg, 0.24 mmol) in dry Me0H (10 mL) at 50 C was added 2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester (146 mg, 0.6 mmol; made according to the procedures reported by Org. lett., 2008, 10, 3525). The mixture was stirred at 50 C overnight. The solvent was removed. The residue was diluted with water (30 mL) and extracted with EA (10 mLx3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2Sa4and concentrated to afford 200 mg of the title compound as a white solid, which was used for next step without further purification.
Intermediate 153: tert-butyl 3-(benzofuran-6-yI)-6-fluoro-1H-indole-1-carboxylate . x.

Boc To a stirred solution of 6-bromobenzo[b]furan (100 mg, 0.507 mmol) in 1,4-dioxane (15 mL), tert-butyl 6-fluoro-3-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-indole-1-carboxylate (Intermediate 2, 180 mg, 0. 507 mmol), K2CO3 (210 mg, 1.52 mmol) and Pd(dppf)Cl2 (19 mg, 0.025 mmol) were added. The mixture was stirred at 80 C
for 15 hrs. The solvent was removed and the residue was purified by prep-TLC
(Et0Ac/Petroleum Ether=1/10) to afford 112.8 mg (63%) of the title compound.
LC-MS
for C21H18FN03+H [M+H] : calcd: 351.1; found: 351.8. 1H NMR (400 MHz, CDCI3) [ppm]: 7.96 (d, J= 4.8 Hz, 1H), 7.79-7.76 (m, 2H),7.71-7.67 (m, 3H),7.50 (dd, J= 8.0 Hz,1.6Hz, 1H),7.06 (dd, J= 8.8, 2.4 Hz, 1H), 6.82 (d, J= 1.0 Hz, 1H), 1.70 (s, 9H).

1.2. SYNTHESIS OF FINAL COMPOUNDS
Compound 1: 6-(6-fluoro-1H-indo1-3-y1)-1H-indazole To a solution of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazole (Intermediate 4;
390 mg; 1.00 mmol) in Me0H (15 mL) was added a solution of NaOH (200 mg; 5.00 mmol) in water (2 mL). The reaction mixture was stirred at 80 C for 2 hours, concentrated, and purified by a silica gel chromatography (petroleum ether/Et0Ac = 5/1 - 2/1) to afford 50 mg (20%) of the title compound as a white solid. LC-MS for C15H10FN3+H [M+H]: calcd. 252.1; found: 252.1. 1H NMR (300 MHz, DMSO-d6) 6 [ppm]: 12.94 (s, 1H), 11.45 (s, 1H), 8.05 (s, 1H), 7.88 (dd, J= 8.8, 5.4 Hz, 1H), 7.79 (d, J
= 8.4 Hz, 1H), 7.77 - 7.73 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.24 (dd, J =
10.0, 2.2 Hz, 1H), 6.99 (ddd, J = 9.3, 8.8, 2.2 Hz, 1H).
Compound 2: 2-(6-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-yl)acetamide A mixture of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazole (Intermediate 4;
300 mg; 0.77 mmol), 2-bromoacetamide (1.05 g; 7.61 mmol), K1(290 mg; 1.75 mmol), K2CO3 (986 mg; 7.13 mmol) in DMF (16.5 mL) was stirred at 60 C for 48 hours under nitrogen. The mixture was cooled to room temperature, diluted with Et0Ac (100 mL), filtered, concentrated, and purified by preparative HPLC to afford 25mg (11%) of the title compound as a yellow solid. LC-MS for C17H13FN4O+H [M+H]: calcd. 309.1;
found:
308.9. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.46 (s, 1H), 8.03 (s, 1H), 7.96 (dd, J= 8.7, 5.4 Hz, 1H), 7.80 -7.77 (m, 2H), 7.76- 7.73 (m, 2H), 7.55 (br s, 1H), 7.46 (dd, J=
8.3, 1.3 Hz, 1H), 7.26 (br s, 1H), 7.22 (dd, J= 9.9, 2.4 Hz, 1H), 6.96 (ddd, J= 9.6, 8.8, 2.4, 1H), 5.11 (s, 2H).
Compound 3: 6-(6-fluoro-1H-indo1-3-y1)-1-(piperidin-4-ylmethyl)-1H-indazole hydrochloride Following the general method as outlined in Compound 1, starting from 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1-(piperidin-4-ylmethyl)-1H-indazole hydrochloride and 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(piperidin-4-ylmethyl)-2H-indazole hydrochloride (Intermediate 6; 136 mg; 0.26 mmol), 3 mg (3%) of the title compound was obtained as a yellow solid after purification by preparative HPLC with 0.1% HCI as buffer. LC-MS for C21 H21FN4+H [M+H]: calcd. 349.2; found: 349Ø 1H NMR (300 MHz, DMSO-d6) 6 [ppm]: 11.52 (s, 1H), 9.26 (br s, 1H), 8.90 (br s, 1H), 8.39 (s, 1H), 7.87 (dd, J= 8.8, 5.4 Hz, 1H), 7.80 (s, 1H), 7.77 ¨ 771 (m, 2H), 7.41 (d, J= 8.6 Hz, 1H), 7.24 (d, J= 9.9, 2.3 Hz, 1H), 6.97 (ddd, J= 9.4, 8.8, 2.3 Hz, 1H), 4.38(d, J= 6.9 Hz, 2H), 3.18 ¨ 3.18 (m, 2H), 2.91 ¨
2.72 (m, 2H), 2.38 ¨ 2.22 (m, 1H), 1.73 ¨ 1.59 (m, 2H), 1.58¨ 1.40 (m, 2H).
Compound 4: 1-(4-((6-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-yl)methyl)piperidin-ypethanone Following the general method as outlined in Compound 1, starting from 1-(4-((6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazol-1-yl)methyl)piperidin-1-ypethanone (Intermediate 7; 267 mg; 0.50 mmol), 12 mg (6%) of the title compound was obtained as a white solid after purification by preparative HPLC. LC-MS for C23H23FN40-H-[M-Hy:
calcd. 389.2; found: 389Ø 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.51 (s, 1H), 8.05 (s, 1H), 7.95 (dd, J= 8.8, 5.4 Hz, 1H), 7.87 (s, 1H), 7.80 ¨ 7.76 (m, 2H), 7.47 (d, J= 8.4 Hz, 1H), 7.25 (dd, J= 9.9, 2.0 Hz, 1H), 6.99 (ddd, J= 9.4, 8.8, 2.0 Hz, 1H), 4.40 ¨4.30 (m, 3H), 3.82 ¨
3.73 (m, 1H), 2.99 ¨ 2.89 (m, 1H), 2.50 ¨ 2.40 (m, 1H), 2.26 ¨ 2.14 (m, 1H), 1.95 (s, 3H), 1.56 ¨
1.44 (m, 2H), 1.30¨ 1.16(m, 2H).
Compound 5: 3-(6-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-yl)propanamide Following the general method as outlined in Compound 1, starting from 3-(6-(6-fluoro-1-(phenylsulfonyI)-1 H-indo1-3-y1)-1 H-indazol-1-yl)propanamide (Intermediate 8;
95 mg;
0.21 mmol), 35 mg (53%) of the title compound was obtained as a white solid after purification by preparative TLC (Et0Ac).
LC-MS for C18H16FN4O+H [M+H]: calcd. 323.1; found: 323.1. 1H NMR (300 MHz, DMSO-d6) 6 [ppm]: 11.48 (s, 1H), 8.05 (dd, J= 8.8, 5.6 Hz, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.79 ¨ 7.73 (m, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.40 (br s, 1H), 7.24 (dd, J = 9.9, 2.2 Hz, 1H), 6.99 (ddd, J = 9.4, 8.8, 2.2 Hz, 1H), 6.87 (br s, 1H), 4.64 (t, J =
6.6 Hz, 2H), 2.70 (t, J= 6.6 Hz, 2H).

Compound 6: 6-(6-fluoro-1H-indo1-3-y1)-1-(piperidin-4-yI)-1H-indazole Following the general method as outlined in Compound 1, starting from 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1-(piperidin-4-y1)-1H-indazole hydrochloride and 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(piperidin-4-y1)-2H-indazole hydrochloride (Intermediate 10; 700 mg crude; 1.37 mmol), 12.3 mg (3%) of the title compound was obtained as a yellow solid after purification by preparative HPLC.
LC-MS for C20H19FN4+H [M+H]: calcd. 335.2; found: 334.9. 1H NMR (300 MHz, DMSO-d6) 6 [Plorn]:
11.49 (s, 1H), 8.04 (s, 1H), 7.94 (dd, J= 9.0, 5.4 Hz, 1H), 7.88 (s, 1H), 7.80 -7.75 (m, 2H), 7.46 (dd, J= 8.4, 1.3 Hz, 1H), 7.25 (dd, J= 9.8, 2.4 Hz, 1H), 6.99 (ddd, J= 9.7, 8.9, 2.4 Hz, 1H), 4.87 -4.75 (m, 1H), 3.20 - 3.10 (m, 2H), 2.86 - 2.75 (m, 2H), 2.10 - 2.00 (m, 2H), 2.00- 1.92 (m, 2H).
Compound 7: 1-(4-(6-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-yl)piperidin-1-y1)ethanone To a solution of 6-(6-fluoro-1H-indo1-3-y1)-1-(piperidin-4-yI)-1H-indazole (Compound 6;
300 mg; 0.90 mmol) and Et3N (5.0 mL; 36 mmol) in DCM (30 mL) was added AcCI
(84.6 mg; 1.08 mmol) under nitrogen. The mixture was stirred for 1 hour and quenched with saturated aqueous NaHCO3 (30 mL). The aqueous layer was extracted with DCM (60 mLx2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative HPLC to afford 15 mg (4%) of the title compound as a yellow solid. LC-MS for C22H21 FN4O+H
[M+H]:
calcd. 377.2; found: 376.9. 1H NMR (400 MHz, DMSO-d6) 6 [PPrn]: 11.49 (s, 1H), 8.05 (s, 1H), 7.96 (dd, J= 8.8, 5.4 Hz, 1H), 7.91 (s, 1H), 7.81 -7.76 (m, 2H), 7.47 (dd, J= 8.4, 1.2 Hz, 1H), 7.25 (dd, J = 9.9, 2.4 Hz, 1H), 6.99 (ddd, J = 9.6, 8.8, 2.4 Hz, 1H), 5.08 -4.95 (m, 1H), 4.58 -4.48 (m, 1H), 4.03 - 3.93 (m, 1H), 3.33 - 3.27 (m, 1H), 2.90 - 2.78 (m, 1H), 2.07 (s, 3H), 2.10 - 1.88 (m, 4H).
Compound 8: 5-(6-fluoro-1H-indo1-3-y1)-1H-indazole Following the general method as outlined in Compound 1, starting from 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazole (Intermediate 12; 270 mg crude;
0.45 mmol), 40 mg (32%) of the title compound was obtained as a yellow solid after purification by preparative HPLC. LC-MS for C15H10FN3+H [M+H]: calcd. 252.1; found: 252.1. 1H

NMR (300 MHz, DMSO-d6) 6 [ppm]: 13.02 (s, 1H), 11.34 (s, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.86 (dd, J= 8.8, 5.4 Hz, 1H), 7.66 (dd, J= 9.0, 1.5 Hz, 1H), 7.64 (d, J= 1.5 Hz, 1H), 7.59 (d, J= 9.0 Hz, 1H), 7.22 (dd, J= 10.0, 2.4 Hz, 1H), 6.95 (ddd, J= 9.7, 8.8, 2.4 Hz, 1H).
Compound 9: 2-(5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-yl)acetamide Following the general method as outlined in Compound 1, starting from 2-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazol-1-yl)acetamide and 2-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2H-indazol-2-yl)acetamide (Intermediate 13;
353 mg;
0.79 mmol), 34.1 mg (14%) of the title compound was obtained as a yellow solid after purification by preparative HPLC and chiral preparative HPLC. LC-MS for C17H13FN40+H [M+H]: calcd. 309.1; found: 308.9. 1H NMR (300 MHz, DMSO-d6) 6 [ppm]: 11.39 (s, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.87 (dd, J= 8.8, 5.3 Hz, 1H), 7.72 ¨7.61 (m, 3H), 7.58 (br s, 1H), 7.30 (br s, 1H), 7.23 (dd, J= 10.0, 2.3 Hz, 2H), 6.99 (dd, J= 9.5, 8.8, 2.3 Hz, 1H), 5.08 (s, 2H).
Compound 10: 5-(6-fluoro-1H-indo1-3-y1)-1-(piperidin-4-ylmethyl)-1H-indazole A solution of tert-butyl 4-((5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate (Intermediate 15; 1.18 g; 2.63 mmol) in saturated HCI in 1,4-dioxane (20 mL) was stirred at room tempreture for 1 hour. The reaction mixture was concentrated in vacuo, diluted with water (100 mL), and extracted with Et0Ac (50 mLx3). The aqueous layer was basified with aqueous NaOH to pH = 13 and extracted with Et0Ac (100 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative TLC (DCM/Me0H = 8/1) to afford 31 mg (33%) of the title compound as a yellow solid. LC-MS for C21H21FN4+11+ [M+H]: calcd.
349.2;
found: 349Ø 1H NMR (300 MHz, DMSO-d6) 6 [ppm]: 11.42 (s, 1H), 8.60 (br s, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.86 (dd, J= 8.8, 5.3 Hz, 1H), 7.79 ¨ 7.65 (m, 3H), 7.30 (dd, J= 10.0, 2.4 Hz, 1H), 6.96 (ddd, J= 9.6, 8.8, 2.4 Hz, 1H), 4.38 (d, J= 6.7 Hz, 2H), 3.26 ¨ 3.15 (m, 2H), 2.86 ¨
2.71 (m, 2H), 2.30 ¨ 2.13 (m, 1H), 1.72 ¨ 1.60 (m, 2H), 1.55¨ 1.36(m, 2H).

Compound 11: 1-(4-((5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-yl)methyl)piperidin-1-ypethanone Following the general method as outlined in Compound 7, starting from 5-(6-fluoro-1H-indo1-3-y1)-1-(piperidin-4-ylmethyl)-1H-indazole (Compound 10; 204 mg; 0.59 mmol), 65 mg (28%) of the title compound was obtained as a white solid after purification by preparative HPLC. LC-MS for C23H23FN4O+H [M+H]: calcd. 391.2; found: 390.9.

NMR (300 MHz, DMSO-d6) 6 [ppm]: 11.38 (s, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.87 (dd, J= 8.9, 5.5 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.71 ¨ 7.66 (m, 2H), 7.22 (dd, J =
10.0, 2.4 Hz, 1H), 6.96 (ddd, J = 9.6, 8.9, 2.3 Hz, 1H), 4.39 ¨4.30 (m, 3H), 3.83 ¨ 3.73 (m, 1H), 3.00 ¨ 2.87 (m, 1H), 2.50 ¨ 2.40 (m, 1H), 2.26 ¨ 2.10 (m, 1H), 1.96(s, 3H), 1.54 ¨ 1.43 (m, 2H), 1.30 ¨ 1.00 (m, 2H).
Compound 12: 3-(5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-yl)propanamide Following the general method as outlined in Compound 1, starting from 3-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazol-1-yl)propanamide and 3-(5-(6-fluoro-(phenylsulfony1)-1H-indol-3-y1)-2H-indazol-2-yl)propanamide (Intermediate 16;
492 mg;
1.06 mmol), 33.9 mg (10%) of the title compound was obtained as a white solid after purification by preparative HPLC and chiral preparative HPLC. LC-MS for C18H15FN40+H [M+H]: calcd. 323.1; found: 322.9. 1H NMR (300 MHz, DMSO-d6) 6 [ppm]: 11.34 (s, 1H), 8.27 (d, J= 0.8 Hz, 1H), 7.93 ¨ 7.91 (m, 1H), 7.88 (dd, J= 8.8, 5.4 Hz, 1H), 7.67 ¨ 7.61 (m, 2H), 7.56 (dd, J = 9.0, 1.6 Hz, 1H), 7.43 (br s, 1H), 7.21 (dd, J = 10.0, 2.3 Hz, 1H), 6.95 (ddd, J= 9.6, 8.8, 2.3 Hz, 1H), 6.92 (br s, 1H), 4.62 (t, J= 6.8 Hz, 2H), 2.79 (t, J= 6.9 Hz, 2H).
Compound 13: 5-(6-fluoro-1H-indo1-3-y1)-1-(piperidin-4-yI)-1H-indazole To a solution of tert-butyl 4-(5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-yl)piperidine-1-carboxylate (Intermediate 18; 180 mg; 0.41 mmol) in 1,4-dioxane (20 mL) was added saturated HCI in 1,4-dioxane (10 mL). The reaction mixture was stirred overnight. The resulting precipitate was collected by filtration and purified by preparative HPLC to afford 56 mg (40%) of the title compound as a yellow solid. LC-MS for C20H19FN4+H
[M+H]:
calcd. 335.2; found: 334.9. 1H NMR (300 MHz, DMSO-d6) 6 [ppm]: 11.36 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.86 (dd, J= 8.8, 5.4 Hz, 1H), 7.77 (d, J= 8.8 Hz, 1H), 7.67 (dd, J= 8.8, 1.6 Hz, 1H), 7.66 (d, J= 1.6 Hz, 1H), 7.22 (dd, J= 10.0, 2.4 Hz, 1H), 6.95 (ddd, J= 9.6, 8.8, 2.4 Hz, 1H), 4.73 - 4.60 (m, 1H), 3.14 - 3.04 (m, 2H), 2.76 - 2.64 (m, 2H), 2.20 (br s, 1H), 2.05- 1.93 (m, 2H), 1.91 - 1.82 (m, 2H).
Compound 14: 1-(4-(5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-yl)piperidin-1-y1)ethanone Following the general method as outlined in Compound 7, starting from 5-(6-fluoro-1H-indo1-3-y1)-1-(piperidin-4-y1)-1H-indazole (Compound 13; 53 mg; 0.16 mmol), 16 mg (27%) of the title compound was obtained as a yellow solid after purification by preparative HPLC. LC-MS for C22H21 FN4O+H [M+H]: calcd. 377.2; found: 376.9.

NMR (300 MHz, Me0H-d4) 6 [ppm]: 8.25 (s, 1H), 7.92 - 7.89 (m, 1H), 7.83 (dd, J= 8.8, 5.3 Hz, 1H), 7.66 - 7.63 (m, 2H), 7.46 (s, 1H), 7.12 (dd, J= 10.0, 2.3 Hz, 1H), 6.88 (ddd, J= 9.6, 8.8, 2.3 Hz, 1H), 4.86 - 4.66 (m, 2H), 4.16 -4.06 (m, 1H), 3.42 - 3.32 (m, 1H), 2.93 - 2.81 (m, 1H), 2.32 - 2.00 (m, 4H), 2.18 (s, 3H).
Compound 15: 2-(6-(6-fluoro-1H-indo1-3-y1)-2H-indazol-2-yl)acetamide A mixture of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazole (Intermediate 4;
300 mg; 0.77 mmol), 2-bromoacetamide (1.05 g; 7.61 mmol), KI (290 mg; 1.75 mmol) and K2CO3 (986 mg; 7.13 mmol) in DMF (16.5 mL) was stirred at 60 C for 48 hours under nitrogen. The mixture was cooled to room temperature, diluted with Et0Ac (100 mL), filtered, concentrated, and purified by preparative HPLC to afford 50 mg (21%) of the title compound as a yellow solid. LC-MS for C17H13FN40+H [M+H]: calcd.
309.1;
found: 308.9. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.42 (s, 1H), 8.32 (s, 1H), 7.90 (dd, J=
8.8, 5.4 Hz, 1H), 7.80 (s, 1H), 7.81 -7.72 (m, 2H), 7.66 (br s, 1H), 7.39 (dd, J= 8.7, 1.4 Hz, 1H), 7.35 (br s, 1H), 7.24 (dd, J = 10.0, 2.4 Hz, 1H), 6.97 (ddd, J = 9.6, 8.8, 2.4 Hz, 1H), 5.09 (s, 2H).
Compound 16: 1-(4-((6-(6-fluoro-1H-indo1-3-y1)-2H-indazol-2-yl)methyl)piperidin-1-ypethanone Following the general method as outlined in Compound 1, starting from 1-(4-((6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2H-indazol-2-yl)methyl)piperidin-1-ypethanone (Intermediate 19; 358 mg; 0.67 mmol), 10 mg (4%) of the title compound was obtained as a white solid after purification by preparative HPLC.
LC-MS for C23H23FN4O+H [M+H]: calcd. 389.9; found: 389.9. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.43 (s, 1H), 8.32 (s, 1H), 7.90 (dd, J= 8.8, 5.4 Hz, 1H), 7.80 (s, 1H), 7.77 ¨7.71 (m, 2H), 7.39 (d, J= 8.6 Hz, 1H), 7.23 (dd, J= 10.0, 2.3 Hz, 1H), 6.97 (dd, J =9.6, 8.8, 2.3 Hz, 1H), 4.40 ¨ 4.30 (m, 3H), 3.85 ¨ 3.75 (m, 1H), 3.05 ¨ 2.90 (m, 1H), 2.50 ¨ 2.42 (m, 1H), 2.31 ¨ 2.22 (m, 1H), 1.97 (s, 3H), 1.60 ¨ 1.40 (m, 2H), 1.30 ¨ 1.00 (m, 2H).
Compound 17: 3-(6-(6-fluoro-1H-indo1-3-y1)-2H-indazol-2-Apropanamide Following the general method as outlined in Compound 1, starting from 3-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2H-indazol-211)propanamide (Intermediate 20;
75 mg;
0.16 mmol), 20 mg (38%) of the title compound was obtained as a white solid after purification by preparative TLC (Et0Ac). LC-MS for C18H15FN4O+H [M+H]: calcd.
323.1; found: 323.1. 1H NMR (300 MHz, Me0H-d4) 6 [ppm]: 8.16 (s, 1H), 7.87 (dd, J=
8.8, 5.3 Hz, 1H), 7.81 (s, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.52 (s, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.13 (dd, J= 9.8, 2.3 Hz, 1H), 6.90 (ddd, J= 9.6, 8.8, 2.3 Hz, 1H), 4.73 (t, J= 6.7 Hz, 2H), 2.94 (t, J= 6.7 Hz, 2H).
Compound 18: 6-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-yI)-2H-indazole The title compound (26 mg, 5%) was obtained as a yellow solid after purification by preparative HPLC during the preparation of Compound 6. LC-MS for C20H19FN4+H
[M+H]: calcd. 335.2; found: 334.9. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.41 (s, 1H), 8.36 (s, 1H), 7.91 (dd, J= 8.6, 5.4 Hz, 1H), 7.83 (s, 1H), 7.75¨ 7.70 (m, 2H), 7.39 (d, J= 8.6, 1.4 Hz, 1H), 7.24 (dd, J= 10.0, 2.4 Hz, 1H), 6.97 (ddd, J= 9.6, 8.8, 2.4 Hz, 1H), 4.62 ¨ 4.50 (m, 1H), 3.22 ¨ 3.13 (m, 2H), 2.82 ¨ 2.70 (m, 2H), 2.16¨ 1.93 (m, 4H).
Compound 19: 1-(4-(6-(6-fluoro-1H-indo1-3-y1)-2H-indazol-2-Apiperidin-1-ypethanone Following the general method as outlined in Compound 7, starting from 6-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-y1)-2H-indazole (Compound 18; 300 mg; 0.90 mmol), 20 mg (6%) of the title compound was obtained as a yellow solid after purification by preparative HPLC. LC-MS for C22H21 FN4O+H [M+H]: calcd. 377.2; found: 376.9.

NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.42 (s, 1H), 8.40 (s, 1H), 7.89 (dd, J= 8.7, 5.4 Hz, 1H), 7.80 (s, 1H), 7.75 ¨ 7.71 (m, 2H), 7.39 (d, J= 8.5 Hz, 1H), 7.23 (dd, J= 10.0, 2.3 Hz, 1H), 6.96 (dd, J= 9.4, 8.7, 2.3 Hz, 1H), 4.81 ¨4.71 (m, 1H), 4.56 ¨ 4.43 (m, 1H), 4.02 ¨3.94 (m, 1H), 3.32 ¨ 3.22 (m, 1H), 2.82 ¨ 2.73 (m, 1H), 2.21 ¨ 1.86 (m, 4H), 2.07 (s, 3H).
Compound 20: 2-(5-(6-fluoro-1H-indo1-3-y1)-2H-indazol-2-yl)acetamide The title compound (71 mg, 29%) was obtained as a yellow solid after purification by preparative HPLC and chiral preparative HPLC as a regio-isomer with Compound 9. LC-MS for C17H13FN4O+H [M+H]: calcd. 309.1; found: 308.9. 1H NMR (300 MHz, DMSO-d6) 6 [ppm]: 11.38(s, 1H), 8.31 (s, 1H), 7.97(s, 1H), 7.90 (dd, J= 8.7, 5.5 Hz, 1H), 7.70 ¨ 7.55 (m, 4H), 7.37 (s, 1H), 7.22 (dd, J= 9.9, 2.3 Hz, 1H), 6.96 (ddd, J= 9.6, 8.7 2.3 Hz, 1H), 5.08 (s, 2H).
Compound 21: 1-(4-((5-(6-fluoro-1H-indo1-3-y1)-2H-indazol-2-yl)methyl)piperidin-1-ypethanone Following the general method as outlined in Compound 7, starting from 5-(6-fluoro-1 H-indo1-3-y1)-2-(piperidin-4-ylmethyl)-2H-indazole (Intermediate 22; 100 mg;
0.29 mmol), 5 mg (4%) of the title compound was obtained as an off-white solid after purification by preparative HPLC. LC-MS for C23H23FN40+H [M+H]: calcd. 391.2; found: 390.9.

NMR (400 MHz, Me0H-d4) 6 [ppm]: 8.14 (s, 1H), 7.90 (s, 1H), 7.84 (dd, J= 8.8, 5.4 Hz, 1H), 7.68 ¨ 7.61 (m, 2H), 7.46 (s, 1H), 7.12 (dd, J= 9.8, 2.3 Hz, 1H), 6.89 (dd, J=
9.7, 8.8, 2.3 Hz, 1H), 4.54 ¨ 4.47 (m, 1H), 4.11 (d, J= 7.0 Hz, 2H), 3.92 ¨ 3.85 (m, 1H), 3.09 ¨
3.00 (m, 1H), 2.62 ¨2.53 (m, 1H), 2.37 ¨2.24 (m, 1H), 2.06 (s, 3H), 1.63 ¨ 1.54 (m, 2H), 1.34¨
1.13 (m, 2H).
Compound 22: 3-(5-(6-fluoro-1H-indo1-3-y1)-2H-indazol-2-yl)propanamide The title compound (48 mg, 14%) was obtained as a white solid after purification by preparative HPLC and chiral preparative HPLC during the preparation of Compound 12.
LC-MS for C18H15FN4O+H [M+H]: calcd. 323.1; found: 322.9. 1H NMR (300 MHz, DMSO-d6) 6 [PPm]: 11.39 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.87 (dd, J= 8.7, 5.4 Hz, 1H), 7.74 ¨7.66 (m, 3H), 7.43 (s, 1H), 7.23 (dd, J= 10.0, 2.0 Hz, 1H), 6.96 (ddd, J=9.3, 8.7 2.0 Hz, 1H), 6.89 (s, 1H), 4.61 (t, J= 6.8 Hz, 2H), 2.70 (t, J= 6.8 Hz, 2H).
Compound 23: 5-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-yI)-2H-indazole To the solution of tert-butyl 4-(5-(6-fluoro-1H-indo1-3-y1)-2H-indazol-2-Apiperidine-1-carboxylate (Intermediate 24; 180 mg; 0.41 mmol) in 1,4-dioxane (20 mL) was added saturated HCI in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature overnight, filtered, and purified by preparative HPLC to afford 59 mg (43%) of the title compound as a yellow solid. LC-MS for C20H19FN4+H [M+H]: calcd.
335.4;
found: 334.9. 1H NMR (300 MHz, DMSO-d6) 6 [ppm]: 11.37 (s, 1H), 8.36 (s, 1H), 7.92 (s, 1H), 7.87 (dd, J= 8.8, 5.4 Hz, 1H), 7.68 ¨ 7.63 (m, 2H), 7.55 (dd, J= 9.0, 1.6 Hz, 1H), 7.22 (dd, J=
10.0, 2.4 Hz, 1H), 6.96 (ddd, J= 9.7, 8.8, 2.4 Hz, 1H), 4.59 ¨ 4.43 (m, 1H), 3.11 ¨3.02 (m, 2H), 2.70 ¨ 2.59 (m, 2H), 2.26 (br s, 1H), 2.10 ¨ 1.89 (m, 4H).
Compound 24: 1-(4-(5-(6-fluoro-1H-indo1-3-y1)-2H-indazol-2-Apiperidin-1-ypethanone Following the general method as outlined in Compound 7, starting from 5-(6-fluoro-1 H-in do1-3 -y1) -2- (pip e ri di n - 4-y1) -2 H-1 nd azol e (Compound 23; 53 mg;
0.16 mmol), 16 mg (27%) of the title compound was obtained as an off-white solid after purification by preparative HPLC. LC-MS for C22H21 FN4O+H [M+H]: calcd. 377.4; found: 376.9.

NMR (300 MHz, DMSO-d6) 6 [PPrn]: 8.25 (s, 1H), 7.90 (s, 1H), 7.83 (dd, J= 8.8, 5.3 Hz, 1H), 7.65 ¨ 7.61 (m, 2H), 7.45 (s, 1H), 7.11 (dd, J= 9.8, 2.4 Hz, 1H), 6.88 (ddd, J= 9.6, 8.8, 2.4 Hz, 1H), 4.78 ¨4.67 (m, 2H), 4.15 ¨4.06 (m, 1H), 3.40 ¨ 3.34 (m, 1H), 2.91 ¨ 2.80 (m, 1H), 2.30 ¨
2.00 (m, 4H), 2.17 (s, 3H).
Compound 25: 5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[climidazole Following the general method as outlined in Compound 1, starting from 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazole (Intermediate 27; 550 mg crude;
0.46 mmol), 5 mg (3%) of the title compound was obtained as a yellow solid after purification by preparative HPLC. LC-MS for C15H10FN3+H [M+H]: calcd. 252.1;
found:
252Ø 1H NMR (300 MHz, DMSO-d6) 6 [ppm]: 12.44 - 12.33 (m, 1H), 11.38 - 11.30 (m, 1H), 8.22 - 8.17 (m, 1H), 7.88 - 7.72 (m, 2H), 7.71 -7.44 (m, 3H), 7.25 - 7.18 (m, 1H), 7.01 -6.90 (m, 1H).
Compound 26: 5-(6-fluoro-1H-indo1-3-y1)-2-methy1-1H-benzo[climidazole Following the general method as outlined in Compound 1, starting from 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-methyl-1H-benzo[climidazole (Intermediate 30; 870 mg crude; 1.99 mmol), 240 mg (45%) of the title compound was obtained as an off-white solid after purification by preparative HPLC. LC-MS for C16H12FN3+H [M+H]:
calcd.
266.1; found: 265.9. 1H NMR (400 MHz, DMSO-d6) 6 [PPm]: 12.16 (s, 1H), 11.34 (s, 1H), 7.82 (dd, J= 8.7, 5.5 Hz, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 7.51 (d, J= 8.2 Hz, 1H), 7.41 (d, J= 8.2 Hz, 1H), 7.22 (dd, J= 10.0, 1.9 Hz, 1H), 6.95 (ddd, J= 9.6, 8.7, 1.9 Hz, 1H), 2.50 (s, 3H).
Compound 27: (6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-yl)methanamine N....,7---NH2 4. N
F 01 N\
H
To a solution of tert-butyl ((6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-yl)methyl)carbamate (Intermediate 48, 429 mg, 1.13 mmol) in THF (30 mL) was added HCI (12 M, 3 mL). The resulting mixture was stirred at 51 C for 3 hours. The reaction mixture was cooled to room temperature and concentrated.The residue was diluted with water (80 mL) and extracted with Et0Ac (30 mLx2). The aqueous phase was basified with NH4OH to pH=13 and extracted with Et0Ac (80 mLx3). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative HPLC to afford 70 mg (22 /0) of the title compound as a white solid. LC-MS for C16H13FN4+H [M+H] :calcd. 281.1; found:
280.9. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]:11.34 (s, 1H), 7.82 (dd, J= 8.8, 5.5 Hz, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 7.54 (d, J= 8.2 Hz, 1H), 7.42 (d, J= 8.3 Hz, 1H), 7.22 (dd, J= 9.9, 2.3 Hz, 1H), 6.95 (td, J= 9.4, 2.1 Hz, 1H), 3.94 (s, 2H).
Compound 28: 1-(6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-y1)-N,N-dimethylmethanamine N /
4. NH
FS N\
H
Following the general method as outlined in Compound 1, starting from 1-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[d]imidazol-2-y1)-N,N-climethylmethanamine (Intermediate 50, 391 mg, 0.87 mmol), 10 mg (4%) of the title compound was obtained as a white solid. LC-MS for C18H17FN4+H [M+H]: Calcd. 309.1; found: 309.1. 1H
NMR
(400 MHz, CDCI3) 6 [ppm]: 10.06- 9.46 (m, 1H), 8.31 (s, 1H), 7.86 (dd, J= 8.6, 5.3 Hz, 1H), 7.80 - 7.62 (m, 1H), 7.52 (d, J= 6.8 Hz, 1H), 7.35 (d, J= 2.3 Hz, 1H), 7.12 (dd, J=
9.5, 2.2 Hz, 1H), 6.96 (td, J = 9.3, 2.3 Hz, 1H), 3.80 (s, 2H), 2.38 (s, 6H).
Compound 30: N-((6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-yl)methypacetamide ox._ Nzz..{--N
4. NH
FIN
Following the general method as outlined in Compound 1, starting from N-((6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazol-2-yl)methypacetamide (Intermediate 53, 400 mg crude, 0.74 mmol), 20 mg (9%) of the title compound was obtained as a white solid after purification by preparative HPLC. LC-MS for C18H16FN4O+H [M+H]: calcd. 323.1; found: 322.1. 1H NMR (400 MHz, Me0H-d4) 6 [ppm]: 7.76 (dd, J= 8.8, 5.2 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J= 8.4 Hz, 1H), 7.48 (d, J=
8.4 Hz, 1H), 7.38 (s, 1H), 7.07 (d, J = 9.6 Hz, 1H), 6.83 (td, J = 9.2, 2.4 Hz, 1H), 4.59 (s, 2H), 2.03 (s, 3H).
Compound 31: 2-amino-N-((6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-yl)methypacetamide N_ /N
---T
. NH H
FS N\
H
To a stirred solution of tert-butyl (2-(((6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-yl)methyl)amino)-2-oxoethyl)carbamate (Intermediate 51, 650 mg, 1.43 mmol) in THF
(20 mL) was added HCI (12 M, 3 mL). The resulting mixture was stirred for 40 mins at room temperature. The solvents was removed under reduced pressure. The residue was diluted with water (80 mL) and extracted with Et0Ac (30 mLx2). The aqueous phase was basified with NH4OH till pH=13 and extracted with Et0Ac (80 mLx3).
The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative HPLC
to afford 70 mg (15%) of the title compound as a white solid. LC-MS for C18H16FN6O+H [M+H]
:
calcd. 338.1; found: 337.9. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.36 (s, 1H), 8.55 (s, 1H), 7.83 (dd, J = 8.7, 5.4 Hz, 1H), 7.73 (s, 1H), 7.63 (d, J = 1.7 Hz, 1H), 7.56 (d, J =
8.3 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.22 (dd, J = 10.0, 2.2 Hz, 1H), 6.95 (td, J = 9.5, 2.2 Hz, 1H), 4.55 (s, 2H), 3.22 (s, 2H).
Compound 32: N-((6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-yl)methyl)methanesulfonamide o =/,(-) N_ .c ti ---------r H
FIN
To a stirred solution of c-[6-(6-fluoro-1H-indo1-3-y1)-1H-benzoimidazol-2-y1]-methylamine (Compound 27, 300 mg, 1.07 mmol) and Et3N (270 mg, 2.68 mmol) in anhydrous DCM
(24 mL) was added M5C1 (123 mg, 1.07 mmol) at -10 C under nitrogen. The reaction mixture was stirred at 5 C overnight. The reaction mixture was diluted with Et0Ac (80 mL) and washed with saturated aqueous Na2CO3. The combined organic layers was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative HPLC to afford 20 mg (44%) of the title compound as a yellow solid. LC-MS
for C17H15FN402S-H- [M-Hy: calcd. 357.1; found: 356.9. 1H NMR (400 MHz, Me0D) [ppm]:7.74 (dd, J= 8.8, 5.3 Hz, 1H), 7.70 (s, 1H), 7.52 (d, J= 8.4 Hz, 1H), 7.46 (dd, J=
8.4, 1.2 Hz, 1H), 7.35 (s, 1H), 7.04 (dd, J = 9.8, 2.3 Hz, 1H), 6.80 (td, J =
9.3, 2.3 Hz, 1H), 4.46 (s, 2H), 2.92 (s, 3H).
Compound 33: 6-(6-fluoro-1H-indo1-3-y1)-2-((4-methylpiperazin-1-yl)methyl)-1 H-benzo[d]imidazole FIN
Following the general method as outlined in Compound 1, starting from 6-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-2-(4-methyl-piperazin-1-ylmethyl)-1 H-benzoimidazole (Intermediate 60, 290 mg, 0.45 mmol, crude), 18 mg (11%) of the title compound was obtained as a brown solid. LC-MS for C21H22FN6+H [M+H]: calcd.
364.2; found: 364.2. 'H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.69 (br s, 1H), 11.10 (br s, 1H), 7.99 (s, 1H), 7.86 - 7.84 (m, 4H), 7.28 (dd, J = 9.8, 2.0 Hz, 1H), 7.02 (td, J = 9.6, 2.0 Hz, 1H), 4.26 (s, 2H), 3.43 - 3.40 (m, 2H), 3.18 - 3.10 (m, 4H), 2.84 -2.76 (m, 5H).

Compound 34: 5-(6-fluoro-1H-indo1-3-y1)-2-((4-(methylsulfonyl)piperazin-1-Amethyl)-1H-benzo[d]imidazole N,cNo N
di FIN
Following the general method as outlined in Compound 1, starting from 6-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-2-(4-methanesulfonyl-piperazin-1-ylmethyl)-1 H-benzoimidazole (Intermediate 67, 80 mg, 0.14 mmol), 15 mg (25%) of the title compound was obtained as a white solid. LC-MS for C21F122FN502S+H [M+H]:
calcd.
428.2; found: 428.2. 1H NMR (400 MHz, CD30D) 6 [ppm]: 7.72 (dd, J= 8.8, 5.2 Hz, 1H), 7.67 (s, 1H), 7.49 (d, J= 8.8 Hz, 1H), 7.43 (dd, J= 8.4, 0.9 Hz, 1H), 7.33 (s, 1H), 7.02 (dd, J= 9.6, 2.0 Hz, 1H), 7.78 (d, J= 8.8, 2.0 Hz, 1H), 3.77 (s, 2H), 3.28-3.20 (m, 4H), 2.75 (s, 3H), 2.62 - 2.52 (m, 4H).
Compound 35: 2-(6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-ypethanamine NH
FS
Following the general method as outlined in Compound 1, starting from 2-[6-(1-Benzenesulfony1-6-fluoro-1H-indo1-3-y1)-1H-benzoimidazol-2-y1]-ethylamine (Intermediate 64, 400 mg, 0.920 mmol), the title compound (40 mg, 15%) was obtained as a white solid. LC-MS for C17H15FN4+H [M+H]: calcd. 295.1; found: 295.1. 1H
NMR
(400 MHz, CD40-d4) 6 [ppm]: 7.86 - 7.82 (m, 2H), 7.61 -7.53 (m, 2H), 7.46 (s, 1H), 7.14 (dd, J= 10.0, 2.4 Hz, 1H), 6.91 (td, J= 9.2, 2.4 Hz, 1H), 3.28 - 3.22 (m, 2H), 3.16 - 3.08 (m, 2H).

Compound 36: N-(2-(6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-ypethypacetamide H--=1\j H fa Following the general method as outlined in Compound 1, starting from N-{246-(1-Benzenesulfony1-6-fluoro-1H-indol-3-y1)-1H-benzoimid-azol-2-y1]-ethy1}-acetamide (Intermediate 66, 424 mg, 0.890 mmol), the title compound (86 mg, 29%) was obtained as a white solid. LC-MS for C19H17FN4O+H [M+H]: calcd. 337.1; found: 337.1.

NMR (400 MHz, CD40-d4) 6 [ppm]: 7.70 (dd, J = 8.8, 5.6 Hz, 2H), 7.64 (s, 1H), 7.47 -7.40 (m, 2H), 7.32 (s, 1H), 7.02 (dd, J = 9.6, 2.2 Hz, 1H), 6.77 (td, J = 9.2, 2.4Hz, 1H), 3.54 (t, J= 6.8 Hz, 2H), 2.99 (t, J= 6.8 Hz, 2H).
Compound 37: N-(2-(6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-ypethyl)methanesulfonamide ,0 =si_NH
d' ____________________________________ H>=N
H V
Following the general method as outlined in Compound 1, starting from N-{246-(1-Benzenesulfony1-6-fluoro-1H-indol-3-y1)-1H-benzoimida-zol-2-y1]-ethy1}-methanesulfonamide (Intermediate 65, 430 mg, 0.840 mmol), the title compound (36 mg, 11%) was botained as a white solid. LC-MS for C18H17FN402S+H [M+H]:
calcd.
373.1; found: 373.1. 1H NMR (400 MHz, CD40-d4) 6 [Ppm]: 7.73 - 7.66 (m, 2H), 7.51-7.44 (m, 2H), 7.34 (s, 1H), 7.02 (dd, J = 10.0, 2.0 Hz, 1H), 6.78 (td, J =
8.8, 2.0 Hz, 1H), 3.48 (t, J= 7.0 Hz, 2H), 3.11 (m, J= 7.0 Hz, 2H), 2.81 (s, 3H).
Compound 38: 5-(6-fluoro-1H-indo1-3-y1)-2-(2-(methylsulfonypethyl)-1 H-benzo[d]imidazole Following the general method as outlined in Compound 1, starting from 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(2-(methylsulfonypethyl)-1H-benzo[climidazole (Intermediate 34; 170 mg; 0.34 mmol), 20 mg (16%) of the title compound was obtained as a white solid after purification by preparative TLC (DCM/Me0H = 10/1) and preparative HPLC. LC-MS for C18H16FN302S+H [M+H]: calcd. 358.1; found: 358.1.

NMR (400 MHz, DMSO-d6) 6 [ppm]: 12.35 (s, 0.45H), 12.35 (s, 0.55H), 11.37 (s, 0.55H), 11.33 (s, 0.45H), 7.85 - 7.79 (m, 1H), 7.77 (s, 0.45H), 7.66 - 7.63 (m, 1H), 7.62 - 7.57 (m, 1H), 7.52 - 7.41 (m, 1.55H), 7.24 - 7.19 (m, 1H), 6.99 - 6.91 (m, 1H), 3.71 -3.65 (m, 2H), 3.32 - 3.27 (m, 2H), 2.32 (s, 3H) as a mixture of tautomers.
Compound 39: 6-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-yI)-1H-benzo[d]imidazole Ns_ 4. NH
FS N\
H
To a solution of tert-butyl 4-(6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[climidazol-yl)piperidine-1-carboxylate (Intermediate 56, 550 mg crude, 1.05 mmol) in THF
(5mL) was added concentrated aqueous HCI (1 mL). The reaction mixture was stirred at for 3 hours before it was concentrated. The mixture was poured into brine and extracted with Et0Ac. The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to afford 200 mg (57%) of the title compound as a yellow solid.
LC-MS for C20H19FN4+H [M+H]: calcd. 335.2; found: 335.1. 1H NMR (400 MHz, Me0H-d4) 6 [ppm]: 7.84 (dd, J= 8.8, 5.2 Hz, 1H), 7.79 (s, 1H), 7.62 (d, J= 8.4 Hz, 1H), 7.56 (d, J=
8.4 Hz, 1H), 7.46 (s, 1H), 7.15 (dd, J= 9.8, 2.2 Hz, 1H), 6.91 (td, J= 9.2, 2.0 Hz, 1H), 3.54 - 3.51 (m, 2H), 3.31-3.28 (m, 1H), 3.21 - 3.15 (m, 2H), 2.38 - 2.35 (m, 2H), 2.20 -2.13 (m, 2H).
Compound 40: 6-(6-fluoro-1H-indo1-3-y1)-2-(1-(methylsulfonyl)piperidin-4-y1)-1 H-benzo[d]imidazole /
Fi)v' N......
= NH
I 0 I N\
F
H
To a solution of 6-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-yI)-1H-benzo[climidazole (Compound 39, 100 mg, 0.30 mmol) and Et3N (290 mg, 2.9 mmol) in DCM (2 mL) was added MsCI (16 mg, 0.14 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 hours, washed with brine, concentrated and purified by preparative HPLC to afford 8 mg (6%) of the title compound as a white solid. LC-MS for C21 H21 FN402S+H [M+H]: calcd. 413.1; found: 413.1. 1H NMR (400 MHz, Me0H-d4) [ppm]: 7.72 (dd, J= 8.4, 5.2 Hz, 1H), 7.65 (s, 1H), 7.47 (d, J= 8.4 Hz, 1H), 7.41 (d, J=
8.4, 1H), 7.33 (s, 1H), 7.02 (dd, J= 9.8, 2.4 Hz, 1H), 6.78 (td, J= 9.2, 2.0 Hz, 1H), 3.75 (d, J = 12.0 Hz, 2H), 3.02 (tt, J = 11.7, 3.6 Hz, 1H), 2.86 - 2.77 (m, 2H), 2.73 (s, 3H), 2.13 - 2.09 (m, 2H), 1.96 - 1.86 (m, 2H).
Compound 41: 6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-amine HN/LN

FN

Following the general method as outlined in Compound 1, starting from 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazol-2-amine (Intermediate 85, 260 mg, 0.64 mmol), 60 mg (35%) of the title compound was obtained as a yellow solid after purification by preparative HPLC. LC-MS for C16H11FN4+H [M+H]: calcd. 267.1;
found:
267.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.21 (br s, 1H), 10.61 (br s, 1H), 7.78 (dd, J= 8.8, 5.5 Hz, 1H), 7.49 (d, J= 2.0 Hz, 1H), 7.34 (s, 1H), 7.18 (dd, J=
10.1, 2.2 Hz, 1H), 7.16 - 7.11 (m, 2H), 6.92 (ddd, J= 9.6, 8.6, 2.2 Hz, 1H), 6.11 (br s, 2H).
Compound 44:
1-(5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[climidazol-2-y1)-N-methylmethanamine To a solution of tert-butyl (5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[climidazol-2-yl)methyl(methyl)carbamate (Intermediate 37; 470 mg crude; 0.87 mmol) in THF
(30 mL) was added concentrated aqueous HCI (3 mL; 37%). The reaction mixture was stirred at 51 C for 3 hours, concentrated in vacuo, diluted with water (80 mL), and extracted with Et0Ac (50 mLx3). The aqueous layer was basified with aqueous NaOH to pH = 13 and extracted with Et0Ac (80 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative TLC
(DCM/Me0H
= 10/1) and preparative HPLC to afford 40 mg (16%) of the title compound as a white solid. LC-MS for C17H15FN4+H [M+H]: calcd. 295.1; found: 294.9. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.34 (s, 1H), 7.82 (dd, J = 8.7, 5.4 Hz, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.22 (dd, J = 10.0, 2.3 Hz, 1H), 6.95 (ddd, J=9.4, 8.7, 2.3 Hz, 1H), 3.87 (s, 2H), 2.34 (s, 3H).
Compound 45: 4-((5-(6-fluoro-1H-indo1-3-y1)-1 H-benzo[climidazol-2-yl)methyl)morpholine Step 1:
4-((5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazol-2-yl)methyl)morpholine A solution of 2-(chloromethyl)-5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-benzo[climidazole (Intermediate 39; 100 mg; 0.23 mmol) and morpholine (59 mg;
0.68 mmol) in DMF (2 mL) was stirred at 80 C for 2 hours. The mixture was diluted with Et0Ac (50 mL), washed with H20 (20 mL), brine (30 mLx2), dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative TLC (DCM/ Me0H
=20/1) to afford 56 mg (50%) of the title compound as a brown solid. LC-MS for C26H23FN403S+H [M+H]: calcd. 491.2; found: 490.9.
Step 2:
Following the general method as outlined in Compound 1, starting from 4-((5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazol-2-yl)methyl)morpholine (Step 1; 56 mg; 0.11 mmol), 13 mg (32%) of the title compound was obtained as a white solid after purification by preparative TLC (DCM/Me0H = 20/1). LC-MS for C20H19FN4O+H
[M+H]:
calcd. 351.2; found: 351.2. 1H NMR (400 MHz, Me0H-d4) 6 [ppm]: 7.71 (dd, J=
8.4, 5.2 Hz, 1H), 7.67 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.01 (dd, J = 10.0, 2.4 Hz, 1H), 6.78 (ddd, J = 9.2, 8.4, 2.4 Hz, 1H), 3.72 (s, 1H), 3.66 ¨
3.61 (m, 4H), 2.50 ¨ 2.44 (m, 4H).
Compound 46: 3-(5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-211)propanamide Step 1: 3-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazol-2-yl)propanamide A solution of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2,3-dihydro-1 H-benzo[cipyrrolo[1,2-a]imidazol-1-one (Intermediate 41; 456 mg crude; 0.92 mmol) in saturated NH3 in THF (100 mL) was stirred at 137 C for 24 hours in an autoclave. The reaction mixture was cooled to room temperature and concentrated to afford 480 mg (100%) of the title compound as a yellow solid, which was used directly without further purification. LC-MS for C24H19FN403S+H [M+H]: calcd. 463.1; found: 462.8.
Step 2:
To a solution of 3-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazol-2-yl)propanamide (Step 1; 480 mg crude; 0.92 mmol) in Et0H (10 mL) was added KOH

(116 mg; 2.07 mmol). The reaction mixture was stirred at 50 C for 4 hours. The mixture was neutralized with 2 M aqueous HCI, concentrated, and purified by preparative HPLC
to afford 50 mg (17%) of the title compound as a white solid. LC-MS for C18H15FN4O+H [M+H]: calcd. 323.1; found: 322.9. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 12.15 (s, 1H), 11.33 (s, 1H), 7.82 (dd, J= 8.7, 5.5 Hz, 1H), 7.67 (s, 1H), 7.61 (d, J= 1.9 Hz, 1H), 7.51 (d, J= 8.1 Hz, 1H), 7.48 - 7.38 (m, 2H), 7.22 (dd, J= 10.0, 2.0 Hz, 1H), 6.95 (ddd, J= 9.6, 8.7, 2.0 Hz, 1H), 6.86 (s, 1H), 3.03 (t, J= 7.6 Hz, 2H), 2.64 (t, J=
7.6 Hz, 2H).
Compound 47: 5-(6-fluoro-1H-indo1-3-yl)benzo[cloxazole Following the general method as outlined in Compound 1, starting from 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[cloxazole (Intermediate 43; 423 mg; 1.08 mmol), 60 mg (22%) of the title compound was obtained as a white solid after purification by a silica gel chromatography (petroleum ether/Et0Ac = 100/1 - 6/1). LC-MS for C15H9FN2O+H [M+H]: calcd. 253.1; found: 253Ø 1H NMR (400 MHz, CDC13) 6 [ppm]:
8.30 (br s, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.84 (dd, J= 8.8, 5.2 Hz, 1H), 7.69 - 7.63 (m, 2H), 7.37 (d, J= 2.4 Hz, 1H), 7.14 (dd, J= 9.4, 2.2 Hz, 1H), 6.98 (ddd, J=
9.4, 8.8, 2.2 Hz, 1H).
Compound 48: 5-(6-fluoro-1H-indo1-3-y1)-2-methylbenzo[cloxazole Following the general method as outlined in Compound 1, starting from 5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-methylbenzo[cloxazole (Intermediate 45; 718 mg; 1.77 mmol), 184 mg (39%) of the title compound was obtained as a brown solid after purification by recrystallization in petroleum ether/Et0Ac = 4/1. LC-MS for C16H11FN2O+H [M+H]: calcd. 267.1; found: 267Ø 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.45 (s, 1H), 7.87 (s, 1H), 7.83 (dd, J= 8.8, 5.2 Hz, 1H), 7.73 -7.68 (m, 2H), 7.63 (d, J= 8.0 Hz, 1H), 7.50 (dd, J= 10.0, 2.4 Hz, 1H), 7.23 (ddd, J= 9.2, 8.8, 2.4 Hz, 1H), 2.63 (s, 3H).
Compound 53: 6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazole I\1.....
. 1 FSH
A mixture of 2-amino-5-(6-fluoro-1H-indo1-3-y1)-phenol (Intermediate 57, 500 mg, 2.66 mmol) in triethyl orthoformate (15 mL) was heated at 120 C for 0.5 hour. The mixture was concentrated, suspended in water (20 mL) and filtered. The cake was recrystalized from a mixture of Et0Ac (5 mL) and petroleum ether (20 mL) to afford 160 mg (35%) of the title compound as a white solid. LC-MS for C16H9FN2O+H [M+H]: calcd.
253.1;
found: 253Ø 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 8.43 (s, 1H), 7.89 (s, 1H), 7.84 -7.82 (m, 1H), 7.75 (d, J= 8.0Hz, 1H), 7.70 (dd, J= 8.4, 1.6 Hz, 1H), 7.52 (s, 1H), 7.12 (dd, J= 10, 2.4 Hz, 1H), 6.90 (m, 1H).
Compound 54: 6-(6-fluoro-1H-indo1-3-y1)-2-methylbenzo[d]oxazole N...,...
FIN
A mixture of 2-amino-5-(6-fluoro-1H-indo1-3-y1)-phenol (Intermediate 57, 500 mg; 2.66 mmol) in 1,1,1-triethoxyethane (15 mL) was heated at 120 C for 0.5 hour. The mixture was concentrated, suspended in water (20 mL) and filtered. The cake was recrystalized from a mixture of Et0Ac (5 mL) and petroleum ether (20 mL) to afford 140 mg (30%) of the title compound as a white solid. LC-MS for C16H11FN20+H [M+H]: calcd.
267.1;
found: 267.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 7.85 (dd, J= 8.8, 5.6 Hz, 1H), 7.82 (s, 1H), 7.66 (s, 2H), 7.53 (s, 1H), 7.16 (dd, J= 9.6, 2.4 Hz, 1H), 6.93 (td, J= 9.2, 2.0 Hz, 1H), 2.67 (s, 3H).
Compound 55: 6-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-yl)benzo[d]oxazole NH
N, =
FS N\
H
A mixture of tert-butyl 4-(6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-211)piperidine-1-carboxylate (Intermediate 106, 1.23 g, 2.82 mmol) in HCl/ether (40 mL) was stirred at room temperature for 1 hour. The mixture was concentrated, diluted with saturated aqueous NaHCO3 (50 mL) and extracted with Et0Ac (50 mLx3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and purified by recystallization to afford 783 mg (83%) of the title compound as a gray solid. LC-MS for C20H18FN3O+H [M+H]: calcd. 335.1;
found:
336.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.49 (br s, 1H), 7.91 (s, 1H), 7.89 (dd, J= 8.8, 3.2 Hz, 1H), 7.75 (d, J= 1.6 Hz, 1H), 7.73 (d, J= 8.4 Hz, 1H), 7.66 (dd, J=
8.6, 1.4 Hz, 1H), 7.25 (dd, J= 9.8, 2.6 Hz, 1H), 6.97 (td, J=10.6, 2.5 Hz, 1H), 3.13 - 3.02 (m, 3H), 2.64 (t, J=
11.2 Hz, 2H), 2.03 (d, J= 10.8 Hz, 2H), 1.72 (td, J= 12.2, 3.0 Hz, 2H).
Compound 56: 1-(4-(6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-211)piperidin-1-yl)ethanone N"\---N

40 N\
F
H
To a stirred solution of 6-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-yl)benzo[d]oxazole (Compound 55, 200 mg, 0.60 mmol) and TEA (182 mg, 1.80 mmo) in DCM (10 mL) at room temperature, was added dropwise acetyl chloride (57 mg, 0.72 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with DCM
(10 mL), washed with water (20 mLx2), dried over Na2Sa4and filtered. The filtrate was concentrated and purified by preparative HPLC to afford 121 mg (54%) of the title compound as a yellow solid. LC-MS for C22H20FN302+H : [M+H]: calcd.
378.2;found:
378.1. 1H NMR (400 MHz, DMSO-d6) 6 [PPm]: 11.48 (s, 1H), 7.92 (s, 1H), 7.89 (dd, J= 5.6, 8.8 Hz, 1H), 7.75 (d, J= 2.8 Hz, 1H), 7.73 (d, J= 7.2 Hz, 1H), 7.66 (dd, J= 1.6, 8.0 Hz, 1H), 7.23 (dd, J= 2.4, 10.0 Hz, 1H), 6.97 (td, J= 2.4, 9.6 Hz, 1H), 4.32 (d, J= 13.6 Hz, 1H), 3.87 (d, J=
13.6 Hz, 1H), 3.35 - 3.27 (m, 2H), 2.88 (t, J= 11.2 Hz, 1H), 2.13 (t, J= 14.0 Hz, 2H), 2.04 (s, 3H), 1.88-1.77 (m, 1H), 1.72 - 1.62 (m, 1H).
Compound 58: N-(6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-211)methanesulfonamide N
a 1 b \mu FIN
To F H
To the mixture of N-[6-(1-Benzenesulfony1-6-fluoro-1H-indo1-3-y1)-benzooxazol-2-yl] -methanesulfonamide (Intermediate 124, 350 mg 0.72 mmol) in ethanol (20 mL) was added potassium hydroxide (55 mg, 2.88 mmol). The mixture was stirred at 50 C
for 4 hrs. The solvent was removed. The residue was redissolved in EA and washed with water and brine. The organic layer was dried, filtered and concentrated. The residue was purified by preparative TLC (DCM/methano1=10/1) and further purified by trituration with EA to afford 8 mg (3%) of the title compound as a black solid. LC-MS for C16H12FN303S+H [M+H]: calcd. 346.1; found: 346Ø 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 12.51(s, 1H), 11.44(s, 1H), 7.86 (dd, J= 9.2, 5.6 Hz, 1H), 7.76(s, 1H), 7.72 (d, J= 2.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.22 (dd, J =
10.0, 2.4 Hz, 1H), 6.98 -6.94 (m, 1H), 3.08 (s, 3H).
Compound 59: 6-(6-fluoro-1H-indo1-3-y1)-2-(piperazin-1-ylmethyl)-1H-benzo[d]imidazole N....,......(--NZ-11 \...õ...õ H
it, NH
FS N\
H
Following the general method as outlined in Compound 1, starting from 6-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-2-piperazin-1-ylmethyl-1H-benzoimidazole (Intermediate 62, 80 mg, 0.16 mmol) , 35 mg (62%) of the title compound was obtained as a white solid. LC-MS for C201-120FN5+H [M+H]: calcd. 350.2; found: 350.1.

(400 MHz, CD30D) 6 [ppm]: 7.73 (dd, J= 8.8, 5.2 Hz, 1H), 7.70 (s, 1H), 7.50 (d, J= 8.8 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.03 (dd, J = 9.6, 2.0 Hz, 1H), 7.79 (d, J =
8.8, 2.0 Hz, 1H), 3.74 (s, 2H), 2.89 (t, J= 4.8 Hz, 4H), 2.52 (t, J= 4.8 Hz, 4H).
Compound 60: 2-(6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2-yl)acetamide FIN
To a stirred solution of [5-(6-fluoro-1H-indo1-3-y1)-1H-benzoimidazol-2-y1]-acetonitrile (Intermediate 68, 186 mg, 0.628 mmol) in DMSO (5 mL) at 0 C was added K2CO3 (173 mg, 1.26 mmol) and then aqueous H202 (0.7 mL, 30% w/w). The mixture was stirred at room temperature for 1 hour before it was diluted with water (50 mL) and extracted with Et0Ac (50 mLx2). The combined organic layer was washed with brine (30 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by a silica gel column chromatography (DCM/Me0H = 20/1 to 5/1) to give the solid.
The solid was suspended with DCM/Me0H = 5/1 (3 mL) and filtered. The filtered cake was evaporated to dryness to afford 40 mg (21%) of the title compound as an off-white solid.
LC-MS for C17H11 FN4O+H [M+H]: calcd. 309.1; found: 309.3. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 12.19 (d, J = 24.0 Hz, 1H), 11.33 (d, J = 12.8 Hz, 1H), 7.82 (dd, J =
8.4, 5.2 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.61 (dd, J = 9.6, 2.4 Hz, 1H), 7.59 -7.47 (m, 1H), 7.43 (td, J= 9.6, 2.4 Hz, 1H), 7.25 - 7.16 (m, 2H), 6.99 - 6.91 (m, 1H), 3.73 (s, 2H).

Compound 61: 5-(6-fluoro-1H-indo1-3-y1)-2-(piperazin-1-ylmethyl)benzo[d]oxazole 0.,_(-N
4. ki .NH
FIN
Following the general method as outlined in Compound 1, starting from 5-(1 -benzenesulfony1-6-fluoro-1H-indo1-3-y1)-2-piperazin-1-ylmethyl-benzooxazole (Intermediate 72, 80 mg, 0.16 mmol) in Me0H (10 mL), 30 mg (52%) of the title compound was obtained as a white solid. LC-MS for C20H19FN4O+H [M+H]: calcd.
351.2; found: 351.1. 1H NMR (400 MHz, CD30D) 6 [ppm]: 7.77 (s, 1H), 7.67 (dd, J=
8.8, 5.2 Hz, 1H), 7.54 (dd, J = 8.8, 1.2 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 7.03 (dd, J= 9.6, 2.0 Hz, 1H), 6.78 (td, J= 9.6, 2.0 Hz, 1H), 3.77 (s, 2H), 2.83 (t, J= 4.8 Hz, 4H), 2.56 (t, J= 4.8 Hz, 4H).
Compound 62: 5-(6-fluoro-1H-indo1-3-y1)-2-((4-methylpiperazin-1-yl)methyl)benzo[d]oxazole 0......r.
N
. k )1, 40 N\
F
H
Following the general method as outlined in Compound 1, starting from 5-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-2-(4-methyl-piperazin-1-ylmethyl)-benzooxazole (Intermediate 73, 160 mg, 0.32 mmol), 27 mg (23%) of the title compound was botained as a white solid. LC-MS for C21 H2iFN4O+H [M+H]: calcd. 365.2; found: 365.1.

NMR (400 MHz, CD30D) 6 [ppm]: 7.89 (d, J= 0.8 Hz, 1H), 7.80 (dd, J= 8.8, 5.2 Hz, 1H), 7.67 (dd, J= 8.8, 1.6 Hz, 1H), 7.62 (d, J= 8.4 Hz, 1H), 7.47 (s, 1H), 7.13 (dd, J=
9.6, 2.0 Hz, 1H), 6.89 (td, J = 9.6, 2.0 Hz, 1H), 3.90 (s, 2H), 2.78 - 2.68 (m, 4H), 2.68 -2.39 (m, 4H), 2.28 (s, 3H).

Compound 63: 5-(6-fluoro-1H-indo1-3-y1)-2-(morpholinomethyl)benzo[d]oxazole 0.....-4, k N3 0 NI\
F
H
Following the general method as outlined in Compound 1, starting from 5-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-2-morpholin-4-ylmethyl-benzooxazole (Intermediate 74, 100 mg, 0.204 mmol), 30 mg (42%) of the title compound was obtained as a white solid. LC-MS for C20H18FN302+H [M+H]: calcd. 352.1;
found:
352.1. 1H NMR (400 MHz, CD30D) 6 [ppm]: 7.86 (s, 1H), 7.75 (dd, J= 8.8, 5.6 Hz, 1H), 7.62 (d, J= 8.4 Hz, 1H), 7.56 (d, J= 8.4 Hz, 1H), 7.44 (s, 1H), 7.12 (dd, J=
9.6, 1.6 Hz, 1H), 6.87 (td, J = 9.6, 2.0 Hz, 1H), 3.82 (s, 2H), 3.69 (t, J = 4.4 Hz, 4H), 2.59 (t, J = 4.4 Hz, 4H).
Compound 64: 2-(6-(6-fluoro-1H-indo1-3-y1)-2-oxobenzo[d]oxazol-3(21-1)-Aacetamide ATIL b \w/
FSH
Following the general method as outlined in Compound 1, starting from 2-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-oxobenzo[d]oxazol-3(21-1)-yl)acetamide (Intermediate 76, 183 mg, 0.4 mmol), 50 mg (38 /0) of the title compound was obtained as a white solid. LC-MS for C17H12FN303+Hr [M+H] : calcd. 326.1; found: 325.8. 1H NMR
(400 MHz, DMSO-d6) 6 [ppm]: 11.43 (br s, 1H), 10.97 (br s, 1H), 9.81 (br s, 1H), 7.81 (dd, J =
8.4, 5.2 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.24 -7.21 (m, 2H), 7.12 (dd, J= 8.0, 1.2 Hz, 1H), 6.97 (td, J= 9.2, 2.0 Hz, 1H), 4.28 (s, 2H).
Compound 65: 5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-2(3H)-one H

, 46, NH
el N\
F
H
Following the general method as outlined in Compound 1, starting from 5-(1-Benzenesulfony1-6-fluoro-1H-indo1-3-y1)-, 3-dihydro-benzoimidazol-2-one (Intermediate 77, 185 mg, 0.45 mmol), 52 mg (43%) of the title compound was obtained as a yellow solid. LC-MS for C16H10FN30-H- [M-H]: calcd. 266.1; found: 265.9. 1H NMR (400 MHz, Me0D-d4) 6 [ppm]: 11.30 (s, 1H), 10.59 (s, 2H), 7.76 (dd, Ji = 8.4 Hz, 4.12 =
5.6 Hz, 1H), 7.56 (d, J= 2.0 Hz, 1H), 7.23 - 7.19 (m, 2H), 7.15 (s, 1H), 6.98 (d, J= 7.6 Hz, 1H), 6.94 (td, J1 = 9.2 Hz, 4.12 = 2.0 Hz, 1H).
Compound 66: 6-(6-fluoro-1H-indo1-3-y1)-2-(morpholinomethyl)benzo[d]oxazole N.....r"--b FIN
Following the general method as outlined in Compound 1, starting from 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(morpholinomethyl)benzo[d]oxazole (Intermediate 80, 240 mg, 0.48 mmol), 63 mg (44%) of the title compound was obtained as a tan solid. LC-MS for C20H18FN302+H [M+H]: calce. 352.1; found: 352.1. 1H
NMR
(400 MHz, DMSO-d6) 6 [ppm]: 11.51 (s, 1H), 7.96 (s, 1H), 7.91 - 7.88 (m, 1H), 7.77 -7.74 (m, 2H),7.69 - 7.67 (m, 1H), 7.24 (dd, J = 2.0, 9.6 Hz, 1H), 6.97 (td, J
= 2.4, 9.6 Hz, 1H), 3.87 (s, 2H), 3.61 - 3.59 (m, 4H), 2.56 - 2.54 (m, 4H).
Compound 67: 3-(6-(6-fluoro-1H-indo1-3-y1)-2-oxobenzo[d]oxazol-3(2H)-Apropanamide 0.11 ,._, Ara dil \virf FIN
Following the general method as outlined in Compound 1, starting from 3-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-oxobenzo[d]oxazol-3(2H)-Apropanamide (Intermediate 81, 280 mg, 0.58 mmol), 50 mg (25%) of the title compound was obtained as a white solid. LC-MS for C181-114FN303-H- [M-Hy : calcd. 338.1; found:
337.9. 1H
NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.40 (br s, 1H), 10.27 (br s, 1H), 9.60 (br s, 1H), 7.81 (dd, J= 8.8, 5.4 Hz, 1H), 7.63 (d, J= 2.8 Hz, 1H), 7.24-7.19 (m, 3H), 7.11 (dd, J=
8.0, 1.6 Hz, 1H), 6.97 (td, J= 9.6, 2.0 Hz, 1H), 3.63 (t, J= 6.6 Hz, 2H), 2.70 (t, J= 6.8 Hz, 2H).
Compound 68: 6-(6-fluoro-1H-indo1-3-y1)-2-((4-methylpiperazin-1-yl)methyl)benzo[d]oxazole N1......:(N/-II

FIN
Following the general method as outlined in Compound 1, starting from 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-((4-methylpiperazin-1-yl)methyl)benzo[d]oxazole (Intermediate 82, 285 mg, 0.56 mmol), 45 mg (22%) of the title compound was obtained as a tan solid. LC-MS for C21 H 21FN4O+H [M+H]: calcd.365.2 ; found: 364.9.

(400 MHz, DMSO-d6) 6 [ppm]: 11.54 (s, 1H), 7.95 - 7.88 (m, 2H), 7.76 - 7.67 (m, 3H), 7.24 (dd, J= 9.6, 1.6 Hz, 1H), 6.99 - 6.95 (m, 1H), 3.84 (s, 2H), 2.55 (s, 4H), 2.34 (s, 4H), 2.15 (s,3H) Compound 69: 2-(5-(6-fluoro-1H-indo1-3-y1)-2-oxobenzo[d]oxazol-3(21-1)-Aacetamide 0¨r o . NJ/
FIN
Following the general method as outlined in Compound 1, starting from 2-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-oxobenzo[c]oxazol-3(2H)-yl)acetamide (Intermediate 84, 600 mg crude, 1.29 mmol), 13 mg (3%) of the title compound was obtained as a white solid after purification by preparative HPLC. LC-MS for C17H12FN303-H-[M-Hy:
calcd. 324.1; found: 323.9. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.31 (br s, 1H), 10.95 (br s, 1H), 9.74 (br s, 1H), 7.80 (dd, J = 8.7, 5.4 Hz, 1H), 7.59 (d, J
= 2.0 Hz, 1H), 7.54 (d, J= 2.0 Hz, 1H), 7.46 ¨7.43 (m, 1H), 7.19 (dd, J= 10.0, 2.0 Hz, 1H), 6.99 ¨ 6.90 (m, 2H), 4.32 (s, 2H).
Compound 70: N-((5-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-yl)methyl)methanesulfonamide 0_ 7 N- Nb 46 ki H
FIN
Following the general method as outlined in Compound 1, starting from N-[5-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-benzooxazol-2-ylmethyl]-methanesulfonamide (Intermediate 87, 83 mg, 0.17 mmol), 30 mg (50%) of the title compound was obtained as a white solid. LC-MS for C17H14FN303S+H [M+H]: calcd. 360.1; found: 360Ø

NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.45 (br s, 1H), 8.01 (br s, 1H), 7.95 (s, 1H), 7.89-7.81 (m, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 2.8 Hz, 1H), 7.70 (d, J =
8.8 Hz, 1H), 7.23 (dd, J= 10.0, 2.0 Hz, 1H), 6.96 (td, J= 8.8, 2.0 Hz, 1H), 4.54 (s, 2H), 3.04 (s, 3H).

Compound 71: 3-(5-(6-fluoro-1H-indo1-3-y1)-2-oxobenzo[d]oxazol-3(2H)-Apropanamide) ,O,o 41, N

F lel N\
H
Following the general method as outlined in Compound 1, starting from 3-[5-(1-Benzenesulfony1-6-fluoro-1H-indo1-3-y1)-2-oxo-benzooxazol -3-y1]-propionamide (Intermediate 88, 270 mg, 0.56 mmol), the title compound (48 mg, 25%) was obtained as a white solid. LC-MS for C18H14FN303-H- [M-Hy: calcd. 338.1; found: 338Ø

(400 MHz, DMSO) 6 11.30 (s, 1H), 10.31 (s, 1H), 9.56(s, 1H), 7.78 (dd, J= 8.8, 5.6 Hz, 1H), 7.54 (d, J= 2.0 Hz, 1H), 7.47 (d, J= 2.0 Hz, 1H), 7.43 (dd, J= 8.4, 2.2 Hz, 1H), 7.19 (dd, J=
9.9, 1.9 Hz, 1H), 6.98 (d, J= 8.4 Hz, 1H), 6.99 ¨6.90 (m, 2H), 3.67 (t, J= 6.6 Hz, 2H), 2.72 (t, J
= 6.6 Hz, 2H).
Compound 72: 3-(benzo[b]thiophen-5-y1)-6-fluoro-1H-indole s it I
FSH
Following the general method as outlined in Compound 1, starting from 3-(benzo[b]thiophen-5-y1)-6-fluoro-1-(phenylsulfony1)-1H-indole (Intermediate 90, 300 mg, 0.74 mmol) , 3-Benzo[b]thiophen-5-y1-6-fluoro-1H-indole(70 mg, 36%) was obtained as a white solid. LC-MS for C16H10FNS-H-[M-Hy: calcd.266.1; found: 265.9. 1H NMR
(400 MHz, DMSO) 6 11.44 (s, 1H), 8.18 (s, 1H), 8.03 (d, J= 8.0 Hz, 1H), 7.92 (dd, J= 8.8, 5.2 Hz, 1H), 7.77 (d, J= 5.2 Hz, 1H), 7.74 (s, 1H), 7.68 (d, J= 8.8 Hz, 1H), 7.51 (d, J= 5.6 Hz, 1H), 7.23 (dd, J= 9.8, 2.0 Hz, 1H), 6.97 (td, J= 9.2, 2.4 Hz, 1H).
Compound 73: N-((5-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-211)methypacetamide X-0.0 FS N\
H
To a stirred mixture of C-[5-(6-fluoro-1H-indo1-3-y1)-benzooxazol-2-y1]-methylamine hydrochloride (Compound 81,40 mg, 0.126 mmol) in DCM (6 mL) at room temperature was added TEA (25 mg, 0.252 mmol) and AcCI (49 mg, 0.63 mmol). The mixture was stirred for a further 30 minutes before it was quenched with ice water (20 mL) and extracted with Et0Ac (20 mLx2). The combined organic layer was washed with brine (20 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by a preparative TLC (DCM/Me0H = 20/1) to afford 13 mg (32%) of the title compound as a yellow solid. LC-MS for C18H14FN302+H [M+H]: calcd. 324.1;
found:
324.1. 1H NMR (400 MHz, CD30D) 6 [ppm]: 7.90 (s, 1H), 7.82 (dd, J= 8.8, 1.6 Hz, 1H), 7.70 (dd, J= 8.4, 1.6 Hz, 1H), 7.66 (d, J= 8.4 Hz, 1H), 7.50 (s, 1H), 7.16 (dd, J= 9.6, 2.0 Hz, 1H), 6.92 (td, J= 9.6, 2.4 Hz, 1H), 4.70 (s, 2H), 2.10 (s, 3H).
Compound 74: N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-yl)methyl)methanesulfonamide NVI' ----FS N\
H
A mixture of tert-butyl tert-butyl ((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-yl)methyl)(methylsulfonyl)carbamate (Intermediate 92, 114 mg, 0.25 mmol) in HCl/1,4-dioxane (15 mL) was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated and purified by preparative HPLC to afford 22 mg (24%) of the title compound as a yellow solid. LC-MS for C17H14FN303S+H [M + H] : calcd. 360.1;
found: 360.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.51 (s, 1H), 8.03- 7.99 (m, 1H), 7.97 (s, 1H), 7.90 (dd, J = 8.8, 5.4 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.70 (dd, J
= 8.3, 1.3 Hz, 1H), 7.24 (dd, J= 10.2, 2.2 Hz, 1H), 6.97 (td, J= 9.2, 2.1 Hz, 1H), 4.54 (d, J= 4.4 Hz, 2H), 3.04 (s, 3H).
Compound 75: N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-211)methypacetamide )L-Npl 4i FS N\
H
To a solution of (6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methanamine hydrochloride (Compound 76, 120 mg, 0.38 mmol) and TEA (115 mg, 1.14 mmol) in DCM (20 mL) was added acetyl chloride (36 mg, 0.45 mmol) under nitrogen. The mixture was stirred at room temperature for 1 hour under nitrogen. The reaction was acidified with HCI (12 M) till pH=5. The mixture was diluted with water (60 mL) and extracted with DCM (30 mL). The combined organic layer was washed with water (60 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative HPLC to afford 55 mg (39%) of the title compound as a white solid. LC-MS for C18H14FN302+H [M+H] : calcd. 324.1; found: 324.5. 1H NMR
(400 MHz, DMSO-d6) 6 [ppm]: 11.50 (s, 1H), 8.69 (t, J= 5.6 Hz, 1H), 7.94 (s, 1H), 7.89 (dd, J
= 9.0, 5.4 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.69 -7.67 (m, 1H), 7.24 (dd, J= 9.9, 2.3 Hz, 1H), 6.97 (td, J= 9.2, 2.0 Hz, 1H), 4.57 (d, J= 5.6 Hz, 2H), 1.93 (s, 3H).
Compound 76: (6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methanamine N...rNH2 git FS N\
H

A mixture of tert-butyl N-[(tert-butoxy)carbony1]-N-([6-(6-fluoro-1H-indol-3-y1)-1,3-benzoxazol-2-yl]methAcarbamate (Intermediate 94; 376 mg, 0.78 mmol) in HC1/1,4-dioxane (20 mL) was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated to afford 219 mg (100%) of the title compound as a yellow solid.
LC-MS
for C16H13CIFN3O+H [M+H] :calcd. 282.1; found: 281.9. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.51 (br s, 1H), 7.92 (s, 1H), 7.90 - 7.87 (m, 1H), 7.77 (s, 1H), 7.74 (d, J =
8.0 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 9.6 Hz, 1H), 6.98 (t, J =
9.0 Hz, 1H), 3.99 (s, 2H).
Compound 77: 5-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-ylmethyl)-2H-indazole NH
FS-N
\
4Ikt N\
A mixture of 4-[5-(6-Fluoro-1H-indo1-3-y1)-indazol-2-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 5-2, 189 mg, 0.42 mmol) in HC1/1,4-dioxane (10 mL) was stirred at room tempreture for 1 hour. The mixture was concentrated and the residue was purified by preparative TLC (dichloro-methane/Me0H = 10/1) to afford 136 mg (93%) of the title compound as a yellow solid. LC-MS for C21 H21FN4+H
[M+H]:
calcd. 349.2; found: 348.9 1H NMR (400 MHz, Me0D-d4) 6 [ppm]: 11.35 (s, 1H), 8.31 (s, 1H), 7.92-7.86 (m, 2H), 7.66-7.63 (m, 2H), 7.55 (dd, J = 9.2, 1.6 Hz, 1H), 7.21 (dd, J = 9.6, 2.4 Hz, 1H), 6.95 (td, J = 9.6, 2.4 Hz, 1H), 4.28 (d, J = 7.2 Hz, 2H), 2.91-2. 89 (m, 2H), 2.41-2.36 (m, 2H), 1.39 (d, J= 10.8 Hz, 2H), 1.12 (td, J= 12.2, 3.4 Hz, 2H).
Compound 78: 6-(6-fluoro-1H-indo1-3-y1)-2-(piperazin-1-ylmethyl)benzo[d]oxazole N1z_zr-Nr-Aul Following the general method as outlined in Compound 1, starting from 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(piperazin-1-ylmethyl)benzo[d]oxazole (Intermediate 95, 277 mg, 0.56 mmol), 84 mg (43%) of the title compound was obtained as a white solid. LC-MS for C20H19FN4O+H [M+H]: calcd. 351.2; found: 351.1. 1H NMR (400 MHz, Me0D) 6 [ppm]: 7.89 - 7.84 (m, 2H), 7.74 - 7.73 (m, 2H), 7.56 (s, 1H), 7.16 (dd, J
= 10, 2.4 Hz, 1H), 6.94 (td, J = 9.2, 2.4 Hz, 1H), 3.96 - 3.95 (m, 2H), 2.97 (br s, 4H), 2.71 (br s, 4H) Compound 79: 3-(benzo[b]thiophen-6-yI)-6-fluoro-1H-indole FSH
Following the general method as outlined in Compound 1, starting from 3-(benzo[b]thiophen-6-y1)-6-fluoro-1-(phenylsulfony1)-1H-indole (Intermediate 97, 338 mg, 0.83 mmol) in Me0H (20 mL), 89 mg (40%) of the title compound was obtained as a yellow solid. LC-MS for C16H10FNS- H [M - : calcd.266.1; found: 266Ø 1H
NMR (400 MHz, DMSO-d6) 6 [PPrn]: 11.47 (s, 1H), 8.29 (s, 1H), 7.97 - 7.91 (m, 2H), 7.78 (d, J= 2.4 Hz, 1H), 7.73 - 7.68 (m, 2H), 7.45 (d, J= 5.2 Hz, 1H), 7.24 (dd, J= 10.0, 2.0 Hz, 1H), 6.98 (td, J=
9.2, 2.4 Hz, 1H).
Compound 80: 5-(6-fluoro-1H-indo1-3-y1)-2-(2-(methylsulfonypethypenzo[d]oxazole 'ft FSH
To a solution of 6-fluoro-342-(2-methanesulfonyl-ethyl)-benzooxazol-5-y1]-indole-1-carboxylic acid tert-butyl ester (Intermediate 101, 45 mg, 0.098 mmol) in Me0H
(1 mL) was added HCl/Et20 (5 mL, 4M) at 0 C. The mixture was stirred at room temperature for 16 hours before it was concentrated. The residue was diluted with Me0H (5 mL) and basified with NH3/THF to pH = 8. The micture was concentrated and purified by a preparative TLC (DCM/Me0H = 20/1) to afford 6 mg (17%) of the title compound as an off-white solid. LC-MS for C18H15FN203S+H [M+H]: calcd. 359.1; found: 359Ø

NMR (400 MHz, CDCI3) 6 [ppm]: 8.26 (brs, 1H), 7.91 (s, 1H), 7.82 (dd, J = 8.8, 5.2 Hz, 1H), 7.61 (d, J= 8.0 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.35 (d, J= 2.0 Hz, 1H), 7.14 (d, J
= 9.6, 2.0 Hz, 1H), 6.97 (td, J= 8.8, 2.0 Hz, 1H), 3.70 (t, J= 7.6 Hz, 2H), 3.54 (t, J= 7.6 Hz, 2H), 3.02 (s, 3H).
Compound 81: (5-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methanamine of-N1d2 'ft FS N\
H
To a solution of [5-(6-fluoro-1H-indo1-3-y1)-benzooxazol-2-ylmethyl]-carbamic acid tert-butyl ester (Intermediate 103, 63 mg, 0.165 mmol) in Me0H (3 mL) was added HCl/Et20 (3 mL, 8M) at 0 C. The mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness to afford 20 mg (43%) of the title compound as a yellow solid.
LC-MS for C16H12FN3O+H [M+H]: calcd. 282.1; found: 282.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.53 (br s, 1H), 8.83 (br s, 3H), 8.00 (s, 1H), 7.86 - 7.82 (m, 2H), 7.77 - 7.75 (m, 2H), 7.25 (dd, J = 10.0, 2.4 Hz, 1H), 6.98 (td, J = 8.8, 2.0 Hz, 1H), 4.54 -4.52 (m, 2H).

Compound 82: 3-(benzofuran-5-yI)-6-fluoro-1H-indole 4. I
FSH
Following the general method as outlined in Compound 1, starting from 3-(benzofuran-5-y1)-6-fluoro-1-(phenylsulfony1)-1H-indole (Intermediate 104, 300 mg, 0.77 mmol), 40 mg (21%) of the title compound was obtained as a yellow solid after purification by silica gel chromatography (petroleum ether/Et0Ac = 5/1, v/v). LC-MS for C16H10FN0-H-[M-1-1]-: calcd. 250.1; found: 250.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.39 (br s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.85 (dd, J = 8.8, 5.5 Hz, 1H), 7.66 (s, 1H), 7.60 (dd, J = 8.4, 2.0 Hz, 2H), 7.23 (dd, J = 9.6, 2.4 Hz, 1H), 6.70 -6.93 (m, 2H).
Compound 83: 3-(6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-211)propanamide N.NH2 4*
FS N\
H
To a mixture of 3-[6-(6-fluoro-1H-indo1-3-y1)-benzooxazol-2-y1]-propionic acid (Intermediate 108, 52 mg, 0.17 mmol) and NH4CI (27 mg, 0.50 mmol) in anhydrous THF
was added HATU (127 mg, 0.33 mmol) and TEA (34 mg, 0.33 mmol) at 0 C. The mixture was stirred at room temperature under nitrogen for 1.5 hours before it was quenched with ice water (30 mL) and extracted with Et0Ac (30 mLx2). The combined organic layer was washed with 1M NaOH (10 mLx2) and brine (20 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated and purified by a preparative TLC (DCM) and a preparative HPLC (NH3/H20 as additive) to afford 10 mg (20%) of the title compound as a white solid. LC-MS for C18H14FN302+H [M+H]:
calcd.
324.1; found: 324.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.48 (brs, 1H), 7.92-7.86 (m, 2H), 7.75(d, J = 2.4 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 8.0, 1.6 Hz, 1H), 7.47 (brs, 1H), 7.24 (dd, J = 9.6, 2.0 Hz, 1H), 6.96 (td, J = 8.4, 2.0 Hz, 1H), 6.91(brs, 1H), 3.14 (t J= 7.2 Hz, 2H), 2.68 (t J= 7.2 Hz, 2H).
Compound 84: 2-(6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-1-yl)acetamide N., 0 F i 46, m - IINH2 40 \H
Following the general method as outlined in Compound 1, starting from 2-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazol-1-yl)acetamide (Intermediate 109A, 100 mg, 0.22 mmol), 14 mg (21%) of the title compound was obtained as a white solid after purification by preparative TLC (DCM/Me0H = 10/1, v/v). LC-MS for C17H13FN4O+H [M+H]: calcd. 309.1; found: 309.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.48 (br s, 1H), 8.14 (s, 1H), 7.88 (dd, J= 8.8, 5.5 Hz, 1H), 7.87 (br s, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.50 (dd, J = 8.4, 1.6 Hz, 1H), 7.37 (br s, 1H), 7.23 (dd, J = 9.9, 2.4 Hz, 1H), 6.95 (m, 1H), 4.98 (s, 2H).
Compound 85: 2-(5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-1-yl)acetamide AIL_Th Ce-A RI
\111W
F 40 N\
H
Following the general method as outlined in Compound 1, starting from 2-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazol-1-yl)acetamide (Intermediate 109B, 60 mg, 0.13 mmol), 13 mg (31%) of the title compound was obtained as a white solid after purification by preparative HPLC. LC-MS for C17H13FN4O+H [M+H]: calcd.
309.1;
found: 309.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.35 (br s, 1H), 8.16 (s, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 8.8, 5.5 Hz, 1H), 7.76 (br s, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.56 (dd, J = 8.4, 1.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.37 (br s, 1H), 7.22 (dd, J= 10.0, 2.4 Hz, 1H), 6.95 (m, 1H), 4.93 (s, 2H).
Compound 86: 3-(5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-y1)-1-morpholinopropan-1-one N
"
N,., /
dil 4It FSH
A mixture of 3-[5-(6-Fluoro-1H-indo1-3-y1)-indazol-1-y1]-propionic acid (Intermediate 111, 180 mg, crude, 0.56 mmol), Morpholine (48 mg, 0.56 mmol), HATU (319 mg, 0.84 mmol) and DIEA (217 mg, 1.68 mmol) in 5 mL of DMF was stirred at room temperature for 2 hr.
Then the mixture was poured into water and extracted with Et0Ac (50 mLx3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (CH3CN/H20 =
30% -75%, NH4HCO3) to afford 10 mg (5%) of the title compound as a white solid. LC-MS for C22H21 FN402+1-1 [M+H]: calcd. 393.1; found: 393.1. 1H NMR (400 MHz, DMSO-d6) [ppm]: 11.37 (br s, 1H), 8.08 (br s, 1H), 7.98 (br s, 1H), 7.86 (dd, J= 8.8, 5.6 Hz, 1H), 7.74 - 7.67 (m, 3H), 7.22 (dd, J = 9.6, 2.4 Hz, 1H), 6.96 (td, J = 9.4, 2.4 Hz, 1H), 4.65 (t, J= 6.8 Hz, 2H), 3.47 - 3.38 (m, 6H), 3.34 - 3.30 (m, 2H), 2.96 (t, J= 6.8 Hz, 2H).
Compound 87: 3-(5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-y1)-1-(4-methylpiperazin-1-yl)propan-1-one N
"
N,, /
41k. N
101 N\
F H

A mixture of 3-[5-(6-Fluoro-1H-indo1-3-y1)-indazol-1-y1]-propionic acid (Intermediate 111, 300 mg, crude, 0.93 mmol), 1-Methyl-piperazine (93 mg, 0.93 mmol), HATU (530 mg, 1.4 mmol) and DIEA (360 mg, 2.8 mmol) in 5 mL of DMF was stirred at room temperature for 2 hr. Then the mixture was poured into water and extracted with Et0Ac (50 mLx3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC
(CH3CN/H20 = 30% - 75%, NH4HCO3) to afford 76 mg (20%) of the title compound as a white solid. LC-MS for C23H24FN6O+H [M+H]: calcd. 406.2; found: 406.2. 1H NMR

(400 MHz, DMSO-d6) 6 [ppm]: 11.36 (s, 1H), 8.08 (s, 1H), 7.98 (s, 1H), 7.88 -7.84 (m, 1H), 7.73 - 7.66 (m, 3H), 7.22 (dd, J = 10.0, 2.4 Hz, 1H), 6.96 (td, J = 8.8, 2.4 Hz, 1H), 4.64 (t, J= 6.8 Hz, 2H), 3.40-3.38 (m, 2H), 3.32- 3.29 (m, 2H), 2.94 (t, J=
6.8 Hz, 2H), 2.14- 2.09 (m, 7H).
Compound 88: N-(2-(dimethylamino)ethyl)-3-(5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-yl)propanamide N'-NN
/ H
N
41i.,--= -....
el N\
F
H
A mixture of 3-[5-(6-Fluoro-1H-indo1-3-y1)-indazol-1-y1]-propionic acid (Intermediate 111, 300 mg, crude, 0.93 mmol), (2-aminoethyl)dimethylamine (82 mg, 0.93 mmol), HATU
(530 mg, 1.4 mmol) and DIEA (360 mg, 2.8 mmol) in 5 mL of DMF was stirred at room temperature for 2 hr. Then the mixture was poured into water and extracted with Et0Ac (50 mLx3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC
(CH3CN/H20 = 30% - 75%, NH4HCO3) to afford 60 mg (16%) of the title compound as a white solid. LC-MS for C22H24FN6O+H [M+H]: calcd. 394.2; found: 394.2. 1H NMR
(400 MHz, DMSO-d6) 6 [ppm]: 11.37 (br s, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.88-7.84 (m, 2H), 7.72 - 7.66 (m, 3H), 7.22 (dd, J = 10.0, 1.6 Hz, 1H), 6.96 (t, J =
5.2 Hz, 1H), 4.62 (t, J= 6.4 Hz, 2H), 3.06 (q, J= 6.4 Hz, 2H), 2.69 (t, J= 6.4 Hz, 2H), 2.11 (t, J= 6.4 Hz, 2H), 2.04 (s, 6H).

Compound 89: 3-(5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-y1)-N-(2-hydroxyethyl)propanamide /N-N)LN
H
H
441i el N\
F
H
A mixture of 3-[5-(6-Fluoro-1H-indo1-3-y1)-indazol-1-y1]-propionic acid (Intermediate 111, 300 mg, crude, 0.93 mmol), 2-Amino-ethanol (57 mg, 0.93 mmol), HATU (530 mg, 1.4 mmol) and DIEA (360 mg, 2.8 mmol) in 5 mL of DMF was stirred at room temperature for 2 hr. Then the mixture was poured into water and extracted with Et0Ac (50 mLx3).
The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC
(CH3CN/H20 =
30% - 75%, NH4HCO3) to afford 53 mg (16%) of the title compound as a white solid.
LC-MS for C20H19FN402+H [M+H]: calcd. 367.2; found: 367.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.37 (br s, 1H), 8.07 (br s, 1H), 7.98 - 7.94 (m, 2H), 7.88 - 7.85 (m, 1H), 7.70 - 7.67 (m, 3H), 7.22 (d, J = 10.0 Hz, 1H), 6.96 (t, J = 9.2 Hz, 1H), 4.63 - 4.61 (m, 3H), 3.36- 3.30 (m, 2H), 3.08- 3.07 (m, 2H), 2.71 (t, J= 6.0 Hz, 2H).
Compound 90: 3-(5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-y1)-N-(2-(methylsulfonyl)ethyl)propanamide N-1\IAN0)=0 / H
= I
FIN
A mixture of 3-[5-(6-Fluoro-1H-indo1-3-y1)-indazol-1-y1]-propionic acid (Intermediate 111, 300 mg, crude, 0.93 mmol), 2-Methanesulfonyl-ethylamine HCI salt (148 mg, 0.93 mmol), HATU (530 mg, 1.4 mmol) and DIEA (360 mg, 2.8 mmol) in 5 mL of DMF was stirred at room temperature for 2 hr. Then the mixture was poured into water and extracted with Et0Ac (50 mLx3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (CH3CN/H20 = 30% - 75%, NH4HCO3) to afford 64 mg (16%) of the title compound as a white solid. LC-MS for C21 F121FN403S+H [M+H]: calcd.
429.1;
found: 429.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.37 (br s, 1H), 8.25 (t, J=
5.6 Hz, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.89 - 7.85 (m, 1H), 7.70 (s, 2H), 7.67 (s, 1H), 7.22 (dd, J = 10.0, 2.0 Hz, 1H), 6.96 (td, J = 9.2, 2.0 Hz, 1H), 4.63 (t, J = 6.8 Hz, 2H), 3.40 (q, J= 6.4 Hz, 2H), 3.12 (t, J= 6.8 Hz, 2H), 2.89 (s, 3H), 2.72 (t, J= 6.8 Hz, 2H).
Compound 91: 3-(5-(6-fluoro-1H-indo1-3-y1)-1H-indazol-1-y1)-1-(piperazin-1-yl)propan-1-one N,õ, z ININ
NH
441, FSH
A solution of 4-{3-[5-(6-Fluoro-1H-indo1-3-y1)-indazol-1-y1]-propiony1}-piperazine-1-carboxylic acid tert-butyl ester (Intermediate 112, 98 mg, 0.2 mmol) in HCl/Et0Ac (25%, 10 mL) was stirred at room temperature for 2 hr. Then the mixture was concentrated.
The residue was purified by preparative HPLC (CH3CN/H20 = 30% - 75%, NH4HCO3) to afford 34 mg (43%) of the title compound as a white solid. LC-MS for C22H22FN6O+H
[M+H]: calcd. 392.2; found: 392.1. 'H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.37 (br s, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.88 - 7.85 (m, 1H), 7.74 - 7.66 (m, 3H), 7.22 (dd, J=
10.0, 2.4 Hz, 1H), 6.96 (td, J = 9.2, 2.4 Hz, 1H), 4.63 (t, J = 6.8 Hz, 2H), 3.32 - 3.30 (m, 2H), 3.25- 3.23 (m, 2H), 2.93 (t, J= 6.8 Hz, 2H), 2.55 -2.47 (m, 4H).
Compound 92: 6-(6-fluoro-1H-indo1-3-yl)indolin-2-one FS N\
H
A mixture of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-yl)indolin-2-one (Intermediate 113, 400 mg, 0.98 mmol), Mg turnings (200 mg, 8.2 mmol) and NH4C1 (106 mg, 2.0 mmol) in THF (2 mL) and Me0H (8 mL) was stirred for 2 hours at room temperature. The reaction mixture was filtered through Celite, concentrated and purified by preparative TLC
(petroleum ether/Et0Ac = 3/1) to afford 26 mg (10%) of the title compound as a yellow solid. LC-MS for C16H11FN20-H- [M-Hy: calcd. 265.1; found: 265.1. 1H NMR (400 MHz, Me0H-d4) 6 [ppm]: 7.68 (dd, J = 8.8, 5.2 Hz, 1H), 7.33 (s, 1H), 7.18 (s, 1H), 7.07 (s, 2H), 7.01 (dd, J= 9.8, 2.2 Hz, 1H), 6.77 (td, J= 9.1, 2.4 Hz, 1H), 3.45 (s, 2H).
Compound 93: 3-(6-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-1-yl)propanamide i .N
FS N\
H
Following the general method as outlined in Compound 1, starting from 3-(6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazol-111)propanamide (Intermediate 114A, 140 mg, 0.30 mmol), 30 mg (31%) of the title compound was obtained as a white solid after purification by preparative HPLC. LC-MS for C18H16FN4O+H [M+H]:
calcd.
323.1; found: 323.2. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.51 (br s, 1H), 8.13 (s, 1H), 7.96 (dd, J = 8.8, 5.6 Hz, 1H), 7.85 (s, 1H), 7.69 -7.67(m, 2H). 7.51 (d, J = 8.0 Hz, 1H), 7.47 (br s, 1H), 7.24 (dd, J = 9.8, 2.2 Hz, 1H), 6.97 (td, J = 9.2, 2.0 Hz, 2H), 4.52 (t, J= 6.4 Hz, 2H), 2.68 (t, J= 6.6 Hz, 2H).
Compound 94: 3-(5-(6-fluoro-1H-indo1-3-y1)-1H-benzo[d]imidazol-1-yl)propanamide Ali)Ki \NW
el N\
F
H
Following the general method as outlined in Compound 1, starting from 3-(5-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-benzo[climidazol-111)propanamide (Intermediate 1146,180 mg, 0.39 mmol), 51 mg (41%) of the title compound was obtained as a white solid after purification by preparative HPLC. LC-MS for C18H16FN4O+H [M+H]:
calcd.
323.1; found: 323.2. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.37 (br s, 1H), 8.16 (s, 1H), 7.87 (s, 1H), 7.84 (dd, J = 8.4, 5.6 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.22 (dd, J = 10.0, 2.4 Hz, 1H), 6.95 (m, 2H), 4.48 (t, J= 6.4 Hz, 2H), 2.66 (t, J= 6.6 Hz, 2H).
Compound 95: 1-(4-(6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-211)piperidin-1-ypethanone pi)L--N

FIN
To a stirred solution of 6-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-yl)benzo[d]oxazole (Compound 55, 200 mg, 0.60 mmol) and TEA (182 mg, 1.80 mmo) in DCM (10 mL) at room temperature, was added dropwise acetyl chloride (57 mg, 0.72 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with DCM
(10 mL), washed with water (20 mLx2), dried over Na2Sa4and filtered. The filtrate was concentrated and purified by preparative HPLC to afford 121 mg (54%) of the title compound as a yellow solid. LC-MS for C22H20FN302+H : [M+H]: calcd.
378.2;found:

378.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.48 (s, 1H), 7.92 (s, 1H), 7.89 (dd, J= 5.6, 8.8 Hz, 1H), 7.75 (d, J= 2.8 Hz, 1H), 7.73 (d, J= 7.2 Hz, 1H), 7.66 (dd, J= 1.6, 8.0 Hz, 1H), 7.23 (dd, J= 2.4, 10.0 Hz, 1H), 6.97 (td, J= 2.4, 9.6 Hz, 1H), 4.32 (d, J= 13.6 Hz, 1H), 3.87 (d, J=
13.6 Hz, 1H), 3.35 - 3.27 (m, 2H), 2.88 (t, J= 11.2 Hz, 1H), 2.13 (t, J= 14.0 Hz, 2H), 2.04 (s, 3H), 1.88-1.77 (m, 1H), 1.72 - 1.62 (m, 1H).
Compound 96: 6-(6-fluoro-1H-indo1-3-y1)-2-(1-(methylsulfonyl)piperidin-4-yl)benzo[d]oxazole ..... NA z-0 N...F) FIN
A solution of 6-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-yl)benzo[d]oxazole (Compound 55, 200 mg, 0.60 mmol) and TEA (182 mg, 1.80 mmo) in DCM (10 mL) was stirred at room temperature for 10 min before it was cooled to 0 C. Then Methanesulfonyl chloride (82 mg, 0.72 mmol) was added dropwise. The reaction was stirred at room temperature for lhour. The mixture was diluted with DCM (10 mL), washed with water (20 mLx2), dried over Na2SO4 and concentrated.The residue was purified by preparative HPLC to afford 159 mg (64%) of the title compound as a pink solid. LC-MS for C21 F120FN303S+H

[M+H]: calcd. 414.12; found: 414.10. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.48 (s, 1H), 7.93 (s, 1H), 7.88 (dd, J = 5.6, 8.8 Hz, 1H), 7.75 (5, 1H), 7.74 (d, J =
11.2 Hz, 2H), 7.66 (dd, J= 1.6, 8.0 Hz, 1H), 7.24 (dd, J= 2.4, 10.0 Hz, 1H), 6.97 (td, J=
2.4, 10.0 Hz, 1H), 3.62 - 3.58 (m, 2H), 3.26-3.19 (m, 1H), 3.00 (td, J= 2.4, 12.0 Hz, 2H), 2.91 (s, 3H), 2.24 (dd, J= 13.6, 3.6 Hz, 2H), 1.93- 1.89 (m, 2H).
Compound 97: 5-(6-fluoro-1H-indo1-3-yl)indolin-2-one HN
=
FIN
The mixture of 1-benzenesulfony1-6-fluoro-1',3'-dihydro-1H-[3,51biindoly1-2'-one(Intermediate 116, 300 mg, 0.74 mmol), Mg(178 mg, 7.4 mmol) and NH4C1(12 mg, 0.22 mmol) in Me0H was stirred at room temperature under nitrogen for about 5 hrs.
After it is done, the mixture was filtered through a pad of celite and concentrated. The residue was purified by pre-TLC (DCM/methano1=20/1) to get the title compound (60 mg, 30%) as a yellow solid. LC-MS for C16H11FN20-H- [M-Hy: calcd. 265.1;
found:
265.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.31 (s, 1H), 10.38 (s, 1H), 7.78 (dd, J
= 8.8, 5.6 Hz, 1H), 7.56 (d, J= 2.4 Hz, 1H), 7.50 (s, 1H), 7.46 (d, J= 8.0 Hz, 1H), 7.19 (dd, J = 10.0, 2.3 Hz, 1H), 6.93 (td, J = 9.5, 2.4 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 3.53 (s, 2H).
Compound 98: 6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-amine Nz.zgNH2 FIN
The mixture of 6-(1-Benzenesulfony1-6-fluoro-1H-indo1-3-y1)-benzooxazol-2-ylamine (Intermediate 118, 300 mg, 0.74 mmol), Mg (178 mg, 7.4 mmol) and NH4C1 (12 mg, 0.22 mmol) in Me0H was stirred at room temperature under nitrogen for about 5 hrs.
After it is done, the mixture was filtered through a pad of celite and concentrated.
The residue was purified by preparative TLC (DCM/methano1=20/1) to get the title compound (40mg, 25%) as a yellow solid. LC-MS for C16H10FN3O+H [M+H]: calcd. 268.1; found:
268Ø
1H NMR (400 MHz, DMSO) 6 11.33 (s, 1H), 7.82 (dd, J= 8.8, 5.4 Hz, 1H), 7.61 (d, J= 2.4 Hz, 1H), 7.56 (d, J= 1.2 Hz, 1H), 7.40 (dd, J= 8.0, 1.2 Hz, 1H), 7.36 (s, 2H), 7.24 (d, J= 8.1 Hz, 1H), 7.20 (dd, J= 10.0, 2.4 Hz, 1H), 6.93 (td, J= 9.6, 2.4 Hz, 1H).

Compound 99: N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-211)methyl)-2-methoxyethanesulfonamide 0 0, v"---/
NI...rhy FS N\
H
To a stirred solution of (6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methanamine hydrochloride (Compound 76, 196 mg, 0.62 mmol) and TEA (0.25 mL, 1.86 mmol) in DCM (30 mL) was added 2-methoxyethanesulfonyl chloride (128 mg, 0.8 mmol) at 0 C
under nitrogen. The mixture was stirred at 0 C for 1 hour before it was diluted with DCM
(20 mL). The organic layer was washed with water (50 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative HPLC to afford 15 mg (5%) of the title compound as a yellow solid. LC-MS for C19H18FN304S+H
[M+H] : Calcd. 404.1; found: 403.8. 1H NMR (400 MHz, Me0D ) 6 [ppm]: 7.77 -7.71 (m, 2H), 7.63 - 7.58 (m, 2H), 7.43 (s, 1H), 7.04 (dd, J= 10.0, 2.4 Hz, 1H), 6.82 (td, J=
9.2, 2.4 Hz, 1H), 4.49 (s, 2H), 3.68 (t, J= 6.0 Hz, 2H), 3.34 (t, J= 6.0 Hz, 2H), 3.22 (s, 3H).
Compound 100: 2-(dimethylamino)-N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methypethanesulfonamide 0 )`I, -:-.-0 N,r¨hr FS
H
To a stirred solution of N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-yl)methyl)ethenesulfonamide (Intermediate 119, 147 mg, 0.396 mmol) in MeCN (10 mL) was added dimethylamine in THF (0.99 mL, 2M). The mixture was stirred at room temperature for 0.5 hours before it was neutralized with HCI (12 M). The mixture was diluted with water (60 mL) and extracted with Et0Ac (60 mLx3). The combined organic layer was washed with water (60 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative HPLC to afford 20 mg (12%) of the title compound as a yellow solid. LC-MS for C20H21FN403S+H [M+H]:
calcd.417.1;
found: 417.5. 1H NMR (400 MHz, CDCI3 ) 6 [ppm]: 8.33 (s, 1H), 7.82 (dd, J=
8.8, 5.2 Hz, 1H), 7.76 (d, J = 0.9 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.62 (dd, J =
8.2, 1.4 Hz, 1H), 7.38 (d, J= 2.3 Hz, 1H), 7.14 (dd, J= 9.4, 2.2 Hz, 1H), 6.99 (td, J= 9.2, 2.3 Hz, 1H), 4.67 (s, 2H), 3.34 (t, J= 6.3 Hz, 2H), 2.86 (t, J= 6.3 Hz, 2H), 2.27 (s, 6H).
Compound 101: 6-(6-fluoro-1H-indo1-3-y1)-2-(2-(methylsulfonyl)ethyl)benzo[d]oxazole I e I N\
F
H
A mixture of 6-fluoro-342-(2-methanesulfonyl-ethyl)-benzooxazol-6-y1]-indole-1-carboxylic acid tert-butyl ester (Intermediate 123, 390 mg, 0.852 mmol) in HCl/Et0Ac (5 mL, 2M) was stirred at room temperature for 3 hours. The mixture was diluted with Et0Ac (50 mL), washed with aq.NaHCO3 (20 mL) and brine (20 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated and purified by a preparative HPLC to afford 132 mg (43%) of the title compound as a white solid. LC-MS
for C18H15FN203S+H [M+H]: calcd. 359.1; found: 359.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.49 (br s, 1H), 7.93 (d, J = 1.2 Hz, 1H), 7.88 (dd, J = 8.8, 1.6 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 8.4, 1.6 Hz, 1H), 7.24 (dd, J =
9.6, 2.4 Hz, 1H), 6.97 (td, J= 9.6, 2.4 Hz, 1H), 3.73 (t, J= 7.6 Hz, 2H), 3.44 (t, J= 7.8 Hz, 2H), 3.11 (s, 3H).
Compound 102: 1-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methypurea N,C11)L-NH2 FS N\
H
To a solution of (6-(6-fluoro-1H-indo1-3-yl)benzo[cloxazol-2-y1)methanamine hydrochloride (Compound 76, 158 mg, 0.50 mmol) and Et3N (176 mg, 1.74 mmol) in DCM (10 mL) was added trimethylsilyl isocyanate (138 mg, 1.20 mmol). The mixture was stirred at room temperature for 12 h. Then it was concentrated and purified by preparative HPLC to afford 15 mg (9%) of the title compound as a white solid.
LC-MS
for C17H13FN402+H [M+H]: calcd. 325.1; found: 325.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.48 (br s, 1H), 7.92 (s, 1H), 7.89 (dd, J= 8.8, 5.5 Hz, 1H), 7.76 (d, J= 1.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 8.4, 1.8 Hz, 1H), 7.24 (dd, J =
9.9, 2.2 Hz, 1H), 6.97 (t, J = 2.0 Hz, 1H), 6.69 (t, J = 6.0 Hz, 1H), 5.77 (br s, 2H), 4.50 (d, J = 6.0 Hz, 2H).
Compound 103: 1-carbamoy1-1-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methypurea 0 Ci)\
NN)---N,----NH2 z'r H H
FSH
The title compound (5 mg, 3%) was obtained as a by-product during the synthesis described for Compound 102. LC-MS for C18H14FN603+H [M+H]: calcd. 368.1;
found:
368.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.49 (br s, 1H), 8.92 (s, 1H), 8.30 (br t, 1H), 7.95 (s, 1H), 7.90 (dd, J = 8.8, 5.5 Hz, 1H), 7.76 (d, J = 2.2 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 10.0, 2.2 Hz, 1H), 6.96 (m, 1H), 6.7d (br s, 2H), 4.66 (d, J= 5.7 Hz, 2H).
Compound 104: 5-(1H-indo1-3-y1)-1H-indazole H
N-N
'I
40 N\
H
Following the general method as outlined in Compound 8, the title compound was obtained as a yellow solid after purification by preparative HPLC. LC-MS for C15H11N3+H [M+H]: calcd. 234.1; found: 234.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 13.01 (br s, 1H), 11.27 (br s, 1H), 8.09 (s, 1H), 8.01 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.45 (d, J
= 8.0 Hz, 1H), 7.18-7.08 (m, 2H).
Compound 105: 6-(6-fluoro-1H-indo1-3-y1)-2-(2-(4-methylpiperazin-1-ypethyl)benzo[d]oxazole me -N,,rNnN
\---/
41, lel \
F H
A solution of 2-(2-chloroethyl)-6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)benzo[d]oxazole (Intermediate 125, 100 mg, 0.22 mmol), sodium hydroxide (44 mg, 1.10 mmol) and N-Methylpiperazine (44 mg, 0.44 mmol) in methanol (10 mL) was stirred at 50 QC overnight. The reaction mixture was cooled to room temperature before it was concentrated.The residue was diluted with water (20 mL) and extracted with Et0Ac (50 mLx3). The organic layer was concentrated and purified by Preparative HPLC
(NH4HCO3) to afford 44 mg (53%) of the title compound as a white solid. LC-MS
for C22H23FN4O+H [M+H]: calcd. 379.2;found: 379.2. 1H NMR (400 MHz, CDCI3) 6 [ppm]:
8.28 (s, 1H), 7.86 - 7.82 (m 1H), 7.76 - 7.67 (m, 2H), 7.58 (d, J= 8.1 Hz, 1H), 7.37 (d, J
= 1.9 Hz, 1H), 7.13 (dd, J= 9.5, 2.1 Hz, 1H), 7.01 -6.96 (m, 1H), 3.19 - 3.15 (m, 2H), 3.01 - 2.97 (m, 2H), 2.66 - 2.47 (m, 8H), 2.32 (s, 3H).
Compound 106: N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-211)methyl)-2-hydroxyethanesulfonamide o OH
N....r IT
41, 0 N\
F
H
To a solution of N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methyl)-2-10 methoxyethanesulfonamide (Compound 99, 120 mg, 0.3 mmol) in DCM (20 mL) was added tribromoborane (0.38 mL, 4.17 mmol) dropwise at 0 C under nitrogen. The mixture was stirred at room temperature for 1 hour under nitrogen before it was diluted with DCM (30 mL) . An aqueous solution of NaHCO3 (15 mL) was added dropwise into the reaction mixture at 0 C and stirred for 20 mins . The reaction mixture was extracted 15 with Et0Ac (30 mLx2) and water (20mLx2). The combined organic layer was washed with brine (60 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative HPLC to afford 20 mg (17%) of the title compound as a yellow solid. LC-MS for C18H16FN304S+H [M+H] : calcd. 390.1;
found:
390.5. 1H NMR (400 MHz, CD3OH ) 6 [ppm]: 7.77 (s, 1H), 7.74 (dd, J= 8.8, 5.3 Hz, 20 1H), 7.640 - 7.58 (m, 2H), 7.43 (s, 1H), 7.04 (dd, J= 9.7, 2.3 Hz, 1H), 6.81 (td, J= 9.2, 2.3 Hz, 1H), 4.52 (s, 2H), 3.88 (t, J = 6.2 Hz, 2H), 3.29 (t, J = 6.2 Hz, 2H).
Compound 107: N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methyl)-2-morpholinoethanesulfonamide FS N\
To a solution of N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methypethenesulfonamide (Intermediate 119, 433 mg, 1.16 mmol) in MeCN (20 mL) was added morpholine (0.5 mL, 5.83 mmol).The mixture was stirred at room temperature for 0.5 hours. The mixture was diluted with water (60 mL) and extracted with Et0Ac (60 mLx3). The combined organic layer was washed with water (60 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by Preparative HPLC to afford 13 mg (2%) of the title compound as a yellow solid.
LC-MS
for C22H23FN404S+H [M+H]: calcd. 459.1; found: 458. 8. 1H NMR (400 MHz, CD3OH
) 6 [ppm]: 7.90 (s, 1H), 7.86 (dd, J= 8.7, 5.4 Hz, 1H), 7.78 - 7.71 (m, 2H), 7.56 (s, 1H), 7.17 (dd, J= 9.7, 2.3 Hz, 1H), 6.94 (td, J= 9.1, 2.2 Hz, 1H), 4.66 (s, 2H), 3.65 (t, J= 4.6 Hz, 4H), 3.39 (t, J= 7.2 Hz, 2H), 2.84 (t, J= 7.6 Hz, 2H), 2.48- 2.47 (m, 4H).
Compound 108: 6-(1H-indo1-3-y1)-1H-indazole N
et NH
40 N\
To a solution of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-1H-indazole (Intermediate 4, 148 mg, 0.4 mmol) in Me0H (20 mL) was added a solution of Na0H(158 mg, 4.0 mmol) at room temperature. The reaction was stirred at 80 C for 1 hour. The mixture was cooled to room temperature and concentrated. The residue was purified by prep-TLC (PE/Et0Ac = 1/1) to afford 32 mg (36%) of the title compound as a yellow solid.
LC-MS for C15H11 N3+1-1+ [M + H]' : calcd. 234.1; found: 234Ø 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 12.93 (s, 1H), 11.40 (s, 1H), 8.04 (s, 1H), 7.91 (d, J= 7.6 Hz, 1H), 7.80 - 7.76 (m, 3H), 7.47 (d, J= 8.4 Hz, 2H), 7.20 - 7.10 (m, 2H).

Compound 109: 6-(1H-indo1-3-yl)benzo[d]oxazole so 40 N\
Following the general method as outlined in Compound 1, starting from 6-(1-Benzenesulfony1-1H-indo1-3-y1)-benzooxazole (Intermediate 127, 330 mg, 0.88 mmol), 6-(1H-Indo1-3-y1)-benzooxazole (100 mg, 49%) was obtained as a white solid. LC-MS for C16H10N2O+H [M+H]: calcd. 235.1; found: 235.5. 1H NMR (300 MHz, DMSO-d6) 6 [PPrn]:
11.45 (s, 1H), 8.71 (s, 1H), 8.01 (d, J= 1.1 Hz, 1H), 7.93 (d, J= 7.6 Hz, 1H), 7.83 (d, J= 8.2 Hz, 1H), 7.79 (d, J= 2.6 Hz, 1H), 7.75 (dd, J= 8.3, 1.5 Hz, 1H), 7.48-7.45 (m, 1H), 7.20 - 7.09 (m, 2H).
Compound 110: 6-(6-fluoro-1H-indo1-3-y1)-2-(2-(piperazin-1-yl)ethyl)benzo[d]oxazole (NH
I\1_1\1) F N\
A solution of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-vinylbenzo[d]oxazole (Intermediate 128, 1.00 g, 2.39 mmol), sodium hydroxide (478 mg, 11.96 mmol) and piperazine (617 mg, 7.17 mmol) in methanol (20 mL) was stirred at 50 QC
overnight. The reaction mixture was cooled to room temperature, concentrated, diluted with water and extracted with Et0Ac. The organic layers was dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and purified by preparative HPLC (NH4HCO3) to afford 609 mg (70%) of the title compound as a white solid. LC-MS for C21 H21FN4O+H
[M+H]:
calcd. 365.1; found: 365.1. 'H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.46 (br s, 1H), 7.90-7.86 (m, 2H), 7.74 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.64 (dd, J = 8.3, 1.5 Hz, 1H), 7.23 (dd, J= 9.9, 2.4 Hz, 1H), 6.96 (td, J= 9.5, 2.4 Hz, 1H), 3.11 (t, J= 7.2 Hz, 2H), 2.80 (t, J= 7.4 Hz, 2H), 2.70- 2.62 (m, 4H), 2.38 (m, 4H).
Compound 111: 5-(6-chloro-1H-indo1-3-yl)benzo[d]oxazole o-_ Ri Mr ci 40 \
H
Following the general method as outlined in Compound 1, starting from 5-(6-chloro-1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazole (Intermediate 129, 330 mg, 0.08 mmol), 115 mg (53%) of the title compound was obtained as a white solid. LC-MS for C15H9C1N2O+H [M+H]: calcd. 269.0; found: 269.3. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.52 (s, 1H), 8.75 (s, 1H), 8.02 (d, J= 1.3 Hz, 1H), 7.88 (d, J= 8.6 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 2.6 Hz, 1H), 7.74 (dd, J = 8.6, 1.7 Hz, 1H), 7.50 (d, J =
1.8 Hz, 1H), 7.12 (dd, J= 8.6, 2.0 Hz, 1H).
Compound 112: 6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazole-2-thiol N SH
. lr FIN
Following F H
Following the general method as outlined in Compound 1, starting from 6-(1-Benzenesulfony1-6-fluoro-1H-indo1-3-y1)-benzooxazole-2-thiol (Intermediate 130, 450 mg), the title compound (80 mg, 36% for 2 steps) was obtained as a yellow solid. LC-MS for C15H9FN20S-H- [M-Hy: calcd. 283.0; found: 283Ø 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 13.85 (s, 1H), 11.48 (s, 1H), 7.86 (dd, J= 9.2, 5.2 Hz, 1H), 7.77 (d, J= 1.1 Hz, 1H), 7.74 (d, J= 2.4 Hz, 1H), 7.62 (dd, J= 8.4, 1.6 Hz, 1H), 7.29 (d, J= 8.4 Hz, 1H), 7.24 (dd, J= 9.6, 2.4 Hz, 1H), 6.97 (td, J= 9.6, 2.4 Hz, 1H).

Compound 113: 6-(6-fluoro-1H-indo1-3-y1)-2-(piperidin-4-ylmethypenzo[d]oxazole Nf--0 41, FIN
Following the general method as outlined in Compound 1, starting from 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-(piperidin-4-ylmethypenzo[d]oxazole (Intermediate 132, 290 mg, 0.59 mmol), the title compound (15 mg, 7%) was obtained as a white solid. LC-MS for C21H2oFN3O+H [M+H]: calcd. 350.2; found: 350.1. 1H NMR (400 MHz, Me0D) 6 [ppm]: 7.73 ¨7.69 (m, 2H), 7.54 (d, J = 0.8 Hz, 2H), 7.40 (s, 1H), 7.03 (dd, J = 10.0, 2.0 Hz, 1H), 6.80 (td, J = 9.2, 2.0 Hz, 1H), 2.99 (d, J =
12.4Hz, 2H), 2.80 (d, J = 7.2 Hz ,2H), 2.57 (td, J = 12.4, 2.4 Hz, 2H), 2.06 ¨ 2.00 (m, 1H), 1.70 (d, J = 12.8 Hz, 2H), 1.31 - 1.20 (m,2H).
Compound 114: N-((6-(1H-indo1-3-yl)benzo[d]oxazol-2-Amethyl)methanesulfonamide µe0 =
40 N\
To a stirred solution of tert-butyl methylsulfonyl((6-(1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)carbamate (Intermediate 133, 1.25 g, 2.15 mmol) in Me0H (30 mL) was added NaOH (420 mg, 10.75 mmol). The mixture was stirred at C for 2 hours. The reaction was neutralized with HCI (12 M). The mixture was diluted with water (60 mL) and extracted with Et0Ac (60 mLx3). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative HPLC to afford 215 mg (30%) of the title compound as a yellow solid. LC-MS for C17H16N303S+H [M+H]: ciced. 342.1;
found:
341.9. 'H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.44 (s, 1H), 8.00 (s, 1H), 7.98 (d, J=
0.9 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.78 (dd, J = 7.0, 5.5 Hz, 2H), 7.72 (dd, J = 8.3, 1.5 Hz, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.20 - 7.15 (m, 1H), 7.14 - 7.09 (m, 1H), 4.54 (s, 2H), 3.04 (s, 3H).
Compound 115: (S)-N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methyl)-1 -methylpyrrolidine-2-carboxamide l(Nc ) N H
FIN
To a stirred solution of (2S)-1-methylpyrrolidine-2-carboxylic acid (258 mg, 2.0 mmol) in THF/DMF(20 mL/2 mL) at room temperature was added HATU (760 mg, 2.0 mmol), DIPEA (387 mg, 3.0 mmol), and c-[5-(6-fluoro-1H-indo1-3-y1)-benzooxazol-2-y1]-methylamine hydrochloride (Compound 81, 317 mg, 1.0 mmol). The mixture was stirred at room temperature for 2 hours, concentrated ,deluted with EtOAC (100 mL) and washed with water (10mLx4). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative HPLC to afford 29 mg of the title compound. LC-MS for C22H21 FN402+H [M+H]: calcd. 393.2; found:
393.1.
1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.48 (br s, 1H), 8.49 (t, J= 5.6 Hz, 1H), 7.91-7.87 (m, 2H), 7.76 (d, J = 2.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H)),7.66 (dd,J=
8.0, 1.2 Hz, 1H), 7.24 (dd, J = 10, 2.4 Hz, 1H), 6.98 (m, 1H), 4.62 - 4.57 (m, 2H), 3.08 -3.07 (m, 1H), 2.83 - 2.80 (m, 1H), 2.36 (s, 3H), 2.30 - 2.28 (m, 1H), 2.11 - 2.07 (m, 1H), 1.78 - 1.74 (m, 3H).
Compound 116: 6-(6-fluoro-1H-indo1-3-y1)-2-methoxybenzo[d]oxazole N.....z.g0, 4.
FSH

Following the general method as outlined in Compound 1, starting from 6-(1-benzenesulfony1-6-fluoro-1H-indo1-3-y1)-2-methoxy-benzooxazole (Intermediate 134, 110 mg, 0.26 mmol), 20 mg (27%) of the title compound was obtained as a white solid.
LC-MS for C16H11FN202+H [M+H]: calcd. 283.1; found: 283Ø 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.43 (brs, 1H), 7.86 (dd, J = 8.8, 5.6 Hz, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.59 (dd, J = 8.0, 1.6 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.22 (dd, J =
9.6, 2.0 Hz, 1H), 6.98 - 6.93 (m, 1H), 4.19 (s, 3H).
Compound 117: Amino ([6-(6-fluoroindo1-3-yl)benzoxazol-2-yl]methyl}sulfonamide Nz--...-01 'NH2 F N\
To the solution of tert-Butoxycarbonylamino ([6-(6-fluoroindo1-3-y1) benzoxazol-2-yl]
methyl}sulfonamide (Intermediate 135, 180 mg, 0.39 mmol) in THF (5 mL) was added EA/HCI (3 mL, 5 N) . The mixture was stirred at room temperature overnight.
The mixture was neutralized with THF/NH3 (10 N) and filtered. The solvent was removed and the residue was purified by pre-TLC (DCM/Methano1=10/1) to give the title compound (50 mg, 34%) as a white solid. LC-MS for C16H13FN403S+H [M+H]: calcd. 361.1;
found:
361Ø 1H NMR (400 MHz, DMSO) 6 11.49 (br s, 1H), 7.94 (s, 1H), 7.89 (dd, J=
8.8, 5.2 Hz, 1H), 7.77 (d, J= 2.4 Hz, 1H), 7.74 (d, J= 8.0 Hz, 1H), 7.68 (dd, J= 8.0, 1.2 Hz, 1H), 7.46 (t, J=
6.0 Hz, 1H), 7.24 (dd, J= 10.0, 2.4 Hz, 1H), 6.97 (td, J= 9.6, 2.4 Hz, 1H), 6.77 (s, 2H), 4.40 (d, J= 6.4 Hz, 2H).
Compound 118: 5-(1H-indo1-3-yl)benzo[d]oxazole 0_11 mit Ri 40 \

Following the general method as outlined in Compound 1, starting from 5-(1-(phenylsulfony1)-1H-indol-3-yl)benzo[d]oxazole (Intermediate 136, 525 mg, 1.4 mmol), 56 mg (36%) of the title compound was obtained as a white solid. LC-MS for C16H10N2O+H [M+H]: calcd. 235.1; found: 235.1. 1H NMR (400 MHz, CDC13) 6 [ppm]:
8.30 (br s, 1H), 8.13 (s, 1H), 8.06 (d, J= 1.1 Hz, 1H), 7.95 (d, J= 7.9 Hz, 1H), 7.71 (dd, J = 8.5, 1.6 Hz, 1H), 7.65 (dd, J = 8.5, 0.5 Hz, 1H), 7.47 - 7.45 (m, 1H), 7.41 (d, J = 2.8 Hz, 1H), 7.30-7.20 (m, 2H).
Compound 119: 6-(6-fluoro-1H-indo1-3-y1)-2-((1-(methylsulfonyl)piperidin-4-yl)methyl)benzo[d]oxazole INF
Following the general method as outlined in Compound 1, starting from 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-((1-(methylsulfonyl)piperidin-4-yl)methyl)benzo[d]oxazole (Intermediate 137, 220 mg, 0.388 mmol), the title compound (40 mg, 24%) was obtained as a white solid. LC-MS for C22H22FN303S+H [M+H]:
calcd. 428.1; found: 428.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.47(s, 1H), 7.90 -7.86 (m, 2H),7.75 - 7.70 (m, 2H), 7.66 - 7.64 (m, 1H), 7.23 (dd, J = 10, 2.4 Hz, 1H), 6.96 (td, J = 9.6, 2.4 Hz, 1H), 3.56 (d, J= 12.0 Hz, 2H), 2.95 (d, J= 6.8 Hz, 2H), 2.85 (s, 3H), 2.74 (td, J= 12.4, 2.4 Hz, 2H), 2.07 - 2.01(m, 1H), 1.84 (dd, J= 12.4, 2.0 Hz, 2H) 1.37(qd, J= 12.4, 4.0 Hz, 2H).
Compound 120: 6-(6-fluoro-1H-indo1-3-y1)-2-(2-(4-(methylsulfonyl)piperazin-1-ypethyl)benzo[d]oxazole o CN' 101 N\
A solution of 2-(2-chloroethyl)-6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)benzo[d]oxazole (Intermediate 125, 110 mg, 0.24 mmol), sodium hydroxide (48 mg, 1.29 mmol) and 1-(methylsulfonyl)piperazine (80 mg, 0.48 mmol) in methanol (10 mL) was stirred at 50 QC overnight. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (20 mL) and extracted with Et0Ac (50 mL). The organic layers was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative HPLC to afford 73mg (68%) of the title compound as a white solid. LC-MS for C22H23FN403S+H [M+H]: calcd. 443.2;
found:
443.2. 1H NMR (400 MHz, DMSO-d6) 6 [PPm]: 11.47 (s, 1H), 7.90-7.86 (m, 2H), 7.75 (d, J = 2.5 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.65 (dd, J = 8.2, 1.5 Hz, 1H), 7.23 (dd, J =
10.1, 2.4 Hz, 1H), 6.97 (td, J= 9.6, 2.6 Hz, 1H), 3.15 (t, J= 7.2 Hz, 2H), 3.11 -3.03 (m, 4H), 2.91 (t, J= 7.2 Hz, 2H), 2.85 (s, 3H), 2.63 - 2.55 (m, 4H).
Compound 121: 5-(5-chloro-1H-indo1-3-yl)benzo[d]oxazole OTh mkt CI
40 \
Following the general method as outlined for Compound 47, the title compound was obtained as a yellow solid after purification by preparative HPLC. LC-MS for C15H9C1N2O+H [M+H]: calcd. 269.0; found: 268.9. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.60 (br s, 1H), 8.76 (s, 1H), 8.01 (d, J= 1.8 Hz, 1H), 7.85 -7.81 (m, 3H), 7.73 (dd, J= 8.4, 1.8 Hz, 1H), 7.49 (d, J= 8.6 Hz, 1H), 7.18 (dd, J= 8.6, 2.0 Hz, 1H).

Compound 122: N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-211)methyl)-2-(4-methylpiperazin-1-ypethanesulfonamide Nfshy FS N\
To a solution of N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methypethenesulfonamide (Intermediate 119, 86 mg, 0.23 mmol) in MeCN /THF
(5 mL / 20mL) was added 1-methylpiperazine (47 mg, 0.46 mmol).The mixture was stirred at room temperature for 72 hours. The mixture was diluted with water (60 mL) and extracted with Et0Ac (60 mLx3). The combined organic layer was washed with brine (60 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative HPLC to afford 50 mg (46%) of the title compound as a white solid. LC-MS for C23H26FN603S+H [M+H]: calcd.472.2; found: 472.8. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.50 (s, 1H), 8.02 (t, J= 6.0 Hz, 1H), 7.96 (d, J= 1.0 Hz, 1H), 7.89 (dd, J= 8.8, 5.4 Hz, 1H), 7.78 - 7.75 (m, 2H), 7.70 (dd, J= 8.3, 1.5 Hz, 1H), 7.24 (dd, J = 9.9, 2.3 Hz, 1H), 6.97 (td, J = 9.6, 2.4 Hz, 1H), 4.55 (d, J = 5.8 Hz, 2H), 3.29 (d, J= 7.8 Hz, 2H), 2.70 - 2.64 (m, 2H), 2.44 - 2.23 (m, 7H), 2.13 (s, 3H).
Compound 123: N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methyl)-2-(piperazin-1-ypethanesulfonamide (---NH
0 hiJ
N....or ---.
FSH
To a solution of piperazine (752 mg, 8.73 mmol) in MeCN /THF(5 mL / 30mL) was added N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-211)methypethenesulfonamide (Intermediate 119, 180 mg, 0.485 mmol). The mixture was stirred at room temperature for 5 hours. The aqueous of NH4CI ( 20 mL) was added. The mixture was extracted with EA (60 mLx3). The organic phase was washed with brine (60 mLx3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative HPLC to afford 85 mg (35%) of the title compound as a yellow solid. LC-MS
for C22H24FN503S+H [M+H] : calcd. 458.2; found: 457.8. 1H NMR (400 MHz, DMS0-d6) 6 [ppm]: 11.50 (s, 1H), 7.96 (d, J= 1.0 Hz, 1H), 7.89 (dd, J= 8.8, 5.4 Hz, 1H), 7.80 -7.74 (m, 2H), 7.70 (dd, J = 8.3, 1.5 Hz, 1H), 7.24 (dd, J = 9.9, 2.3 Hz, 1H), 6.97 (td, J =
9.5, 2.4 Hz, 1H), 4.55 (s, 2H), 3.29 (t, J = 7.6 Hz, 2H), 2.66 - 2.61 (m, 6H), 2.33 - 2.24 (m, 4H).
Compound 124: N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-211)methyl)-2-(pyrrolidin-1-ypethanesulfonamide µ1,7-----/
O
N....r H-441t FIN
To a solution of pyrrolidine (752 mg, 8.73 mmol) in MeCN /THF(5 mL/30 mL) was added N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-211)methypethenesulfonamide (Intermediate 119, 180 mg, 0.485 mmol). The mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated and purified by Preparative HPLC to afford 120 mg (50%) of the title compound as a white solid. LC-MS for C22H23FN403S+H [M+H]: calcd. 443.2; found: 443.6. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.50 (s, 1H), 8.03 (s, 1H), 7.95 (d, J= 1.0 Hz, 1H), 7.89 (dd, J= 8.8, 5.4 Hz, 1H), 7.79 - 7.74 (m, 2H), 7.70 (dd, J = 8.3, 1.4 Hz, 1H), 7.24 (dd, J = 9.9, 2.4 Hz, 1H), 6.97 (td, J= 9.4, 2.4 Hz, 1H), 4.54 (s, 2H), 3.31 - 3.28 (m, 2H), 2.79 - 2.75 (m, 2H), 2.41 (s, 4H), 1.64 (dt, J = 6.3, 3.0 Hz, 4H).
Compound 125: 6-(6-fluoro-1H-indo1-3-y1)-2-((1-methylpiperidin-4-yl)methyl)benzo[d]oxazole N1f--0 =-..
.
I e I N\
F
H
Following the general method as outlined in Compound 1, starting from 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-((1-methylpiperidin-4-yl)methyl)benzo[d]oxazole (Intermediate 138, 200 mg, 0.4 mmol), the title compound (90 mg, 62%) was obtained as a yellow solid. LC-MS for C22H22FN3O+H [M+H]: calcd.364.2; found: 364.1.

NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.47(s, 1H), 7.89- 7.86(m, 2H), 7.74(d, J=2.4Hz,1H), 7.70 (d, J=8.4Hz, 1H), 7.64 (dd, J=1.6Hz, J=8.8Hz, 1H), 7.23(dd, J =
2.4Hz, J=9.6Hz, 1H), 6.96 (td, J = 2.4Hz, J=9.6Hz, 1H), 2.87 (d, J=8.8Hz, 2H), 2.73 (d, J=11.6Hz, 2H), 2.13(s, 3H), 1.88 - 1.81 (m, 3H), 1.68 (d, J=12.8Hz, 2H) 1.36-1.28 (m, 2H), Compound 126: N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-211)methyl)-2-(4-(methylsulfonamido)piperidin-1-ypethanesulfonamide N_so 0 b N....or 41, FIN
To a stirred solution of N-(piperidin-4-yl)methanesulfonamide hydrochloride (833 mg, 3.88 mmol) and DBU ( 591 mg, 3.88 mmol ) in MeCN / THF (5 mL/30 mL) was added N-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methypethenesulfonamide (Intermediate 119, 160 mg, 0.43 mmol).The mixture was stirred at room temperature for 3 hours before it was quenched with aqueous NH4C1 (30 mL).The mixture was extracted with EA
(60 mLx 3), washed with brine (60 mLx3), dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and purified by Preparative HPLC to afford 110 mg (47%) of the title compound as a white solid. LC-MS for C24H28FN606S2+H [M+H] :
calcd.
550.2; found: 550.7. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.51 (br s, 1H), 8.06 -8.01 (m, 1H), 7.96 (d, J = 1.0 Hz, 1H), 7.89 (dd, J = 8.8, 5.4 Hz, 1H), 7.80 -7.75 (m, 2H), 7.70 (dd, J = 8.3, 1.5 Hz, 1H), 7.24 (dd, J = 9.9, 2.4 Hz, 1H), 7.03 -6.95 (m, 2H), 4.54 (d, J = 5.6 Hz, 2H), 3.30 (s, 2H), 3.08 (br s, 1H), 2.86 (s, 3H), 2.76 -2.74 (m, 2H), 2.69 - 2.67 (m, 2H), 2.03 - 1.98 (m, 2H), 1.77 - 1.75 (m, 2H), 1.45 -1.40 (m, 2H).
Compound 127: N-((6-(6-chloro-1H-indo1-3-yl)benzo[d]oxazol-2-yl)methyl)methanesulfonamide g Nhl-8 e 40 N\
CI H
Following the general method as outlined for Compound 74, the title compound was obtained as a yellow solid after purification by preparative TLC (DCM/Me0H =
10/1, v/v).

LC-MS for C17H14C1N303S+H [M+H]: calcd. 376.0; found: 376Ø 1H NMR (400 MHz, DMSO-d6) 6 [PPm]: 11.58 (br s, 1H), 7.98 - 7.95 (m, 2H), 7.92 (d, J= 8.6 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.70 (dd, J = 8.3, 1.6 Hz, 1H), 7.51 (d, J =
1.9 Hz, 1H), 7.12 (dd, J= 8.6, 2.0 Hz, 1H), 4.54 (s, 2H), 3.03 (s, 3H).
Compound 128: N-((6-(5-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-yl)methyl)methanesulfonamide =
F
N\
Following the general method as outlined for Compound 74, the title compound was obtained as a yellow solid after purification by preparative TLC (DCM/Me0H =
10/1, v/v).
LC-MS for C17H14FN303S+H [M+H]: calcd. 360.1; found: 360.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.59 (br s, 1H), 8.02 (br t, J= 6.1 Hz, 1H), 7.98 (d, J=
1.6 Hz, 1H), 7.87 (d, J = 2.2 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.70 (dd, J = 8.4, 1.6 Hz, 1H), 7.64 (dd, J = 10.6, 2.4 Hz, 1H), 7.47 (dd, J = 8.8, 4.8 Hz, 1H), 7.03 (ddd, J =
9.5, 8.8, 2.4 Hz, 1H), 4.54 (d, J = 6.0 Hz, 2H), 3.04 (s, 3H).
Compound 129: 5-((6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-y1)methypimidazolidine-2,4-dione NH
H
40 \
To a solution of tert-butyl 3-(2-((2,5-dioxoimidazolidin-4-yl)methyl)benzo[c]oxazol-6-y1)-6-fluoro-1H-indole-1-carboxylate (Intermediate 141,50 mg, 0.11 mmol) in DCM
(1.5 mL) was added TFA (1.0 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated. The residue was diluted with Et0Ac, washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative TLC (DCM/Me0H = 5/1, v/v) to afford 9 mg (23%) of the title compound as a yellow solid. LC-MS for C19H13FN403-H- [M-Hy:
calcd.
363.1; found: 363.1. 1H NMR (400 MHz, Me0H-d4) 6 [ppm]: 7.74-7.71 (m, 2H), 7.60-7.58 (m, 2H), 7.42 (s, 1H), 7.09 (dd, J = 9.6, 2.0 Hz, 1H), 6.81 (td, J = 8.8, 2.4 Hz, 1H), 4.59 (dd, J= 7.2, 4.8 Hz, 1H), 3.43 (dd, J= 16.4, 4.8 Hz, 1H), 3.27-3.25 (m, 1H).
Compound 130: 5-(6-fluoro-1H-indo1-3-yl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide ()-Nid fk =
FSH
Step 1: tert-butyl 3-(1,1-dioxido-3-oxo-2,3-dihydrobenzo[clisothiazol-5-y1)-6-fluoro-1 H-indole-1-carboxylate -NH
qit 0 Fl \
hoc To a mixture of 5-bromobenzo[c]isothiazol-3(21-1)-one 1,1-dioxide (310 mg, 1.18 mmol, prepared as described in Tetrahedron 2006, 62, 7902.), tert-butyl 6-fluoro-3-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-indole-1-carboxylate (Intermediate 2, 514 mg, 1.42 mmol) and K2CO3 (489 mg, 3.54 mmol) in dioxane (20 mL) and water (2 mL) was added Pd(PPh3)4 (69 mg, 0.06 mmol). The mixture was stirred at 110 C for 2 hours before it was concentrated. The residue was diluted with Et0Ac, washed with saturated aqueous NaHCO3, dried over anhydrous Na2504 and filtered. The filtrate was concentrated to afford 300 mg (61%) of the title compound as a yellow solid, which was used directly without further purification.
Step 2:
A solution of tert-butyl 3-(1,1-dioxido-3-oxo-2,3-dihydrobenzo[clisothiazol-5-y1)-6-fluoro-1H-indole-1-carboxylate (Step 1, 300 mg, 0.72 mmol) in HCl/Et0Ac (10 mL, 2 M) was stirred at 60 C for 2 hours. The reaction mixture was quenched with ammonia, concentrated and purified by silica gel chromatography (DCM) to afford 31 mg (14%) of the title compound as a yellow solid. LC-MS for C16H9FN2035-H- [M-Hy: calcd.
315.0;
found: 315Ø 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.80 (br s, 1H), 8.26 (dd, J= 8.4, 1.6 Hz, 1H), 8.17 (d, J= 1.6 Hz, 1H), 8.12 (d, J= 8.4 Hz, 1H), 8.10 (d, J= 2.4 Hz, 1H), 7.93 (dd, J=
8.8, 5.3 Hz, 1H), 7.28 (dd, J= 9.8, 2.4 Hz, 1H), 7.05 (m, 1H).
Compound 131: 2-(6-(5-fluoro-1H-indo1-3-y1)-2-oxobenzo[d]oxazol-3(2H)-yl)acetamide C?7-11.0 Aitii b \w/
F
0 \
H
To a solution of 2-(6-(5-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-oxobenzo[d]oxazol-3(2H)-yl)acetamide (Intermediate 143, 281 mg, 0.6 mmol) in Me0H (30 mL) was added NaOH (241 mg, 6.04 mmol). The mixture was stirred at 85 C for 1 hour. The reaction was neutralized with HCI (12 M). The mixture was diluted with water (60 mL) and extracted with Et0Ac (60 mLx3). The combined organic layer was washed with water (60 mLx3), dried over anhydrous Na2504 and filtered. The filtrate was concentrated and purified by preparative HPLC to afford 100 mg (43%) of the title compound as a white solid. LC-MS for C17H12FN303-H- [M-Hy : calcd. 324.1; found: 324Ø 1H NMR
(400 MHz, DMSO-d6) 6 [ppm]: 11.48 (s, 1H), 11.00 (s, 1H), 9.78 (s, 1H), 7.74 (d, J=
2.6 Hz, 1H), 7.54 (dd, J= 10.4, 2.4 Hz, 1H), 7.45 (dd, J= 8.9, 4.7 Hz, 1H), 7.30 (d, J= 8.1 Hz, 1H), 7.24 (d, J= 1.9 Hz, 1H), 7.12 (dd, J= 8.1, 1.9 Hz, 1H), 7.01 (td, J= 9.1, 2.4 Hz, 1H), 4.28 (s, 2H).

Compound 132: 5-(6-fluoro-1H-indo1-3-yl)isoindoline-1,3-dione NH

A mixture of 4-(6-Fluoro-1H-indo1-3-y1)-phthalic acid (Intermediate 145, 136 mg, 0.45 mmol), imidazole (46 mg, 0.68 mmol) and urea (54 mg, 0.90 mmol) were well triturated and placed in a flask followed by the addition of 4 drops of DMF. The mixture was heated at 150 C in an oil bath for 3 hrs. The mixture was cooled down and poured into a 10% v/v aqueous HCI solution and stirred for 10 min. The solid was filtered off and purified by preparative HPLC to give 90 mg (58%) of the title compound as a yellow solid. LC-MS for C16H9FN202-H- [M-Hy: calcd. 279.1; found: 279Ø 1H NMR (400 MHz, DMSO-d6) O[pprn]: 11.75 (br s, 1H), 11.25 (br s, 1H), 8.14(d, J= 8.0 Hz, 1H), 8.06(s, 1H), 8.05 (s, 1H),7.92 (dd, J= 8.8, 5.2 Hz, 1H), 7.85 (d, J= 7.6 Hz, 1H), 7.27 (dd, J=
9.8, 2.8 Hz, 1H), 7.03 (td, J= 9.3, 2.4 Hz, 1H).
Compound 133: 6-fluoro-3-(isoindolin-5-yI)-1H-indole NH
F N\
A solution of tert-butyl 3-(2-(tert-butoxycarbonyl)isoindolin-5-y1)-6-fluoro-1H-indole-1-carboxylate (Intermediate 146, 525 mg, 1.4 mmol) and CF3COOH (8 mL) in DCM (20 mL) was stirred at room temperature overnight. The mixture was concentrated.
The residue was diluted with water (100 mL) and extracted with Et0Ac (300 mL).The organic layers was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by Preparative HPLC to afford 17 mg (15%) of the title compound as a white solid. LC-MS for C16H13FN2+Hr [M+H] : calcd. 253.1; found: 253.1. 1H NMR (400 MHz, Me0D) 6 [ppm]: 7.81 - 7.78 (m, 1H), 7.58 (s, 1H), 7.54 (d, J= 7.6 Hz, 1H), 7.45 (s, 1H), 7.35 (d, J= 7.8 Hz, 1H), 7.13 (dd, J= 9.9, 2.4 Hz, 1H), 6.89 (td, J=9.6, 2.4 Hz, 1H), 4.27 (d, J= 10.0 Hz, 4H).
Compound 134: 6-(6-fluoro-1H-indo1-3-yl)benzo[d]isothiazol-3(21-I)-one 1,1-dioxide I\IH
= e FIN

To a stirred mixture of 3-(1,1-dioxo-2,3-dihydro-1H-116-benzo[d]isothiazol-6-y1)-6-fluoro-indole-1-carboxylic acid tert-butyl ester (Intermediate 147, 50 mg, 0.11 mmol) in DCM(10.0 mL) at room temperature was added TFA (1.0 mL). The mixture reaction was stirred for 2 hours and then it was concentrated under vacuum. The residue was purified by a preparative HPLC to afford 14 mg (31%) of the title compound as a yellow solid.
LC-MS for C16H11FN202S-H- [M-Hy: calcd. 301.1; found: 301Ø 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.60 (s, 1H), 8.03-8.00 (m, 2H), 7.92 (d, J = 2.4 Hz, 1H), 7.88 -7.86 (m, 2H), 7.86 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.26 (dd, J = 9.6, 2.0 Hz, 1H), 7.03 -6.99 (m, 1H), 4.44 (s, 2H).
Compound 135: 5-(6-fluoro-1H-indo1-3-y1)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide C)-NH
FIN
Step1: tert-butyl 3-(1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-y1)-6-fluoro-1H-indole-1-carboxylate NH
O
F 401 \
A solution of 5-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (200 mg, 0.8 mmol), tert-butyl 6-fluoro-3-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-y1)-1H-indole-carboxylate (Intermediate 2, 292 mg, 0.8 mmol), Pd(PPh3)4 (46 mg, 0.08 mmol) and K2CO3 (221 mg, 2.4 mmol) in 20 mL of dixoane and 2 mL of water was stirred for 2 hrs at 110 C. The mixture was filtered and the filtrate was evaporated in vacuum.
The residue was purified by preparative TLC (Et0Ac/Petroleum Ether = 1/3), 240 mg (74%) of the title compound as a white solid.
Step2:
A solution of tert-butyl 3-(1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-y1)-6-fluoro-1 H-indole-1-carboxylate (240 mg, 0.59 mmol ) was dissolved in 10 mL of EA/HCI.
The solution was stirred for 2 hrs under 60 C. The mixture was filtered and the filtrate was evaporated in vacuum. The residue was purified by Preparative TLC
(Et0Ac/Petroleum Ether = 1/3), yielding 32 mg (17%) of the final product as a yellow solid. LC-MS for C15H11FN202S-1-1- [M-Hy: calcd. 301.0; found: 301Ø 1H NMR (400 MHz, DMSO-d6) [ppm]: 11.64 (br s, 1H), 7.95 (dd, J= 8.4, 5.6 Hz, 1H), 7.90 -7.80 (m, 4H), 7.74 (s, 1H), 7.27-7.25 (m, 1H), 7.03 - 6.98 (m, 1H), 4.45 (d, J = 4.3 Hz, 2H).
Compound 136: 6-(6-fluoro-1H-indo1-3-y1)-3-(piperidin-4-yl)benzo[d]oxazol-2(3H)-one H
c\N

*
F 40 \
H

To a stirred solution of 3-[3-(1-tert-butoxycarbonyl-piperidin-4-y1)-2-oxo-2,3-dihydro-benzooxazol-6-y1]-6-fluoro-indole-1-carboxylic acid tert-butyl ester (Intermediate 150, 125 mg, 0.227 mmol) in DCM (5 mL) was added TFA (1 mL) dropwise at -60 C. The mixture was slowly warmed to room temperature and stirred for a further 16 hours before it was recooled to -78 C. The reaction was quenched with TEA (1.5 mL).
The mixture was slowly warmed to room temperature, diluted with water (30 mL) and extracted with Et0Ac (50 mLx2). The combined organic layer was washed with brine (20 mLx2), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative HPLC (NH4HCO3 as additive) to afford 50 mg (63%) of the title compound as an off-white solid. LC-MS for C20H18FN302+H [M+H]: calcd. 352.1;
found: 352.1. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.42 (br s, 1H), 7.81 (dd, J= 8.8, 5.6 Hz, 1H), 7.68 (d, J= 2.4 Hz, 1H), 7.60 (s, 1H), 7.53 - 7.45 (m, 2H), 7.22 (dd, J= 10.0, 2.4 Hz, 1H), 6.95 (td, J= 9.2, 2.4 Hz, 1H), 4.21 -4.15 (m, 1H), 3.08 (d, J=
12.0 Hz, 2H), 2.59 (t, J= 12.0 Hz, 2H), 2.19 - 2.07 (m, 3H), 1.76- 1.72 (m, 2H).
Compound 137: (6-(6-fluoro-1H-indo1-3-y1)-2-methylbenzo[d]oxazol-5-yl)methanol N--..
H=*
F lel \
H
To the solution of 6-(6-Fluoro-1H-indo1-3-y1)-2-methyl-benzooxazole-5-carboxylic acid methyl ester (Intermediate 154, 220 mg, 0.68 mmol) in THF (10 mL) was added diisobutylaluminum hydride (1.02 mL, 1.02 mmol 1M in THF). The mixture was stirred at 0 C for 1 hr. Another batch of diisobutylaluminum hydride (1.02 mL, 1.02 mmol) was added and the mixture was stirred at rt for 4 hrs more before it was quenched with saturated NH4C1. The mixture was extracted with Et0Ac (30 mL x 3). The combined organic layer was washed with brine and dried over Na2SO4. The solvent was removed and the residue was purified by pre-TLC (DCM/ methano1=20/1) and preparative HPLC
to give to afford the title compound (23 mg, 11%) as a white solid. LC-MS for C17H13FN202+H [M+H]: calcd. 297.1; found: 297.1. 1H NMR (400 MHz, DMSO) 6 11.40 (s, 1H), 7.81 (s, 1H), 7.59 (s, 1H), 7.55 (d, J= 2.0 Hz, 1H), 7.41 (dd, J= 8.4, 5.4 Hz, 1H), 7.24 (dd, J= 10.0, 2.4 Hz, 1H), 6.89 (td, J= 9.6, 2.4 Hz, 1H), 5.19 (t, J= 5.6 Hz, 1H), 4.50 (d, J = 5.6 Hz, 2H), 2.63 (s, 3H).
Compound 138: 5-(6-fluoro-1H-indo1-3-y1)-2-methylbenzo[d]isothiazol-3(21-I)-one 1,1-dioxide 0A_Nr # =
FIN
A solution of tert-butyl 6-fluoro-3-(2-methy1-1,1-dioxido-3-oxo-2,3-dihydrobenzo[clisothiazol-5-y1)-1H-indole-1-carboxylate (Intermediate 151, 60 mg, 0.14 mmol) in HCl/Et0Ac (10 mL, 2 M) was stirred at 60 C for 2 hours. The reaction mixture was quenched with ammonia, concentrated and purified by silica gel chromatography (DCM) to afford 35 mg (32%) of the title compound as a yellow solid. LC-MS for C16H11 FN203S-H- [M-Hy: calcd. 329.0; found: 329Ø
1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.86 (br s, 1H), 8.35-8.29 (m, 3H), 8.16 (d, J=
2.4 Hz, 1H), 7.95 (dd, J = 8.6, 5.0 Hz, 1H), 7.29 (dd, J = 9.6, 2.0 Hz, 1H), 7.06-7.05 (m, 1H), 3.19 (s, 3H).
Compound 139: 2-(2-(cis-3,5-dimethylpiperazin-1-ypethyl)-6-(6-fluoro-1H-indol-y1)benzo[d]oxazole Me e--NH me =N..,r FSH
A solution of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-vinylbenzo[d]oxazole (Intermediate 128, 100 mg, 0.24 mmol), sodium hydroxide (47.8 mg, 1.19 mmol) and cis-2,6-dimethyl-piperazine (133 mg, 1.16 mmol) in methanol (20 mL) was stirred at 50 QC overnight. The reaction mixture was cooled to room temperature and concentrated.
The residue was diluted with water (100 mL) and extracted with Et0Ac (100 mL*3). The organic layers was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative HPLC (NH4HCO3) to afford 30 mg (32%) of the title compound as a white solid. LC-MS for C23H26FN4O+H [M+H]: calcd.393.2;
found:
393.2. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.46 (br s, 1H), 7.89 - 7.86 (m, 2H), 7.74 (s, 1H), 7.70 (d, J= 8.3 Hz, 1H), 7.64 (dd, J= 8.2, 1.5 Hz, 1H), 7.23 (dd, J= 9.9, 2.2 Hz, 1H), 6.96 (td, J= 9.3, 2.4 Hz, 1H), 3.11 (t, J= 7.3 Hz, 2H), 2.85 -2.73 (m, 4H), 2.67 (s, 2H), 1.82 (s, 1H), 1.54 (t, J = 10.3 Hz, 2H), 0.91 (d, J = 6.3 Hz, 6H).
Compound 140: 1-(2-(6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-ypethyl)piperidin-4-ol OH
FSN\
A solution of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-vinylbenzo[d]oxazole (Intermediate 128, 100 mg, 0.24 mmol), sodium hydroxide (48 mg, 1.19 mmol) and piperidin-4-ol (125 mg, 1.23 mmol) in methanol (20 mL) was stirred at 50 QC
overnight.
The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (100 mL) and extracted with Et0Ac (300 mL). The organic layers was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by Preparative HPLC (NH4HCO3) to give 33 mg (36%) of the title compound as a white solid. LC-MS for C22H22FN302+Hr [M + : calcd. 380.2; found:
380.2. 1H
NMR (400 MHz, DMSO-d6) 6 [PPm]: 11.46 (br s 1H), 7.90-7.86 (m, 2H), 7.74 (d, J
= 2.5 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.64 (dd, J = 8.2, 1.5 Hz, 1H), 7.23 (dd, J
= 10.0, 2.4 Hz, 1H), 6.96-6.93 (m, 1H), 4.51 (s,1H), 3.34 - 3.29 (m, 1H), 3.12 - 3.08 (m, 2H), 2.83 -2.75 (m, 4H), 2.14 - 2.11 (m, 2H), 1.71 -1.62 (m, 2H), 1.39 - 1.30 (m, 2H).

Compound 141: 2-(2-(trans-2,5-dimethylpiperazin-1-ypethyl)-6-(6-fluoro-1H-indol-3-y1)benzo[d]oxazole C--NH
4Ik \
A solution of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-vinylbenzo[d]oxazole (Intermediate 128, 110 mg, 0.26 mmol), sodium hydroxide (53 mg, 1.31 mmol) and trans-2,5-dimethyl-piperazine (150 mg, 1.31 mmol) in methanol (20 mL) was stirred at 50 QC overnight. The reaction mixture was cooled to room temperature and concentrated.The residue was diluted with water (100 mL) and extracted with Et0Ac.
The organic layers was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative HPLC (NH4HCO3) to afford 6 mg (6%) of the title compound as a white solid. LC-MS for C23H25FN4O+H [M+H]: calcd: 393.2;
found:
393.2. 1H NMR (400 MHz, Me0D) 6 [ppm]: 7.71-7.68 (m, 2H), 7.52 (s, 2H), 7.38 (s, 1H), 6.99 (dd, J= 10.0, 2.4 Hz, 1H), 6.77 (td, J= 9.2, 2.4 Hz, 1H), 3.25-3.19 (m, 1H), 3.05-3.00 (m, 2H), 2.85-2.79 (m, 2H), 2.78-2.67 (m, 2H), 2.36-2.21 (m, 1H), 2.20 (s, 1H), 2.04 (t, J= 10.9 Hz, 1H), 1.10 (m, 6H).
Compound 142: (+)-2-(2-((3R,5R)-3,5-dimethylpiperazin-1-ypethyl)-6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazole NH
INF
To a stirred solution of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-vinylbenzo[d]oxazole (Intermediate 128, 100 mg, 0.24 mmol) in Me0H (10 mL) was added (2R,6R)-2,6-dimethylpiperazine (273 mg, 2.39 mmol; made according to the procedures reported by J. Org. Chem.1995, 60, 4177) and NaOH (48 mg, 1.20 mmol) at room temperature. The mixture was stirred at 50 C under N2 for 16 hrs. The mixture was concentrated and the residue was suspended with Et0Ac (50 mL). The suspension was dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative HPLC (NH4OH as additive) to afford the title compound 30 mg (32%) as a white solid.
LC-MS for C23H26FN40 +H [M+H] : calcd: 393.2; found: 393.2 1H NMR (300 MHz, DMSO-d6) 6 [ppm]: 11.46 (br s, 1H), 7.90-7.85 (m, 2H), 7.74 (d, J=
1.8 Hz, 1H), 7.69 (d, J= 8.1 Hz, 1H), 7.64 (dd, J= 8.1, 1.8 Hz, 1H), 7.23 (dd, J= 9.6, 2.4 Hz, 1H), 6.96 (td, J= 9.6, 2.4 Hz, 1H), 3.12-3.00 (m, 2H), 2.99-2.95 (m, 2H), 2.81-2.68 (m, 2H), 2.43-2.38 (m, 2H), 2.11-2.08 (m, 2H), 1.68 (brs, 1H), 0.95 (d, J
= 6.6 Hz, 6H).
[a]20D +10.9 (c=0.2,Me0H).
Compound 143: 2-(2-(2,6-diazaspiro[3.3]heptan-2-ypethyl)-6-(6-fluoro-1H-indol-yl)benzo[d]oxazole N---' N...,..
\
F' N
H
To a solution of tert-butyl 6-(2-(6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-ypethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 152, 170 mg, 0.35 mmol) in DCM (3 mL) was added TFA (1mL). The mixture was stirred at room temperature for 2 hs before it was concentrated. The residue was purified by Preparative HPLC to afford the product 66 mg (49%) as a white solid. LC-MS for C22F121 FN40 [M+ H]: calcd. 376.2;
found:
376.8. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.50 (br s, 1H), 7.90-7.86 (m, 2H), 7.75 (s, 1H), 7.71-7.63 (m, 2H), 7.23 (dd, J= 10.0, 2.4 Hz, 1H), 6.96 (td, J= 18.8, 2.0 Hz, 1H), 3.82 (s, 2H), 3.48 (s, 2H), 3.20 (s, 4H), 2.94-2.90 (m, 2H), 2.83-2.81 (m, 2H).
Compound 144: (-)-2-(2-((3S,5S)-3,5-dimethylpiperazin-1-ypethyl)-6-(6-fluoro-1H-indol-3-y1)benzo[d]oxazole 441k F N\
To a stirred solution of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-vinylbenzo[d]oxazole (Intermediate 128, 100 mg, 0.24 mmol) in Me0H (10 mL) was added (2S,6S)-2,6-dimethylpiperazine (136 mg, 1.19 mmol; made according to the procedures reported by J. Org. Chem.1995, 60, 4177) and NaOH (48 mg, 1.20 mmol) at room temperature. The mixture was stirred at 50 C under N2 for 16 hrs. Me0H
was removed under vacuum and the residue was suspended with EA (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by preparative HPLC (NH4OH as additive) to afford 45 mg (49%) of the title compound as white powder.
LC-MS for C23H26FN4O+H [M+H]: calcd: 393.2; found: 393.2 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.48 (br s, 1H), 7.89-7.86 (m, 2H), 7.75 (d, J=
2.4 Hz, 1H), 7.67 (d, J = 13.6 Hz, 2H), 7.24 (dd, J = 10.0, 2.0 Hz, 1H), 6.96 (td, J = 9.6, 2.4 Hz, 1H), 3.12-3.00 (m, 2H), 3.00-2.98 (m, 2H), 2.80-2.77 (m, 2H), 2.43-2.40 (m, 2H), 2.12-2.10 (m, 2H), 1.68 (brs, 1H), 0.97 (d, J= 6.4 Hz, 6H).
Compound 145: 4-(2-(6-(6-fluoro-1H-indo1-3-yl)benzo[d]oxazol-2-ypethyl)piperazine-2-carboxylic acid AL-sr/
40 \
A solution of 6-(6-fluoro-1-(phenylsulfony1)-1H-indol-3-y1)-2-vinylbenzo[d]oxazole (Intermediate 128, 120 mg, 0.28 mmol), sodium hydroxide (57 mg, 1.43 mmol) and piperazine-2-carboxylic acid (438 mg, 3.4 mmol) in methanol (20 mL) was stirred at 50 QC overnight. The reaction mixture was cooled to room temperature and concentrated.
The residue was diluted with water (100 mL) and extracted with Et0Ac (200 mL).
The organic layers was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by preparative HPLC (NH4HCO3) to afford 12 mg (10%) of the title compound as a white solid. LC-MS for C22H21 FN403+11+ [M + H]: calcd:
409.2;
found: 408.8. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.51 (br s, 1H), 7.90 ¨ 7.87 (m, 2H), 7.75 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 10.4 Hz, 1H), 6.96 (t, J = 9.6 Hz, 1H), 3.34-3.09 (m, 5H), 3.05 (d, J = 11.6 Hz, 1H), 2.92-2.87 (m, 3H), 2.78 (t, J= 11.6 Hz, 1H), 2.27 -2.18 (m, 2H).
Compound 146: 3-(benzofuran-6-yI)-6-fluoro-1H-indole . Nil lei N\
F H
To a stirred solution of tert-butyl 3-(benzofuran-6-yI)-6-fluoro-1H-indole-1-carboxylate (Intermediate 153, 58 mg, 0.32 mmol) in DCM (2.0 mL), anisole (0.2 mL) and TFA
(1 mL) were added. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was purified with preparative TLC
(Et0Ac/
Petroleum Ether=1/5) and preparative HPLC to afford 16 mg of the title compound. LC-MS for C16H10FNO+H [M+H] : calcd: 252.1; found: 251.9. 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 11.47 (br s, 1H), 7.98 (d, J= 1.6 Hz, 1H), 7.90 (dd, J=8.8, 5.2 Hz, 1H), 7.84 (s, 1H), 7.55 (d, J= 2.4 Hz, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.59 (d, J= 8.0 Hz, 1H), 7.24 (dd, J= 9.8, 2.4 Hz, 1H), 6.97 (td, J= 9.2, 2.4 Hz, 2H).
II. BIOLOGY EXAMPLES
11.1. Assay for TD02 enzymatic activity determination The compounds of formula I inhibit the enzymatic activity of human TD02.
To measure the TD02 activity, the procedure described in Dolusic et al. J.
Med. Chem.;
2011, 54, 5320-533was adapted: the reaction mixture contained (final concentrations) potassium phosphate buffer (50 mM, pH 7.5), ascorbic acid (0.25 M), methylene blue (0.125 pM), catalase (40 units/mL, from bovine liver, Sigma), and human recombinant TD02 enzyme (prepared as described in Dolusic et al. J. Med. Chem.; 2011, 54, 5334; 0.9 pg) without or with the compounds of the present invention at the indicated concentrations (total volume 112.5 pL). The reaction was initiated by the addition of 37.5 pL of L-Trp (final concentration 1 mM) at room temperature. The reaction was conducted at room temperature during one hour and stopped by the addition of 30 pL of 30% (w/v) trichloroacetic acid.
To convert N-formylkynurenine into kynurenine, the reaction mixture was incubated at 65 C for 30 min. Then 150 pL of the reaction mixture was mixed with 120 pL of 2.5%
(w/v) 4-(dimethylamino)-benzaldehyde in acetic acid and incubated for 5 min at room temperature. Kynurenine concentrations were determined by measuring the absorbance at 480 nm. A standard curve was made with pure kynurenine. The TDO activity was measured as described above using ten serial concentrations of the compounds of the present invention. Data were fitted using the Prism TM software (Graph Pad Software, Inc.) using standard parameters.
The biological activity of representative Compounds is summarized in the following table:
Compound IC50 (nM) Compound IC50 (nM) In one embodiment, compounds having an IC50 <2000 nm, preferably compound having an 1050< 1000 nm are selected.
11.2. Cellular Assay for TD02 Activity determination II.2.a hTD02-overexpressing P815 cells The compounds of Formula I inhibit the activity of human TD02 in cells.
The assay (adapted from Pilotte L etal., Proc Natl Acad Sci U S A, 2012, 109(7), 2497-502) was performed in 96-well flat bottom plates seeded with murine mastocytoma P815 cells overexpressing hTD02 (prepared as described in Pilotte et al., PNAS, 2012, 109(7), 2497-2502), at a concentration of 5 x 104 cells/well in a final volume of 200 pL.
To determine TDO or IDO activity, the cells were incubated overnight at 37 C
at 5%
CO2 in IMDM (Invitrogen) supplemented with 2% FBS and 2%
penicillin/streptomycin in the presence of the compounds of the present invention, at different concentrations.
The cells may be obtained from the American Type Cuylture Collecion [ATCC TIB-64Tm or commercially, e.g., from Sigma-Aldrich or Life Technologies.]

The plates were then centrifuged 5 min at 1000 rpm, and 100 pL of the supernatant were collected in a conical plate, 30 uL of TCA 30% were added and a further centrifugated at 3000 x g for 10 minutes. 100 pL of the supernatant were collected in a flat bottomed plate and 100 pL of 2% (w/v) 4-(dimethylamino)-benzaldehyde in acetic acid and incubated for 5 min at room temperature. Kynurenine concentrations were determined by measuring the absorbance at 480 nm. A standard curve was made with pure kynurenine. The TDO activity was measured as described above using ten serial concentrations of the compounds of the present invention. Data were fitted using the Prism TM software (GraphPad Software, Inc.) using standard parameters.
The biological activity of representative compounds is summarized in the following table:
Compound IC50 (nM)

31 2299

32 460

33 635

34 863

35 689

36 1131

37 1534

38 505

39 2864

40 750 Compound IC50 (nM) In one embodiment, compounds having an IC50 < 2000 nm are selected. In another embodiment, compounds having an IC50< 1000 nm are selected.
II.2.b A172 cells The compounds of formula I inhibit the activity of human TD02 in cells that constitutively express TD02, such as A172 cells. A172 is a cell line derived from human brain glioblastoma cells. The cells are available from the American Type Culture Collection (ATCCe) as CRL-1620TM.
The assay (adapted from Pilotte Let al., Proc Natl Acad Sci U S A, 2012, 109(7), 2497-502) was performed in 96-well flat bottom plates seeded with human glioblastoma A172 cells, naturally expressing hTD02 (prepared as described in Tilman et al., Mol Cancer, 2007, 17(6), 80), at a concentration of 1.25 x 104 cells/well in a final volume of 200 pL.
To determine TDO, the cells were incubated overnight at 37 C at 5% CO2 in IMDM
(Invitrogen) supplemented with 2% FBS and 2% penicillin/streptomycin in the presence of the compounds of the present invention, at different concentrations.
The plates were then centrifuged 5 min at 1000 rpm, and 100 pL of the supernatant were collected in a conical plate, 30 uL of TCA 30% were added and a further centrifugated at 3000 x g for 10 minutes. 100 pL of the supernatant were collected in a flat bottomed plate and 100 pL of 2% (w/v) 4-(dimethylamino)-benzaldehyde in acetic acid and incubated for 5 min at room temperature. Kynurenine concentrations were determined by measuring the absorbance at 480 nm. A standard curve was made with pure kynurenine. The TDO activity was measured as described above using ten serial concentrations of the compounds of the present invention. Data were fitted using the Prism TM software (GraphPad Software, Inc.) using standard parameters.
The biological activity of representative compounds is summarized in the following table:
Compound 1050 (nM)

41 1092 In one embodiment, compounds having an IC50 < 2000 nm are selected. In another embodiment, compounds having an 1050< 1000 nm are selected.
11.3. Pharmacodynamic assay for TD02 in vivo activity determination: increase of blood tryptophan levels in mice The compounds of the present invention increase the amount of Tryptophan in mouse blood. Briefly, female BALB/c mice (7-8 weeks old) were treated with either a suspension of one of the compounds of the present invention in 0.5%
hydroxypropyl methyl cellulose (HPMC) K4M (4000 mPa.s (cPs), MethocellTM, Dow chemical) /
0.25%
Tweene 20 (Signma Aldrich) at different doses (30, 60 and 100mg/kg), or with a vehicle control (0.5% HPMC K4M / 0.25% Tween 20), by the oral route by gavage (dosing volume 5 mL/kg, 10 mice per group). After two hours, blood was harvested, plasma was prepared and the amount of Tryptophan present was determined by LC-MS-MS (HPLC

column Unison UK-Phenyl, 75 x 4.6, 3 m, flow rate 0.8 mL/min, 8 minutes gradient from 95% water + 0.1% formic acid / 5% Acetonitrile + 0.1% formic acid to 5%
water +
0.1% formic acid / 95% Acetonitrile + 0.1% formic acid, retention time 2.4 min; API4000 MS-MS system from AB Sciex, ESI+ mode, parent ion 205.1, daughter ion 146.1).
Compound 110 increased circulating Tryptophan by 46% at 30 mg/kg (p<0.0001), by 52% at 60 mg/kg (p<0.0001) and by 78% at 100 mg/kg (p<0.0001) compared to vehicle-treated controls, as evidenced in the table below.
Tryptophan concentration in plasma (average standard error of the mean, nM):
Vehicle 30 mg/kg 60 mg/kg 100 mg/kg Compound 110 85900 3900 All publications cited in this specification and priority applications including US
Provisional Patent Application No. 61/996,975, filed March 18, 2014, are incorporated herein by reference. While the invention has been described with reference to particular embodiments, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.

Claims

254

1. A compound of Formula I
or a pharmaceutically acceptable enantiomer, salt or solvate thereof, wherein:

and X2 represent each independently H, halogen, alkyl, or haloalkyl;
R1, R2 and R3 represent each independently H, halogen, C1-C6 alkyl, alkoxy, or haloalkyl, optionally substituted by one or more substituents selected from halogen, hydroxyl, OR4, COOR4, CONR4R5, NR4COR5, NR4R6, SO2R4, SO2NR4R5, NR4SO2R5, 802R4, aryl, CO-alkyl, or C1-C6 alkyl which is optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R4 and R5 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino;
A1, A2 and A3 represent each independently C, N, S or O, wherein when A1, A2 or A3 is S, A1-Y1, A2-Y2 or A3-Y3 is optionally SO2;
each of Y1, Y2 and Y3 is either absent or represent independently e) a hydrogen atom;
f) oxo;
g) SH
h) CR6R7R8, NR6R7 and OR6 wherein R6, R7 and R8 represent each independently:
i) a hydrogen atom:
ii) halogen;

iii) hydroxyl;
iv) OR9 or NR9R10 wherein R9 and R10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, amino, CO-alkyl, or SO2R11, wherein R11 represents a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, hydroxyl, or amino;
v) C1-C10 alkyl, linear or branched; optionally substituted with up to three substituents selected from halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SOR9, aryl, or CO-alkyl, wherein R9 and R10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, heterocyclyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino;
vi) heterocyclyl or C1-C2 alkyl -heterocyclyl. the heterocyclyl being optionally substituted with up to three substituents halogen, hydroxyl, oxo, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, aryl, CO-alkyl, or alkyl, the alkyl group being optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino;
vii) -CO-R11 or -SO2R11 wherein R11 represents a group selected from hydroxy, amine, alkyl, heterocyclyl; optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SOR9, aryl, CO-alkyl, or C1-C6 alkyl which is optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino;

viii) optionally when Y1, Y2 or Y3 is CR6R7R8, R6, R7 and the carbon atom to which they are attached form together a ring selected from:
cycloalkyl, optionally substituted with up to three substituents selected from halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, aryl, CO-alkyl, or C1-C6 alkyl which is optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino; or heterocyclyl, optionally substituted with up to three substituents selected from the group comprising halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R10, SO2R9, aryl, CO-alkyl, or a C1-C6 alkyl which is optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino; or ix) optionally when Y1, Y2 or Y3 is NR6R7, R6, R7 and the nitrogen atom to which they are attached form together a ring; optionally substituted with up to three substituents selected from halogen, hydroxyl, OR9, COOR9, CONR9R10, NR9COR10, NR9R10, SO2R9, SO2NR9R10, NR9SO2R11, SO2R9, aryl, CO-alkyl, or C1-C6 alkyl which is optionally substituted by one or more groups selected from halogen, hydroxyl, amino or COOH; wherein R9 and R10 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino;
and wherein R11 represents a hydrogen atom or an optionally substituted group selected from aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino; or R11 represents an alkyl group optionally substituted with up to three substituents selected from halogen, hydroxyl, OR12, COOR12, CONR12R13, NR12COR13, NR12R13, SO2R12, SO2NR12R13, NR12SO2R13, SO2R12, or aryl; wherein R12 and R13 represent each independently a hydrogen atom or a group, optionally substituted, selected from C1-C6 alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, or amino;
dotted lines stand for single or double bonds;
provided that A1, A2 and A3 are not all C;
provided that when one of A1 and A3 is N, the two others are not both C; and provided that when one of A1, A2 and A3 is S, only one S is present, at least one C is present, and the other is C or N;
provided that compound of Formula l is not 3-(benzofuran-5-yl)-6-chloro-1H-indole or 3-(benzo[d][1,3]dioxol-5-yl)-1H-indole.

2. The compound according to claim 1, wherein X1 and X2 are independently H or F.

3. The compound according to claim 2, wherein R1, R2 and R3 represent each independently H, halogen or methyl.

4. The compound according to claim 1 or claim 2, wherein R1, R2 and R3 are each H.

5. The compound according to any one of claims 1 to 4, wherein when R6, R7 or represent a halogen, the halogen is F.

6. The compound according to any one of claims 1 to 4, wherein when R6, R7 or R8 is heterocyclyl or C1-heterocycyl, the heterocyclyl is piperidine, pyrrolidine, piperazine, morpholine, or 2,6-diazaspiro[3.3]heptane , any of which may be optionally substituted with one or more of C1-C3 alkyl, amino, hydroxyl, halogen, COCH3 , COOH, or SO2CH3.

7. The compound according to any one of claims 1 to 4, wherein when R6, R7 or R8 is C1-C10 alkyl, the alkyl is methyl, ethyl or propyl.

8. The compound according to claim 1, wherein when R11 is heterocycle, the heterocycle is piperidine, pyrrolidine, piperazine or tetrahydrothiopyrandioxide.

9. The compound according to claim 1, wherein when R6, R7 and the carbon atom to which they are attached form a ring which is a heterocycl, the heterocycle is morpholine, piperazine or piperidine, any of which may be optionally substituted.

10. The compound according to claim 1, wherein when R6, R7, and the nitrogen atom to which they are attached form a heterocyclyl ring.

11. The compound according to claim 10, wherein the heterocycl is morpholine, piperazine or piperidine, any of which may be optionally substituted.

12. The compound according to any one of claims 1 to 11, wherein a first one of A1, A2 and A3 is N, a second one of A1, A2 and A3 is C and the third one of A1, A2 and A3 is N or O.

13. The compound according to any one of claim 1 to 12, wherein A2 is N and one of A1 and A3 is N or S and the other is C.

14. The compound according to claim 13, wherein when A1 or A3 is S, A1-Y1 or A3-Y3 is SO2.

15. The compound according to any one of claims 1 to 11, wherein A2 is C and one of A1 and A3 is N and the other is N or O.

16. The compound according to claim 15, wherein A1 or A3 is O, and another of A1, A2 or A3 is C is substituted with CR6R7R8 and R6, R7 or R8 is heterocyclyl or C1-alkyl- heterocycyl, the heterocyclyl is piperidine, pyrrolidine, piperazine, morpholine, or azetidine substituted with azetidine, any of which may be optionally substituted with one or more of C1-C3 alkyl, amino, hydroxyl, halogen, COCH3 , COOH, or SO2CH3.

17. The compound according to any one of claims 1 to 11, wherein one of A1, A2 or A3 is S or A1-Y1, A2-Y2, or A3-Y3 is SO2; one of A1, A2 or A3 is N or C and one of A1, A2 and A3 is C.

18. The compound according to claim 1, selected from the group consisting of:
- 6-(6-fluoro-1H-indol-3-yl)-1H-indazole;
- 2-(6-(6-fluoro-1H-indol-3-yl)-1H-indazol-1-yl)acetamide;
- 6-(6-fluoro-1H-indol-3-yl)-1-(piperidin-4-ylmethyl)-1H-indazole;
- 1-(4-((6-(6-fluoro-1H-indol-3-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone;
- 3-(6-(6-fluoro-1H-indol-3-yl)-1H-indazol-1-yl)propanamide;

- 6-(6-fluoro-1H-indol-3-yl)-1-(piperidin-4-yl)-1H-indazole;
- 1-(4-(6-(6-fluoro-1H-indol-3-yl)-1H-indazol-1-yl)piperidin-1-yl)ethanone;
- 5-(6-fluoro-1H-indol-3-yl)-1H-indazole;
- 2-(5-(6-fluoro-1H-indol-3-yl)-1H-indazol-1-yl)acetamide;
- 5-(6-fluoro-1H-indol-3-yl)-1-(piperidin-4-ylmethyl)-1H-indazole;
- 1-(4-((5-(6-fluoro-1H-indol-3-yl)-1H-indazol-1-yl)methyl)piperidin-1-yl)ethanone;
- 3-(5-(6-fluoro-1H-indol-3-yl)-1H-indazol-1-yl)propanamide;
- 5-(6-fluoro-1H-indol-3-yl)-1-(piperidin-4-yl)-1H-indazole;
- 1-(4-(5-(6-fluoro-1H-indol-3-yl)-1H-indazol-1-yl)piperidin-1-yl)ethanone;
- 2-(6-(6-fluoro-1H-indol-3-yl)-2H-indazol-2-yl)acetamide;
- 1-(4-((6-(6-fluoro-1H-indol-3-yl)-2H-indazol-2-yl)methyl)piperidin-1-yl)ethanone;
- 3-(6-(6-fluoro-1H-indol-3-yl)-2H-indazol-2-yl)propanamide;
- 6-(6-fluoro-1H-indol-3-yl)-2-(piperidin-4-yl)-2H-indazole;
- 1-(4-(6-(6-fluoro-1H-indol-3-yl)-2H-indazol-2-yl)piperidin-1-yl)ethanone;
- 2-(5-(6-fluoro-1H-indol-3-yl)-2H-indazol-2-yl)acetamide;
- 1-(4-((5-(6-fluoro-1H-indol-3-yl)-2H-indazol-2-yl)methyl)piperidin-1-yl)ethanone;
- 3-(5-(6-fluoro-1H-indol-3-yl)-2H-indazol-2-yl)propanamide;
- 5-(6-fluoro-1H-indol-3-yl)-2-(piperidin-4-yl)-2H-indazole;
- 1-(4-(5-(6-fluoro-1H-indol-3-yl)-2H-indazol-2-yl)piperidin-1-yl)ethanone;
- 5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazole;
- 5-(6-fluoro-1H-indol-3-yl)-2-methyl-1H-benzo[d]imidazole;
- (5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-yl)methanamine;
- 1-(5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-yl)-N,N-dimethylmethanamine;
- 2-(((5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)amino)ethanol;
- N-((5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)acetamide;
- 2-amino-N-((5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)acetamide;
- N-((5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)methanesulfonamide;

- 5-(6-fluoro-1H-indol-3-yl)-2-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole;
- 5-(6-fluoro-1H-indol-3-yl)-2-((4-(methylsulfonyl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole;
- 2-(5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-yl)ethanamine;
- N-(2-(5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-yl)ethyl)acetamide;
- N-(2-(5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-yl)ethyl)methanesulfonamide;
- 5-(6-fluoro-1H-indol-3-yl)-2-(2-(methylsulfonyl)ethyl)-1H-benzo[d]imidazole;
- 5-(6-fluoro-1H-indol-3-yl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole;
- 5-(6-fluoro-1H-indol-3-yl)-2-(1-(methylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazole;
- 5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-amine;
- N-(5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-yl)acetamide;
- N-(5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-yl)methanesulfonamide;
- 1-(5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-yl)-N-methylmethanamine;
- 4-((5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)morpholine;
- 3-(5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-yl)propanamide;
- 5-(6-fluoro-1H-indol-3-yl)benzo[d]oxazole;
- 5-(6-fluoro-1H-indol-3-yl)-2-methylbenzo[d]oxazole;
- 5-(6-fluoro-1H-indol-3-yl)-2-(piperidin-4-yl)benzo[d]oxazole;
- 1-(4-(5-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)piperidin-1-yl)ethanone;
- N-(5-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)acetamide;
- N-(5-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methanesulfonamide;
- 6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazole;
- 6-(6-fluoro-1H-indol-3-yl)-2-methylbenzo[d]oxazole;
- 6-(6-fluoro-1H-indol-3-yl)-2-(piperidin-4-yl)benzo[d]oxazole;
- 1-(4-(6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)piperidin-1-yl)ethanone;
- N-(6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)acetamide;
- N-(6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methanesulfonamide;
- 6-(6-fluoro-1H-indol-3-yl)-2-(piperazin-1-ylmethyl)-1H-benzo[d]imidazole;
- 2-(6-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2-yl)acetamide;
- 5-(6-fluoro-1H-indol-3-yl)-2-(piperazin-1-ylmethyl)benzo[d]oxazole;

- 5-(6-fluoro-1H-indol-3-yl)-2-((4-methylpiperazin-1 -yl)methyl)benzo[d]oxazole;
- 5-(6-fluoro-1H-indol-3-yl)-2-(morpholinomethyl)benzo[d]oxazole;
- 2-(6-(6-fluoro-1H-indol-3-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetamide;
- 5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-2(3H)-one;
- 6-(6-fluoro-1H-indol-3-yl)-2-(morpholinomethyl)benzo[d]oxazole;
- 3-(6-(6-fluoro-1H-indol-3-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)propanamide;
- 6-(6-fluoro-1H-indol-3-yl)-2-((4-methylpiperazin-1 -yl)methyl)benzo[d]oxazole;
- 2-(5-(6-fluoro-1H-indol-3-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetamide;
- N-((5-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)methanesulfonamide;
- 3-(5-(6-fluoro-1H-indol-3-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)propanamide;
- 3-(benzo[b]thiophen-5-yl)-6-fluoro-1H-indole;
- N-((5-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)acetamide;
- N-((6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)methanesulfonamide;
- N-((6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)acetamide;
- (6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methanamine;
- 5-(6-fluoro-1H-indol-3-yl)-2-(piperidin-4-ylmethyl)-2H-indazole;
- 6-(6-fluoro-1H-indol-3-yl)-2-(piperazin-1 -ylmethyl)benzo[d]oxazole;
- 3-(benzo[b]thiophen-6-yl)-6-fluoro-1H-indole;
- 5-(6-fluoro-1H-indol-3-yl)-2-(2-(methylsulfonyl)ethyl)benzo[d]oxazole;
- (5-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methanamine;
- 3-(benzofuran-5-yl)-6-fluoro-1H-indole;
- 3-(6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-211)propanamide;
- 2-(6-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-1 -yl)acetamide;
- 2-(5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-1 -yl)acetamide;
- 3-(5-(6-fluoro-1H-indol-3-yl)-1H-indazol-1 -yl)-1 -morpholinopropan-1 -one;
- 3-(5-(6-fluoro-1H-indol-3-yl)-1H-indazol-1 -yl)-1 -(4-methylpiperazin-1 -yl)propan-1 -one;
- N-(2-(dimethylamino)ethyl)-3-(5-(6-fluoro-1H-indol-3-yl)-1H-indazol-1 -yl)propanamide;

- 3-(5-(6-fluoro-1H-indol-3-yl)-1H-indazol-1-yl)-N-(2-hydroxyethyl)propanamide;
- 3-(5-(6-fluoro-1H-indol-3-yl)-1H-indazol-1-yl)-N-(2-(methylsulfonyl)ethyl)propanamide;
- 3-(5-(6-fluoro-1H-indol-3-yl)-1H-indazol-1-yl)-1-(piperazin-1-yl)propan-1-one;
- 6-(6-fluoro-1H-indol-3-yl)indolin-2-one;
- 3-(6-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-1-yl)propanamide;
- 3-(5-(6-fluoro-1H-indol-3-yl)-1H-benzo[d]imidazol-1-yl)propanamide;
- 1-(4-(6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)piperidin-1-yl)ethanone;
- 6-(6-fluoro-1H-indol-3-yl)-2-(1-(methylsulfonyl)piperidin-4-yl)benzo[d]oxazole;
- 5-(6-fluoro-1H-indol-3-yl)indolin-2-one;
- 6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-amine;
- N-((6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2-methoxyethanesulfonamide;
- 2-(dimethylamino)-N-((6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)ethanesulfonamide;
- 6-(6-fluoro-1H-indol-3-yl)-2-(2-(methylsulfonyl)ethyl)benzo[d]oxazole;
- 1-((6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)urea;
- 1-carbamoyl-1-((6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)urea;
- 5-(1H-indol-3-yl)-1H-indazole;
- 6-(6-fluoro-1H-indol-3-yl)-2-(2-(4-methylpiperazin-1-yl)ethyl)benzo[d]oxazole;
- N-((6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2-hydroxyethanesulfonamide;
- N-((6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2-morpholinoethanesulfonamide;
- 6-(1H-indol-3-yl)-1H-indazole;
- 6-(1H-indol-3-yl)benzo[d]oxazole;
- 6-(6-fluoro-1H-indol-3-yl)-2-(2-(piperazin-1-yl)ethyl)benzo[d]oxazole;
- 5-(6-chloro-1H-indol-3-yl)benzo[d]oxazole;
- 6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazole-2-thiol;
- 6-(6-fluoro-1H-indol-3-yl)-2-(piperidin-4-ylmethyl)benzo[d]oxazole;
- N-((6-(1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)methanesulfonamide;

- (S)-N-((6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-1-methylpyrrolidine-2-carboxamide;
- 6-(6-fluoro-1H-indol-3-yl)-2-methoxybenzo[d]oxazole;
- Amino ([6-(6-fluoroindol-3-yl)benzoxazol-2-yl]methyl}sulfonamide;
- 5-(1H-indol-3-yl)benzo[d]oxazole;
- 6-(6-fluoro-1H-indol-3-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)methyl)benzo[d]oxazole;
- 6-(6-fluoro-1H-indol-3-yl)-2-(2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)benzo[d]oxazole;
- 5-(5-chloro-1H-indol-3-yl)benzo[d]oxazole;
- N-((6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2-(4-methylpiperazin-1-yl)ethanesulfonamide;
- N-((6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2-(piperazin-1-yl)ethanesulfonamide;
- N-((6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2-(pyrrolidin-1-yl)ethanesulfonamide;
- 6-(6-fluoro-1H-indol-3-yl)-2-((1-methylpiperidin-4-yl)methyl)benzo[d]oxazole;
- N-((6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)-2-(4-(methylsulfonamido)piperidin-1-yl)ethanesulfonamide;
- N-((6-(6-chloro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)methanesulfonamide;
- N-((6-(5-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)methanesulfonamide - 5-((6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)methyl)imidazolidine-2,4-dione;
- 5-(6-fluoro-1H-indol-3-yl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide;
- 2-(6-(5-fluoro-1H-indol-3-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetamide;
- 5-(6-fluoro-1H-indol-3-yl)isoindoline-1,3-dione;
- 6-fluoro-3-(isoindolin-5-yl)-1H-indole;
- 6-(6-fluoro-1H-indol-3-yl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide;
- 5-(6-fluoro-1H-indol-3-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide;
- 6-(6-fluoro-1H-indol-3-yl)-3-(piperidin-4-yl)benzo[d]oxazol-2(3H)-one;
- (6-(6-fluoro-1H-indol-3-yl)-2-methylbenzo[d]oxazol-5-yl)methanol;
- 5-(6-fluoro-1H-indol-3-yl)-2-methylbenzo[d]isothiazol-3(2H)-one 1,1-dioxide;

- 2-(2-(cis-3,5-dimethylpiperazin-1-yl)ethyl)-6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazole;
- 1-(2-(6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)ethyl)piperidin-4-ol;
- 2-(2-(trans-2,5-dimethylpiperazin-1-yl)ethyl)-6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazole;
- (+)-2-(2-((3R,5R)-3,5-dimethylpiperazin-1-yl)ethyl)-6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazole;
- 2-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethyl)-6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazole;
- (-)-2-(2-((3S,5S)-3,5-dimethylpiperazin-1-yl)ethyl)-6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazole;
- 4-(2-(6-(6-fluoro-1H-indol-3-yl)benzo[d]oxazol-2-yl)ethyl)piperazine-2-carboxylic acid; or - 3-(benzofuran-6-yl)-6-fluoro-1H-indole;
or a pharmaceutically acceptable enantiomer, salt or solvate thereof.

19. A pharmaceutical composition comprising a compound according to anyone of claims 1 to 18, or a pharmaceutically acceptable enantiomer, salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.

20. Medicament comprising a compound according to anyone of claims 1 to 18, or a pharmaceutically acceptable enantiomer, salt or solvate thereof.

21. A compound according to anyone of claims 1 to 18 or a pharmaceutically acceptable enantiomer, salt or solvate thereof for use in the treatment and/or prevention of cancer, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity.

22. A compound according to claim 21, wherein the cancer is wherein said cancer is selected from the group consisting of: bladder carcinoma, hepatocarcinoma, melanoma, mesothelioma, neuroblastoma, sarcoma, breast carcinoma, leukemia, renal cell carcinoma, colorectal carcinoma, head & neck carcinoma, lung carcinorna, brain tumor, gliablastoma, astrocytoma, myeloma and pancreatic carcinoma.

23. A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable enantiomer, salt or solvate thereof for use as TDO2 inhibitor.

24. A method of treating and/or preventing of cancer, neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease, chronic viral infections such as HCV and HIV, depression, and obesity, or inhibiting TD02, said method comprsing administering a compound according to any of 1 to 18 to a subject in need thereof.

25. The method according to claim 24, wherein said cancer is selected from the group consisting of: bladder carcinoma, hepatocarcinoma, melanoma, mesothelioma, neurobiastoma, sarcoma, breast carcinoma, leukemia, renal cell carcinoma, colorectal carcinoma, head & neck carcinoma, lung carcinoma, brain tumor, gliablastoma, astrocytoma, myeloma and pancreatic carcinoma.

26.
Process for manufacturing a compound of Formula l according to claims 1 to 18 or a pharmaceutically acceptable enantiomer, salt or solvate thereof, characterized in that it comprises:
(al) reacting a compound of Formula (i) wherein X1 and X2 represent each independently H, halogen, alkyl, haloalkyl;
Z1 represents H or an amino protecting group;
Y represents an halogen, an alkylsulfonyloxy having 1-6 carbon atoms or arylsulfonyloxy having 6-10 carbon atoms;
with a compound of Formula (ii) wherein R1, R2, R3, A1, A2, A3, Y1, Y2 and Y3 are defined in claim 1; and Z2 and Z3 represent H or alkyl groups, with the possibility for Z2 and Z3 to form a ring;
so as to obtain a compound of Formula (iii), wherein z, X1, X2, R1, R2, R3, A1, A2, A3, Y1 and Y3 are above;

and (b1) in the case wherein Z1 is not H, deprotecting the indole amine of compound of Formula (iii), to afford compound of Formula l.

27. The process according to claim 26, wherein the amino protecting group of Z1 is an arylsulphonyl, a tert-butoxy carbonyl, a methoxymethyl, a para-methoxy benzyl, or a benzyl.

28. The process according to claim 26 or claim 27, wherein when Y is the halogen, Y is iodine, bromine or chlorine.

29. The process according to claim 26 or claim 27, wherein when Y is the alkylsulfonyl, it is methylsulfonyloxy or trifluoromethylsulfonyloxy.

30. The process according to claim 26 or claim 27, wherein when Y is the arylsulfonyl, it is phenyl- or p-tolylsulfonyloxy.